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2-Methylbutyryl-CoA dehydrogenase deficiency Other names2-Methylbutyryl glycinuria or Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD),[1] 2-Methylbutyryl-CoA 2-Methylbutyryl-CoA dehydrogenase deficiency, is an autosomal recessive metabolic disorder.[2] It causes the body to be unable to process the amino acid isoleucine properly. Initial case reports identified individuals with developmental delay and epilepsy, however most cases identified through newborn screening have been asymptomatic. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] SBCADD is included as a secondary target condition in most newborn screening programs, as the key analyte is the same as is used to identify isovaleric acidemia.[3][4] Most cases have been Hmong individuals, who are asymptomatic.[5] There are isolated case reports where individuals have been identified with SBCADD in addition to developmental delay and epilepsy. It is currently unclear what the complete clinical presentation of SBCADD looks like. There is some concern that these cases with additional symptoms may reflect an ascertainment bias rather than being a true representation of the clinical spectrum of the disease.[1] Currently, there is no accepted treatment, as most affected individuals do not require any. Some recommend avoidance of valproic acid, as it can be a substrate for 2-methylbutyryl-CoA dehydrogenase.[5] ## Cause[edit] 2-Methylbutyryl-CoA dehydrogenase deficiency has an autosomal recessive pattern of inheritance. The disorder is caused by a mutation in the ACADSB gene, located on the long arm of human chromosome 10 (10q25-q26).[1][6] It is inherited in an autosomal recessive manner, which means an affected individual must inherit one copy of the mutation from each parent.[2] ## Diagnosis[edit] Most individuals with SBCADD are identified through newborn screening, where they present with an elevation of a five carbon acylcarnitine species.[1] Confirmatory testing includes plasma and urine analysis to identify the carnitine and glycine conjugates of 2-methylbutyryl-CoA.[1] ## Treatment[edit] This section is empty. You can help by adding to it. (April 2018) ## References[edit] 1. ^ a b c d e Online Mendelian Inheritance in Man (OMIM): 2-Methylbutyryl-CoA dehydrogenase deficiency - 610006 2. ^ a b Kanavin, O. J.; Woldseth, B.; Jellum, E.; Tvedt, B.; Andresen, B. S.; Stromme, P. (Sep 2007). "2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and mental retardation: A case report". Journal of Medical Case Reports (Free full text). 1: 98. doi:10.1186/1752-1947-1-98. PMC 2045671. PMID 17883863. 3. ^ Watson, M. S.; Mann, M. Y.; Lloyd-Puryear, M. A.; Rinaldo, P.; Howell, R. R. (2006). "Executive Summary". Genetics in Medicine. 8 (Suppl 1): 1S–252S. doi:10.1097/01.gim.0000223891.82390.ad. PMC 3111605. PMID 16783161. 4. ^ American College of Medical Genetics Newborn Screening Expert Group (2006). "Newborn screening: Toward a uniform screening panel and system--executive summary". Pediatrics. 117 (5 Pt 2): S296–S307. doi:10.1542/peds.2005-2633I. PMID 16735256. 5. ^ a b de Baulny, Helene Ogier; Dionisi-Vici, Carlo; Wendel, Udo (2012). "Branched-chain Organic Acidurias/Acidaemias". In Saudubray, Jean-Marie; van den Berghe, Georges; Walter, John H. (eds.). Inborn Metabolic Diseases: Diagnosis and Treatment (5th ed.). New York: Springer. pp. 277–296. ISBN 978-3-642-15719-6. 6. ^ Sass, J.; Ensenauer, R.; Röschinger, W.; Reich, H.; Steuerwald, U.; Schirrmacher, O.; Engel, K.; Häberle, J.; Andresen, B.; Mégarbané, A.; Lehnert, W.; Zschocke, J. (Jan 2008). "2-Methylbutyryl-coenzyme a dehydrogenase deficiency: Functional and molecular studies on a defect in isoleucine catabolism". Molecular Genetics and Metabolism. 93 (1): 30–35. doi:10.1016/j.ymgme.2007.09.002. PMID 17945527. ## External links[edit] Classification D * OMIM: 610006 * MeSH: C566487 * DiseasesDB: 34413 * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

2-Methylbutyryl-CoA dehydrogenase deficiency

c1864912

wikipedia

https://en.wikipedia.org/wiki/2-Methylbutyryl-CoA_dehydrogenase_deficiency

{"gard": ["10322"], "mesh": ["C566487"], "umls": ["C1864912"], "orphanet": ["79157"], "wikidata": ["Q4596905"]}

Ring chromosome 16 is characterized by postnatal growth deficiency, intellectual disability, microcephaly, broad flat nasal bridge, down-turned mouth, low-set and dysmorphic (abnormally-shaped) ears and speech delay. To date, less than 10 cases have been reported in the medical literature. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Ring chromosome 16

c4706449

gard

https://rarediseases.info.nih.gov/diseases/10855/ring-chromosome-16

{"orphanet": ["96178"], "synonyms": ["Ring chromosome 16", "Ring 16", "Chromosome 16 ring", "R16"]}

Extramammary Paget disease is a cancerous disease seen at various sites, most often in the anogenital region. The clinical features are usually those of eczematous eruptions with weeping and crust formation. This disease has been shown to be a skin manifestation of internal malignancy. In a study of 40 patients with Paget disease of the anogenital region, Helwig and Graham (1963) did not find a family history of the disease in any of the cases. Kuehn et al. (1973) described a case occurring in a father and son. The father, aged 66, presented with extramammary Paget disease in the right scrotal area. No mention was made of other family history. Oncology \- Extramammary Paget disease \- Internal malignancy Inheritance \- Rare familial cases Skin \- Eczematous eruptions with weeping and crust formation ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

PAGET DISEASE, EXTRAMAMMARY

c0030186

omim

https://www.omim.org/entry/167300

{"mesh": ["D010145"], "omim": ["167300"], "orphanet": ["2800"]}

A group of disorders characterized by congenital limb contractures manifesting as limitation of movement of multiple limb joints at birth that is usually non-progressive and may include muscle weakness and fibrosis. This disorder is always associated with decreased intrauterine fetal movement which leads secondarily to the contractures. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Arthrogryposis multiplex congenita

c0003886

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1037

{"gard": ["777"], "mesh": ["C536613", "D001176"], "umls": ["C2931264"], "icd-10": ["Q74.3"], "synonyms": ["AMC", "Multiple congenital arthrogryposis"]}

## Clinical Features Huson et al. (1993) described what they considered to be a previously unrecognized form of autosomal recessive spondyloepiphyseal dysplasia tarda in 3 sibs, the offspring of first-cousin Pakistani parents. In addition to the skeletal dysplasia, microcephaly, unusual facies, and moderate developmental delay were present. As illustrated in their report, the nasal root and tip were broad, the philtrum short and broad, and the lips thick. Two sisters and a brother, ranging in age from 6.6 to 12.5 years, were affected. The oldest, a girl, was 125 cm tall; head circumference was 48 cm. X-rays showed progressive narrowing of the interpedicular distance in the lumbar spine and flattened knee epiphyses. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly Face \- Short philtrum \- Broad philtrum Nose \- Broad nasal root \- Broad nasal tip Mouth \- Thick lips SKELETAL \- Spondyloepiphyseal dysplasia tarda Spine \- Progressive narrowing of lumbar spinal interpedicular distance Limbs \- Flattened knee epiphyses NEUROLOGIC Central Nervous System \- Developmental delay, moderate ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPONDYLOEPIPHYSEAL DYSPLASIA TARDA WITH CHARACTERISTIC FACIES

c1838653

omim

https://www.omim.org/entry/600093

{"mesh": ["C564003"], "omim": ["600093"]}

A rare syndrome with combined immunodeficiency characterized by a variable clinical presentation ranging from asymptomatic individuals to potentially life-threatening, recurrent bacterial infections associated with progressive loss of serum immunoglobulins and B cells. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Pancytopenia due to IKZF1 mutations

c4225173

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=317473

{"omim": ["616873"], "icd-10": ["D81.8"], "synonyms": ["CID due to IKAROS deficiency", "Combined immunodeficiency due to IKAROS deficiency"]}

Steroid dementia syndrome SpecialtyNeurology/psychiatry Steroid dementia syndrome describes the signs and symptoms of hippocampal and prefrontal cortical dysfunction, such as deficits in memory, attention, and executive function, induced by glucocorticoids.[1] Dementia-like symptoms have been found in some individuals who have been exposed to glucocorticoid medication, often dispensed in the form of asthma, arthritis, and anti-inflammatory steroid medications. The condition reverses, but not always completely, within months after steroid treatment is stopped.[2] The term "steroid dementia" was coined by Varney et al. (1984) in reference to the effects of long-term glucocorticoid use in 1,500 patients.[3] While the condition generally falls under the classification of Cushing's syndrome, the term "steroid dementia syndrome" is particularly useful because it recognizes both the cause of the syndrome and the specific effects of glucocorticoids on cognitive function. Further, the more precise terminology clearly distinguishes the condition from full-blown Cushing's syndrome, which is extremely broad regarding the causes (endogenous or exogenous, pituitary or adrenal) and the multitude of symptoms (ranging from skin disorders to osteoporosis), and from hypercortisolemia, which identifies neither the source nor the symptoms of excess circulatory cortisol. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 History * 5.1 Case Studies * 6 References * 7 Further reading ## Signs and symptoms[edit] Cognitive symptoms from steroids appear within the first few weeks of treatment, appear to be dose dependent, and may or may not be accompanied by steroid psychosis or other Cushing's-type symptoms.[4] The symptoms include deficits in * verbal and non-verbal memory * working memory * attention * sustained concentration * executive function * psychomotor speed * academic or occupational performance. These symptoms have been shown to improve within months to a year after discontinuing glucocorticoid medication, but residual impairments following prolonged steroid use can remain.[3] ## Pathophysiology[edit] Regions of the brain with a high density of glucocorticoid receptors (GRs) including the hippocampus, hypothalamus, and prefrontal cortex are particularly sensitive to elevated circulating levels of glucocorticoids even in the absence of stress. Scientific studies have mainly focused on the impact of glucocorticoids on the hippocampus because of its role in memory processes and on the prefrontal cortex for its role in attention and executive function.[citation needed] Elevated glucocorticoid activity is associated with down-regulation of GRs (known as "glucocorticoid cascade hypothesis"[5]), which diminishes neuroreparative activity and attenuates neurogenesis that can result in decreased hippocampal volume with prolonged glucocorticoid exposure.[6] Variations in individual sensitivity to glucocorticoid medications may be due to either GR hypofunction or hyperfunction.[7] Similarly, variations in individual hypothalamic-pituitary-adrenal (HPA) axis responsiveness can modulate the type and number of side effects. ## Diagnosis[edit] This section is empty. You can help by adding to it. (March 2018) ## Treatment[edit] Aside from discontinuation of glucocorticoid medication, potential treatments discussed in the research literature include:[citation needed] * anti-glucocorticoids * psychoactive drugs that up-regulate the GRII glucocorticoid receptor:[8] * tricyclic antidepressants: Desipramine,[9][10] Imipramine,[9] and Amitriptyline[10] (SSRIs do not [10][11]) * serotonin antagonists: Ketanserin[9] * mood stabilizers: Lithium[9] * corticotropin-releasing hormone (CRH) antagonists * glutamate antagonists * dehydroepiandrosterone (DHEA) * small molecule brain-derived neurotrophic factor (BDNF) analogs * stress reduction therapies and exercise. ## History[edit] Glucocorticoid medications have been known to be associated with significant side effects involving behavior and mood, regardless of previous psychiatric or cognitive condition, since the early 1950s.[12] But cognitive side effects of steroid medications involving memory and attention are not as widely publicized and may be misdiagnosed as separate conditions, such as attention deficit disorder (ADHD or ADD) in children or early Alzheimer's disease in elderly patients. ### Case Studies[edit] Wolkowitz et al. (2001) presented a 10-year-old male patient, with no prior psychiatric history, who showed significant declines in academic performance that began during a 5-week course of glucocorticoid treatment for acute asthma flare.[1] The medications included prednisone, and methylprednisolone, plus albuterol, beclomethasone, dexamethasone, cromolyn, salmeterol and clarithromycin. Within days of beginning the glucocorticoid treatment, however, the patient began to show symptoms that included major depression, irritability, muscle weakness, and hallucinations ("stars" or "spots"). The patient had a fraternal twin brother, and the two previously performed in parallel academically, but following the steroid treatment the patient exhibited poor memory, attention, concentration, insomnia, and avoidance of eye contact. As a result, he began to fall behind his twin brother in academic, developmental, and social areas. The treatment with steroids was stopped and three years later (while still taking buspirone, albuterol, fluticasone and salmeterol inhalers, loratadine and theophylline) the boy showed gradual improvement, but MRI brain scans revealed that the patient's hippocampal volume was 19.5% smaller than that of his twin. His teachers reported continued deficits in memory function, new learning efficiency, verbal reasoning skills, organizational skills, attention, and concentration, deficits which were confirmed by neuropsychological testing; as such, stopping the treatment with steroids brought on a substantial but incomplete relief, the damage being possibly permanent.[1] Sacks et al. (2005) reported the case of a 72-year-old man, described as professionally successful, intelligent, and cultivated, with polymyalgia rheumatica, who after being treated with prednisone developed a psychosis and dementia, which several behavioral neurology and neuropsychiatry consultants initially diagnosed as early dementia or Alzheimer's disease.[13] Large dosage variations in the patient's medication (including a self-increased dosage from 10 mg/day to as much as 100 mg/day for at least 3 months) produced extreme behavioral changes, from missed appointments to physical altercations, and eventually admission to a psychiatric ward and later to a locked Alzheimer facility. During this time, neuropsychological testing showed a decline in the patient's previously superior IQ as well as deficits in memory, language, fluency, and visuospatial function, which given the patient's age was considered to be compatible with early dementia. When the steroid treatment ended after a year, the patent's confusion and disorganized appearance stopped immediately. Within several weeks, testing showed strong improvement in almost all cognitive functions. His doctors were surprised at the improvement, since the results were inconsistent with a diagnosis of dementia or Alzheimer's. Testing after 14 months showed a large jump in Full Scale IQ from 87 to 124, but mild dysfunction in executive function, memory, attentional control, and verbal/nonverbal memory remained.[13] ## References[edit] 1. ^ a b c Wolkowitz, Owen M.; Lupien, Sonia J.; Bigler, Erin D. (2007). "The 'Steroid Dementia Syndrome': A Possible Model of Human Glucocorticoid Neurotoxicity". Neurocase. 13 (3): 189–200. doi:10.1080/13554790701475468. PMID 17786779. S2CID 39340010. 2. ^ Ancelin, Marie-Laure; Carrière, Isabelle; Helmer, Catherine; Rouaud, Olivier; Pasquier, Florence; Berr, Claudine; Chaudieu, Isabelle; Ritchie, Karen (2012). "Steroid and nonsteroidal anti-inflammatory drugs, cognitive decline, and dementia". Neurobiology of Aging. 33 (9): 2082–90. doi:10.1016/j.neurobiolaging.2011.09.038. PMID 22071123. S2CID 11008868. 3. ^ a b Varney, NR; Alexander, B; MacIndoe, JH (1984). "Reversible steroid dementia in patients without steroid psychosis". The American Journal of Psychiatry. 141 (3): 369–72. doi:10.1176/ajp.141.3.369. PMID 6703100. 4. ^ Brown, E. Sherwood; Suppes, Trisha (1998). "Mood Symptoms during Corticosteroid Therapy: A Review". Harvard Review of Psychiatry. 5 (5): 239–46. doi:10.3109/10673229809000307. PMID 9493946. S2CID 33237915. 5. ^ Sapolsky, Robert M.; Krey, Lewis C.; McEwen, Bruce S. (1986). "The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis". Endocrine Reviews. 7 (3): 284–301. doi:10.1210/edrv-7-3-284. PMID 3527687. 6. ^ Wolkowitz, Owen M.; Lupien, Sonia J.; Bigler, Erin; Levin, R Bronson; Canick, Jonathan (1 December 2004). "The "Steroid Dementia Syndrome": An Unrecognized Complication of Glucocorticoid Treatment". Annals of the New York Academy of Sciences. 1032 (1): 191–194. doi:10.1196/annals.1314.018. ISSN 1749-6632. PMID 15677408. 7. ^ Marques, Andrea H.; Silverman, Marni N.; Sternberg, Esther M. (2009). "Glucocorticoid Dysregulations and Their Clinical Correlates". Annals of the New York Academy of Sciences. 1179: 1–18. doi:10.1111/j.1749-6632.2009.04987.x. PMC 2933142. PMID 19906229. 8. ^ McQUADE, R. (1 November 2000). "Future therapeutic targets in mood disorders: the glucocorticoid receptor". The British Journal of Psychiatry. 177 (5): 390–395. doi:10.1192/bjp.177.5.390. PMID 11059990. 9. ^ a b c d Peiffer, Andy; Veilleux, Sylvie; Barden, Nicholas (January 1991). "Antidepressant and other centrally acting drugs regulate glucocorticoid receptor messenger RNA levels in rat brain". Psychoneuroendocrinology. 16 (6): 505–515. doi:10.1016/0306-4530(91)90034-Q. PMID 1811246. S2CID 43798108. 10. ^ a b c Seckl, Jonathan R.; Fink, George (1992). "Antidepressants Increase Glucocorticoid and Mineralocorticoid Receptor mRNA Expression in Rat Hippocampus in vivo". Neuroendocrinology. 55 (6): 621–626. doi:10.1159/000126180. PMID 1321353. 11. ^ Paul Rossby, S.; Nalepa, Irena; Huang, Mei; Perrin, Charles; Burt, Alvin M.; Schmidt, Dennis E.; Gillespie, David D.; Sulser, Fridolin (July 1995). "Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant". Brain Research. 687 (1–2): 79–82. doi:10.1016/0006-8993(95)00459-4. PMID 7583316. S2CID 36641273. 12. ^ Hall, Richard C W; Popkin, Michael K; Stickney, Sondra K; Gardner, Earl R (1979). "Presentation of the Steroid Psychoses". Journal of Nervous & Mental Disease. 167 (4): 229–36. doi:10.1097/00005053-197904000-00006. PMID 438794. S2CID 45515092. 13. ^ a b Sacks, Oliver; Shulman, Melanie (2005). "Steroid dementia: An overlooked diagnosis?". Neurology. 64 (4): 707–9. doi:10.1212/01.WNL.0000151977.18440.C3. PMID 15728296. S2CID 216052576. ## Further reading[edit] * Brown, ES (2009). "Effects of glucocorticoids on mood, memory, and the hippocampus. Treatment and preventive therapy". Ann N Y Acad Sci. 1179: 41–55. doi:10.1111/j.1749-6632.2009.04981.x. PMID 19906231. * Wolkowitz, Owen M.; Burke, Heather; Epel, Elissa S.; Reus, Victor I. (2009). "Glucocorticoids" (PDF). Annals of the New York Academy of Sciences. 1179: 19–40. doi:10.1111/j.1749-6632.2009.04980.x. PMID 19906230. * Belanoff, Joseph K; Gross, Kristin; Yager, Alison; Schatzberg, Alan F (2001). "Corticosteroids and cognition". Journal of Psychiatric Research. 35 (3): 127–45. doi:10.1016/S0022-3956(01)00018-8. PMID 11461709. * Keenan, PA; Jacobson, MW; Soleymani, RM; Mayes, MD; Stress, ME; Yaldoo, DT (1996). "The effect on memory of chronic prednisone treatment in patients with systemic disease". Neurology. 47 (6): 1396–402. doi:10.1212/WNL.47.6.1396. PMID 8960717. S2CID 20430943. * Sapolsky, Robert M. (1994). "Glucocorticoids, stress and exacerbation of excitotoxic neuron death". Seminars in Neuroscience. 6 (5): 323–31. doi:10.1006/smns.1994.1041. * v * t * e Major chemical drug groups Gastrointestinal tract/ metabolism (A) * stomach acid * Antacids * H2 antagonists * Proton pump inhibitors * Antiemetics * Laxatives * Antidiarrhoeals/Antipropulsives * Anti-obesity drugs * Anti-diabetics * Vitamins * Dietary minerals Blood and blood forming organs (B) * Antithrombotics * Antiplatelets * Anticoagulants * Thrombolytics/fibrinolytics * Antihemorrhagics * Platelets * Coagulants * Antifibrinolytics Cardiovascular system (C) * cardiac therapy/antianginals * Cardiac glycosides * Antiarrhythmics * Cardiac stimulants * Antihypertensives * Diuretics * Vasodilators * Beta blockers * Calcium channel blockers * renin–angiotensin system * ACE inhibitors * Angiotensin II receptor antagonists * Renin inhibitors * Antihyperlipidemics * Statins * Fibrates * Bile acid sequestrants Skin (D) * Emollients * Cicatrizants * Antipruritics * Antipsoriatics * Medicated dressings Genitourinary system (G) * Hormonal contraception * Fertility agents * SERMs * Sex hormones Endocrine system (H) * Hypothalamic–pituitary hormones * Corticosteroids * Glucocorticoids * Mineralocorticoids * Sex hormones * Thyroid hormones/Antithyroid agents Infections and infestations (J, P, QI) * Antimicrobials: Antibacterials (Antimycobacterials) * Antifungals * Antivirals * Antiparasitics * Antiprotozoals * Anthelmintics * Ectoparasiticides * IVIG * Vaccines Malignant disease (L01–L02) * Anticancer agents * Antimetabolites * Alkylating * Spindle poisons * Antineoplastic * Topoisomerase inhibitors Immune disease (L03–L04) * Immunomodulators * Immunostimulants * Immunosuppressants Muscles, bones, and joints (M) * Anabolic steroids * Anti-inflammatories * NSAIDs * Antirheumatics * Corticosteroids * Muscle relaxants * Bisphosphonates Brain and nervous system (N) * Analgesics * Anesthetics * General * Local * Anorectics * Anti-ADHD agents * Antiaddictives * Anticonvulsants * Antidementia agents * Antidepressants * Antimigraine agents * Antiparkinson agents * Antipsychotics * Anxiolytics * Aphrodisiacs * Depressants * Entactogens * Entheogens * Euphoriants * Hallucinogens * Psychedelics * Dissociatives * Deliriants * Hypnotics/Sedatives * Mood Stabilizers * Neuroprotectives * Nootropics * Neurotoxins * Orexigenics * Serenics * Stimulants * Wakefulness-promoting agents Respiratory system (R) * Decongestants * Bronchodilators * Cough medicines * H1 antagonists Sensory organs (S) * Ophthalmologicals * Otologicals Other ATC (V) * Antidotes * Contrast media * Radiopharmaceuticals * Dressings * Senotherapeutics * v * t * e Mineralocorticoids and antimineralocorticoids (H02) Mineralocorticoids * 11-Deoxycorticosterone (desoxycortone) * 11-Deoxycortisol (cortodoxone) * Aldosterone * Corticosterone * Cortisol (hydrocortisone) * Desoxycortone acetate * Desoxycortone enanthate * Fludrocortisone * Fludrocortisone acetate Antimineralocorticoids * Amlodipine * Benidipine * Canrenoate potassium (potassium canrenoate) * Canrenoic acid * Canrenone * Drospirenone * Eplerenone * Felodipine * Finerenone * Gestodene * Nifedipine * Nimodipine * Nitrendipine * Progesterone * Spironolactone Synthesis modifiers * Acetoxolone * Aminoglutethimide * Carbenoxolone * Enoxolone * Ketoconazole * Metyrapone * Mitotane * Osilodrostat * Trilostane * #WHO-EM * ‡Withdrawn from market * Clinical trials: * †Phase III * §Never to phase III * v * t * e Glucocorticoids and antiglucocorticoids (D07, H02) Glucocorticoids Natural * Cortisone * Cortisone acetate * Cortodoxone (cortexolone, 11-deoxycortisol) * Desoxycortone (deoxycortone, cortexone, 11-deoxycorticosterone) * Desoxycortone esters * Hydrocortisone (cortisol)# * Hydrocortisone esters * Prebediolone acetate * Pregnenolone * Pregnenolone acetate * Pregnenolone succinate Synthetic * Cortisol-like and related (16-unsubstituted): Chloroprednisone * Cloprednol * Difluprednate * Fludrocortisone * Flugestone acetate (flurogestone acetate) * Fluocinolone * Fluorometholone * Fluorometholone acetate * Fluperolone * Fluperolone acetate * Fluprednisolone * Fluprednisolone esters * Loteprednol * Medrysone * Methylprednisolone * Methylprednisolone esters * Prednicarbate * Prednisolone# * Prednisone * Tixocortol * Tixocortol pivalate * Methasones and related (16-substituted): Alclometasone * Beclometasone * Beclometasone esters * Betamethasone# * Betamethasone esters * Clobetasol * Clobetasol propionate * Clobetasone * Clocortolone * Clocortolone esters * Cortivazol * Desoximetasone * Dexamethasone * Dexamethasone esters * Diflorasone * Diflucortolone * Diflucortolone valerate * Fluclorolone * Flumetasone * Fluocortin * Fluocortolone * Fluocortolone esters * Fluprednidene acetate * Fluticasone * Fluticasone furoate * Fluticasone propionate * Halometasone * Meprednisone * Mometasone * Mometasone furoate * Paramethasone * Prednylidene * Rimexolone * Triamcinolone * Ulobetasol (halobetasol) * Cyclic ketals (16,17-cyclized): Amcinonide * Budesonide * Ciclesonide * Deflazacort * Desonide * Fluclorolone acetonide (flucloronide) * Fludroxycortide (flurandrenolone, flurandrenolide) * Flunisolide * Fluocinolone acetonide * Fluocinonide * Formocortal (fluoroformylone) * Halcinonide * Triamcinolone acetonide * Triamcinolone acetonide esters Antiglucocorticoids * Antagonists: Aglepristone * Ketoconazole * Mifepristone * Ulipristal acetate Synthesis modifiers * Acetoxolone * Aminoglutethimide * Carbenoxolone * Enoxolone * Ketoconazole * Metyrapone * Mitotane * Trilostane * #WHO-EM * ‡Withdrawn from market * Clinical trials: * †Phase III * §Never to phase III See also Glucocorticoid receptor modulators Mineralocorticoids and antimineralocorticoids List of corticosteroids *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Steroid dementia syndrome

None

wikipedia

https://en.wikipedia.org/wiki/Steroid_dementia_syndrome

{"wikidata": ["Q17155309"]}

A number sign (#) is used with this entry because of evidence that this Marfan-like syndrome can be caused by mutation in the gene encoding fibrillin (FBN1; 134797) on chromosome 15q21.1. Clinical Features Glesby and Pyeritz (1989) pointed out that more than half of a large number of patients evaluated in the medical genetics clinic at Johns Hopkins for a possible heritable disorder of connective tissue could not be precisely classified. As a group, these patients showed many manifestations of the Marfan syndrome (154700), including long limbs, deformity of the thoracic cage, striae atrophicae, mitral valve prolapse, and mild dilatation of the aortic root. Clinical clustering did not emerge when patients were stratified by mitral valve prolapse or aortic dilatation. The clinical phenotype of patients with mitral valve prolapse constituted a continuum, from Marfan syndrome at one extreme to isolated mitral valve prolapse due to myxomatous change of the valve leaflets (see 157700). In the absence of biochemical or DNA markers, the diagnosis of the Marfan syndrome was impossible when a patient had mitral valve prolapse and mild aortic root dilatation but no ectopia lentis or family history of definite Marfan syndrome. Glesby and Pyeritz (1989) suggested that until subclassification based on genetic and biochemical indicators is possible, these patients should be considered as having an overlap heritable connective disorder. They further suggested the acronym 'MASS phenotype' to designate the involvement of the mitral valve, aorta, skeleton, and skin. Molecular Genetics Dietz et al. (1993) demonstrated that one basis for the MASS phenotype can be a nonsense frameshift mutation in the FBN1 gene; see 134797.0012. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MASS SYNDROME

c1858556

omim

https://www.omim.org/entry/604308

{"mesh": ["C536030"], "omim": ["604308"], "orphanet": ["99715"], "synonyms": ["Alternative titles", "Mitral valve-aorta-skeleton-skin syndrome", "MASS PHENOTYPE", "OVERLAP CONNECTIVE TISSUE DISEASE"]}

Human disease Adult T-cell leukemia/lymphoma Human T-cell(normal) SpecialtyOncology, hematology Adult T-cell leukemia/lymphoma (ATL or ATLL) is a rare cancer of the immune system's T-cells[1][2][3] caused by human T cell leukemia/lymphotropic virus type 1 (HTLV-1).[4] ## Contents * 1 Signs and symptoms * 2 Transmission * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 Research * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] ATL is usually a highly aggressive non-Hodgkin's lymphoma with no characteristic histologic appearance except for a diffuse pattern and a mature T-cell phenotype.[citation needed] Circulating lymphocytes with an irregular nuclear contour (leukemic cells) are frequently seen. Several lines of evidence suggest that HTLV-1 causes ATL. This evidence includes the frequent isolation of HTLV-1 from patients with this disease and the detection of HTLV-1 proviral genome in ATL leukemic cells. ATL is frequently accompanied by visceral involvement, hypercalcemia, skin lesions, and lytic bone lesions. Bone invasion and osteolysis, features of bone metastases, commonly occur in the setting of advanced solid tumors, such as breast, prostate, and lung cancers, but are less common in hematologic malignancies. However, patients with HTLV-1–induced ATL and multiple myeloma are predisposed to the development of tumor-induced osteolysis and hypercalcemia. One of the striking features of ATL and multiple myeloma induced bone disease is that the bone lesions are predominantly osteolytic with little associated osteoblastic activity. In patients with ATL, elevated serum levels of IL-1, TGFβ, PTHrP, macrophage inflammatory protein (MIP-1α), and receptor activator of nuclear factor-κB ligand (RANKL) have been associated with hypercalcemia. Immunodeficient mice that received implants with leukemic cells from patients with ATL or with HTLV-1–infected lymphocytes developed hypercalcemia and elevated serum levels of PTHrP.[5] Most patients die within one year of diagnosis.[6] Infection with HTLV-1, like infection with other retroviruses, probably occurs for life and can be inferred when antibody against HTLV-1 is detected in the serum.[citation needed] ## Transmission[edit] Transmission of HTLV-1 is believed to occur from mother to child; by sexual contact; and through exposure to contaminated blood, either through blood transfusion or sharing of contaminated needles.[7] ## Diagnosis[edit] This section is empty. You can help by adding to it. (February 2018) ## Treatment[edit] Treatment options that have been tried include zidovudine and the CHOP regimen.[8] Pralatrexate has also been investigated.[9] Most therapy is directed towards the cancer rather than the virus itself.[citation needed] Recently, it has been reported that the traditional glucocorticoid-based chemotherapy toward ATL are largely mediated by thioredoxin binding protein-2 (TBP-2/TXNIP/VDUP1), suggesting the potential use of a TBP-2 inducer as a novel therapeutic target.[10][11] Recently,[when?] mogamulizumab, has been approved for the treatment of ATL in Japan.[12] At a medical conference in December 2013, researchers reported anywhere from 21-50% of ATL patients have disease expressing CD30.[13] This suggests treatment with CD30-targeting brentuximab vedotin may be beneficial.[citation needed] ## Epidemiology[edit] HTLV-1 infection in the United States appears to be rare. Although little serologic data exist, prevalence of infection is thought to be highest among blacks living in the Southeast. A prevalence rate of 30% has been found among black intravenous drug abusers in New Jersey, and a rate of 49% has been found in a similar group in New Orleans. It is possible that prevalence of infection is increasing in this risk group. Studies of HTLV-1 antibody indicate that the virus is endemic in southern Japan, in the Caribbean, South America, and in Africa.[citation needed] ATL is relatively uncommon among those infected with HTLV-1. The overall incidence of ATL is estimated at about 1 per 1,500 adult HTLV-1 carriers per year. Those cases that have been reported have occurred mostly among persons from the Caribbean or blacks from the Southeast (National Institutes of Health, unpublished data). There appears to be a long latent period between HTLV-1 infection and the start of ATL.[citation needed] ## Research[edit] Novel approaches to the treatment of PTCL in the relapsed or refractory setting are under investigation. Pralatrexate is one compound currently under investigations for the treatment of PTCL.[citation needed] ## References[edit] 1. ^ Yodoi, J; Takatsuki, K; Masuda, T (1974). "Letter: Two cases of T-cell chronic lymphocytic leukemia in Japan". New England Journal of Medicine. 290 (10): 572–3. doi:10.1056/NEJM197403072901018. PMID 4544052. 2. ^ Uchiyama, T; Yodoi, J; Sagawa, K; Takatsuki, K; Uchino, H (1977). "Adult T-cell leukemia: Clinical and hematologic features of 16 cases". Blood. 50 (3): 481–92. doi:10.1182/blood.V50.3.481.481. PMID 301762. 3. ^ Yodoi, J; Maeda, M (2011). "The discovery of ATL: an odyssey in restrospect". International Journal of Hematology. 94 (5): 423–8. doi:10.1007/s12185-011-0957-x. PMID 22068231. S2CID 9299403. 4. ^ Nicot, Christophe (2005). "Current views in HTLV-I-associated adult T-cell leukemia/lymphoma". American Journal of Hematology. 78 (3): 232–9. doi:10.1002/ajh.20307. PMID 15726602. S2CID 30160899. 5. ^ Gao L, Deng H, Zhao H, Hirbe A, Harding J, Ratner L, Weilbaecher K (December 2005). "HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition". Blood. 106 (13): 4294–302. doi:10.1182/blood-2005-04-1730. PMC 1895233. PMID 16118323. 6. ^ "Treatment and prognosis of adult T cell leukemia-lymphoma". Retrieved 27 July 2012. 7. ^ Gotuzzo E, Verdonck K. "HTLV-1: CLINICAL IMPACT OF A CHRONIC INFECTION". NCBI. Retrieved 22 July 2013. 8. ^ Taylor, Graham P; Matsuoka, Masao (2005). "Natural history of adult T-cell leukemia/lymphoma and approaches to therapy". Oncogene. 24 (39): 6047–57. doi:10.1038/sj.onc.1208979. PMID 16155611. 9. ^ Marneros, A. G.; Grossman, M. E.; Silvers, D. N.; Husain, S.; Nuovo, G. J.; Macgregor-Cortelli, B.; Neylon, E.; Patterson, M.; O'Connor, O. A. (2009). "Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions". Blood. 113 (25): 6338–41. doi:10.1182/blood-2009-03-210989. PMID 19389878. 10. ^ Chen, Z; Lopez-Ramos, D (2011). "Thioredoxin-binding protein-2 (TBP-2/VDUP1/TXNIP) regulates T-cell sensitivity to glucocorticoid during HTLV-I-induced transformation". Leukemia. 25 (3): 440–8. doi:10.1038/leu.2010.286. PMC 3072512. PMID 21151022. 11. ^ Chen, Z; Yoshihara E (2010). "Differential roles of Annexin A1 (ANXA1/lipocortin-1/lipomodulin) and thioredoxin binding protein-2 (TBP-2/VDUP1/TXNIP) in glucocorticoid signaling of HTLV-I-transformed T cells". Immunology Letters. 131 (1): 11–18. doi:10.1016/j.imlet.2010.04.003. hdl:2433/126715. PMID 20398702. 12. ^ Subramaniam, JM; Whiteside, G; McKeage, K; Croxtall, JC (June 2012). "Mogamulizumab: first global approval". Drugs. 72 (9): 1293–8. doi:10.2165/11631090-000000000-00000. PMID 22686619. 13. ^ Campuzano-Zuluaga, G; Pimentel, A; Diaz, L; Chapman-Fredricks, JR; and Ramos, JC " CD30 Expression Is Associated With Decreased Survival In Patients With Acute and Unfavorable Chronic Types Of Adult T-Cell Leukemia-Lymphoma" December 2013 https://ash.confex.com/ash/2013/webprogram/Paper64702.html ## Further reading[edit] * Franchini, Genoveffa; Nicot, Christophe; Johnson, Julie M. (2003). "Seizing of T Cells by Human T-Cell Leukemia/Lymphoma Virus Type 1". In Vande Woude, George F.; Klein, George (eds.). Seizing of T Cells by Human T-Cell Leukemia⧸Lymphoma Virus Type 1. Advances in Cancer Research. 89. pp. 69–132. doi:10.1016/S0065-230X(03)01003-0. ISBN 978-0-12-006689-6. PMID 14587871. * Centers for Disease Control (CDC) (1987). "Adult T-cell leukemia/lymphoma associated with human T-lymphotropic virus type I (HTLV-I) infection--North Carolina". Morbidity and Mortality Weekly Report. 36 (49): 804–6, 812. PMID 2891025. * Genoveffa Franchini's NCI page: Human Retroviral Diseases: Pathogenesis and Prevention * International Retrovirology Association ## External links[edit] Classification D * ICD-10: C83-C88 * ICD-9-CM: 204.0-208.9 * ICD-O: M9827/3 * MeSH: D015459 * DiseasesDB: 29486 External resources * Orphanet: 86875 * v * t * e Leukaemias, lymphomas and related disease B cell (lymphoma, leukemia) (most CD19 * CD20) By development/ marker TdT+ * ALL (Precursor B acute lymphoblastic leukemia/lymphoma) CD5+ * naive B cell (CLL/SLL) * mantle zone (Mantle cell) CD22+ * Prolymphocytic * CD11c+ (Hairy cell leukemia) CD79a+ * germinal center/follicular B cell (Follicular * Burkitt's * GCB DLBCL * Primary cutaneous follicle center lymphoma) * marginal zone/marginal zone B-cell (Splenic marginal zone * MALT * Nodal marginal zone * Primary cutaneous marginal zone lymphoma) RS (CD15+, CD30+) * Classic Hodgkin lymphoma (Nodular sclerosis) * CD20+ (Nodular lymphocyte predominant Hodgkin lymphoma) PCDs/PP (CD38+/CD138+) * see immunoproliferative immunoglobulin disorders By infection * KSHV (Primary effusion) * EBV * Lymphomatoid granulomatosis * Post-transplant lymphoproliferative disorder * Classic Hodgkin lymphoma * Burkitt's lymphoma * HCV * Splenic marginal zone lymphoma * HIV (AIDS-related lymphoma) * Helicobacter pylori (MALT lymphoma) Cutaneous * Diffuse large B-cell lymphoma * Intravascular large B-cell lymphoma * Primary cutaneous marginal zone lymphoma * Primary cutaneous immunocytoma * Plasmacytoma * Plasmacytosis * Primary cutaneous follicle center lymphoma T/NK T cell (lymphoma, leukemia) (most CD3 * CD4 * CD8) By development/ marker * TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma) * prolymphocyte (Prolymphocytic) * CD30+ (Anaplastic large-cell lymphoma * Lymphomatoid papulosis type A) Cutaneous MF+variants * indolent: Mycosis fungoides * Pagetoid reticulosis * Granulomatous slack skin aggressive: Sézary disease * Adult T-cell leukemia/lymphoma Non-MF * CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma * Pleomorphic T-cell lymphoma * Lymphomatoid papulosis type B * CD30+: CD30+ cutaneous T-cell lymphoma * Secondary cutaneous CD30+ large-cell lymphoma * Lymphomatoid papulosis type A Other peripheral * Hepatosplenic * Angioimmunoblastic * Enteropathy-associated T-cell lymphoma * Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma) * Subcutaneous T-cell lymphoma By infection * HTLV-1 (Adult T-cell leukemia/lymphoma) NK cell/ (most CD56) * Aggressive NK-cell leukemia * Blastic NK cell lymphoma T or NK * EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma) * Large granular lymphocytic leukemia Lymphoid+ myeloid * Acute biphenotypic leukaemia Lymphocytosis * Lymphoproliferative disorders (X-linked lymphoproliferative disease * Autoimmune lymphoproliferative syndrome) * Leukemoid reaction * Diffuse infiltrative lymphocytosis syndrome Cutaneous lymphoid hyperplasia * Cutaneous lymphoid hyperplasia * with bandlike and perivascular patterns * with nodular pattern * Jessner lymphocytic infiltrate of the skin General * Hematological malignancy * leukemia * Lymphoproliferative disorders * Lymphoid leukemias * v * t * e Sexually transmitted infections (STI) Bacterial * Chancroid (Haemophilus ducreyi) * Chlamydia, lymphogranuloma venereum (Chlamydia trachomatis) * Donovanosis (Klebsiella granulomatis) * Gonorrhea (Neisseria gonorrhoeae) * Mycoplasma hominis infection (Mycoplasma hominis) * Syphilis (Treponema pallidum) * Ureaplasma infection (Ureaplasma urealyticum) Protozoal * Trichomoniasis (Trichomonas vaginalis) Parasitic * Crab louse * Scabies Viral * AIDS (HIV-1/HIV-2) * Cancer * cervical * vulvar * penile * anal * Human papillomavirus (HPV) * Genital warts (condyloma) * Hepatitis B (Hepatitis B virus) * Herpes simplex * HSV-1 & HSV-2 * Molluscum contagiosum (MCV) General inflammation female Cervicitis Pelvic inflammatory disease (PID) male Epididymitis Prostatitis either Proctitis Urethritis/Non-gonococcal urethritis (NGU) * v * t * e Infectious diseases – viral systemic diseases Oncovirus DNA virus HBV Hepatocellular carcinoma HPV Cervical cancer Anal cancer Penile cancer Vulvar cancer Vaginal cancer Oropharyngeal cancer KSHV Kaposi's sarcoma EBV Nasopharyngeal carcinoma Burkitt's lymphoma Hodgkin lymphoma Follicular dendritic cell sarcoma Extranodal NK/T-cell lymphoma, nasal type MCPyV Merkel-cell carcinoma RNA virus HCV Hepatocellular carcinoma Splenic marginal zone lymphoma HTLV-I Adult T-cell leukemia/lymphoma Immune disorders * HIV * AIDS Central nervous system Encephalitis/ meningitis DNA virus Human polyomavirus 2 Progressive multifocal leukoencephalopathy RNA virus MeV Subacute sclerosing panencephalitis LCV Lymphocytic choriomeningitis Arbovirus encephalitis Orthomyxoviridae (probable) Encephalitis lethargica RV Rabies Chandipura vesiculovirus Herpesviral meningitis Ramsay Hunt syndrome type 2 Myelitis * Poliovirus * Poliomyelitis * Post-polio syndrome * HTLV-I * Tropical spastic paraparesis Eye * Cytomegalovirus * Cytomegalovirus retinitis * HSV * Herpes of the eye Cardiovascular * CBV * Pericarditis * Myocarditis Respiratory system/ acute viral nasopharyngitis/ viral pneumonia DNA virus * Epstein–Barr virus * EBV infection/Infectious mononucleosis * Cytomegalovirus RNA virus * IV: Human coronavirus 229E/NL63/HKU1/OC43 * Common cold * MERS coronavirus * Middle East respiratory syndrome * SARS coronavirus * Severe acute respiratory syndrome * SARS coronavirus 2 * Coronavirus disease 2019 * V, Orthomyxoviridae: Influenza virus A/B/C/D * Influenza/Avian influenza * V, Paramyxoviridae: Human parainfluenza viruses * Parainfluenza * Human orthopneumovirus * hMPV Human digestive system Pharynx/Esophagus * MuV * Mumps * Cytomegalovirus * Cytomegalovirus esophagitis Gastroenteritis/ diarrhea DNA virus Adenovirus Adenovirus infection RNA virus Rotavirus Norovirus Astrovirus Coronavirus Hepatitis DNA virus HBV (B) RNA virus CBV HAV (A) HCV (C) HDV (D) HEV (E) HGV (G) Pancreatitis * CBV Urogenital * BK virus * MuV * Mumps Authority control * BNF: cb12157900t (data) * GND: 4509988-1 * LCCN: sh94002377 * NDL: 01151369 * SUDOC: 030093716 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Adult T-cell leukemia/lymphoma

c0023493

wikipedia

https://en.wikipedia.org/wiki/Adult_T-cell_leukemia/lymphoma

{"gard": ["13103"], "mesh": ["D015459"], "umls": ["C0023493"], "icd-9": ["204.0", "208.9"], "orphanet": ["86875"], "wikidata": ["Q379054"]}

A number sign (#) is used with this entry because 15 to 20% of cases of familial amyotrophic lateral sclerosis (FALS), referred to here as ALS1, are associated with mutations in the superoxide dismutase-1 gene (SOD1; 147450) on chromosome 21q22. Although most cases of SOD1-related familial ALS follow autosomal dominant inheritance, rare cases of autosomal recessive inheritance have been reported. Description Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. Rowland and Shneider (2001) and Kunst (2004) provided extensive reviews of ALS. Some forms of ALS occur with frontotemporal dementia (FTD). Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (105500) (Espinosa et al., 1962; Husquinet and Franck, 1980), in which the histology is different and dementia and parkinsonism complicate the clinical picture. ### Genetic Heterogeneity of Amyotrophic Lateral Sclerosis ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci. ALS6 (608030) is caused by mutation in the FUS gene (137070) on chromosome 16p11; ALS8 (608627) is caused by mutation in the VAPB gene (605704) on chromosome 13; ALS9 (611895) is caused by mutation in the ANG gene (105850) on chromosome 14q11; ALS10 (612069) is caused by mutation in the TARDBP gene (605078) on 1p36; ALS11 (612577) is caused by mutation in the FIG4 gene (609390) on chromosome 6q21; ALS12 (613435) is caused by mutation in the OPTN gene (602432) on chromosome 10p; ALS14 (613954) is caused by mutation in the VCP gene (601023) gene on chromosome 9p13; ALS15 (300857) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11; ALS17 (614696) is caused by mutation in the CHMP2B gene (609512) on chromosome 3p11; ALS18 (614808) is caused by mutation in the PFN1 gene (176610) on chromosome 17p13; ALS19 (615515) is caused by mutation in the ERBB4 gene (600543) on chromosome 2q34; ALS20 (615426) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13; ALS21 (606070) is caused by mutation in the MATR3 gene (164015) on chromosome 5q31; ALS22 (616208) is caused by mutation in the TUBA4A gene (191110) on chromosome 2q35; and ALS23 (617839) is caused by mutation in the ANXA11 gene (602572) on chromosome 10q23. See also FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on chromosome 9p21. Loci associated with ALS have been found on chromosomes 18q21 (ALS3; 606640) and 20p13 (ALS7; 608031). Intermediate-length polyglutamine repeat expansions in the ATXN2 gene (601517) contribute to susceptibility to ALS (ALS13; 183090). Susceptibility to ALS24 (617892) is conferred by mutation in the NEK1 gene (604588) on chromosome 4q33, and susceptibility to ALS25 (617921) is conferred by mutation in the KIF5A gene (602821) on chromosome 12q13. Susceptibility to ALS has been associated with mutations in other genes, including deletions or insertions in the gene encoding the heavy neurofilament subunit (NEFH; 162230); deletions in the gene encoding peripherin (PRPH; 170710); and mutations in the dynactin gene (DCTN1; 601143). Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (205100), caused by mutation in the alsin (606352) gene on 2q33; ALS4 (602433), caused by mutation in the senataxin gene (SETX; 608465) on 9q34; ALS5 (602099), caused by mutation in the SPG11 gene (610844) on 15q21; and ALS16 (614373), caused by mutation in the SIGMAR1 gene (601978) on 9p13. Clinical Features Horton et al. (1976) suggested that there are 3 phenotypic forms of familial ALS, each inherited as an autosomal dominant disorder. The first form they delineated is characterized by rapidly progressive loss of motor function with predominantly lower motor neuron manifestations and a course of less than 5 years. Pathologic changes are limited to the anterior horn cells and pyramidal tracts. The second form is clinically identical to the first, but at autopsy additional changes are found in the posterior columns, Clarke column, and spinocerebellar tracts. The third form is similar to the second except for a much longer survival, usually beyond 10 and often 20 years. Examples of type 1 include the families of Green (1960), Poser et al. (1965) and Thomson and Alvarez (1969). Examples of type 2 include the families of Kurland and Mulder (1955) and Engel et al. (1959). Engel et al. (1959) described 2 American families, 1 of which was of Pennsylvania Dutch stock with at least 11 members of 4 generations affected with what was locally and popularly termed 'Pecks disease.' Examples of type 3 include the families of Amick et al. (1971) and Alberca et al. (1981). In the Spanish kindred reported by Alberca et al. (1981), early onset and persistence of muscle cramps, unilateral proximal segmental myoclonus, and early abolition of ankle jerks were conspicuous clinical features. Brown (1951, 1960) described 2 New England families, Wetherbee and Farr by name, with autosomal dominant inheritance of a rapidly progressive neurodegenerative disorder with loss of anterior horn cells of the spinal cord and bulbar palsy. (See also Hammond, 1888 and Myrianthopoulos and Brown, 1954). Neuropathology showed a classic 'middle-root zone' pattern of posterior column demyelination in addition to involvement of the anteriolateral columns and ventral horn cells. Although the disorder was clinically indistinguishable from ALS, the pattern of posterior column demyelinations was unexpected. Osler (1880) had described the Farr family earlier (McKusick, 1976). Variability in disease severity in the Farr family was indicated by the case of a 78-year-old woman with relatively minor findings who had buried a son and whose mother had been affected (Siddique, 1993). Powers et al. (1974) reported the first autopsy in a member of the Wetherbee family from Vermont. The patient was a 35-year-old woman who began to experience weakness in the left leg 1 year before her terminal admission. She then gradually developed weakness and atrophy of the left hand, right lower limb, and right hand. One month before admission she developed dyspnea which steadily worsened, and she was admitted to hospital because of severe ventilatory insufficiency secondary to muscle weakness. She showed atrophy of all extremities, areflexia, and, except for slight movement of the left shoulder and right foot, quadriplegia. The patient died on the second hospital day. Autopsy showed severe demyelination type of atrophy of all muscles. Gray atrophy of the lumbar and cervical anterior roots was evident grossly. Microscopic neuronal changes included a moderate loss of neurons from the hypoglossal nuclei and dorsal motor vagal nuclei, severe neuronal loss from the anterior horns of the cervical and lumbar cord with reactive gliosis, eosinophilic intracytoplasmic inclusions in many of the remaining lumbar anterior horn cells, and a moderately symmetric loss of neurons from the Clarke column. A severe asymmetric loss of axons and myelin was demonstrated throughout the cervical dorsal spinocerebellar tracts and lumbar posterior columns, with moderate loss in the lumbar lateral corticospinal tracts. Powers et al. (1974) concluded that the disorder corresponded exactly to a subgroup of familial ALS described by Hirano et al. (1967). Engel (1976) concluded that the 'Wetherbee ail' and the Farr family disease were consistent with ALS (Engel et al., 1959). Alter and Schaumann (1976) reported 14 cases in 2 families and attempted a refinement of the classification of hereditary ALS. Hudson (1981) stated that posterior column disease is found in association with ALS in 80% of familial cases. In a kindred with an apparently 'new' microcephaly-cataract syndrome (212540), reported by Scott-Emuakpor et al. (1977), 10 persons had died of a seemingly unrelated genetic defect--amyotrophic lateral sclerosis. Veltema et al. (1990) described adult ALS in 18 individuals from 6 generations of a Dutch family. Onset occurred between ages 19 and 46; duration of disease averaged 1.7 years. The clinical symptoms were predominantly those of initial shoulder girdle and ultimate partial bulbar muscle involvement. Iwasaki et al. (1991) reported a Japanese family in which members in at least 3 generations had ALS. At least 2 individuals in the family also had Ribbing disease (601477), a skeletal dysplasia that was presumably unrelated to the ALS. Inheritance Familial ALS caused by mutations in the SOD1 gene usually causes autosomal dominant disease, but can also cause autosomal recessive ALS. In Germany, Haberlandt (1963) concluded that ALS is an 'irregular' autosomal dominant disorder in many instances. Gardner and Feldmahn (1966) described adult-onset ALS in a family in which 15 members spanning 7 generations were affected. Husquinet and Franck (1980) reported a family with ALS suggesting autosomal dominant inheritance with incomplete penetrance. Twelve men and 6 women were affected; 4 unaffected members of the family transmitted the disease. The first signs of the disease, which ran its course in 5 to 6 years, were in either the arms or the legs. As in most cases of ALS, death was caused by bulbar paralysis. Mean age at death was about 57 years. In a review of a familial ALS, de Belleroche et al. (1995) found autosomal dominant inheritance with incomplete penetrance; by age 85 years, about 80% of carriers had manifested the disorder, and it was not uncommon to see obligate carriers in a family who died without manifesting the disease. Phenotypic heterogeneity was also common within families: for example, age of onset varying over 30 years within a family and duration of illness varying from 6 months to 5 years. Signs at onset were variable, but the disease usually began with focal and asymmetric wasting of hand muscles. Lower motor neuron involvement was usually conspicuous, whereas involvement of upper motor neurons was less marked. Bradley et al. (2005) found no evidence for preferential maternal or paternal transmission among 185 families in which at least 2 individuals were diagnosed with ALS. Initial evidence suggesting anticipation was rejected following further analysis. By analysis of a Swedish multigeneration registry spanning from 1961 to 2005, Fang et al. (2009) identified 6,671 probands with ALS. There was a 17-fold increased risk for development of ALS among sibs, and a 9-fold increased risk among children of probands. Sibs and children had a greater risk if the proband was diagnosed at a younger age, and the risk decreased with increasing age at diagnosis of the proband. Two cases were identified among the cotwins of ALS probands, yielding a relative risk of 32 for monozygotic twins. Spouses of probands had no significantly increased risk compared to controls. The findings indicated that there is a major genetic role in the development of ALS. ### Possible X-linked Inheritance In a family with ALS reported by Wilkins et al. (1977), X-linked dominant inheritance was suggested by the late onset in females and the lack of male-to-male transmission. Siddique et al. (1987) did linkage studies in a family with 13 affected persons in 4 generations. There was no instance of male-to-male transmission. Kunst (2004) referenced an X-linked dominant, late-onset form linked to Xp11-q12 but reported only in abstract (Siddique et al., 1998). Mapping Siddique et al. (1989) presented preliminary data from genetic linkage analysis in 150 families with familial ALS. Two regions of possible linkage were identified on chromosomes 11 and 21. The highest lod score observed was 1.46, obtained with D21S13 at theta = 0.20. The next highest lod score was observed with marker D11S21 (lod score = 1.05 at maximum theta of 0.001). Siddique et al. (1991) presented evidence for linkage of familial ALS, termed ALS1, to markers on chromosome 21q22.1-q22.2 (maximum lod score of 5.03 10 cM telomeric to marker D21S58). Tests for heterogeneity in these families yielded a probability of less than 0.0001 that of genetic-locus heterogeneity, i.e., a low probability of homogeneity. ### Genetic Heterogeneity King et al. (1993) failed to find linkage to loci on chromosome 21 in 8 U.K. families with ALS, indicating genetic heterogeneity. ### Associations Pending Confirmation In a genomewide association study (GWAS) of 1,014 deceased patients with sporadic ALS and 2,258 controls from the U.S. and Europe, Landers et al. (2009) found a significant association between rs1541160 in intron 8 of the KIFAP3 gene (601836) on chromosome 1q24 and survival (p = 1.84 x 10(-8), p = 0.021 after Bonferroni correction). Homozygosity for the favorable allele, CC, conferred a 14-month survival advantage compared to TT. There was linkage disequilibrium between rs1541160 and rs522444 within the KIFAP3 promoter, and the favorable alleles of both SNPs correlated with decreased KIFAP3 expression in brain. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. The findings suggested that genetic factors may modify phenotypes in ALS. 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. Analysis of the genomewide data revealed genomewide significance for 1 SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort, and a combined analysis over the 2 stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A (609894), which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. ### Exclusion Studies Wills et al. (2009) conducted a metaanalysis of 10 published studies, including 4 GWAS, and 1 unpublished study that had reported findings on association of sporadic ALS and paraoxonase (see PON1; 168820) SNPs on chromosome 7q21.3. The metaanalysis found no association between sporadic ALS and the PON locus and encompassed 4,037 ALS patients and 4,609 controls, including GWAS data from 2,018 ALS cases and 2,425 controls. The authors stated that this was the largest metaanalysis of a candidate gene in ALS to date and the first ALS metaanalysis to include data from GWAS. Pathogenesis Bradley and Krasin (1982) suggested that a defect in DNA repair may underlie ALS. Rothstein et al. (1992) found in in vitro studies that synaptosomes in neural tissue obtained from 13 ALS patients showed a marked decrease in the maximal velocity of transport for high-affinity glutamate uptake in spinal cord, motor cortex, and somatosensory cortex compared to controls. The decrease in glutamate uptake was not observed in tissue from visual cortex, striatum, or hippocampus. Neural tissue from patients with other neurodegenerative disorders did not show this defect. In ALS tissue, there was no defect in affinity of the transporter for glutamate and no decrease in the transport of other molecules (gamma-aminobutyric acid and phenylalanine). Rothstein et al. (1992) suggested that defects in a high-affinity glutamate transporter (see, e.g., SLC1A1, 133550) could lead to neurotoxic levels of extracellular glutamate, contributing to neurodegeneration in ALS. Liu et al. (1998) demonstrated increased free radical production in the spinal cord but not the brain of transgenic mice expressing mutant human SOD1 (G93A; 147450.0008), which preceded the degeneration of motor neurons. They hypothesized that in situ production of free radicals initiates oxidative injury and that antioxidants that penetrate into the central nervous system may be of therapeutic benefit. Li et al. (2000) demonstrated an 81.5% elevation of caspase-1 (CASP1; 147678) activity in the spinal cord of humans with ALS when compared with normal controls, and, using an animal model, suggested that caspases play an instrumental role in the neurodegenerative processing of ALS. Caspase inhibition using zVAD-fmk delayed disease onset and mortality in the mouse model of ALS. Moreover, zVAD-fmk was found to inhibit caspase-1 activity as well as caspase-1 and caspase-3 (600636) mRNA upregulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. The findings also showed that zVAD-fmk decreased IL1-beta (147720), an indication that caspase-1 activity was inhibited. Okado-Matsumoto and Fridovich (2002) proposed a mechanism by which missense mutations in SOD1 lead to ALS. They suggested that the binding of mutant SOD1 to heat-shock proteins leads to formation of sedimentable aggregates, making the heat shock proteins unavailable for their antiapoptotic functions and leading ultimately to motor neuron death. Kawahara et al. (2004) extracted RNA from single motor neurons isolated with a laser microdissector from 5 individuals with sporadic ALS and 5 normal control subjects. GluR2 (GRIA2; 138247) RNA editing was 100% efficient in the control samples, but the editing efficiency varied between 0 and 100% in the motor neurons from each individual with ALS and was incomplete in 44 (56%) of them. Mice transgenic for GluR2 made artificially permeable to calcium ions developed motor neuron disease late in life (Feldmeyer et al., 1999), indicating that motor neurons may be specifically vulnerable to defective RNA editing. Kawahara et al. (2004) suggested that defective GluR2 RNA editing at the Q/R site may be relevant to ALS etiology. Shibata et al. (1994) found SOD1-like immunoreactivity within Lewy body-like inclusions in the spinal cords of 10 of 20 patients with sporadic ALS. Skein-like inclusions and Bunina bodies, which were found in all 20 ALS cases, showed no SOD1-like immunoreactivity. He and Hays (2004) identified Lewy body-like ubiquitinated (see UBB; 191339) inclusions in motor neurons from 9 of 40 ALS patients; all of the inclusions expressed peripherin. Similar inclusions were not identified in 39 controls. Neumann et al. (2006) identified TDP43 (605078) as the major disease protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal lobar degeneration (see 607485) and ALS. Pathologic TDP43 is hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected CNS regions, including hippocampus, neocortex, and spinal cord. Neumann et al. (2006) concluded that TDP43 represents the common pathologic substrate linking these neurodegenerative disorders. In mice, Miller et al. (2006) demonstrated that human SOD1 mutant-mediated damage within muscles was not a significant contributor to non-cell-autonomous pathogenesis of ALS. In addition, enhancement of muscle mass and strength provided no benefit in slowing disease onset or progression. Pradat et al. (2007) found muscle NOGOA (604475) expression in 17 of 33 patients with spinal lower motor neuron syndrome observed for 12 months. NOGOA expression correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. NOGOA was detected as early as 3 months after symptom onset in patients who later developed typical ALS. Pradat et al. (2007) suggested that muscle NOGOA may be a prognostic marker for ALS in lower motor neuron syndromes. Tagerud et al. (2007) and Askanas et al. (2007) both commented that studies have demonstrated that NOGOA expression is increased in denervated muscles in mouse models and in other human neuropathies and myopathies. Both groups suggested that it may be premature to consider NOGOA muscle expression as a specific biomarker for ALS, as suggested by Pradat et al. (2007). Using a specific antibody to monomer or misfolded forms of SOD1 (Rakhit et al., 2007), Liu et al. (2009) detected monomer/misfolded SOD1 in spinal cord sections of all 5 patients with familial ALS due to mutations in the SOD1 gene. The antibody localized primarily to hyaline conglomerate inclusions in motor neuron perikarya and occasionally to neuritic processes. In contrast, no immunostaining was observed in spinal cord tissue from ALS patients without SOD1 mutations, including 13 with sporadic disease and 1 with non-SOD1 familial ALS. The findings indicated a distinct difference between familial ALS1 and sporadic ALS, and supported the idea that monomer or misfolded SOD1 is not a common disease mechanism. Rabin et al. (2010) studied exon splicing directly in 12 sporadic ALS and 10 control lumbar spinal cords. ALS patients had rostral onset and caudally advancing disease and abundant residual motor neurons in this region. Whole-genome exon splicing was profiled from RNA pools collected from motor neurons and from the surrounding anterior horns. In the motor neuron-enriched mRNA pool, there were 2 distinct cohorts of mRNA signals, most of which were upregulated: 148 differentially expressed genes and 411 aberrantly spliced genes. The aberrantly spliced genes were highly enriched in cell adhesion, especially cell-matrix as opposed to cell-cell adhesion. Most of the enriching genes encoded transmembrane or secreted as opposed to nuclear or cytoplasmic proteins. The differentially expressed genes were not biologically enriched. In the anterior horn enriched mRNA pool, there were no clearly identified mRNA signals or biologic enrichment. Rabin et al. (2010) suggested possible mechanisms in cell adhesion for the contiguously progressive nature of motor neuron degeneration. Using unbiased transcript profiling in the SOD1G93A mouse model of ALS, Lincecum et al. (2010) identified a role for the costimulatory pathway, a key regulator of immune responses. Furthermore, Lincecum et al. (2010) observed that this pathway is upregulated in the blood of 56% of human patients with ALS. Kudo et al. (2010) used laser capture microdissection coupled with microarrays to identify early transcriptome changes occurring in spinal cord motor neurons or surrounding glial cells in models of ALS. Two transgenic mouse models of familial motor neuron disease, Sod1G93A and TAUP301L (157140.0001), were used at the presymptomatic stage. Identified gene expression changes were predominantly model-specific. However, several genes were regulated in both models. The relevance of identified genes as clinical biomarkers was tested in the peripheral blood transcriptome of presymptomatic Sod1G93A animals using custom-designed ALS microarray. To confirm the relevance of identified genes in human sporadic ALS (SALS), selected corresponding protein products were examined by high-throughput immunoassays using tissue microarrays constructed from human postmortem spinal cord tissues. Genes that were identified by these experiments and were located within a linkage region associated with familial ALS/frontotemporal dementia were sequenced in several families. This large-scale gene and protein expression study pointing to distinct molecular mechanisms of TAU- and SOD1-induced motor neuron degeneration identified several novel SALS-relevant proteins, including CNGA3 (600053), CRB1 (604210), OTUB2 (608338), MMP14 (600754), SLK (FYN; 137025), DDX58 (609631), RSPO2 (610575) and the putative blood biomarker Mgll (609699). Pedrini et al. (2010) showed that the toxicity of mutant SOD1 (147450) relies on its spinal cord mitochondria-specific interaction with BCL2 (151430). Mutant SOD1 induced morphologic changes and compromised mitochondrial membrane integrity leading to the release of cytochrome c only in the presence of BCL2. In cells and in mouse and human spinal cord homogenates with SOD1 mutations, binding to mutant SOD1 triggered a conformational change in BCL2 that resulted in the exposure of its BH3 domain. Mutagenized BCL2 carrying a nontoxic (inactive) BH3 domain failed to support mutant SOD1-mediated mitochondrial toxicity. Ferri et al. (2010) exploited the ability of glutaredoxins (Grxs) to reduce mixed disulfides to protein thiols either in the cytoplasm and IMS, where Grx1 (GLRX; 600443) is localized, or in the mitochondrial matrix, where Grx2 (GLRX2; 606820) is localized, as a tool for restoring a correct redox environment and preventing aggregation of mutant SOD1 (G93A; 147450.0008). Overexpression of Grx1 increased the solubility of mutant SOD1 in the cytosol but did not inhibit mitochondrial damage and apoptosis induced by mutant SOD1 in neuronal cells or in immortalized motoneurons. Conversely, the overexpression of Grx2 increased the solubility of mutant SOD1 in mitochondria, interfered with mitochondrial fragmentation by modifying the expression pattern of proteins involved in mitochondrial dynamics, preserved mitochondrial function and strongly protected neuronal cells from apoptosis. The authors concluded that the toxicity of mutant SOD1 primarily arises from mitochondrial dysfunction, and that rescue of mitochondrial damage may represent a therapeutic strategy. Meissner et al. (2010) found that G93A mutant SOD1 activated caspase-1 (CASP1; 147678) and CASP1-mediated secretion of mature IL1-beta (147720) in a dose-dependent manner in microglia and macrophages. In cells in which CASP1 was activated, there was rapid endocytosis of mutant SOD1 into the cytoplasm; autophagy of mutant SOD1 within the cytoplasm dampened the proinflammatory response. Mutant SOD1 induced caspase activation through a gain of amyloid conformation, not through its enzymatic activity. Deficiency in caspase-1 or IL1-beta extended the life span of mutant Sod1 mice and was associated with decreased microgliosis and astrogliosis; however, age at disease onset was not affected. Treatment of mutant mice with an IL1 receptor inhibitor also extended survival and improved motor performance. The findings suggested that IL1-beta contributes to neuroinflammation and disease progression in ALS. To determine whether increased SOD1 protects the heart from ischemia Armakola et al. (2012) reported results from 2 genomewide loss-of-function TDP43 (605078) toxicity suppressor screens in yeast. The strongest suppressor of TDP43 toxicity was deletion of DBR1 (607024), which encodes an RNA lariat debranching enzyme. Armakola et al. (2012) showed that, in the absence of DBR1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of DBR1 in a human neuronal cell line or in primary rat neurons was also sufficient to rescue TDP43 toxicity. Armakola et al. (2012) concluded that their findings provided insight into TDP43-mediated cytotoxicity and suggested that decreasing DBR1 activity could be a potential therapeutic approach for ALS. Molecular Genetics ### Autosomal Dominant Mutations In affected members of 13 unrelated families with ALS, Rosen et al. (1993) identified 11 different heterozygous mutations in exons 2 and 4 of the SOD1 gene (147450.0001-147450.0011). Deng et al. (1993) identified 3 mutations in exons 1 and 5 of the SOD1 gene in affected members of ALS families. Eight families had the same mutation (A4V; 147450.0012). One of the families with the A4V mutation was the Farr family reported by Brown (1951, 1960). Pramatarova et al. (1995) estimated that approximately 10% of ALS cases are inherited as an autosomal dominant and that SOD1 mutations are responsible for at least 13% of familial ALS cases. Jones et al. (1993) demonstrated that mutation in the SOD1 gene can also be responsible for sporadic cases of ALS. They found the same mutation (I113T; 147450.0011) in 3 of 56 sporadic cases of ALS drawn from a population-based study in Scotland. Among 233 sporadic ALS patients, Broom et al. (2004) found no association between disease susceptibility or phenotype and a deletion and 4 SNPs spanning the SOD1 gene, or their combined haplotypes, arguing against a major role for wildtype SOD1 in sporadic ALS. In a review of familial ALS, de Belleroche et al. (1995) listed 30 missense mutations and a 2-bp deletion in the SOD1 gene. Siddique and Deng (1996) reviewed the genetics of ALS, including a tabulation of SOD1 mutations in familial ALS. Millecamps et al. (2010) identified 18 different SOD1 missense mutations in 20 (12.3%) of 162 French probands with familial ALS. Compared to those with ALS caused by mutations in other genes, those with SOD1 tended to have disease onset predominantly in the lower limbs. One-third of SOD1 patients survived for more than 7 years: these patients had an earlier disease onset compared to those presenting with a more rapid course. No patients with SOD1 mutations developed cognitive impairment. ### Autosomal Recessive Mutations Andersen et al. (1995) found homozygosity for a mutation in the SOD1 gene (D90A; 147450.0015) in 14 ALS patients from 4 unrelated families and 4 apparently sporadic ALS patients from Sweden and Finland. Consanguinity was present in several of the families, consistent with autosomal recessive inheritance. Erythrocyte SOD1 activity was essentially normal. The findings suggested that this mutation caused ALS by a gain of function rather than by loss, and that the D90A mutation was less detrimental than previously reported mutations. Age at onset ranged from 37 to 94 years in 1 family in which all patients showed very similar disease phenotypes; symptoms began with cramps in the legs, which progressed to muscular atrophy and weakness. Upper motor neuron signs appeared after 1 to 4 years' disease duration in all patients, and none of the patients showed signs of intellectual impairment. In a second family, onset in 2 sibs was at the age of 40, with a phenotype like that in the first family. In a third family, 3 sibs had onset at ages 20, 36, and 22 years, respectively. Thus, familial ALS due to mutation in the SOD1 gene exists in both autosomal dominant and autosomal recessive forms. Al-Chalabi et al. (1998) concluded that a 'tightly linked protective factor' in some families modifies the toxic effect of the mutant SOD1, resulting in recessive inheritance. ### Susceptibility Genes and Association Studies Siddique et al. (1998) could demonstrate no relationship between APOE genotype (107741) and sporadic ALS. Previous studies had resulted in contradictory results. Siddique et al. (1998) found no significant difference in age at onset between patients with 1, 2, or no APOE*4 alleles. In 1 of 189 ALS patients, Gros-Louis et al. (2004) identified a 1-bp deletion in the peripherin gene (170710.0001), suggesting that the mutation conferred an increased susceptibility to development of the disease. Among 250 patients with a putative diagnosis of ALS, Munch et al. (2004) identified 3 mutations in the DCTN1 gene (601143.0002-601143.0004) in 3 families. One of the mutations showed incomplete penetrance. The authors suggested that mutations in the DCTN1 gene may be a susceptibility risk factor for ALS. Veldink et al. (2005) presented evidence suggesting that SMN genotypes producing less SMN protein increased susceptibility to and severity of ALS. Among 242 ALS patients, the presence of 1 SMN1 (600354) copy, which represents spinal muscular atrophy (SMA; 253300) carrier status, was significantly increased in patients (6.6%) compared to controls (1.7%). The presence of 1 copy of SMN2 (601627) was significantly increased in patients (58.7%) compared to controls (29.7%), whereas 2, 3, or 4 SMN2 copies were significantly decreased in patients compared to controls. In 167 ALS patients and 167 matched controls, Corcia et al. (2002) found that 14% of ALS patients had an abnormal copy number of the SMN1 gene, either 1 or 3 copies, compared to 4% of controls. Among 600 patients with sporadic ALS, Corcia et al. (2006) found an association between disease and 1 or 3 copies of the SMN1 gene (p less than 0.0001; odds ratio of 2.8). There was no disease association with SMN2 copy number. Dunckley et al. (2007) provided evidence suggestive of an association between the FLJ10986 gene (611370) on chromosome 1 and sporadic amyotrophic lateral sclerosis in 3 independent patient populations. The susceptibility allele of rs6690993 conferred an odds ratio of 1.35 (p = 3.0 x 10(-4)). Simpson et al. (2009) performed a multistage association study using 1,884 microsatellite markers in 3 populations totaling 781 ALS patients and 702 control individuals. They identified a significant association (p = 1.96 x 10(-9)) with the 15-allele marker D8S1820 in intron 10 of the ELP3 gene (612722). Fine mapping with SNPs in and around the ELP3 gene identified a haplotype consisting of allele 6 of D8S1820 and rs12682496 strongly associated with ALS (p = 1.05 x 10(-6)). Lambrechts et al. (2009) performed a metaanalysis of 11 published studies comprising over 7,000 individuals examining a possible relationship between variation in the VEGF gene (192240) and ALS. After correction, no specific genotypes or haplotypes were significantly associated with ALS. However, subgroup analysis by gender found that the -2578AA genotype (rs699947; 192240.0002), which lowers VEGF expression, increased the risk of ALS in males (odds ratio of 1.46), even after correction for publication bias and multiple testing. Sabatelli et al. (2009) identified nonsynonymous variants in the CHRNA3 (118503) and CHRNB4 (118509) genes on chromosome 15q25.1 and the CHRNA4 gene (118504) on chromosome 20q13.2-q13.3, encoding neuronal nicotinic acetylcholine receptor (nAChR) subunits, in 19 sporadic ALS patients and in 14 controls. NAChRs formed by mutant alpha-3 and alpha-4 and wildtype beta-4 subunits exhibited altered affinity for nicotine (Nic), reduced use-dependent rundown of Nic-activated currents, and reduced desensitization leading to sustained intracellular calcium concentration, in comparison with wildtype nAChR. Sabatelli et al. (2009) suggested that gain-of-function nAChR variants may contribute to disease susceptibility in a subset of ALS patients because calcium signals mediate the neuromodulatory effects of nAChRs, including regulation of glutamate release and control of cell survival. In a 3-generation kindred with familial ALS, Mitchell et al. (2010) found linkage to markers D12S1646 and D12S354 on chromosome 12q24 (2-point lod score of 2.7). Screening of candidate genes identified a heterozygous arg199-to-trp (R199W) mutation in exon 7 of the DAO gene (124050) in 3 affected members and in 1 obligate carrier, who died at age 73 years of cardiac failure and reportedly had right-sided weakness and dysarthria. The proband had onset at age 40, and the mean age at death in 7 cases was 44 years (range, 42 to 55 years). The mutation was also present in 3 at-risk individuals of 33, 44, and 48 years of age, respectively. The R199W mutation was not found in 780 Caucasian controls. Postmortem examination of the obligate carrier showed some loss of motor neurons in the spinal cord and degeneration of 1 of the lateral corticospinal tracts. There was markedly decreased DAO enzyme activity in the spinal cord compared to controls. Coexpression of mutant protein with wildtype protein in COS-7 cells indicated a dominant-negative effect for the mutant protein. Rat neuronal cell lines expressing the R199W-mutant protein showed decreased viability and increased ubiquitinated aggregates compared to wildtype. Mitchell et al. (2010) suggested a role for the DAO gene in ALS, but noted that a causal role for the R199W-mutant protein remained to be unequivocally established. In a study of 847 patients with ALS and 984 controls, Blauw et al. (2012) found that SMN1 duplications were associated with increased susceptibility to ALS (odds ratio (OR) of 2.07; p = 0.001). A metaanalysis with previous data including 3,469 individuals showed a similar effect, with an OR of 1.85 (p = 0.008). SMN1 deletions or point mutations and SMN2 copy number status were not associated with ALS, and SMN1 or SMN2 copy number variants had no effect on survival or the age at onset of the disease. For discussion of a possible association between variation in the SS18L1 gene and ALS, see 606472.0001-606472.0003. ### Modifier Genes Giess et al. (2002) reported a 25-year-old man with ALS who died after a rapid disease course of only 11 months. Genetic analysis identified a heterozygous mutation in the SOD1 gene and a homozygous mutation in the ciliary neurotrophic factor gene (CNTF; 118945.0001). The patient's mother, who developed ALS at age 54, had the SOD1 mutation and was heterozygous for the CNTF mutation. His healthy 35-year-old sister had the SOD1 mutation, but did not have the CNTF mutation. Two maternal aunts had died from ALS at 56 and 43 years of age, and a maternal grandmother and a great-grandmother had died from progressive muscle weakness and atrophy at ages 62 and less than 50 years, respectively. Giess et al. (2002) found that transgenic SOD1 mutant mice who were Cntf-deficient had a significantly earlier age at disease onset compared to in transgenic mice that were wildtype for CNTF. Although linkage analysis in mice revealed that the SOD1 gene was solely responsible for the disease, disease onset as a quantitative trait was regulated by the CNTF locus. In addition, patients with sporadic ALS who had a homozygous CNTF gene defect showed significantly earlier disease onset, but did not show a significant difference in disease duration. Giess et al. (2002) concluded that CNTF acts as a modifier gene that leads to early onset of disease in patients with SOD1 mutations. Genotype/Phenotype Correlations De Belleroche et al. (1995) noted that the SOD1 H46R mutation (147450.0013) was associated with a more benign form of ALS with average duration of 17 years and only slightly reduced levels of SOD1 enzyme activity. The authors referred to a family with an I113T mutation (147450.0011) in which 1 affected member of the family died after a short progression and another member survived more than 20 years. Cudkowicz et al. (1997) registered 366 families in a study of dominantly inherited ALS. They screened 290 families for mutations in the SOD1 gene and detected mutations in 68 families; the most common SOD1 mutation, A4V (147450.0012), was present in 50% of the families. The presence of either of 2 SOD1 mutations, G37R (147450.0001) or L38V (147450.0002), predicted an earlier age at onset. Additionally, the presence of the A4V mutation correlated with shorter survival, whereas G37R, G41D (147450.0004), and G93C (147450.0007) mutations predicted longer survival. The clinical characteristics of patients with familial ALS arising from SOD1 mutations were similar to those without SOD1 defects. However, Cudkowicz et al. (1997) reported that mean age at onset was earlier in the SOD1 group than in the non-SOD1 group, and Kaplan-Meier plots demonstrated shorter survival in the SOD1 group compared with the non-SOD1 group at early survival times. Sato et al. (2005) measured the ratio of mutant-to-normal SOD1 protein in 29 ALS patients with mutations in the SOD1 gene. Although there was no relation to age at onset, turnover of mutant SOD1 was correlated with a shorter disease survival time. Regal et al. (2006) reported the clinical features of 20 ALS patients from 4 families with the SOD1 G93C mutation (147450.0007). Mean age at onset was 45.9 years, and all patients had slowly progressive weakness and atrophy starting in the distal lower limbs. Although symptoms gradually spread proximally and to the upper extremities, bulbar function was preserved. None of the patients developed upper motor neuron signs. Postmortem findings of 1 patient showed severe loss of anterior horn cells and loss of myelinated fibers in the posterior column and spinocerebellar tracts, but only mild changes in the lateral corticospinal tracts. Lipofuscin and hyaline inclusions were observed in many neurons. Patients with the G93C mutation had significantly longer survival compared to patients with other SOD1 mutations. Clinical Management Amyotrophic lateral sclerosis is a disorder that has prominently been mentioned as justification for assisted suicide. Ganzini et al. (1998) found that in the states of Oregon and Washington most patients with ALS whom they surveyed would consider assisted suicide. Many would request a prescription for a lethal dose of medication well before they intended to use it. Rowland (1998) reviewed the question of what it is about ALS that raised the question of suicide. The progressive paralysis leads to increase of loss of function, culminating in complete dependence on the help of others for all activities of daily living and, if life is sustained by assisted ventilation, loss of the ability to communicate or swallow. Ten percent of patients are under the age of 40 years. Some patients, wanting to live as long as possible, opted for tracheostomy and assisted ventilation at home. In a study of 92 patients receiving long-term assisted ventilation with tracheostomy, 20 lived for 8 to 17 years with the tracheostomy, and 9 became 'locked in' (they were conscious but severely paralyzed and unable to communicate except by eye movements). In the Oregon series, however, only 2 patients opted for tracheostomy with long-term mechanical ventilation, and among patients at the ALS Center at Columbia Presbyterian Medical Center, only 2.9% chose it (Rowland, 1998). The last year in the life of an ALS victim, Professor Morris Schwartz, was chronicled in a bestselling book written by Albom (1997). In a prospective randomized control trial of 44 ALS patients, Fornai et al. (2008) reported that treatment of 16 patients with lithium plus riluzole resulted in slower disease progression compared to 28 patients treated with riluzole alone. All 16 patients treated with lithium survived for 15 months; 29% of the patients receiving riluzole alone did not survive by this endpoint. Studies in transgenic ALS mice showed a similar delay in disease progression and longer survival. Mice treated with lithium showed delayed cell death in spinal cord motor neurons, increased numbers of normal mitochondria in motor neurons, decreased SOD1 aggregation, and decreased reactive astrogliosis. Studies of cultured mutant murine motor neurons suggested that lithium treatment increased endosomal autophagy of aggregated proteins or abnormal mitochondria, which may have contributed to the observed neuroprotective effects. Population Genetics In 2 regions of northwestern Italy with a total population of approximately 4.5 million, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (2001) determined a mean annual incidence rate of 2.5 per 100,000 from 1995 to 1996. The data were comparable to similar studies in other Western countries, suggesting diffuse genetic or environmental factors in the pathogenesis of ALS. Chio et al. (2008) found that 5 of 325 patients with ALS in Turin province of the Piemonte region of Italy had mutations in the SOD1 gene. Mutations were identified in 3 (13.6%) of 22 patients with a family history of ALS, and 2 (0.7%) of 303 sporadic cases. Chio et al. (2008) noted that the frequency of FALS (5.7%) was lower in this population-based series compared to series reported from ALS referral centers. Animal Model See also ANIMAL MODEL in 147450. The murine Mnd (motor neuron degeneration) mutation causes a late-onset, progressive degeneration of upper and lower motor neurons. Using endogenous retroviruses as markers, Messer et al. (1992) mapped the Mnd gene in the mouse to proximal chromosome 8. Messer et al. (1992) suggested that examination of human chromosome 8, which shows homology of synteny, in human kindreds with ALS as well as related hereditary neurologic diseases might be fruitful. They presented evidence suggesting that a combination of genetic and environmental modifiers can alter the time course of the phenotypic expression in the mouse model. Gurney et al. (1994) found that expression of high levels of human SOD containing the gly93-to-ala mutation (G93A; 147450.0008), a change that had little effect on enzyme activity, resulted in motor neuron disease in transgenic mice. The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. Ongoing reinnervation and remodeling of muscle innervation suggested that 'sprouting' probably compensates for the loss of motor neurons until late in the course of the disease. Gurney et al. (1994) suggested that the toxicity of SOD1 from motor neurons could involve the formation of the strong oxidant peroxynitrite from oxygen and nitric oxide free radicals, representing a dominant, gain-of-function role for SOD1 mutations in the pathogenesis of familial ALS. The fact that mice with the abnormal human SOD became paralyzed even though copies of the animals' own normal Sod gene remained intact supported the gain-of-function role. Gurney et al. (1994) and other groups studying transgenic mice found that animals making the highest amounts of mutant Sod proteins were the ones that become paralyzed, a finding that runs counter to the idea that decreased SOD activity is at fault in ALS. Wong et al. (1995) generated transgenic mice carrying a gly37-to-arg (G37R; 147450.0001) mutation in the SOD1 gene associated with a subset of familial ALS cases. The mice developed severe, progressive motor neuron disease and provided an animal model for ALS. Wong et al. (1995) observed that at lower levels of mutant accumulation, pathology was restricted to lower motor neurons, whereas higher levels caused more severe abnormalities and affected a variety of other neuronal populations. The authors noted that the most obvious cellular abnormality in the mutant mice was the presence in axons and dendrites of membrane-bound vacuoles, which they hypothesized were derived from degenerating mitochondria. Wong et al. (1995) concluded that the disease in mice expressing G37R arises from the acquisition of an adverse property by the mutant enzyme rather than elevation or loss of SOD1 activity. Ripps et al. (1995) produced a transgenic mouse model of familial ALS by introducing an SOD1 mutation (gly86-to-arg). In 2 lines of mice that produced high levels of transgene mRNA in the CNS, motor paralysis developed and was associated with degenerative changes of motor neurons within the spinal cord, brainstem, and neocortex. Biochemical measurements in these animals revealed no diminution of Sod activity, indicating a dominant gain-of-function mutation. Tu et al. (1996) reported that transgenic mice expressing a human SOD1 gene containing the G92A mutation developed a motor neuron disease similar to familial ALS, but transgenic mice expressing a wildtype human SOD1 transgene did not. Neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of ALS. Tu et al. (1996) found that such inclusions were detectable in spinal cord motor neurons of the mutant carrying transgenic mice at 82 days of age and about the time that the mice first showed clinical evidence of the disease. In contrast, NF inclusions were not seen in the mice with the wildtype transgene until they were 132 days old, and ubiquitin immunoreactivity, which likewise started at about 82 days in mutant-bearing mice, was not increased in wildtype mice even at 199 days of age. A striking similarity between the cytoskeletal pathology of the mutant transgenic mice and the patients with ALS was demonstrated. Using immunohistochemistry and immunoblot experiments, Nguyen et al. (2001) found that the p25/p35 (see 603460) ratio and Cdk5 (123831) activity were abnormally elevated in the spinal cord of transgenic mice with the G37R mutation in SOD1 (Wong et al., 1995). This elevation was associated with the hyperphosphorylation of neurofilament and tau (157140) proteins. By analyzing transgenic mouse lines with differing G37R transgene expression levels, Nguyen et al. (2001) observed a correlation between Cdk5 activity and the longevity of the mutant mice. Nguyen et al. (2001) bred the G37R transgene onto neurofilament mutant backgrounds and observed that the absence of neurofilament light subunit (NEFL; 162280) provoked an accumulation of unassembled neurofilament subunits in the perikaryon of motor neurons and extended the average life span of the mutant mice. Using double immunofluorescence microscopy, Nguyen et al. (2001) confirmed that Cdk5 and p25 colocalized with perikaryal neurofilament accumulations in G37R mice on the neurofilament mutant background. Using immunoblotting, Nguyen et al. (2001) observed that the occurrence of perikaryal neurofilament accumulations in the mutant mice was associated with a reduction in the elevated phosphorylation of tau, another p25/cdk5 substrate. Nguyen et al. (2001) hypothesized that perikaryal accumulations of neurofilament proteins in motor neurons may alleviate ALS pathogenesis in SOD1(G37R) mice by acting as a phosphorylation sink for Cdk5 activity, thereby reducing the detrimental hyperphosphorylation of tau and other neuronal substrates. LaMonte et al. (2002) generated a mouse model of ALS by overexpressing dynamitin (DCTN2; 607376) in postnatal motor neurons of transgenic mice. They found that dynamitin overexpression disrupted the dynein-dynactin complex, resulting in an inhibition of retrograde axonal transport. The authors observed a late-onset, slowly progressive motor neuron degenerative disease characterized by muscle weakness, spontaneous trembling, abnormal posture and gaits, and deficits in strength and endurance. LaMonte et al. (2002) detected histologic changes in spinal cord motor neurons and skeletal muscle indicative of degeneration of motor neurons and denervation atrophy of muscle. The transgenic mice also displayed neurofilament accumulations. LaMonte et al. (2002) concluded that their mouse model confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease. Raoul et al. (2002) showed that Fas (134637), a member of the death receptor family, triggers cell death specifically in motor neurons by transcriptional upregulation of neuronal nitric oxide synthase (nNOS; 163731) mediated by p38 kinase (600289). ASK1 (602448) and Daxx (603186) act upstream of p38 in the Fas signaling pathway. The authors also showed that synergistic activation of the NO pathway and the classic FADD (602457)/caspase-8 (601763) cell death pathway were needed for motor neuron cell death. No evidence for involvement of the Fas/NO pathway was found in other cell types. Motor neurons from transgenic mice expressing ALS-linked SOD1 mutations displayed increased susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002) emphasized that this signaling pathway was unique to motor neurons and suggested that these cell death pathways may contribute to motor neuron loss in ALS. Raoul et al. (2006) reported that exogenous NO triggered expression of Fas ligand (FASL; 134638) in cultured motoneurons. In motoneurons from ALS model mice with mutations in the SOD1 gene, this upregulation resulted in activation of Fas, leading through Daxx and p38 to further NO synthesis. The authors suggested that chronic low activation of this feedback loop may underlie the slowly progressive motoneuron loss characteristic of ALS. To evaluate the contribution of motoneuronal Ca(2+)-permeable (GluR2 subunit-lacking) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (see GLUR2, 138247) to SOD1-related motoneuronal death, Tateno et al. (2004) generated choline acetyltransferase (ChAT; 118490)-GluR2 transgenic mice with significantly reduced Ca(2)+ permeability of these receptors in spinal motoneurons. Crossbreeding of the SOD1(G93A) transgenic mouse model of ALS with ChAT-GluR2 mice led to marked delay of disease onset, mortality, and the pathologic hallmarks such as release of cytochrome c from mitochondria, induction of cox2 (600262), and astrogliosis. Subcellular fractionation analysis revealed that unusual SOD1 species accumulated in 2 fractions (P1, composed of nuclei and certain kinds of cytoskeletons such as neurofilaments and glial fibrillary acidic protein (GFAP; 137780), and P2, composed of mitochondria) long before disease onset and then extensively accumulated in the P1 fractions by disease onset. All these processes for unusual SOD1 accumulation were considerably delayed by GluR2 overexpression. Ca(2+) influx through atypical motoneuronal AMPA receptors thus promoted a misfolding of mutant SOD1 protein and eventual death of these neurons. Using mice carrying a deletable mutant Sod1 gene, Boillee et al. (2006) demonstrated that expression within motor neurons is a primary determinant of ALS disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early phase but sharply slowed later disease progression. Boillee et al. (2006) concluded that onset and progression thus represent distinct ALS disease phases defined by mutant action within different cell types to generate non-cell autonomous killing of motor neurons; their findings validate therapies, including cell replacement, targeted to the nonneuronal cells. Miller et al. (2006) demonstrated that human SOD1 mutant-mediated damage within muscles of mice was not a significant contributor to non-cell-autonomous pathogenesis of ALS. In addition, enhancement of muscle mass and strength provided no benefit in slowing disease onset or progression. Marden et al. (2007) evaluated the effects of NADPH oxidase-1 (NOX1; 300225) or Nox2 (CYBB; 300481) deletion on transgenic mice overexpressing human SOD1 with the G93A mutation by monitoring the onset and progression of disease using various indices. Disruption of either Nox1 or Nox2 significantly delayed progression of motor neuron disease in these mice. However, 50% survival rates were enhanced significantly more by Nox2 deletion than Nox1 deletion. Female mice lacking 1 copy of the X-chromosomal Nox1 or Nox2 genes also exhibited significantly increased survival rates, suggesting that in the setting of random X-inactivation, a 50% reduction in Nox1- or Nox2-expressing cells has a substantial therapeutic benefit in ALS mice. Marden et al. (2007) concluded that NOX1 and NOX2 contribute to the progression of ALS. Kieran et al. (2007) detected a significant upregulation of Puma (BBC3; 605854), a proapoptotic protein, in motoneurons of G93A-mutant mice before symptom onset. Deletion of Puma in these mice improved motoneuron survival and delayed disease onset and motor dysfunction, but did not extend life span. The findings suggested that Puma may play a role in the early stages of neurodegeneration in ALS by increasing ER stress-mediated apoptosis. Awano et al. (2009) found that canine degenerative myelopathy, a spontaneously occurring adult-onset neurodegenerative disease, was highly associated with a homozygous glu40-to-lys (E40K) mutation in the canine Sod1 gene. The mutation was found in affected breeds including Pembroke Welsh corgi, boxer, Rhodesian ridgeback, Chesapeake Bay retriever, and German shepherd. The disorder was characterized clinically by adult onset of spasticity and proprioceptive ataxia, followed by weakness, paraplegia, and hyporeflexia. Histopathologic examination of the spinal cord of 46 affected dogs showed white matter degeneration with axonal and myelin loss and cytoplasmic Sod1-positive inclusions in surviving neurons. The disorder closely resembled human ALS. Tateno et al. (2009) demonstrated that, starting from the pre-onset stage of ALS, misfolded SOD1 species associated specifically with Kap3 (KIFAP3; 601836) in the ventral white matter of SOD1G93A-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargoes including ChAT. Motor axons in SOD1G93A-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. Using a purified hybrid mouse neuroblastoma/rat glioma cell line NG108-15 transfected with SOD1 mutations, the authors showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species and that impairment was normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in spinal motor neurons from human ALS patients as well. Tateno et al. (2009) suggested that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the pathophysiology of ALS. Wong and Martin (2010) created transgenic mice expressing wildtype, G37R (147450.0001), and G93A (147450.0008) human SOD1 in only skeletal muscle. These mice developed age-related neurologic and pathologic phenotypes consistent with ALS. Affected mice showed limb weakness and paresis with motor deficits. Skeletal muscles developed severe pathology involving oxidative damage, protein nitration, myofiber cell death, and marked neuromuscular junction abnormalities. Spinal motor neurons developed distal axonopathy, formed ubiquitinated inclusions, and degenerated through an apoptotic-like pathway involving caspase-3 (600636). Mice expressing wildtype and mutant forms of SOD1 developed motor neuron pathology. The authors concluded that SOD1 in skeletal muscle has a causal role in ALS, and they proposed a nonautonomous mechanism to explain the degeneration and selective vulnerability of these motor neurons. ### Therapeutic Strategies Transgenic mice overexpressing a mutated form of human SOD1 with a gly93-to-ala substitution (G93A; 147450.0008) develop progressive muscle wasting and paralysis as a result of spinal motor neuron loss and die at 5 to 6 months. Bordet et al. (2001) found that intramuscular injection of an adenoviral vector encoding CTF1 (600435) in SOD1(G93A) newborn mice delayed the onset of motor impairment as assessed in the rotarod test. By CTF1 treatment, axonal degeneration was slowed, skeletal muscle atrophy was largely reduced, and the time-course of motor impairment was significantly decreased. In a transgenic mouse model of ALS with the human G93A SOD1 mutation, Drachman et al. (2002) demonstrated that treatment with the cyclooxygenase-2 (COX2; 600262) inhibitor celecoxib resulted in significant delay of onset of weakness and weight loss, prolonged survival, preservation of ventral gray neurons in the spinal cord, and reduced spinal cord astroglial and microglial proliferation. The authors suggested that COX2 inhibition prevents prostaglandin-mediated release of glutamate from astrocytes and interrupts the inflammatory processes that result in the production of toxic reactive oxygen species. Adeno-associated virus (AAV) can be retrogradely transported efficiently from muscle to motor neurons of the spinal cord (Davidson et al., 2000; Boulis et al., 2003). In the Sod1-overexpressing model of ALS in the mouse, Kaspar et al. (2003) found that IGF1 (147440) administered through an AAV vector by intramuscular injection into hindlimb quadriceps and intercostal muscles at 60 days of age, approximately 30 days prior to disease onset, delayed onset by 31 days, twice as long as that seen in mice given GDNF (600837) through an AAV vector. GDNF-treated animals showed a smaller, 11-day increase in median survival compared to GFP-treated controls. IGF1-treated animals showed a larger, significant improvement in life span, with a 37-day increase in median survival compared to controls. The maximal life span of IGF1-treated animals was 265 days, compared to 140 days in the control group. Kaspar et al. (2003) concluded that injection of IGF1 not only delayed the onset of disease but also slowed the rate of disease progression. In contrast, GDNF appeared only to have delayed the onset of symptoms. IGF1 treatment was even able to expand life span when administered after disease onset at 90 days of age. Azzouz et al. (2004) reported that a single injection of a vascular endothelial growth factor (VEGF; 192240)-expressing lentiviral vector into various muscles delayed onset and slowed progression of ALS in mice engineered to overexpress the gene encoding the mutated G93A form of SOD1 (147450.0008), even when treatment was initiated at the onset of paralysis. VEGF treatment increased the life expectancy of ALS mice by 30% without causing toxic side effects, thereby achieving one of the most effective therapies reported in the field to that time. Storkebaum et al. (2005) found that intracerebroventricular delivery of recombinant Vegf in a rat model of ALS with the G93A SOD1 mutation delayed onset of paralysis by 17 days, improved motor performance, and prolonged survival by 22 days. By protecting cervical motoneurons, intracerebroventricular delivery of Vegf was particularly effective in rats with the most severe form of disease ALS with forelimb onset, which may be analogous to patients with bulbar onset of ALS. Urushitani et al. (2007) reported that active vaccination with mutant SOD1 and passive immunization with anti-SOD1 antibody were effective in alleviating disease symptoms and delaying mortality of in ALS mice with a G37R SOD1 mutation and moderate expression of the mutant gene. Western blot analysis showed clearance of SOD1 species in the spinal cord of vaccinated mice. Vaccination was not effective in a different mouse strain with extreme overexpression of mutant SOD1. The results were consistent with the hypothesis that neurotoxicity of extracellular secreted SOD1 may also play a role in disease pathogenesis. Dimos et al. (2008) generated induced pluripotent stem (iPS) cells from skin fibroblasts collected from an 82-year-old woman diagnosed with a familial form of ALS caused by a mutation in the SOD1 gene (L144F; 147450.0017). These patient-specific iPS cells possessed properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS. Williams et al. (2009) showed that a key regulator of signaling between motor neurons and skeletal muscle fibers is miR206 (611599), a skeletal muscle-specific microRNA that is dramatically induced in the mouse model of ALS. Mice that are genetically deficient in miR206 form normal neuromuscular synapses during development, but deficiency of miR206 in the ALS mouse model accelerates disease progression. miR206 is required for efficient regeneration of neuromuscular synapses after acute nerve injury, which probably accounts for its salutary effects in ALS. miR206 mediates these effects at least in part through histone deacetylase 4 (605314) and fibroblast growth factor (see 131220) signaling pathways. Thus, Williams et al. (2009) concluded that miR206 slows ALS progression by sensing motor neuron injury and promoting the compensatory regeneration of neuromuscular synapses. Based on their demonstration that the costimulatory pathway is activated in multiple tissues in the Sod1(G93A) preclinical model of ALS as well as in the blood of a subset of individuals with ALS, Lincecum et al. (2010) developed a therapy using a monoclonal antibody to CD40L (300386). Weight loss was slowed, paralysis delayed, and survival extended in an ALS mouse model. Corti et al. (2010) investigated a cell therapy using intravascular injection to transplant a specific population of c-kit+ (164920) stem/progenitor cells from bone marrow into the SOD1G93A mouse model of ALS. Transplanted cells engrafted within the host spinal cord. Cell transplantation significantly prolonged disease duration and lifespan in SOD1G93A mice, promoted the survival of motor neurons, and improved neuromuscular function. Neuroprotection was mediated by multiple effects, in particular by the expression of primary astrocyte glutamate transporter GLT1 (SLC1A2; 600300) and by the nonmutant genome. The authors suggested that somatic cell transplantation may be an effective therapy for ALS and other neurodegenerative diseases. INHERITANCE \- Autosomal dominant \- Autosomal recessive MUSCLE, SOFT TISSUES \- Muscle weakness and atrophy \- Fasciculations \- Muscle cramps NEUROLOGIC Central Nervous System \- Spasticity \- Hyperreflexia \- Ocular motility spared \- Upper and lower neuron manifestations \- Bulbar dysfunction (e.g. dysarthria and dysphagia) \- Sleep apnea \- Pseudobulbar palsy (e.g. involuntary weeping or laughter) \- Pathologic changes in anterior horn cells and lateral corticospinal tracts LABORATORY ABNORMALITIES \- Reduced cytosolic superoxide dismutase-1 (SOD1) MISCELLANEOUS \- Approximately 10% of ALS cases are familial \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the superoxide dismutase-1 gene (SOD-1, 147450.0001 ) Susceptibility conferred by mutation in the neurofilament, heavy polypeptide gene (NEFH, 162230.0001 ) \- Susceptibility conferred by mutation in the peripherin gene (PRPH, 170710.0001 ) \- Susceptibility conferred by mutation in the dynactin 1 gene (DCTN1, 601143.0002 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

AMYOTROPHIC LATERAL SCLEROSIS 1

c0002736

omim

https://www.omim.org/entry/105400

{"doid": ["0060193"], "mesh": ["D000690"], "omim": ["105400"], "orphanet": ["803"], "synonyms": ["Alternative titles", "AMYOTROPHIC LATERAL SCLEROSIS 1, FAMILIAL", "AMYOTROPHIC LATERAL SCLEROSIS 1, AUTOSOMAL DOMINANT"], "genereviews": ["NBK1450"]}

A number sign (#) is used with this entry because primary pigmented nodular adrenocortical disease-1 (PPNAD1) is caused by heterozygous mutation in the protein kinase A regulatory subunit 1-alpha gene (PRKAR1A; 188830) on chromosome 17q. Description Primary pigmented micronodular adrenocortical disease is a form of ACTH-independent adrenal hyperplasia resulting in Cushing syndrome. It is usually seen as a manifestation of the Carney complex (CNC1; 160980), a multiple neoplasia syndrome. However, PPNAD can also occur in isolation (Groussin et al., 2002). ### Genetic Heterogeneity of Primary Pigmented Micronodular Adrenocortical Disease See also PPNAD2 (610475), caused by mutation in the PDE11A gene (604961) on chromosome 2q31; PPNAD3 (614190), caused by mutation in the PDE8B gene (603390) on chromosome 5q13; and PPNAD4 (615830), caused by a duplication on chromosome 19p13 that includes the PRKACA gene (601639). Clinical Features Arce et al. (1978) reported 4 sibs with 'familial Cushing syndrome.' Three sibs had onset around adolescence of moon facies, obesity, hypertrichosis, purple striae, and osteoporosis. Skull radiographs showed no enlargement of the sella turcica, and dexamethasone suppression resulted in no change of circulating steroid levels. Measurement of serum ACTH was not available. Functional studies showed adrenal autonomy. Adrenalectomy resulted in complete remission in 3 sibs; the fourth died from a presumed virilizing adrenal carcinoma. Histology of the 3 sibs demonstrated enlarged adrenal glands containing numerous yellow cortical nodules ranging in size from 0.3 to 1.5 cm. Lipochromic pigment was reported. Although data were lacking, this family may have had PPNAD. Donaldson et al. (1981) described a brother and sister with bilateral micronodular adrenal hyperplasia manifesting at birth. Both had clinical features of adrenal Cushing syndrome, including hypertension, increased serum cortisol, and decreased serum ACTH. Shenoy et al. (1984) reported 4 patients, aged 12 to 21 years, with Cushing syndrome due to autonomously functioning bilateral adrenocortical neoplasms. All underwent curative adrenalectomy. Pathologic findings included decreased, normal, or slightly increased total gland weight, multiple small (less than 4 mm) black, brown, dark-green, red, or yellow nodules, and cortical atrophy and disorganization of the normal zonation between the nodules. Lipofuscin was present within most of the enlarged cortical cells. Shenoy et al. (1984) suggested the term 'primary pigmented nodular adrenocortical disease' to describe the disease entity. Hodge and Froesch (1988) described 2 sisters with primary micronodular adrenocortical dysplasia leading to Cushing syndrome. Bilateral adrenalectomy was performed at ages 14 and 30 years, respectively. The disease appeared to be characterized by autonomous overactivity of nests of abnormal adrenal cells with suppression of endogenous corticotropin. Teding van Berkhout et al. (1989) described Cushing syndrome due to pigmented nodular adrenocortical dysplasia in 2 sisters. The disorder was successfully treated by complete adrenalectomy. No evidence of associated disorders suggesting Carney syndrome was found in the 2 sisters or their first-degree relatives. However, the serum of both girls and their mother contained immunoglobulins capable of stimulating adrenal cortisol production in vitro. The results were interpreted as indicating that the disorder is an inherited disease of immunologic origin (Wulffraat et al., 1988). Diagnosis Stratakis et al. (1999) found that 9 (70%) of 13 patients with PPNAD demonstrated a paradoxical increase in urinary free cortisol on day 6 of the dexamethasone suppression test, a finding that distinguished patients with PPNAD from those with ACTH-independent macronodular adrenocortical hyperplasia (AIMAH; 219080). Molecular Genetics Groussin et al. (2002) identified mutations in the PRKAR1A gene (see, e.g., 188830.0009) in 5 unrelated patients with isolated PPNAD who had no clinical signs or symptoms of Carney complex. All of the mutations were predicted to result in truncation of the protein. The authors concluded that mutations in the PRKAR1A gene can result in isolated cases of PPNAD. INHERITANCE \- Autosomal dominant GROWTH Weight \- Truncal obesity HEAD & NECK Face \- Round face CARDIOVASCULAR Vascular \- Hypertension SKELETAL \- Decreased bone mineral density \- Osteoporosis Spine \- Kyphosis SKIN, NAILS, & HAIR Skin \- Thin skin \- Striae \- Easy bruising NEUROLOGIC Central Nervous System \- Cognitive decline Behavioral Psychiatric Manifestations \- Mood changes \- Depression \- Agitation \- Anxiety \- Psychosis ENDOCRINE FEATURES \- Cushing syndrome \- Pigmented micronodular adrenocortical disease \- ACTH-independent hypercortisolemia \- Adrenal glands may be normal, atrophic, or slightly enlarged LABORATORY ABNORMALITIES \- Increased serum cortisol \- Paradoxical increased cortisol secretion on dexamethasone suppression test \- Decreased serum ACTH MISCELLANEOUS \- Onset in childhood or young adulthood \- Manifestations of Cushing syndrome may be mild \- Genetic heterogeneity, see PPNAD2 ( 610475 ) \- Usually a manifestation of the Carney complex (CNC1, {1609890}) MOLECULAR BASIS \- Caused by mutation in the cAMP-dependent protein kinase, regulatory, type I, alpha gene (PRKAR1A, 188830.0009 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1

c1864846

omim

https://www.omim.org/entry/610489

{"doid": ["0060280"], "mesh": ["C566469"], "omim": ["610489"], "orphanet": ["189439"], "synonyms": ["CUSHING SYNDROME, ADRENAL, DUE TO PPNAD1", "Primary pigmented nodular adrenal dysplasia", "PPNAD", "Alternative titles", "PIGMENTED MICRONODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1", "ADRENOCORTICAL NODULAR DYSPLASIA, PRIMARY"]}

Colitis X, equine colitis X or peracute toxemic colitis is a catchall term for various fatal forms of acute or peracute colitis found in horses, but particularly a fulminant colitis where clinical signs include sudden onset of severe diarrhea, abdominal pain, shock, and dehydration. Death is common, with 90% to 100% mortality, usually in less than 24 hours. The causative factor may be Clostridium difficile, but it also may be caused by other intestinal pathogens. Horses under stress appear to be more susceptible to developing colitis X, and like the condition pseudomembranous colitis in humans, an association with prior antibiotic use also exists. Immediate and aggressive treatment can sometimes save the horse, but even in such cases, 75% mortality is considered a best-case scenario. ## Contents * 1 Clinical signs * 2 Causes * 3 Diagnosis * 4 Treatment * 5 See also * 6 References ## Clinical signs[edit] Colitis-X is a term used for colitis cases in which no definitive diagnosis can be made and the horse dies.[1] Clinical signs include sudden, watery diarrhea that is usually accompanied by symptoms of hypovolemic shock and usually leads to death in 3 to 48 hours, usually in less than 24 hours. Other clinical signs include tachycardia, tachypnea, and a weak pulse. Marked depression is present. An explosive diarrhea develops, resulting in extreme dehydration. Hypovolemic and endotoxic shock are manifest by increased capillary refill time, congested or cyanotic (purplish) mucous membranes, and cold extremities. While there may initially be a fever, temperature usually returns to normal.[1][2] Clinical signs are similar to those of other diarrheal diseases, including toxemia caused by Clostridium, Potomac horse fever, experimental endotoxic shock, and anaphylaxis.[1] ## Causes[edit] To date, the precise causative factor has not been verified, and the disease has been attributed by various sources to viruses, parasites, bacteria, use of antibiotics and sulfonamides, and heavy metal poisoning.[1][2][3] Other possible causes include peracute salmonellosis, clostridial enterocolitis, and endotoxemia.[1] Clostridium difficile toxins isolated in the horse have a genotype like the current human "epidemic strain", which is associated with human C. difficile-associated disease of greater than historical severity.[4] C. difficile can cause pseudomembranous colitis in humans,[5] and in hospitalized patients who develop it, fulminant C. difficile colitis is a significant and increasing cause of death.[6] Horses under stress appear to be more susceptible to developing colitis X.[2] Disease onset is often closely associated with surgery or transport.[1] Excess protein and lack of cellulose content in the diet (a diet heavy on grain and lacking adequate hay or similar roughage) is thought to be the trigger for the multiplication of clostridial organisms.[3] A similar condition may be seen after administration of tetracycline or lincomycin to horses.[1] These factors may be one reason the condition often develops in race horses, having been responsible for the deaths of the Thoroughbred filly Landaluce,[7][8] the Quarter Horse stallion Lightning Bar,[9] and is one theory for the sudden death of Kentucky Derby winner Swale.[7] The link to stress suggests the condition may be brought on by changes in the microflora of the cecum and colon that lower the number of anaerobic bacteria, increase the number of Gram-negative enteric bacteria, and decrease anaerobic fermentation of soluble carbohydrates, resulting in damage to the cecal and colonic mucosa and allowing increased absorption of endotoxins from the lumen of the gut.[10] The causative agent may be Clostridium perfringens, type A, but the bacteria are recoverable only in the preliminary stages of the disease.[3] The suspect toxin could also be a form of Clostridium difficile. In a 2009 study at the University of Arizona, C. difficile toxins A and B were detected, large numbers of C. difficile were isolated, and genetic characterization revealed them to be North American pulsed-field gel electrophoresis type 1, polymerase chain reaction ribotype 027, and toxinotype III. Genes for the binary toxin were present, and toxin negative-regulator tcdC contained an 18-bp deletion. The individual animal studied in this case was diagnosed as having peracute typhlocolitis, with lesions and history typical of those attributed to colitis X.[4] Use of antibiotics may also be associated with some forms of colitis-X.[11] In humans, C. difficile is the most serious cause of antibiotic-associated diarrhea, often a result of eradication of the normal gut flora by antibiotics.[12] In one equine study, colitis was induced after pretreatment with clindamycin and lincomycin, followed by intestinal content from horses which had died from naturally occurring idiopathic colitis.[11] (A classic adverse effect of clindamycin in humans is C. difficile-associated diarrhea.[13]) In the experiment, the treated horses died.[11] After necropsy, Clostridium cadaveris was present, and is proposed as another possible causative agent in some cases of fatal colitis.[11] ## Diagnosis[edit] Micrograph of a human colonic pseudomembrane in Clostridium difficile colitis At necropsy, edema and hemorrhage in the wall of the large colon and cecum are pronounced, and the intestinal contents are fluid and often blood-stained.[1] Macroscopic and microscopic findings include signs of disseminated intravascular coagulation, necrosis of colonic mucosa and presence of large numbers of bacteria in the devitalized parts of the intestine.[3] Typically, the PCV is >65% even shortly after the onset of clinical signs. The leukogram ranges from normal to neutropenia with a degenerative left shift. Metabolic acidosis and electrolyte disorders are also present.[1] There is leucopenia, initially characterized by neutropenia, which might evolve in neutrophilia. Moreover, haemoconcentration is noted with an increase in the packed cell volume; total proteins are initially increased, but changes into a lower than normal value. The most significant laboratory finding in colitis X is the increase of total cortisol concentration in blood plasma. Histopathologically, the mucosa of the large colon is hemorrhagic, necrotic and covered with fibrohemorrhagic exudate, while the submucosa, the muscular tunic and the local lymphonodes are edematous.[2] ## Treatment[edit] Treatment for colitis-X usually does not save the horse. The prognosis is average to poor, and mortality is 90% to 100%.[1][2] However, treatments are available, and one famous horse that survived colitis-X was U.S. Triple Crown winner Seattle Slew, that survived colitis-X in 1978 and went on to race as a four-year-old.[7][8][14] Large amounts of intravenous fluids are needed to counter the severe dehydration, and electrolyte replacement is often necessary. Flunixin meglumine (Banamine) may help block the effects of toxemia.[1] Mortality rate has been theorized to fall to 75% if treatment is prompt and aggressive, including administration of not only fluids and electrolytes, but also blood plasma, anti-inflammatory and analgesic drugs, and antibiotics. Preventing dehydration is extremely important. Nutrition is also important. Either parenteral or normal feeding can be used to support the stressed metabolism of the sick horse. Finally, the use of probiotics is considered beneficial in the restoration of the normal intestinal flora. The probiotics most often used for this purpose contain Lactobacillus and Bifidobacterium.[2] ## See also[edit] * Horse colic ## References[edit] 1. ^ a b c d e f g h i j k "Colitis-X". Merck Veterinary Manual. Merck & Co., Inc.W. 2008. Retrieved 2010-01-10. 2. ^ a b c d e f Diakakis, N. (January–March 2008). "Equine colitis X". Journal of the Hellenic Veterinary Medical Society. 59 (1): 23–28(6). doi:10.12681/jhvms.14944. 3. ^ a b c d Schiefer HB (May 1981). "Equine colitis "X", still an enigma?". The Canadian Veterinary Journal. 22 (5): 162–5. PMC 1790040. PMID 6265055. 4. ^ a b Songer JG, Trinh HT, Dial SM, Brazier JS, Glock RD (May 2009). "Equine colitis X associated with infection by Clostridium difficile NAP1/027". Journal of Veterinary Diagnostic Investigation. 21 (3): 377–80. doi:10.1177/104063870902100314. PMID 19407094. 5. ^ Wells CL, Wilkins TD (1996). "Antibiotic-Associated Diarrhea, Pseudomembranous Colitis, and Clostridium difficile". In Baron S, et al. (eds.). Baron's Medical Microbiology (4th ed.). Univ of Texas Medical Branch. ISBN 978-0-9631172-1-2. 6. ^ Dallal RM, Harbrecht BG, Boujoukas AJ, et al. (March 2002). "Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications". Annals of Surgery. 235 (3): 363–72. doi:10.1097/00000658-200203000-00008. PMC 1422442. PMID 11882758. 7. ^ a b c DeVito, Carlo (2002). D. Wayne: The High-Rolling and Fast Times of America's Premier Horse Trainer. McGraw-Hill Professional. pp. 93–94. ISBN 978-0-07-138737-8. 8. ^ a b Leggett, William (June 25, 1984). "Suddenly A Young Champion Is Gone". Sports Illustrated. Retrieved 2010-01-13. 9. ^ Simmons, Diane (1994). "Lightning Bar". In Simmons, Diane; Jim Goodhue; Holmes, Frank Wakefield; Phil Livingston (eds.). Legends 2: Outstanding Quarter Horse Stallions and Mares. Colorado Springs, CO: Western Horseman. p. 149. ISBN 978-0-911647-30-3. 10. ^ Srivastava, K. "Colitis X (Peracute Toxemic Colitis)". Biomedical Research and Graduate Studies Resources, Large Animal Laboratory Animal Medicine. Tuskegee University. Archived from the original on 2012-12-10. Retrieved 2010-01-10. 11. ^ a b c d Prescott JF, Staempfli HR, Barker IK, Bettoni R, Delaney K (November 1988). "A method for reproducing fatal idiopathic colitis (colitis X) in ponies and isolation of a clostridium as a possible agent". Equine Veterinary Journal. 20 (6): 417–20. doi:10.1111/j.2042-3306.1988.tb01563.x. PMID 3215166. 12. ^ Curry J (2007-07-20). "Pseudomembranous Colitis". eMedicine. WebMD. Retrieved 2008-11-17. 13. ^ Thomas C, Stevenson M, Riley TV (June 2003). "Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review". Journal of Antimicrobial Chemotherapy. 51 (6): 1339–50. doi:10.1093/jac/dkg254. PMID 12746372. 14. ^ Sparkman, John P. (2010). "A veritable slew of sons". The Thoroughbred Times. Retrieved 2010-01-13. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Colitis-X

c0267550

wikipedia

https://en.wikipedia.org/wiki/Colitis-X

{"wikidata": ["Q5145774"]}

This article is about humans. For other mammals, see pseudopregnancy. False pregnancy Other namesPhantom pregnancy, hysterical pregnancy, pseudocyesis, delusional pregnancy SpecialtyPsychiatry False pregnancy (or pseudocyesis, from the Greek pseudes "false" and kyesis "pregnancy"[1]) is the appearance of clinical or subclinical signs and symptoms associated with pregnancy although the individual is not physically carrying a baby.[2] The false belief that one is pregnant includes signs and symptoms such as tender breasts with secretions, abdominal growth, delayed menstrual periods, and subjective feelings of a moving fetus.[2] Examination, ultrasound, and pregnancy tests can be used to rule out false pregnancy.[1] False pregnancy has a prominent psychiatric component as well as physical manifestations of pregnancy.[2] It can be caused by trauma (either physical or mental), a chemical imbalance of hormones,[2][3] and some medical conditions.[1] Contributing psychological factors include a strong desire for pregnancy or misinterpretation of objective bodily sensations.[2][3] Although rare,[1] men can experience false pregnancy symptoms,[2] called Couvade syndrome or "sympathetic pregnancy", which can occur when their significant other is pregnant and dealing with pregnancy symptoms.[3] Psychotherapy, pharmacotherapy with antidepressants or antipsychotics, hormonal therapy, and uterine curettage are sometimes needed as treatment.[1] While extremely rare in the United States because of the frequent use of medical imaging, in developing regions such as India and sub-Saharan Africa, the incidence of false pregnancy is higher.[2][3] Rural areas see more instances of false pregnancy because such women are less often examined by a health care professional or midwife during the duration of believed pregnancy.[2] ## Contents * 1 Classification * 2 Signs and symptoms * 3 Causes and mechanism * 3.1 Risk factors * 4 Diagnosis * 4.1 Differential * 5 Management * 6 Epidemiology * 7 History * 8 Society and culture * 9 See also * 10 References ## Classification[edit] In the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), false pregnancy is a somatic symptom disorder; it is listed as "not elsewhere classified", meaning it is in a category by itself, different from other somatic symptom disorders such as functional neurological symptom disorder (formerly known as conversion disorders).[2] The word pseudocyesis comes from the Greek words pseudes which means "false" and kyesis which means "pregnancy".[1] False pregnancy is sometimes referred to as "delusional pregnancy", but the distinction between the two conditions is inexact.[3] Delusional pregnancy is typically used when there are no physical signs of pregnancy, but false pregnancy can also be delusional.[4][5] Some authors consider the two conditions can be used interchangeably for research purposes.[3][5] ## Signs and symptoms[edit] The symptoms of pseudocyesis are similar to the symptoms of a true pregnancy.[1] Signs of false pregnancy include amenorrhea (missed periods), galactorrhea (flow of milk from breast), breast enlargement, weight gain, abdominal growth, sensations of fetal movement and contractions,[1] nausea and vomiting,[1] changes in the uterus and cervix,[1] and frequent urination.[3] Abdominal distention is the most common symptom.[2] In pseudocyetic abdominal swellings, the abdomen becomes uniformly swollen, and the navel stays inverted. The wall of the abdomen adopts a muscular, tympanic character.[2] Duration of symptoms typically ranges from several weeks to nine months.[1] ## Causes and mechanism[edit] The exact mechanisms behind false pregnancy are not completely understood, but psychological and endocrine components may play a substantial role. Women who experience false pregnancy often experience related feelings of stress, fear, anticipation, and general emotional disturbance.[3] These strong emotions, along with dysfunctional changes in hormonal regulation, can significantly increase prolactin levels. Prolactinemia (high prolactin levels) can lead to many of the symptoms of true pregnancy, such as amenorrhea, galactorrhea, and tender breasts.[2][3] Heightened activity of the central nervous system may contribute to the abdominal distension, sensations of fetal movement, and assumed contraction pains experienced by many women with false pregnancy.[2] Endocrine changes observed in pseudocyesis include an increase in dopamine levels, nervous system activity, or dysfunction in the central nervous system.[1] These changes may be responsible for amenorrhea, galactorrhea, and hyperprolactinemia seen in falsely pregnant women.[2] Elevated sympathetic activity has been linked to the increased in abdominal size as well as the apparent feel of fetal movement and contractions.[2] How abdominal distension develops is not fully understood and several causes have been proposed. A buildup in fat around the abdominal cavity, heavy constipation, habitual lordosis, and other causes may produce the appearance of a distended abdomen, and the resulting swelling can remain for months. After women with false pregnancy are placed under anesthesia, or are successfully persuaded that they are not pregnant, the distention promptly disappears, indicating that the proposed mechanisms are supplementary factors behind, but not the ultimate causes of, abdominal swelling.[2] Manipulation of abdominal wall muscles, such as the diaphragm, is the most likely contributor to abdominal distention. For example, continuously contracting the diaphragm may give the appearance of a distended abdomen while forcing the intestinal units downwards.[2] The sensations of fetal movement may also be related to contractions of the abdominal wall due to peristalsis, or movements of the gastrointestinal tract.[6] About one in six false pregnancies is potentially influenced by concomitant medical or surgical conditions including gallstones, abdominal tumors, hyperprolactinaemia, constipation, tubal cysts, esophageal achalasia.[5] Psychiatric disorders, such as anxiety or mood disorders, personality disorders, and schizophrenia are common among women with false pregnancy, and may be linked to its development.[1] Some women with depression may gain weight due to decreased physical activity and poor eating habits.[1] Antipsychotics can induce pregnancy-like symptoms such as amenorrhea, galactorrhea, breast tenderness, and weight gain via raising prolactin levels.[3] ### Risk factors[edit] Psychological factors are associated with false pregnancy, including a strong desire for pregnancy; a misunderstanding of sensory changes in the body (for example, bloating or increased pressure on the pelvis); and depressive disorders that can lead to changes in the neuroendocrine system.[7] Other social factors impacting include low educational status, marital issues, unstable relationship patterns, history of partner abuse, social deprivation, poverty, lower socioeconomic status, and unemployment.[1] Other factors such as mental and physical trauma—like experiencing a miscarriage, infertility, loss of child, or sexual abuse— can manifest false pregnancy.[8] Symptoms may arise in women who are experiencing grief after loss in their reproductive abilities, rejecting the idea of motherhood and pregnancy, or facing challenges in gender identity.[1] Other psychological factors include recurrent abortions, stress of imminent menopause, tubal ligation (sterilization surgery), and hysterectomy.[1] ## Diagnosis[edit] Evaluation required to confirm false pregnancies includes a pelvic exam, a blood or urine pregnancy test, and an ultrasound.[8][9][10] A pelvic exam can show if conception has occurred, blood and urine can be tested for hormones released in pregnancy, and ultrasound shows the absence of the fetus. An ultrasound can accurately distinguish between a false and true pregnancy.[8] There is no universal laboratory profile for women with false pregnancy; measured concentrations for prolactin, progesterone, follicle stimulating hormone, estrogen, and luteinizing hormone vary widely.[6][11] In some cases, false pregnancy symptoms may mask underlying medical conditions such as abdominal tumors, central nervous tumors, ovarian cysts, or gallstones. Medical tests and imaging are recommended to rule out potentially life-threatening conditions.[5] ### Differential[edit] Delusional pregnancy is distinct from false pregnancy; although the distinction is "blurred",[3] physical signs of pregnancy are not present in delusional pregnancy,[12] while false pregnancy includes symptoms of true pregnancy.[4] According to Gogia et al. (2020), false pregnancy "involves a false belief that one is pregnant, but differs from delusional pregnancy in that it is a psychosomatic rather than psychotic or purely delusional belief".[5] In delusional pregnancy, schizophrenia accounts for more than a third of cases.[4] The symptoms of false pregnancy can be misinterpreted by the individual as a true pregnancy when the symptoms are actually caused by diseases (like hormone-secreting tumors, alcoholic liver disease, cholecystitis, urinary tract infection, gallstones) or exposure to a substance (like a medication),[2] or other conditions like constipation.[1] ## Management[edit] Additional interventions such as psychotherapy and pharmacotherapy are sometimes needed.[1] Psychotherapy may be used when individuals have difficulty coming to terms with their false pregnancy, or remain symptomatic after knowing their false diagnosis. It allows patients to confront reality and accept the symptoms as illusions and provides an opportunity resolve other psychological stressors and trauma that may be implicated in manifestations of false pregnancy.[13] There is no direct evidence for treating false pregnancy with pharmacotherapy, but medications may be used to restore hormonal and neurotransmitter imbalances which are implicated in physical manifestations of false pregnancy.[1] Reduction in catecholamine levels have been observed in people with symptoms such as hyperprolactinemia and abdominal distentions.[2] For most people, psychotherapy, pharmacotherapy (with antidepressants or antipsychotics), hormonal therapy, and uterine tissue removal is adequate to treat the condition.[1] Antipsychotics have been shown to increase lactation and amenorrhea,[14] and can trigger delusions.[5] The delusion may be resolved with medication changes or adjustments.[5] When underlying medical conditions or surgical conditions including gallstones, abdominal tumors, hyperprolactinemia, and constipation are identified, treatment may reduce the severity of the delusion.[5] ## Epidemiology[edit] The rate of pseudocyesis in the United States has declined significantly since 1940. The rate in 1940 of one occurrence for approximately every 250 pregnancies had dropped by 2007 to between one and six occurrences for every 22,000 births.[1] In Nigeria, the frequency of false pregnancies was 1 in 344 true pregnancies, and in Sudan false pregnancies were reported to be 1 in 160.[1] There were about 550 cases documented in the literature as of 2016, with most cases in those between the ages of 20 and 44.[12] Women of reproductive age comprise the majority of pseudocyesis occurrences.[3] About 80% of women who experience pseudocyesis are married.[3] False pregnancies are more common in societies with certain cultures and religions, particularly in areas where there is a high degree of pressure for women to have multiple children, and for those children to be male.[1] Although rare, pseudocyesis occurs more commonly in developing countries. It is reported more frequently in countries that place heavy emphasis on fertility and childbearing; such pronatalist beliefs are often highly prominent in developing countries. In sub-Saharan Africa, a woman is allowed to share her husband's property only if she bears children. In these countries (and other developing nations), infertile women often experience abuse, blame, and discrimination. In Africa, it is reported to occur in 1 out of every 344 pregnancies. Societal factors enforce the importance of female fertility in these countries, thus possibly contributing to pseudocyesis rates.[3] In addition to men, mothers of pregnant women may experience Couvade syndrome, and a woman can experience multiple episodes of pseudocyesis in her lifetime.[15] ## History[edit] The perception of false pregnancy has evolved over time. In the late 17th century, French obstetrician François Mauriceau believed that the enlarged abdomens of falsely pregnant patients were caused by bad air. Physicians slowly began to acknowledge other potential causes of pseudocyesis, including its origin in the mind and in the body. In 1877, a physician named Joshua Whittington Underhill observed that physical symptoms can convince a woman of pregnancy, or a “disordered brain” can convince her that ordinary abdominal pains or bowel movements are instead fetal movements. The idea that pseudocyesis could result from a woman's perception of herself led to investigation into the role of emotions in cases of pseudocyesis. An investigator in the early 20th century observed that strong emotions can dry a woman's milk supply. The investigator went on to infer that the opposite was also true, and it was believed that strong emotions could bring about its production in women who are not pregnant. Alternatively, some physicians questioned the legitimacy of pseudocyesis as a condition. For instance, French obstetrician Charles Pajot stated in the 19th century, “there are no false pregnancies, only false diagnoses.”[16][17] ## Society and culture[edit] In the mid-1960s, a woman who appeared to be in labor was not properly examined because delivery appeared imminent; it was thought that her water broke but the expelled liquid was urine.[18][19] In 2010, a woman in the United States who was suspected of being in labor was given a C-section but there was no fetus.[20] Mary Tudor, also known as "Bloody Mary", had a false pregnancy. After coming to terms with it, she reportedly believed that God had not made her pregnant because she had not sufficiently punished heretics.[16][17] Anna O (Josef Breuer's patient as mentioned in 1895 by Breuer and Sigmund Freud in Studies on Hysteria), experienced false pregnancy in the context of preexisting mental health problems.[21][22] After being diagnosed with hysteria, she believed she was pregnant by Breuer, her therapist. She even believed she was in labor as she was trying to have another session with Breuer.[21] More recent publications suggest she had central neurological signs with a chronic cough that improved during high altitude stays. Those characteristics well as the ineffectiveness of psychoanalytic cures seem to indicate a more organic diagnosis such as tuberculous meningitis or tuberculous encephalitis with partial temporal epileptic component.[22] ## See also[edit] * Denial of pregnancy ## 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 Azizi M, Elyasi F (September 2017). "Biopsychosocial view to pseudocyesis: A narrative review". International Journal of Reproductive Biomedicine (Review). 15 (9): 535–542. PMC 5894469. PMID 29662961. 2. ^ a b c d e f g h i j k l m n o p q r s Tarín JJ, Hermenegildo C, García-Pérez MA, Cano A (May 2013). "Endocrinology and physiology of pseudocyesis". Reproductive Biology and Endocrinology (Review). 11: 39. doi:10.1186/1477-7827-11-39. PMC 3674939. PMID 23672289. 3. ^ a b c d e f g h i j k l m n Seeman MV (August 2014). "Pseudocyesis, delusional pregnancy, and psychosis: The birth of a delusion". World Journal of Clinical Cases (Review). 2 (8): 338–44. doi:10.12998/wjcc.v2.i8.338. PMC 4133423. PMID 25133144. 4. ^ a b c Bera SC, Sarkar S (2015). "Delusion of pregnancy: a systematic review of 84 cases in the literature". Indian J Psychol Med. 37 (2): 131–7. doi:10.4103/0253-7176.155609. PMC 4418242. PMID 25969595. 5. ^ a b c d e f g h Gogia S, Grieb A, Jang A, Gordon MR, Coverdale J (June 2020). "Medical considerations in delusion of pregnancy: a systematic review". J Psychosom Obstet Gynecol: 1–7. doi:10.1080/0167482X.2020.1779696. PMID 32597281. 6. ^ a b Trivedi AN, Singh S (November 1998). "Pseudocyesis and its modern perspective". The Australian & New Zealand Journal of Obstetrics & Gynaecology (Case reports). 38 (4): 466–8. doi:10.1111/j.1479-828X.1998.tb03114.x. PMID 9890236. S2CID 39631778. 7. ^ Ibekwe PC, Achor JU (April 2008). "Psychosocial and cultural aspects of pseudocyesis". Indian Journal of Psychiatry (Case report). 50 (2): 112–6. doi:10.4103/0019-5545.42398. PMC 2738334. PMID 19742215. 8. ^ a b c "Pseudocyesis: what exactly is a false pregnancy?". American Pregnancy Association. Retrieved July 30, 2020. 9. ^ Li X, Zhang C, Li Y, Yuan J, Lu Q, Wang Y (2019). "Predictive values of the ratio of beta-human chorionic gonadotropin for failure of salpingostomy in ectopic pregnancy". Int J Clin Exp Pathol. 12 (3): 901–908. PMC 6945191. PMID 31933899. 10. ^ Ahmad MF, Abu MA, Chew KT, Sheng KL, Zakaria MA (March 2018). "A positive urine pregnancy test (UPT) with adnexal mass; ectopic pregnancy is not the ultimate diagnosis". Horm Mol Biol Clin Investig. 34 (2). doi:10.1515/hmbci-2018-0004. PMID 29558344. S2CID 4039766. 11. ^ Starkman MN, Marshall JC, La Ferla J, Kelch RP (1985). "Pseudocyesis: psychologic and neuroendocrine interrelationships". Psychosomatic Medicine (Case reports). 47 (1): 46–57. doi:10.1097/00006842-198501000-00005. PMID 3975327. S2CID 2029697. 12. ^ a b Campos SJ, Link D (June 1, 2016). "Pseudocyesis". The Journal for Nurse Practitioners. 12 (6): 390–394. doi:10.1016/j.nurpra.2016.03.009. 13. ^ Mortimer A, Banbery J (April 1988). "Pseudocyesis preceding psychosis". The British Journal of Psychiatry (Case reports). 152 (4): 562–5. doi:10.1192/bjp.152.4.562. PMID 3167413. 14. ^ Babu GN, Desai G, Chandra PS (July 2015). "Antipsychotics in pregnancy and lactation". Indian Journal of Psychiatry (Review). 57 (Suppl 2): S303-7. doi:10.4103/0019-5545.161497. PMC 4539875. PMID 26330648. 15. ^ Thippaiah SM, George V, Birur B, Pandurangi A (March 2018). "A case of concomitant pseudocyesis and Couvade syndrome variant". Psychopharmacology Bulletin (Case report). 48 (3): 29–32. PMC 5875365. PMID 29713103. 16. ^ a b Rutherford RN (April 10, 1941). "Pseudocyesis". New England Journal of Medicine. 224 (15): 639–644. doi:10.1056/NEJM194104102241505. ISSN 0028-4793. 17. ^ a b Daley MD (December 1946). "Pseudocyesis". Postgraduate Medical Journal. 22 (254): 395–9. doi:10.1136/pgmj.22.254.395. PMC 2478462. PMID 20287291. 18. ^ Svoboda, Elizabeth (December 5, 2006). "All the signs of pregnancy except one: a baby". The New York Times. ISSN 0362-4331. Retrieved February 16, 2020. 19. ^ Radebaugh, John F (Spring 2005). "House calls with John" (PDF). Dartmouth Medicine: 48–63. 20. ^ James, Susan Donaldson (April 10, 2010). "Doctors perform C-Section and find no baby". ABC News. Retrieved February 16, 2020. 21. ^ a b Hunter D (1983). "Hysteria, psychoanalysis, and feminism: the case of Anna O". Feminist Studies. 9 (3): 465–88. doi:10.2307/3177609. JSTOR 3177609. PMID 11620548. 22. ^ a b Charlier P, Deo S (October 2017). "The Anna O. mystery: Hysteria or neuro-tuberculosis?". J. Neurol. Sci. 381: 19. doi:10.1016/j.jns.2017.08.006. PMID 28991678. S2CID 39296427. Classification D * ICD-10: F45.8 * ICD-9-CM: 300.11 * MeSH: D011555 * DiseasesDB: 29264 * v * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy * v * t * e Pathology of pregnancy, childbirth and the puerperium Pregnancy Pregnancy with abortive outcome * Abortion * Ectopic pregnancy * Abdominal * Cervical * Interstitial * Ovarian * Heterotopic * Embryo loss * Fetal resorption * Molar pregnancy * Miscarriage * Stillbirth Oedema, proteinuria and hypertensive disorders * Gestational hypertension * Pre-eclampsia * HELLP syndrome * Eclampsia Other, predominantly related to pregnancy Digestive system * Acute fatty liver of pregnancy * Gestational diabetes * Hepatitis E * Hyperemesis gravidarum * Intrahepatic cholestasis of pregnancy Integumentary system / dermatoses of pregnancy * Gestational pemphigoid * Impetigo herpetiformis * Intrahepatic cholestasis of pregnancy * Linea nigra * Prurigo gestationis * Pruritic folliculitis of pregnancy * Pruritic urticarial papules and plaques of pregnancy (PUPPP) * Striae gravidarum Nervous system * Chorea gravidarum Blood * Gestational thrombocytopenia * Pregnancy-induced hypercoagulability Maternal care related to the fetus and amniotic cavity * amniotic fluid * Oligohydramnios * Polyhydramnios * Braxton Hicks contractions * chorion / amnion * Amniotic band syndrome * Chorioamnionitis * Chorionic hematoma * Monoamniotic twins * Premature rupture of membranes * Obstetrical bleeding * Antepartum * placenta * Circumvallate placenta * Monochorionic twins * Placenta accreta * Placenta praevia * Placental abruption * Twin-to-twin transfusion syndrome Labor * Amniotic fluid embolism * Cephalopelvic disproportion * Dystocia * Shoulder dystocia * Fetal distress * Locked twins * Nuchal cord * Obstetrical bleeding * Postpartum * Pain management during childbirth * placenta * Placenta accreta * Preterm birth * Postmature birth * Umbilical cord prolapse * Uterine inversion * Uterine rupture * Vasa praevia Puerperal * Breastfeeding difficulties * Low milk supply * Cracked nipples * Breast engorgement * Childbirth-related posttraumatic stress disorder * Diastasis symphysis pubis * Postpartum bleeding * Peripartum cardiomyopathy * Postpartum depression * Postpartum psychosis * Postpartum thyroiditis * Puerperal fever * Puerperal mastitis Other * Concomitant conditions * Diabetes mellitus * Systemic lupus erythematosus * Thyroid disorders * Maternal death * Sexual activity during pregnancy * Category Authority control * GND: 4337195-4 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

False pregnancy

c1827755

wikipedia

https://en.wikipedia.org/wiki/False_pregnancy

{"mesh": ["D011555"], "icd-9": ["300.11"], "icd-10": ["F45.8"], "wikidata": ["Q1065846"]}

Late-onset focal dermal elastosis is a rare, acquired, dermis elastic tissue disorder characterized by a pseudoxanthoma elasticum-like papular eruption consisting of multiple, slowly progressive, asymptomatic, 2-5 mm, white to yellowish, non-follicular papules (that tend to form cobblestone plaques) predominantly distributed over the neck, axillae and flexural areas, with no systemic involvement. Skin biopsy reveals a focal increase of normal-appearing elastic tissue in the reticular dermis with no calcium deposits. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Late-onset focal dermal elastosis

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228227

{"synonyms": ["PXE-like late-onset focal dermal elastosis", "Pseudoxanthoma-like late-onset focal dermal elastosis"]}

Meningiomas are tumors that originate in the meninges, the membranes that surround the brain and spinal cord. Most meningiomas are not cancerous (benign), though a minority of meningiomas can be classified as atypical or cancerous (malignant). Though rare, malignant meningiomas can be highly aggressive. However, even benign meningiomas can cause problems if their growth affects neighboring areas of the brain. Though most meningiomas grow slowly, there is no way to predict the rate of growth for a particular meningioma or to know how long a specific meningioma was growing before it was diagnosed. Signs and symptoms can vary but may include seizures, headaches, weakness in the arms and legs, and vision loss. Sometimes memory loss, carelessness, and unsteadiness are the only symptoms. Management depends on the location of the meningioma and symptoms present and may include observation, surgery, and/or radiation therapy. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Meningioma

c0025286

gard

https://rarediseases.info.nih.gov/diseases/7015/meningioma

{"mesh": ["D008579"], "orphanet": ["2495"], "synonyms": []}

A number sign (#) is used with this entry because of evidence that spermatogenic failure-14 (SPGF14) is caused by homozygous mutation in the ZMYND15 gene (614312) on chromosome 17p13. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of spermatogenic failure, see SPGF1 (258150). Clinical Features Ayhan et al. (2014) studied a highly consanguineous Turkish family in which 3 brothers were infertile. The brothers had each been married for 20 to 26 years but had no naturally conceived children; 1 brother had twins after assisted reproduction using testicular sperm aspiration. Serum levels of luteinizing hormone (LH; 152780), prolactin (176760), and testosterone were normal, but follicle-stimulating hormone (FSH; 136530) level was increased. Testicular biopsy in the azoospermic brothers showed maturation arrest in the spermatid stage, with spermatogonia and spermatocytes in phases I and II, but very few spermatids and no spermia in the lumen of germ epithelia. Some tubular membranes were thickened, and in some areas, the thickening blocked the tubules. Molecular Genetics In a highly consanguineous Turkish family in which 3 brothers were infertile but had a normal male karyotype and no microdeletions in the AZF region at Yq11, Ayhan et al. (2014) performed linkage analysis and exome sequencing, followed by filtering, to identify homozygosity for a 4-bp deletion in the ZMYND15 gene (614312.0001) in the 3 affected brothers. A fertile brother who had 1 child was heterozygous for the mutation, which was not found in 120 population controls. INHERITANCE \- Autosomal recessive GENITOURINARY Internal Genitalia (Male) \- Azoospermia \- Maturation arrest in spermatid stage \- Thickening of tubular membranes ENDOCRINE FEATURES \- Elevated follicle-stimulating hormone level \- Normal luteinizing hormone level \- Normal prolactin level \- Normal testosterone level MISCELLANEOUS \- Based on report of 1 consanguineous Turkish family (last curated June 2014) MOLECULAR BASIS \- Caused by mutation in zinc finger MYND-containing protein-15 gene (ZMYND15, 614312.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPERMATOGENIC FAILURE 14

c4014454

omim

https://www.omim.org/entry/615842

{"doid": ["0070179"], "omim": ["615842"], "orphanet": ["399805"], "synonyms": []}

A rare hereditary ataxia characterized by neurogenic muscular atrophy associated with signs of cerebellar ataxia, hypesthesia, degeneration of the retina, and diabetes mellitus. Onset of the disease is in adolescence and the course is slowly progressive. There have been no further descriptions in the literature since 1983. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome

c0342281

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2579

{"gard": ["2417"], "mesh": ["C562774", "C538193"], "omim": ["158500"], "umls": ["C0342281", "C2931765"], "icd-10": ["G11.0"], "synonyms": ["Furukawa-Takagi-Nakao syndrome"]}

A number sign (#) is used with this entry because of evidence that Pilarowski-Bjornsson syndrome (PILBOS) is caused by heterozygous mutation in the CHD1 gene (602118) on chromosome 5q. Description Pilarowski-Bjornsson syndrome is an autosomal dominant neurodevelopmental disorder characterized by delayed development, intellectual disability, often with autistic features, speech apraxia, and mild dysmorphic features. Some patients may have seizures. The phenotype is somewhat variable (summary by Pilarowski et al., 2018). Clinical Features Pilarowski et al. (2018) reported 6 girls with a neurodevelopmental disorder and heterozygous missense mutations in the CHD1 gene. The patients were identified through whole-exome sequencing studies and collaboration with other researchers through the GeneMatcher database. Two of the girls were sisters conceived by separate in vitro fertilization cycles from an egg donor for whom genetic data were not available. One of the girls had biallelic, likely pathogenic mutations in the WDR62 gene (613583), and she was not studied further. All 5 patients with specific missense CHD1 mutations had developmental delay and hypotonia, including a 10-year-old girl with developmental regression. Four patients, aged 4 to 10 years, had speech apraxia, 3 had autism with stereotypies, and 5 had seizures or abnormal EEG. The youngest child was 7 months old. Two patients had persistent intellectual disability, and one 5-year-old girl did not have intellectual disability; information on intellectual ability in the 2 other girls was not available. Two patients showed postnatal growth retardation. Dysmorphic features, which were also variable, included macrocephaly, depressed midface, pointed chin, translucent skin, almond-shaped eyes, downslanting palpebral fissures, periorbital fullness, and flared eyebrows. Two patients had mild immune defects. Molecular Genetics In 5 unrelated girls with PILBOS, Pilarowski et al. (2018) identified heterozygous missense mutations in the CHD1 gene (see, e.g., 602118.0001-602118.0004). They identified a heterozygous mutation in CHD1 in another girl with a neurodevelopmental disorder, but she also carried biallelic, likely pathogenic mutations in the WDR62 gene (613583) and was therefore not studied further. The 5 remaining patients all had mutations affecting loss of an arginine, and several of the mutations were located in structurally important regions. Cells derived from one of the patients showed a global increase of a closed chromatin modification compared to controls, suggesting that the mutation had functional effects. In vitro functional studies and studies of patient cells were not performed in the other patients. The authors identified 3 previously described patients in large surveys of individuals with autism who had de novo missense (L1016V and R1203Q) and nonsense (Leu1517fsTer) mutations in the CHD1 gene; however, the phenotypic information provided in these reports was limited. An additional patient with a deletion encompassing the RGMB gene (612687) and most of the CHD1 gene had been reported, but this child did not have neurodevelopmental abnormalities. Pilarowski et al. (2018) concluded that missense mutations in the CHD1 gene may cause neurodevelopmental defects through a dominant-negative effect rather than through haploinsufficiency. INHERITANCE \- Autosomal dominant GROWTH Other \- Growth retardation, postnatal HEAD & NECK Head \- Macrocephaly \- Frontal bossing Face \- Depressed midface \- Pointed chin Eyes \- Almond-shaped eyes \- Flared eyebrows \- Downslanting palpebral fissures \- Periorbital fullness SKIN, NAILS, & HAIR Skin \- Translucent skins MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Developmental delay \- Intellectual disability \- Speech apraxia \- Seizures (in some patients) Behavioral Psychiatric Manifestations \- Autistic features \- Stereotypies IMMUNOLOGY \- Immune deficiency, mild \- Allergic manifestations MISCELLANEOUS \- Onset in infancy \- Highly variable phenotype \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the chromodomain helicase DNA-binding protein 1 gene (CHD1, 602118.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

PILAROWSKI-BJORNSSON SYNDROME

c4540131

omim

https://www.omim.org/entry/617682

{"omim": ["617682"], "orphanet": ["529965"], "synonyms": ["Pilarowski-Bjornsson syndrome", "Alternative titles", "DEVELOPMENTAL DELAY AND SPEECH APRAXIA WITH OR WITHOUT SEIZURES"]}

Disease caused by nematodes of the genus Capillaria Capillariasis is a disease caused by nematodes in the genus Capillaria.[1] The two principal forms of the disease are: * Intestinal capillariasis, caused by Capillaria philippinensis * Hepatic capillariasis, caused by Capillaria hepatica ## References[edit] 1. ^ Berger SA, Marr JS. Human Parasitic Diseases Sourcebook. Jones and Bartlett Publishers: Sudbury, Massachusetts, 2006. * v * t * e Parasitic disease caused by helminthiases Flatworm/ platyhelminth infection Fluke/trematode (Trematode infection) Blood fluke * Schistosoma mansoni / S. japonicum / S. mekongi / S. haematobium / S. intercalatum * Schistosomiasis * Trichobilharzia regenti * Swimmer's itch Liver fluke * Clonorchis sinensis * Clonorchiasis * Dicrocoelium dendriticum / D. hospes * Dicrocoeliasis * Fasciola hepatica / F. gigantica * Fasciolosis * Opisthorchis viverrini / O. felineus * Opisthorchiasis Lung fluke * Paragonimus westermani / P. kellicotti * Paragonimiasis Intestinal fluke * Fasciolopsis buski * Fasciolopsiasis * Metagonimus yokogawai * Metagonimiasis * Heterophyes heterophyes * Heterophyiasis Cestoda (Tapeworm infection) Cyclophyllidea * Echinococcus granulosus / E. multilocularis * Echinococcosis * Taenia saginata / T. asiatica / T. solium (pork) * Taeniasis / Cysticercosis * Hymenolepis nana / H. diminuta * Hymenolepiasis Pseudophyllidea * Diphyllobothrium latum * Diphyllobothriasis * Spirometra erinaceieuropaei * Sparganosis * Diphyllobothrium mansonoides * Sparganosis Roundworm/ Nematode infection Secernentea Spiruria Camallanida * Dracunculus medinensis * Dracunculiasis Spirurida Filarioidea (Filariasis) * Onchocerca volvulus * Onchocerciasis * Loa loa * Loa loa filariasis * Mansonella * Mansonelliasis * Dirofilaria repens * D. immitis * Dirofilariasis * Wuchereria bancrofti / Brugia malayi / |B. timori * Lymphatic filariasis Thelazioidea * Gnathostoma spinigerum / G. hispidum * Gnathostomiasis * Thelazia * Thelaziasis Spiruroidea * Gongylonema Strongylida (hookworm) * Hookworm infection * Ancylostoma duodenale / A. braziliense * Ancylostomiasis / Cutaneous larva migrans * Necator americanus * Necatoriasis * Angiostrongylus cantonensis * Angiostrongyliasis * Metastrongylus * Metastrongylosis Ascaridida * Ascaris lumbricoides * Ascariasis * Anisakis * Anisakiasis * Toxocara canis / T. cati * Visceral larva migrans / Toxocariasis * Baylisascaris * Dioctophyme renale * Dioctophymosis * Parascaris equorum Rhabditida * Strongyloides stercoralis * Strongyloidiasis * Trichostrongylus spp. * Trichostrongyliasis * Halicephalobus gingivalis Oxyurida * Enterobius vermicularis * Enterobiasis Adenophorea * Trichinella spiralis * Trichinosis * Trichuris trichiura (Trichuriasis / Whipworm) * Capillaria philippinensis * Intestinal capillariasis * C. hepatica This article related to parasites 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

Capillariasis

c0006897

wikipedia

https://en.wikipedia.org/wiki/Capillariasis

{"mesh": ["D017189"], "umls": ["C0006897"], "wikidata": ["Q1034620"]}

For a general phenotypic description and a discussion of genetic heterogeneity of the punctate type of palmoplantar keratoderma, see PPKP1A (148600). Clinical Features Zhang et al. (2004) studied 2 unrelated Chinese families segregating autosomal dominant punctate palmoplantar keratoderma. In the first family, which had 9 affected individuals in 4 generations, the proband was a 50-year-old woman who first noticed symptoms at 15 years of age. In the second family there were 5 affected individuals over 3 generations; the proband was a 42-year-old man who at 14 years of age developed several pinhead-size hyperkeratotic papules, first on the soles, then on the palms, which were barely noticeable. Skin biopsy of the lesions showed notable hyperkeratosis with large, wide, and cup-like keratin plugs. At the edge of the lesion, instead of small spikes, there were projections of keratin plugs. The depth of the stratum granulosum was increased, the stratum spinosum was thickened, and there were prominent extensions of epithelial pegs. The proliferation of the epidermis and upward extension of the dermal papillae resulted in papillomatous hyperplasia. Mapping In a 4-generation Chinese family segregating autosomal dominant punctate palmoplantar keratoderma, Zhang et al. (2004) performed a genomewide scan and obtained a supportive lod score at marker D8S514. Fine mapping showed strong evidence for linkage to chromosome 8q, with a maximum lod score of 5.41 (theta = 0) at markers D8S1793 and D8S1774. Recombination events suggested that the causative gene was located in a 9.20-cM critical interval between D8S1804 and D8S1720. Analysis of another 3-generation Chinese family with PPKP confirmed mapping of the locus to chromosome 8q24.13-q24.21. Molecular Genetics In 4 affected and 2 unaffected members of a 4-generation Chinese family with autosomal dominant punctate palmoplantar keratoderma mapping to chromosome 8q24, previously studied by Zhang et al. (2004), Guo et al. (2012) performed exome capture and sequencing and identified a heterozygous missense mutation in the COL14A1 gene (P1502L; 120324.0001) that was present in the 4 affected but not the 2 unaffected family members. Sanger sequencing revealed that the mutation was present in 4 additional affected family members, as well as 2 unaffected family members, a 15-year-old boy and his uncle. The mutation was not found in 676 unrelated ethnically and geographically matched controls, or in 718 unrelated ethnically and geographically matched patients with other diseases. Guo et al. (2012) suggested that COL14A1 might be a causal gene for PPKP, noting that the unaffected 15-year-old boy with the mutation was at the lower limit for average age at onset of disease in this family and might yet develop symptoms. Sequencing of the coding exons and intron-exon boundaries of COL14A1 in a second 3-generation Chinese family with PPKP mapping to 8q24, also previously studied by Zhang et al. (2004), did not reveal any potential pathogenic mutations. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Keratoderma, palmoplantar punctate Skin Histology \- Hyperkeratosis, marked \- Keratin plugs, large and cup-like \- Stratum granulosum increased \- Stratum spinosum thickened \- Papillomatous hyperplasia MISCELLANEOUS \- Onset in the second to fourth decades of life ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

PALMOPLANTAR KERATODERMA, PUNCTATE TYPE IB

c3554145

omim

https://www.omim.org/entry/614936

{"omim": ["614936"], "orphanet": ["79501"], "synonyms": ["Buschke-Fischer-Brauer syndrome", "Keratodermia palmoplantaris papulosa, Buschke-Fischer-Brauer type", "PPKP1"]}

A number sign (#) is used with this entry because of evidence that Blau syndrome (BLAUS) is caused by heterozygous mutation in the NOD2/CARD15 gene (605956) on chromosome 16q12. Description Blau syndrome is characterized by the triad of granulomatous arthritis, uveitis, and dermatitis. First described in 1985, it was considered to be distinct from sarcoidosis due to the early age of onset and autosomal dominant inheritance pattern. Published reports of sporadic cases of children with 'early-onset sarcoidosis' (EOS) with granulomatous involvement of different organs, primarily affecting joints, eyes, and skin, were suspected to represent the same disorder because the patients' characteristics were nearly identical. Subsequently, identical NOD2 mutations were identified in patients with Blau syndrome as well as in patients diagnosed with EOS, confirming earlier suspicions that they represented the same disease (summary by Borzutzky et al., 2010). Unlike older children diagnosed with sarcoidosis, these patients have no apparent pulmonary involvement; however, the disease is progressive and may result in severe complications such as blindness and/or joint destruction (Shetty and Gedalia, 1998). Clinical Features Blau (1985) reported a large 4-generation family in which 11 members had a variable constellation of granulomatous arthritis, iritis, and skin rash. Ten had arthritis, 2 had skin, eye, and joint involvement, 1 had skin and joint disease, and 1 had iritis only. The disease was transmitted as an autosomal dominant trait. The major long-term problems were iritis and joint contractures. The disorder was distinguished from that described by Rotenstein et al. (1982) (see 108050) by the absence of fever, hypertension, and large vessel vasculitis. Jabs et al. (1985) reported a family in which 4 individuals had a syndrome of granulomatous synovitis and nongranulomatous uveitis. The proband, his brother, their father, and the deceased paternal grandmother were affected. Disease onset was in childhood. All patients had symmetric, boggy polysynovitis of the hands and wrists, resulting in nearly identical boutonniere deformities. Synovectomy specimens in the proband and his brother showed granulomatous inflammation with giant cells. Recurrent, nongranulomatous, acute iridocyclitis with visual impairment occurred in the proband, brother, and father. Hand radiographs showed no erosions or joint destruction despite more than 20 years of disease. In addition, the proband had corticosteroid-responsive hearing loss, and another patient had a transient sixth nerve palsy, which Jabs et al. (1985) referred to as 'cranial neuropathies.' Pastores et al. (1989) described a mother and 2 daughters with uveitis and symmetric polyarthritis. Both daughters also had cysts over the wrist and ankle joints and an intermittent generalized erythematous papular rash, which on histopathologic examination was found to represent noncaseating granulomatous infiltration. Response to intermittent, low-dose steroid therapy was dramatic. Pastores et al. (1989, 1990) thought the disorder was distinct from that reported by Jabs et al. (1985) because there was no cranial neuropathy and because Jabs' cases had no cysts. The authors also thought it was distinct from the disorder reported by Rotenstein et al. (1982), but they thought it was the same as the disorder reported by Blau (1985); indeed, they referred to it as 'Blau syndrome.' In a follow-up of the family reported by Blau (1985), Raphael (1993) found flexion contractures of the fingers and toes (camptodactyly) as a phenotypic characteristic. Raphael (1993) was impressed with earlier onset and worsening of symptoms in succeeding generations, i.e., anticipation. Raphael et al. (1993) concluded that the illness in the original family was distinct from classic sarcoidosis (181000). All 3 subjects tested with Kveim skin-test reagent showed no reactivity by visual inspection; however, both subjects who had had skin biopsies performed had evidence of granulomatous inflammation. No specific HLA association could be demonstrated. Ukae et al. (1994) studied a Japanese girl who presented at age 3.3 years with brown 3- to 5-mm scaly papules on her trunk and extremities. At age 4, the skin lesions were unchanged, and she developed painless swelling of her right knee joint; over the next month, painless nonerythematous joint swelling eventually involved both wrists, knees, and ankles. Ophthalmologic examination revealed bilateral mild uveitis of the posterior globe. She had no lymph node swelling and no cardiopulmonary or neurologic findings. Skin biopsy showed noncaseating granuloma, which the authors noted was consistent with a diagnosis of sarcoidosis. She was treated with aspirin alone, and at 5.3 years of age, she had mild uveitis, but the joint swelling and skin lesions had improved, and she did not exhibit pulmonary involvement. Ukae et al. (1994) designated the patient's disease 'preschool sarcoidosis.' Saini and Rose (1996) described a family with Blau syndrome in which liver granulomata were found in one member of the family in whom liver biopsy was performed. A mother and 2 sons of mixed Caucasian and black ancestry were described. Camptodactyly-like contractures of the proximal interphalangeal joints was noted. In a large affected family, Tromp et al. (1996) based the diagnosis of Blau syndrome on any one or combination of the following: (1) persistent inflammation of any joint or tendon or both, characterized by marked edema and giant cyst formation or biopsy-proved granulomatous joint inflammation, or both; (2) ophthalmologist-diagnosed anterior- or posterior-tract uveitis, or both, in one or both eyes at any age, in the absence of trauma or any other identifiable cause; and (3) persistent rash characterized by biopsy-proved granulomatous inflammation. Color photographs of striking arthritic, retinal, and cutaneous lesions were provided. The retinal view showed multifocal chorioretinal lesions, several pigmented scars, and marked perivascular sheathing. Manouvrier-Hanu et al. (1998) described what they considered to be the sixth family with Blau syndrome. Affected individuals were monozygotic twin brothers, the son of one and the daughter of the other. Latkany et al. (2002) reviewed the ophthalmologic findings in 16 patients with juvenile systemic granulomatosis from 8 families examined at 6 academic medical centers. Of the 16 patients, 15 had evidence of panuveitis with multifocal choroiditis. One patient had only an anterior uveitis. One patient each had ischemic optic neuropathy, presumably due to small vessel vasculopathy, and retinal vasculopathy. Ocular complications were common, including cataract in 11, glaucoma in 6, band keratopathy in 6, cystoid macular edema in 6, and optic disc edema in 6. All 16 patients had polyarthritis, and at least 9 had skin rash. Patients were often misdiagnosed initially as having either juvenile rheumatoid arthritis or sarcoidosis. Latkany et al. (2002) concluded that patients with a diagnosis of juvenile rheumatoid arthritis but with a family history of the disorder and multifocal choroiditis should be suspected of having familial juvenile systemic granulomatosis. ### Clinical Variability Dhondt et al. (2008) reported a 63-year-old man with Blau syndrome who had severe camptodactyly and bilateral large recalcitrant leg ulcers. Biopsies of 1 of the ulcers showed granulomas. There was no family history of the disorder. Borzutzky et al. (2010) reported a 9-month-old Caucasian boy who presented at 2 weeks of age with intermittent fevers, feeding intolerance, failure to thrive, migratory rash, and nontender subcutaneous nodules. Evaluation at 9 months of age showed systemic inflammation and disseminated granulomatous disease, including the triad of granulomatous arthritis, uveitis, and dermatitis. Esophageal biopsy showed nonnecrotizing granulomata in the lamina propria. The authors stated that this was the first report of gastrointestinal tract granulomas in this disorder. Inheritance The transmission pattern of Blau syndrome in the family reported by Blau (1985) was consistent with autosomal dominant inheritance. Alonso et al. (2003) described a kindred in which a mother and 3 of her children with Blau syndrome demonstrated autosomal dominant inheritance and anticipation. The patients had classic findings including cutaneous and joint involvement with camptodactyly. Only the mother and daughter had chronic uveitis. Mapping In an extended family in which 16 members had Blau syndrome, Tromp et al. (1996) demonstrated linkage to DNA markers in the 16p12-q21 interval. With 2-point analysis, the marker D16S298 gave a maximum lod score of 3.75 at theta = 0.04. Most affected patients were examined by one of the authors, S. Raphael. Molecular Genetics Because mutations in the NOD2/CARD15 gene had been found in Crohn disease (266600), a disorder characterized by episodic intestinal inflammation with epithelioid granulomas, and because CARD15 is expressed predominantly in monocytes, a cell type that can differentiate into giant and epithelioid cells aggregating in granuloma formations, Miceli-Richard et al. (2001) did a mutation screen of 4 families with Blau syndrome and identified 3 different missense mutations in the CARD15 gene (605956.0004-605956.0006). One of the families had been reported by Manouvrier-Hanu et al. (1998). In a 27-year-old Japanese man with systemic granulomatous disease, in whom lack of a family history of the disease led to a diagnosis of 'early-onset sarcoidosis' rather than Blau syndrome, Kanazawa et al. (2004) identified 1 of the same CARD15 mutations (R334W; 605056.0006) that had previously been detected in Blau syndrome. Kanazawa et al. (2005) retrospectively collected Japanese 'early-onset sarcoidosis' cases in search of CARD15 mutations. Among 10 EOS cases, missense mutations were identified in 9: 4 patients, including a patient originally reported by Sakurai et al. (1997) and the 27-year-old man previously studied by Kanazawa et al. (2004), were heterozygous for the R334W mutation that had been reported in patients diagnosed with Blau syndrome; and 4 patients, including a 32-year-old woman originally diagnosed with 'ocular sarcoidosis' by Shimomura et al. (1982), carried different novel missense mutations (see, e.g., 605956.0008). In addition, a 16-year-old girl who was reported by Ukae et al. (1994) to have 'preschool sarcoidosis' was found to have 2 missense mutations (D382E, 605956.0009 and A612T, 605956.0010). (The pathogenicity of the A612T variant was later called into question.) All of these variants of CARD15 showed increased basal NFKB activity. Kanazawa et al. (2005) concluded that most patients given a diagnosis of early-onset sarcoidosis or Blau syndrome share a common genetic etiology of CARD15 mutations that cause constitutive NFKB activation, and noted that this supported the long-standing hypothesis that sporadic cases of EOS and familial cases of Blau syndrome represent different types of the same juvenile systemic granulomatosis syndrome. In a 63-year-old man who exhibited features of Blau syndrome and also had severe camptodactyly and recalcitrant leg ulcers, Dhondt et al. (2008) sequenced the candidate gene NOD2 and identified heterozygosity for the R334W mutation. In a 9-month-old Caucasian boy with Blau syndrome, who also exhibited gastrointestinal granulomas, Borzutzky et al. (2010) identified heterozygosity for the IVS8+158 variant (605056.0007) in the NOD2 gene. Clinical Management Goyal et al. (2007) reported an unusual case of a 12-year-old girl who presented with persistent focal seizures and MRI signal abnormalities. Brain biopsies showed marked dural granulomatous inflammation with focal extension into the brain parenchyma. Studies for systemic sarcoidosis were negative. Treatment with infliximab, a TNF-alpha inhibitor, resulted in clinical improvement. Family history revealed a paternal uncle and grandfather with Crohn disease, and molecular analysis identified 3 missense mutations in the NOD2 gene in the proband. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Uveitis \- Iritis \- Multifocal choroiditis \- Cataracts \- Glaucoma \- Band keratopathy \- Cystoid macular edema \- Optic disc edema SKELETAL \- Granulomatous synovitis \- Granulomatous arthritis \- Synovial cysts \- Joint swelling \- Joint contractures \- Tendonitis Hands \- Flexion contractures of the fingers \- Camptodactyly Feet \- Flexion contractures of the toes SKIN, NAILS, & HAIR Skin \- Granulomatous dermatitis \- Intermittent generalized erythematous papular rash \- Skin ulceration \- Skin biopsy shows noncaseating granulomas \- Cysts over wrist and ankle joints MISCELLANEOUS \- Onset in first 2 decades of life \- Variable manifestation of features \- Favorable response to intermittent, low-dose steroid therapy \- Allelic disorder to early-onset sarcoidosis ( 609464 ) MOLECULAR BASIS \- Caused by mutation in the nucleotide-binding oligomerization domain protein 2 gene (NOD2, 605956.0004 ). ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

BLAU SYNDROME

c1861303

omim

https://www.omim.org/entry/186580

{"doid": ["0050678"], "mesh": ["C538157"], "omim": ["186580"], "icd-10": ["M04.8"], "orphanet": ["90340", "90341"], "synonyms": ["Alternative titles", "SARCOIDOSIS, EARLY-ONSET", "GRANULOMATOSIS, FAMILIAL JUVENILE SYSTEMIC", "ARTHROCUTANEOUVEAL GRANULOMATOSIS", "JABS SYNDROME", "GRANULOMATOUS INFLAMMATORY ARTHRITIS, DERMATITIS, AND UVEITIS, FAMILIAL", "GRANULOMATOSIS, FAMILIAL, BLAU TYPE"]}

Hyperinsulinism due to HNF1A deficiency is a form of diazoxide-sensitive diffuse hyperinsulinism (DHI), characterized by transient or persistent hyperinsulinemic hypoglycemia (HH) in infancy that is responsive to diazoxide, evolving in to maturity-onset diabetes of the young subtype 1 (MODY-1; see this term) later in life. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hyperinsulinism due to HNF1A deficiency

c4303475

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324575

{"icd-10": ["E16.1"], "synonyms": ["Hyperinsulinemic hypoglycemia due to HNF1A deficiency"]}

Wells syndrome is characterised by the presence of recurrent cellulitis-like eruptions with eosinophilia. ## Epidemiology Approximately 80 cases have been described in the literature. ## Clinical description The lesions are usually filled with fluid, tender and progress to form hardened plaques of edema and erythema. They usually resolve without scarring. ## Diagnostic methods Histological studies reveal flame figures and heavy infiltration of eosinophils and histiocytes. ## Genetic counseling The syndrome is usually sporadic but familial cases have been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Wells syndrome

c0343101

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=901

{"gard": ["329"], "mesh": ["C536693"], "umls": ["C0343101"], "icd-10": ["L98.3"], "synonyms": ["Eosinophilic cellulitis"]}

See also: Agnosia Akinetopsia (Greek: a for "without", kine for "to move" and opsia for "seeing"), also known as cerebral akinetopsia or motion blindness, is a neuropsychological disorder in which a patient cannot perceive motion in their visual field, despite being able to see stationary objects without issue.[1] There are varying degrees of akinetopsia: from seeing motion as frames of a cinema reel[2] to an inability to discriminate any motion. There is currently no effective treatment or cure for akinetopsia. ## Contents * 1 Signs and symptoms * 1.1 Inconspicuous akinetopsia * 1.2 Gross akinetopsia * 2 Causes * 2.1 Brain lesions * 2.2 Transcranial magnetic stimulation * 2.3 Alzheimer's disease * 2.4 Antidepressants * 3 Areas of visual perception * 3.1 V5 * 3.2 V1 * 3.3 Ventral and dorsal streams * 4 Case studies * 4.1 Potzl and Redlich's patient * 4.2 Goldstein and Gelb's patient * 4.3 "LM" * 4.4 "TD" * 4.5 Pelak and Hoyt's Alzheimer's patient * 4.6 Pelak and Hoyt's TBI patient * 5 References ## Signs and symptoms[edit] Akinetopsia can be separated into two categories, "inconspicuous akinetopsia" or "gross akinetopsia", based on symptom severity and the amount the akinetopsia affects the patient's quality of life.[citation needed] ### Inconspicuous akinetopsia[edit] See also: Illusory palinopsia Inconspicuous akinetopsia is often described by seeing motion as a cinema reel or a multiple exposure photograph. This is the most common kind of akinetopsia and many patients consider the stroboscopic vision as a nuisance. The akinetopsia often occurs with visual trailing (palinopsia), with afterimages being left at each frame of the motion. It is caused by prescription drugs, hallucinogen persisting perception disorder (HPPD), and persistent aura without infarction. The pathophysiology of akinetopsia palinopsia is not known, but it has been hypothesized to be due to inappropriate activation of physiological motion suppression mechanisms which are normally used to maintain visual stability during eye movements (e.g. saccadic suppression).[3][4] ### Gross akinetopsia[edit] Gross akinetopsia is an extremely rare condition. Patients have profound motion blindness and struggle in performing the activities of daily living. Instead of seeing vision as a cinema reel, these patients have trouble perceiving gross motion. Most of what is known about this extremely rare condition was learned through the case study of one patient, LM. LM described pouring a cup of tea or coffee difficult "because the fluid appeared to be frozen, like a glacier".[5] She did not know when to stop pouring, because she could not perceive the movement of the fluid rising. LM and other patients have also complained of having trouble following conversations, because lip movements and changing facial expressions were missed.[5][6] LM stated she felt insecure when more than two people were walking around in a room: "people were suddenly here or there but I have not seen them moving".[5] Movement is inferred by comparing the change in position of an object or person. LM and others have described crossing the street and driving cars to also be of great difficulty.[5][6] LM started to train her hearing to estimate distance. A change in brain structure (typically lesions) disturbs the psychological process of understanding sensory information, in this case visual information. Disturbance of only visual motion is possible due to the anatomical separation of visual motion processing from other functions. Like akinetopsia, perception of color can also be selectively disturbed as in achromatopsia.[1] There is an inability to see motion despite normal spatial acuity, flicker detection, stereo and color vision. Other intact functions include visual space perception and visual identification of shapes, objects, and faces.[7] Besides simple perception, akinetopsia also disturbs visuomotor tasks, such as reaching for objects[8] and catching objects.[9] When doing tasks, feedback of one's own motion appears to be important.[9] ## Causes[edit] ### Brain lesions[edit] Akinetopsia may be an acquired deficit from lesions in the posterior side of the visual cortex. Lesions more often cause gross akinetopsia. The neurons of the middle temporal cortex respond to moving stimuli and hence the middle temporal cortex is the motion-processing area of the cerebral cortex. In the case of LM, the brain lesion was bilateral and symmetrical, and at the same time small enough not to affect other visual functions.[10] Some unilateral lesions have been reported to impair motion perception as well. Akinetopsia through lesions is rare, because damage to the occipital lobe usually disturbs more than one visual function.[5] Akinetopsia has also been reported as a result of traumatic brain injury.[6] ### Transcranial magnetic stimulation[edit] Inconspicuous akinetopsia can be selectively and temporarily induced using transcranial magnetic stimulation (TMS) of area V5 of the visual cortex in healthy subjects.[11] It is performed on a 1 cm² surface of the head, corresponding in position to area V5. With an 800-microsecond TMS pulse and a 28 ms stimulus at 11 degrees per second, V5 is incapacitated for about 20–30 ms. It is effective between −20 ms and +10 ms before and after onset of a moving visual stimulus. Inactivating V1 with TMS could induce some degree of akinetopsia 60–70 ms after the onset of the visual stimulus. TMS of V1 is not nearly as effective in inducing akinetopsia as TMS of V5.[11] ### Alzheimer's disease[edit] Besides memory problems, Alzheimer's patients may have varying degrees of akinetopsia.[12] This could contribute to their marked disorientation. While Pelak and Hoyt have recorded an Alzheimer's case study, there has not been much research done on the subject yet.[6] ### Antidepressants[edit] Inconspicuous akinetopsia can be triggered by high doses of certain antidepressants[13] with vision returning to normal once the dosage is reduced. ## Areas of visual perception[edit] Two relevant visual areas for motion processing are V5 and V1. These areas are separated by their function in vision.[14] A functional area is a set of neurons with common selectivity and stimulation of this area, specifically behavioral influences.[15] There have been over 30 specialized processing areas found in the visual cortex.[16] ### V5[edit] V5, also known as visual area MT (middle temporal), is located laterally and ventrally in the temporal lobe, near the intersection of the ascending limb of the inferior temporal sulcus and the lateral occipital sulcus. All of the neurons in V5 are motion selective, and most are directionally selective.[1] Evidence of functional specialization of V5 was first found in primates.[7] Patients with akinetopsia tend to have unilateral or bi-lateral damage to the V5.[17][18] ### V1[edit] V1, also known as the primary visual cortex, is located in Brodmann area 17. V1 is known for its pre-processing capabilities of visual information; however, it is no longer considered the only perceptually effective gateway to the cortex.[11] Motion information can reach V5 without passing through V1 and a return input from V5 to V1 is not required for seeing simple visual motion.[11] Motion-related signals arrive at V1 (60–70 ms) and V5 (< 30 ms) at different times, with V5 acting independently of V1.[11] Patients with blindsight have damage to V1, but because V5 is intact, they can still sense motion.[16] Inactivating V1 limits motion vision, but does not stop it completely.[11] ### Ventral and dorsal streams[edit] Another thought on visual brain organization is the theory of streams for spatial vision, the ventral stream for perception and the dorsal stream for action.[8] Since LM has impairment in both perception and action (such as grasping and catching actions), it has been suggested that V5 provides input to both perception and action processing streams.[8][9] ## Case studies[edit] ### Potzl and Redlich's patient[edit] In 1911, Potzl and Redlich reported a 58-year-old female patient with bilateral damage to her posterior brain.[1] She described motion as if the object remained stationary but appeared at different successive positions. Additionally, she also lost a significant amount of her visual field and had anomic aphasia. ### Goldstein and Gelb's patient[edit] In 1918, Goldstein and Gelb reported a 24-year-old male who suffered a gunshot wound in the posterior brain.[1] The patient reported no impression of movement. He could state the new position of the object (left, right, up, down), but saw "nothing in between".[1] While Goldestein and Gelb believed the patient had damaged the lateral and medial parts of the left occipital lobe, it was later indicated that both occipital lobes were probably affected, due to the bilateral, concentric loss of his visual field. He lost his visual field beyond a 30-degree eccentricity and could not identify visual objects by their proper names.[1] ### "LM"[edit] Most of what is known about akinetopsia was learned from LM, a 43-year-old female admitted into the hospital October 1978 complaining of headache and vertigo.[5] LM was diagnosed with thrombosis of the superior sagittal sinus which resulted in bilateral, symmetrical lesions posterior of the visual cortex.[5] These lesions were verified by PET and MRI in 1994.[7] LM had minimal motion perception that was preserved as perhaps a function of V1, as a function of a "higher" order visual cortical area, or some functional sparing of V5.[1][10] LM found no effective treatment, so she learned to avoid conditions with multiple visual motion stimuli, i.e. by not looking at or fixating them. She developed very efficient coping strategies to do this and nevertheless lived her life. In addition, she estimated the distance of moving vehicles by means of sound detection in order to continue to cross the street.[5][10] LM was tested in three areas against a 24-year-old female subject with normal vision: Visual functions other than movement vision LM had no evidence of a color discrimination deficit in either center or periphery of visual fields. Her recognition time for visual objects and words was slightly higher than the control, but not statistically significant. There was no restriction in her visual field and no scotoma. Disturbance of movement vision LM's impression of movement depended on the direction of the movement (horizontal vs vertical), the velocity, and whether she fixated in the center of the motion path or tracked the object with her eyes. Circular light targets were used as stimuli. In studies, LM reported some impression of horizontal movement at a speed of 14 degrees of her predetermined visual field per second (deg/s) while fixating in the middle of the motion path, with difficulty seeing motion both below and above this velocity. When allowed to track the moving spot, she had some horizontal movement vision up to 18 deg/s. For vertical movement, the patient could only see motion below 10 deg/s fixated or 13 deg/s when tracking the target. The patient described her perceptual experience for stimulus velocities higher than 18 and 13 deg/s, respectively as "one light spot left or right" or "one light spot up or down" and "sometimes at successive positions in between", but never as motion.[5] Motion in depth To determine perception of motion in depth, studies were done in which the experimenter moved a black painted wooden cube on a tabletop either towards the patient or away in line of sight. After 20 trials at 3 or 6 deg/s, the patient had no clear impression of movement. However she knew the object had changed in position, she knew the size of the cube, and she could correctly judge the distance of the cube in relation to other nearby objects.[5] Inner and outer visual fields Detection of movement in the inner and outer visual fields was tested. Within her inner visual field, LM could detect some motion, with horizontal motion more easily distinguished than vertical motion. In her peripheral visual field, the patient was never able to detect any direction of movement. LM's ability to judge velocities was also tested. LM underestimated velocities over 12 deg/s.[5] Motion aftereffect and Phi phenomenon Motion aftereffect of vertical stripes moving in a horizontal direction and a rotating spiral were tested. She was able to detect motion in both patterns, but reported motion aftereffect in only 3 of the 10 trials for the stripes, and no effect for the rotating spiral. She also never reported any impression of motion in depth of the spiral. In Phi phenomenon two circular spots of light appear alternating. It appears that the spot moves from one location to the other. Under no combination of conditions did the patient report any apparent movement. She always reported two independent light spots.[5] Visually guided pursuit eye and finger movements LM was to follow the path of a wire mounted onto a board with her right index finger. The test was performed under purely tactile (blindfolded), purely visual (glass over the board), or tactile-visual condition. The patient performed best in the purely tactile condition and very poorly in the visual condition. She did not benefit from the visual information in the tactile-visual condition either. The patient reported that the difficulty was between her finger and her eyes. She could not follow her finger with her eyes if she moved her finger too fast.[5] Additional experiments In 1994, several other observations of LM's capabilities were made using a stimulus with a random distribution of light squares on a dark background that moved coherently.[7] With this stimulus, LM could always determine the axis of motion (vertical, horizontal), but not always the direction. If a few static squares were added to the moving display, identification of direction fell to chance, but identification of the axis of motion was still accurate. If a few squares were moving opposite and orthogonal to the predominant direction, her performance on both direction and axis fell to chance. She was also unable to identify motion in oblique directions, such as 45, 135, 225, and 315 degrees, and always gave answers in cardinal directions, 0, 90, 180, and 270 degrees.[7] ### "TD"[edit] In 2019, Heutink and colleagues described a 37-year old female patient (TD) with akinetopsia, who was admitted to Royal Dutch Visio, Centre of Expertise for blind and partially sighted people. TD suffered an ischaemic infarction of the occipitotemporal region in the right hemisphere and a smaller infarction in the left occipital hemisphere.[19] MRI confirmed that the damaged brain areas contained area V5 in both hemispheres. TD experienced problems with perceiving visual motion and also reported that bright colours and sharp contrasts made her feel sick. TD also had problems perceiving objects that were more than ± 5 meters away from her. Although TD had some impairments of lower visual functions, these could not explain the problems she experienced with regard to motion perception. Neuropsychological assessment revealed no evidence of Balint's Syndrome, hemispatial neglect or visual extinction, prosopagnosia or object agnosia. There was some evidence for impaired spatial processing. On several behavioural tests, TD showed a specific and selective impairment of motion perception that was comparable to LM's performance.[citation needed] Effect of target speed on motion perception in TD TD's ability to determine the direction of movement was tested using a task in which small grey blocks all moved in the same direction with the same speed against a black background. The blocks could move in four directions: right to left, left to right, upward and downward. Speed of movement was varied from 2, 4.5, 9, 15 and 24 degrees per second. Speed and direction were varied randomly across trials. TD had perfect perception of motion direction at speed up to 9 degrees per second. When speed of targets was above 9 degrees per second, TD's performance dropped dramatically to 50% correct at a speed of 15 degrees per second and 0% correct at 24 degrees per second. When the blocks moved at 24 degrees per second, TD consistently reported the exact opposite direction of the actual movement.[19] ### Pelak and Hoyt's Alzheimer's patient[edit] In 2000, a 70-year-old man presented with akinetopsia. He had stopped driving two years prior because he could no longer "see movement while driving".[6] His wife noted that he could not judge the speed of another car or how far away it was. He had difficulty watching television with significant action or movement, such as sporting events or action-filled TV shows. He frequently commented to his wife that he could not "see anything going on".[6] When objects began to move they would disappear. He could, however, watch the news, because no significant action occurred. In addition he had signs of Balint's syndrome (mild simultanagnosia, optic ataxia, and optic apraxia).[6] ### Pelak and Hoyt's TBI patient[edit] In 2003, a 60-year-old man complained of the inability to perceive visual motion following a traumatic brain injury, two years prior, in which a large cedar light pole fell and struck his head.[6] He gave examples of his difficulty as a hunter. He was unable to notice game, to track other hunters, or to see his dog coming towards him. Instead, these objects would appear in one location and then another, without any movement being seen between the two locations. He had difficulties driving and following a group conversation. He lost his place when vertically or horizontally scanning a written document and was unable to visualize three-dimensional images from two-dimensional blueprints.[6] ## References[edit] 1. ^ a b c d e f g h Zeki S (April 1991). "Cerebral akinetopsia (visual motion blindness). A review". Brain. 114 ( Pt 2) (2): 811–24. doi:10.1093/brain/114.2.811. PMID 2043951. 2. ^ https://www.bbc.com/future/article/20140624-the-man-who-saw-time-freeze 3. ^ Gersztenkorn D, Lee AG (2015). "Palinopsia revamped: a systematic review of the literature". Surv Ophthalmol. 60 (1): 1–35. doi:10.1016/j.survophthal.2014.06.003. PMID 25113609. 4. ^ Wurtz RH (September 2008). "Neuronal mechanisms of visual stability". Vision Res. 48 (20): 2070–89. doi:10.1016/j.visres.2008.03.021. PMC 2556215. PMID 18513781. 5. ^ a b c d e f g h i j k l m Zihl J, von Cramon D, Mai N (June 1983). "Selective disturbance of movement vision after bilateral brain damage". Brain. 106 (Pt 2) (2): 313–40. doi:10.1093/brain/106.2.313. PMID 6850272. 6. ^ a b c d e f g h i Pelak Victoria S.; Hoyt William F. (2005). "Symptoms of akinetopsia associated with traumatic brain injury and Alzheimer's Disease". Neuro-Ophthalmology. 29 (4): 137–142. doi:10.1080/01658100500218046. 7. ^ a b c d e Shipp S, de Jong BM, Zihl J, Frackowiak RS, Zeki S (October 1994). "The brain activity related to residual motion vision in a patient with bilateral lesions of V5". Brain. 117 ( Pt 5) (5): 1023–38. doi:10.1093/brain/117.5.1023. PMID 7953586. S2CID 25409218. 8. ^ a b c Schenk T, Mai N, Ditterich J, Zihl J (September 2000). "Can a motion-blind patient reach for moving objects?". Eur. J. Neurosci. 12 (9): 3351–60. doi:10.1046/j.1460-9568.2000.00194.x. PMID 10998118. 9. ^ a b c Schenk T, Ellison A, Rice N, Milner AD (2005). "The role of V5/MT+ in the control of catching movements: an rTMS study" (PDF). Neuropsychologia. 43 (2): 189–98. doi:10.1016/j.neuropsychologia.2004.11.006. PMID 15707904. 10. ^ a b c Zihl, J., ULM Munich (Max Planck Institute of Psychiatry), interviewed by R. Hamrick, Oct. 28, 2009. 11. ^ a b c d e f Beckers G, Zeki S (February 1995). "The consequences of inactivating areas V1 and V5 on visual motion perception". Brain. 118 ( Pt 1): 49–60. doi:10.1093/brain/118.1.49. PMID 7895014. 12. ^ Rizzo M, Nawrot M (December 1998). "Perception of movement and shape in Alzheimer's disease". Brain. 121 ( Pt 12) (12): 2259–70. doi:10.1093/brain/121.12.2259. PMID 9874479. 13. ^ Pinel, John P.J. (2011). Biopsychology (8th ed.). Boston: Allyn & Bacon. p. 160. ISBN 978-0-205-83256-9. 14. ^ Zeki S, Watson JD, Lueck CJ, Friston KJ, Kennard C, Frackowiak RS (March 1991). "A direct demonstration of functional specialization in human visual cortex". J. Neurosci. 11 (3): 641–9. doi:10.1523/JNEUROSCI.11-03-00641.1991. PMC 6575357. PMID 2002358. 15. ^ Wandell BA, Dumoulin SO, Brewer AA (October 2007). "Visual field maps in human cortex". Neuron. 56 (2): 366–83. doi:10.1016/j.neuron.2007.10.012. PMID 17964252. 16. ^ a b LaRock Eric. "Why neural synchrony fails to explain the unity of visual consciousness". Behavior and Philosophy. 34: 39–58. 17. ^ Schenk T, Zihl J (September 1997). "Visual motion perception after brain damage: I. Deficits in global motion perception". Neuropsychologia. 35 (9): 1289–97. doi:10.1016/S0028-3932(97)00004-3. PMID 9364498. 18. ^ Vaina LM, Solomon J, Chowdhury S, Sinha P, Belliveau JW (September 2001). "Functional neuroanatomy of biological motion perception in humans". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11656–61. Bibcode:2001PNAS...9811656V. doi:10.1073/pnas.191374198. PMC 58785. PMID 11553776. 19. ^ a b Heutink, Joost; de Haan, Gera; Marsman, Jan-Bernard; van Dijk, Mart; Cordes, Christina (December 2018). "The effect of target speed on perception of visual motion direction in a patient with akinetopsia". Cortex. 119: 511–518. doi:10.1016/j.cortex.2018.12.002. PMID 30661737. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Akinetopsia

None

wikipedia

https://en.wikipedia.org/wiki/Akinetopsia

{"wikidata": ["Q784564"]}

Thought insertion is defined by the ICD-10 as feeling as if one's thoughts are not one's own, but rather belong to someone else and have been inserted into one's mind.[1][2][3][4] The person experiencing thought insertion will not necessarily know where the thought is coming from, but makes a distinction between their own thoughts and those inserted into their minds.[5] However, patients do not experience all thoughts as inserted; only certain ones, normally following a similar content or pattern. This phenomenon is classified as a delusion.[1] A person with this delusional belief is convinced of the veracity of their beliefs and is unwilling to accept such diagnosis.[6] Thought insertion is a common symptom of psychosis and occurs in many mental disorders and other medical conditions.[1] However, thought insertion is most commonly associated with schizophrenia. Thought insertion, along with thought broadcasting, thought withdrawal, thought blocking and other first rank symptoms, is a primary symptom and should not be confused with the delusional explanation given by the respondent. Although normally associated with some form of psychopathology, thought insertion can also be experienced in those considered nonpathological, usually in spiritual contexts, but also in culturally influenced practices such as mediumship and automatic writing.[1][2] Some patients have also stated that at some point in time they were being manipulated by an exterior or interior force depending on the delusion that the patient faced and only later realized that thoughts weren't theirs, this is linked to patients "losing control" of what they do. Examples of thought insertion: > She said that sometimes it seemed to be her own thought 'but I don't get the feeling that it is'. She said her 'own thoughts might say the same thing', 'but the feeling isn't the same', 'the feeling is that it is somebody else's.'[5] > I look out the window and I think that the garden looks nice and the grass looks cool, but the thoughts of Eamonn Andrews come into my mind. There are no other thoughts there, only his [sic]. He treats my mind like a screen and flashes thoughts onto it like you flash a picture.[5] > The subject has thoughts that she thinks are the thoughts of other people, somehow occurring in her own mind. It is not that the subject thinks that other people are making her think certain thoughts as if by hypnosis or psychokinesis, but that other people think the thoughts using the subject's mind as a psychological medium.[7] ## Contents * 1 Unbidden thoughts * 2 Auditory verbal hallucinations * 3 Theories * 3.1 Standard approach * 3.2 Causal-contextual * 4 Mind-to-mind paradigm * 5 Neurology * 5.1 Theory of misattributed inner speech * 5.2 Comparator-model (forward model) * 5.3 Executive control model * 6 Treatment * 7 References ## Unbidden thoughts[edit] Unbidden thoughts are thoughts that come to mind without the subject directly or consciously meaning to think them. Inserted thoughts, while sharing the characteristic of unconsciously or indirectly being conjured, are distinct from unbidden thoughts because of the author of the thoughts. During an experience of unbidden thinking, the subject knows that they are the author of the thought even though they may not have consciously meant to think it. During the feeling of thought insertion, however, the subject feels as though the thought belongs to another person and was inserted into their own mind, making the author of the thought someone other than themselves. ## Auditory verbal hallucinations[edit] Auditory hallucinations have two essential components: audibility and alienation.[8] While people who experience thought insertion do share the experience of alienation (they cannot recognize that the thoughts they are having are self-generated) with auditory hallucinations, they lack the sense of audibility (experiencing the thoughts as occurring outside of their mind or spoken to them). The person experiencing thought insertion recognizes that the thought is being thought of inside their mind, but they fail to recognize they are the one thinking it. ## Theories[edit] ### Standard approach[edit] The "standard approach" is characterized by a lack of sense of agency. Most philosophers define a sense of agency as a subject's awareness that they are initiating or controlling one's own actions. According to standard approach theory, the subject does not have an awareness that they are the initiators of a thought, but they do recognize that they own the thought in that it exists within their own mind. Many have argued that the standard approach does not explain the details and the unusual pathology behind thought insertion.[5][9] Typically, critiques argue that this account fails to provide a reason that distinguishes inserted thoughts from either ordinary thoughts that the subject did not deliberately try to conjure (unbidden thoughts) or other thoughts that are thought to be controlled by forces outside of the subject.[9] As a result, other theories of thought insertion have been proposed in order to try to explain the complexities behind the phenomenon. ### Causal-contextual[edit] The causal-contextual theory of thought insertion focuses on a lack of a feeling of ownership. This theory differs from the standard approach because rather than explaining thought insertion by saying the subject lacks a sense of agency, this model explains thought insertion by theorizing that the subject lacks a sense of ownership, which in turn creates a lack of agency.[5] Patients with schizophrenia are hypothesized to have a generalized deficit in their integration of information, illustrated through the many other symptoms of schizophrenia and psychosis.[5] According to causal-contextual theory, sense of ownership depends on integrating causal-contextual information and a deficit in this process account for the abnormal experience of thought insertion. This model has come under criticism due to its definition of sense of ownership. In philosophy, a sense of ownership is defined as a thought that occurs within the space of one's own mind. However, in the causal-contextual model of thought insertion, sense of ownership is defined as feeling as if a thought belongs to the person thinking it.[10] Because of this distinction, many (e.g. Seeger, Coliva, etc.) argue that the causal-contextual model is not a separate model of thought insertion, but rather a corollary of the standard approach.[3][10] ## Mind-to-mind paradigm[edit] Swiney and Sousa (2013) conducted an experiment to investigate thought insertion in a normal population.[11] They attempted to create situations in which nonpathological populations would have the ability to make sense of agency misattributions in their thoughts. Participants were told that they were attached to a machine that could "transfer thoughts" from one person to another. They were then told a target word, and were to click a mouse every time they thought about the target word. However, they were only to click the mouse when they believed the target word they were thinking of was not generated by their own mind. It was stressed that the paradigm did not always work and that it was okay to not experience another person's thoughts. The vast majority (72%) of participants made at least one misattribution of agency, meaning they attributed a thought they experienced as belonging to the other participant and believed the machine had transferred the thought into their mind through the machine. This occurred after only 5 minutes. These misattributions were more frequent when the target thought was an arousing negative thought as compared to a neutral control. ## Neurology[edit] Identifying brain regions associated with thought insertion has proven difficult. First, it is difficult to find subjects who experience thought insertion frequently. Second, it is difficult to do brain imaging techniques on these subjects while they are experiencing thought insertion. Therefore, most of the findings in this field come from cases of normal people under hypnosis, as evidenced in an experiment by Walsh and colleges (2015).[2] The supplementary motor area is thought to be involved in the phenomenon of thought insertion. Thought insertion is associated with reduced activation of networks that support language, movement, and self-related processing.[2] Specifically, thought insertion is associated with a reduction in the activity of the left supplementary motor area, basal ganglia, striatal areas, right superior occipital cortex and thalamus. An altered functional connectivity between the supplementary motor area and brain regions involved in language processing and movement implementation was also found.[2] ### Theory of misattributed inner speech[edit] According to the model of misattributed inner speech, during the generation of inner speech, speech production areas fail to inhibit the speech perception area and this leads to a misattribution of one's thoughts to an external source.[8] ### Comparator-model (forward model)[edit] The comparator-model, also known as the forward model, is an elaboration of theory of misattributed inner speech. This theory relies on a model involved in inner speech known as the forward model. Specifically, the comparator-model of thought insertion describes processing of movement-related sensory feedback involving a parietal-cerebellar network as subject to feedforward inhibition during voluntary movements and this is thought to contribute to the subject feeling as though thoughts are inserted into his or her mind. It has been proposed that the loss of sense of agency results from a disruption of feedforward inhibition of somatosensory processing for self-generated movements. Frith (2012) argues that delusions and hallucination are associated with a failure in the predictive component of the model.[12] Critics of this model argue that it makes the unsupported claim that a model for movement can be transferred to account for thoughts.[13] These critics argue that this jump cannot be made because it is not known that movements and thoughts are processed in the same way. Support for the comparator-model has also been spotty. In an experiment done by Walsh and colleges (2015), the theory behind the forward model of thought insertion was not supported.[2] They found that thought insertion was not associated with overactivation of somatosensory or other self-monitoring networks that occurs in movement. They argue that this provides evidence that a model for motor agency cannot explain thought agency. ### Executive control model[edit] The executive control model argues that thought insertion may be mediated by altered activity in motor planning regions, specifically the supplementary motor area. In one experiment, reduced connectivity between the supplementary motor area and motor implementation regions during suggested involuntary compared to voluntary movements was observed.[2] ## Treatment[edit] Most of the treatments for thought insertion are not specific to the symptom, but rather the symptom is treated through treatment of the psychopathology that causes it. However, one case report considers a way to manage thought insertion through performing thoughts as motor actions of speech.[14] In other words, the patient would speak his thoughts out loud in order to re-give himself the feeling of agency as he could hear himself speaking and then contributing the thought to himself. ## References[edit] 1. ^ a b c d Mullins, S (2003). "Re-Examining Thought Insertion: Semi-Structured Literature Review And Conceptual Analysis". British Journal of Psychiatry. 182 (4): 293–298. doi:10.1192/bjp.182.4.293. PMID 12668403. 2. ^ a b c d e f g Walsh, E.; Oakley, D. A.; Halligan, P. W.; Mehta, M. A.; Deeley, Q. (2015). "The functional anatomy and connectivity of thought insertion and alien control of movement" (PDF). Cortex. 64: 380–393. doi:10.1016/j.cortex.2014.09.012. PMID 25438744. 3. ^ a b Coliva, A (2002). "Thought insertion and immunity to error through misidentification". Philosophy, Psychiatry, & Psychology. 9 (1): 27–34. CiteSeerX 10.1.1.405.754. doi:10.1353/ppp.2003.0004. 4. ^ World Health Organization (January 1992). Thought blocking and thought insertion are also terms developed by the mental health system and professionals to define a phenomenon describing a technique used with so-called "synthetic telepathy" operations. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. World Health Organization. ISBN 978-92-4-154422-1. Retrieved 16 December 2010. 5. ^ a b c d e f Martin, J.R. (2013). "Out of Nowhere: Thought Insertion, Ownership and Context-Integration". Conscious and Cognition. 22 (1): 111–122. CiteSeerX 10.1.1.676.1811. doi:10.1016/j.concog.2012.11.012. PMID 23262256. 6. ^ Xavier Francisco Amador; Anthony S. David (2004). Insight and psychosis: awareness of illness in schizophrenia and related disorders. Oxford University Press. pp. 67–69. ISBN 978-0-19-852568-4. Retrieved 12 December 2010. 7. ^ Young, G (2008). "On how a child's awareness of thinking informs explanations of thought insertion". Consciousness and Cognition. 17 (3): 848–862. doi:10.1016/j.concog.2007.05.005. PMID 17596965. 8. ^ a b Sommer, I. E.; Selten, J.; Diederen, K. M.; Blom, J. D. (2010). "Dissecting auditory verbal hallucinations into two components: Audibility (gedankenlautwerden) and alienation (thought insertion)". Psychopathology. 43 (2): 137–40. doi:10.1159/000277003. PMID 20110766. 9. ^ a b Bortolotti, L (2009). "A role for ownership and authorship in the analysis of thought insertion". Phenomenology and the Cognitive Sciences. 8 (2): 205–224. doi:10.1007/s11097-008-9109-z. 10. ^ a b Seeger, M (2013). "Commentary on Martin & Pacherie. Out of nowhere: Thought insertion, ownership and context-integration". Consciousness and Cognition. 22 (1): 262–263. doi:10.1016/j.concog.2013.01.003. PMID 23376347. 11. ^ Swiney, L; Sousa, P (2013). "When Our Thoughts Are Not Our Own: Investigating Agency Misattributions Using The Mind-To-Mind Paradigm". Conscious and Cognition. 22 (2): 589–602. doi:10.1016/j.concog.2013.03.007. PMID 23619312. 12. ^ Frith, C (2012). "Explaining delusions of control: The comparator model 20 years on". Consciousness and Cognition. 21 (1): 52–54. doi:10.1016/j.concog.2011.06.010. PMID 21802318. 13. ^ Gallagher, S (2004). "Neurocognitive models of schizophrenia: A neurophenomenological critique". Psychopathology. 37 (1): 8–19. CiteSeerX 10.1.1.711.4188. doi:10.1159/000077014. PMID 14988645. 14. ^ Area, R.; Garcia-Caballero, A.; Gomez, I.; Somoza, M. J. (2003). "Conscious compensations for thought insertion". Psychopathology. 36 (3): 129–31. doi:10.1159/000071257. PMID 12845283. ProQuest 230486334. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Thought insertion

c0233687

wikipedia

https://en.wikipedia.org/wiki/Thought_insertion

{"wikidata": ["Q7796994"]}

Posterior amorphous corneal dystrophy (PACD) is a very rare form of stromal corneal dystrophy (see this term) characterized by irregular amorphous sheet-like opacities in the posterior corneal stroma and in Descemet membrane and mildly impaired vision. ## Epidemiology Prevalence of this form of corneal dystrophy is not known. To date cases have been reported primarily in the USA. ## Clinical description Patients usually develop corneal abnormalities in infancy or childhood. The condition is non-progressive or slowly progressive. Visual acuity is usually only minimally affected but in some more severe cases, penetrating keratoplasty (PK) may be warranted. Unlike other corneal dystrophies, non-corneal manifestations have been observed and include abnormalities of the iris (iridocorneal adhesions, corectopia, and pseudopolycoria). ## Etiology The etiology of the condition is not known but it is thought to be genetic. The chromosomal locus of the gene responsible for PACD has not been determined. ## Diagnostic methods Opacities are diffuse gray-white and sheet-like and can involve any layer of the stroma but are most prominent posteriorly. The lesions can be centroperipheral, extending to the limbus, or peripheral, the latter with less pronounced findings and symptoms. There are often transparent stromal breaks in the opacification. ## Genetic counseling An autosomal dominant pattern of inheritance has been reported. ## Management and treatment Since the entire stroma is involved, a penetrating kertopasty is indicated if visual impairment is clinically significant. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Posterior amorphous corneal dystrophy

c2748502

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98971

{"mesh": ["C567546"], "omim": ["612868"], "umls": ["C2748502"], "icd-10": ["H18.5"], "synonyms": ["PACD", "Posterior amorphous stromal dystrophy"]}

Aphthous stomatitis Other namesRecurrent aphthous stomatitis, recurring oral aphthae, recurrent aphthous ulceration Canker sore on the lower lip SpecialtyOral medicine, dermatology Frequency~20% of people to some degree[1] Aphthous stomatitis is a common condition characterized by the repeated formation of benign and non-contagious mouth ulcers (aphthae) in otherwise healthy individuals. The informal term canker sores is also used, mainly in North America, although this may also refer to any mouth ulcers. The cause is not completely understood but involves a T cell-mediated immune response triggered by a variety of factors which may include nutritional deficiencies, local trauma, stress, hormonal influences, allergies, genetic predisposition, certain foods, dehydration or some food additives. These ulcers occur periodically and heal completely between attacks. In the majority of cases, the individual ulcers last about 7–10 days, and ulceration episodes occur 3–6 times per year. Most appear on the non-keratinizing epithelial surfaces in the mouth – i.e. anywhere except the attached gingiva, the hard palate and the dorsum of the tongue – although the more severe forms, which are less common, may also involve keratinizing epithelial surfaces. Symptoms range from a minor nuisance to interfering with eating and drinking. The severe forms may be debilitating, even causing weight loss due to malnutrition. The condition is very common, affecting about 20% of the general population to some degree.[1] The onset is often during childhood or adolescence, and the condition usually lasts for several years before gradually disappearing. There is no cure, and treatments such as corticosteroids aim to manage pain, reduce healing time and reduce the frequency of episodes of ulceration. The term is from Greek: αφθα, translit. aphtha meaning "mouth ulcer". ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Immunity * 2.2 Mucosal barrier * 2.3 Antigenic sensitivity * 2.4 Systemic disease * 3 Diagnosis * 3.1 Classification * 3.1.1 Minor aphthous ulceration * 3.1.2 Major aphthous ulceration * 3.1.3 Herpetiform ulceration * 3.1.4 RAS type ulceration * 4 Treatment * 4.1 Medication * 4.2 Other * 5 Prognosis * 6 Epidemiology * 7 History, society and culture * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Aphthous ulcers on the labial mucosa (lower lip is retracted). Note erythematous "halo" surrounding ulcer. Persons with aphthous stomatitis have no detectable systemic symptoms or signs (i.e., outside the mouth).[2] Generally, symptoms may include prodromal sensations such as burning, itching, or stinging, which may precede the appearance of any lesion by some hours; and pain, which is often out of proportion to the extent of the ulceration and is worsened by physical contact, especially with certain foods and drinks (e.g., if they are acidic or abrasive). Pain is worst in the days immediately following the initial formation of the ulcer, and then recedes as healing progresses.[3] If there are lesions on the tongue, speaking and chewing can be uncomfortable, and ulcers on the soft palate, back of the throat, or esophagus can cause painful swallowing.[3] Signs are limited to the lesions themselves. Ulceration episodes usually occur about 3–6 times per year.[4] However, severe disease is characterized by virtually constant ulceration (new lesions developing before old ones have healed) and may cause debilitating chronic pain and interfere with comfortable eating. In severe cases, this prevents adequate nutrient intake leading to malnutrition and weight loss.[3] Aphthous ulcers typically begin as erythematous macules (reddened, flat area of mucosa) which develop into ulcers that are covered with a yellow-grey fibrinous membrane that can be scraped away. A reddish "halo" surrounds the ulcer.[5] The size, number, location, healing time, and periodicity between episodes of ulcer formation are all dependent upon the subtype of aphthous stomatitis. ## Causes[edit] The cause is not entirely clear,[2] but is thought to be multifactorial.[6] It has been suggested that aphthous stomatitis is not a single entity but rather a group of conditions with different causes.[2] Multiple research studies have attempted to identify a causative organism, but aphthous stomatitis appears to be non-contagious, non-infectious, and not sexually transmissible.[2] The mucosal destruction is thought to be the result of a T cell (T lymphocyte) mediated immune response which involves the generation of interleukins and tumor necrosis factor alpha (TNF-α).[6] Mast cells and macrophages are also involved, secreting TNF-α along with the T cells. When early aphthous ulcers are biopsied, the histologic appearance shows a dense inflammatory infiltrate, 80% of which is made up of T cells.[5] Persons with aphthous stomatitis also have circulating lymphocytes which react with peptides 91–105 of heat shock protein 65–60,[2] and the ratio of CD4+ T cells to CD8+ T cells in the peripheral blood of individuals with aphthous stomatitis is decreased.[5] Aphthous stomatitis has been associated with other autoimmune diseases, namely systemic lupus erythematosus, Behçet's disease and inflammatory bowel diseases. However, common autoantibodies are not detected in most patients, and the condition tends to resolve spontaneously with advancing age rather than worsen. Evidence for the T cell-mediated mechanism of mucosal destruction is strong, but the exact triggers for this process are unknown and are thought to be multiple and varied from one person to the next. This suggests that there are a number of possible triggers, each of which is capable of producing the disease in different subgroups. In other words, different subgroups appear to have different causes for the condition. These can be considered in three general groups, namely primary immuno-dysregulation, decrease of the mucosal barrier and states of heightened antigenic sensitivity (see below).[5] Risk factors in aphthous stomatitis are also sometimes considered as either host-related or environmental.[7] ### Immunity[edit] At least 40% of people with aphthous stomatitis have a positive family history, suggesting that some people are genetically predisposed to suffering with oral ulceration.[6] HLA-B12, HLA-B51, HLA-Cw7, HLA-A2, HLA-A11, and HLA-DR2 are examples of human leukocyte antigen types associated with aphthous stomatitis.[2][5] However, these HLA types are inconsistently associated with the condition, and also vary according to ethnicity.[8] People who have a positive family history of aphthous stomatitis tend to develop a more severe form of the condition, and at an earlier age than is typical.[8] Stress has effects on the immune system, which may explain why some cases directly correlate with stress. It is often stated that in studies of sufferers who are students, ulceration is exacerbated during examination periods and lessened during periods of vacation.[2][5] Alternatively, it has been suggested that oral parafunctional activities such as lip or cheek chewing become more pronounced during periods of stress, and hence the mucosa is subjected to more minor trauma.[8] Aphthous-like ulceration also occurs in conditions involving systemic immuno-dysregulation, e.g. cyclic neutropenia and human immunodeficiency virus infection. In cyclic neutropenia, more severe oral ulceration occurs during periods of severe immuno-dysregulation, and resolution of the underlying neutropenia is associated with healing of the ulcers. The relative increase in percentage of CD8+ T cells, caused by a reduction in numbers of CD4+ T cells may be implicated in RAS-type ulceration in HIV infection.[5] ### Mucosal barrier[edit] The thickness of the mucosa may be an important factor in aphthous stomatitis. Usually, ulcers form on the thinner, non-keratinizing mucosal surfaces in the mouth. Factors which decrease the thickness of the mucosa increase the frequency of occurrence, and factors which increase the thickness of the mucosa correlate with decreased ulceration.[5] The nutritional deficiencies associated with aphthous stomatitis (vitamin B12, folate, and iron) can all cause a decrease in the thickness of the oral mucosa (atrophy).[5] Local trauma is also associated with aphthous stomatitis, and it is known that trauma can decrease the mucosal barrier. Trauma could occur during injections of local anesthetic in the mouth, or otherwise during dental treatments, frictional trauma from a sharp surface in the mouth such as broken tooth, or from tooth brushing.[8] Hormonal factors are capable of altering the mucosal barrier. In one study, a small group of females with aphthous stomatitis had fewer occurrences of aphthous ulcers during the luteal phase of the menstrual cycle or with use of the contraceptive pill.[2][5] This phase is associated with a fall in progestogen levels, mucosal proliferation and keratinization. This subgroup often experiences remission during pregnancy. However, other studies report no correlation between aphthous stomatitis and menstrual period, pregnancy or menopause.[8] Aphthous stomatitis is more common in people who smoke,[6][9][unreliable medical source] and there is also a correlation between habit duration and severity of the condition.[10] Tobacco use is associated with an increase in keratinization of the oral mucosa.[5] In extreme forms, this may manifest as leukoplakia or stomatitis nicotina (smoker's keratosis). This increased keratinization may mechanically reinforce the mucosa and reduce the tendency of ulcers to form after minor trauma, or present a more substantial barrier to microbes and antigens, but this is unclear. Nicotine is also known to stimulate production of adrenal steroids and reduce production of TNF-α, interleukin-1 and interleukin-6.[8] Smokeless tobacco products also seem to protect against aphthous stomatitis.[10] Cessation of smoking is known to sometimes precede the onset of aphthous stomatitis in people previously unaffected, or exacerbate the condition in those who were already experiencing aphthous ulceration.[2] Despite this correlation, starting smoking again does not usually lessen the condition.[11] ### Antigenic sensitivity[edit] Various antigenic triggers have been implicated as a trigger, including L forms of streptococci, herpes simplex virus, varicella-zoster virus, adenovirus, and cytomegalovirus.[5] Some people with aphthous stomatitis may show herpes virus within the epithelium of the mucosa, but without any productive infection. In some persons, attacks of ulceration occur at the same time as asymptomatic viral shedding and elevated viral titres.[5] In some instances, recurrent mouth ulcers may be a manifestation of an allergic reaction.[12] Possible allergens include certain foods (e.g., chocolate, coffee, strawberries, eggs, nuts, tomatoes, cheese, citrus fruits, benzoates, cinnamaldehyde, and highly acidic foods), toothpastes, and mouthwashes.[7][12] Where dietary allergens are responsible, mouth ulcers usually develop within about 12–24 hours of exposure.[7] Sodium lauryl sulphate (SLS), a detergent present in some brands of toothpaste and other oral healthcare products, may produce oral ulceration in some individuals.[2] It has been shown that aphthous stomatitis is more common in people using toothpastes containing SLS, and that some reduction in ulceration occurs when a SLS-free toothpaste is used.[8] Some have argued that since SLS is almost ubiquitously used in oral hygiene products, there is unlikely to be a true predisposition for aphthous stomatitis caused by SLS.[8] ### Systemic disease[edit] Systemic disorders associated with aphthous-like ulceration[5] Behçet's disease Celiac disease Cyclic neutropenia Nutritional deficiencies IgA deficiency Immunocompromised states, e.g. HIV/AIDS Inflammatory bowel disease MAGIC syndrome PFAPA syndrome Reactive arthritis Sweet's syndrome Ulcus vulvae acutum Main article: Oral ulceration Aphthous-like ulceration may occur in association with several systemic disorders (see table). These ulcers are clinically and histopathologically identical to the lesions of aphthous stomatitis, but this type of oral ulceration is not considered to be true aphthous stomatitis by some sources.[6][13] Some of these conditions may cause ulceration on other mucosal surfaces in addition to the mouth such as the conjunctiva or the genital mucous membranes. Resolution of the systemic condition often leads to decreased frequency and severity of the oral ulceration.[5] Behçet's disease is a triad of mouth ulcers, genital ulcers and anterior uveitis.[7] The main feature of Behçet's disease is aphthous-like ulceration, but this is usually more severe than seen in aphthous stomatitis without a systemic cause, and typically resembles major or herpetiforme ulceration or both.[6][14] Aphthous-like ulceration is the first sign of the disease in 25–75% of cases.[5] Behçet's is more common in individuals whose ethnic origin is from regions along the Silk Road (between the Mediterranean and the Far East).[15] It tends to be rare in other countries such as the United States and the United Kingdom.[7] MAGIC syndrome is a possible variant of Behçet's disease, and is associated with aphthous-like ulceration. The name stands for "mouth and genital ulcers with inflamed cartilage" (relapsing polychondritis).[8] PFAPA syndrome is a rare condition that tends to occur in children.[8] The name stands for "periodic fever, aphthae, pharyngitis (sore throat) and cervical adenitis" (inflammation of the lymph nodes in the neck). The fevers occur periodically about every 3–5 weeks. The condition appears to improve with tonsillectomy or immunosuppression, suggesting an immunologic cause.[14] In cyclic neutropenia, there is a reduction in the level of circulating neutrophils in the blood that occurs about every 21 days. Opportunistic infections commonly occur and aphthous-like ulceration is worst during this time.[14] Hematinic deficiencies (vitamin B12, folic acid and iron), occurring singly or in combination,[7] and with or without any underlying gastrointestinal disease, may be twice as common in people with RAS. However, iron and vitamin supplements only infrequently improve the ulceration.[14] The relationship to vitamin B12 deficiency has been the subject of many studies. Although these studies found that 0–42% of those with recurrent ulcers suffer from vitamin B12 deficiency, an association with deficiency is rare. Even in the absence of deficiency, vitamin B12 supplementation may be helpful due to unclear mechanisms.[16] Hematinic deficiencies can cause anemia, which is also associated with aphthous-like ulceration.[6] Gastrointestinal disorders are sometimes associated with aphthous-like stomatitis, e.g. most commonly celiac disease, but also inflammatory bowel disease such as Crohn's disease or ulcerative colitis.[6] The link between gastrointestinal disorders and aphthous stomatitis is probably related to nutritional deficiencies caused by malabsorption.[14] Less than 5% of people with RAS have celiac disease, which usually presents with severe malnutrition, anemia, abdominal pain, diarrhea and glossitis (inflammation of the tongue).[8] Sometimes aphthous-like ulcerations can be the only sign of celiac disease.[8] Despite this association, a gluten-free diet does not usually improve the oral ulceration.[14] Other examples of systemic conditions associated with aphthous-like ulceration include reactive arthritis,[6] and recurrent erythema multiforme.[6] ## Diagnosis[edit] See also: Oral ulceration § Diagnostic approach Photographic comparison of: 1) a canker sore – inside the mouth, 2) herpes, 3) angular cheilitis, and 4) chapped lips.[17] Blood is often taken to assess the hemoglobin, iron, folate and vitamin B12 levels A patch test is sometimes carried out. Areas of the skin on the back are stimulated with various common allergens. The ones which cause an inflammatory reaction may also be involved in recurrent oral ulceration Diagnosis is mostly based on the clinical appearance and the medical history.[2] The most important diagnostic feature is a history of recurrent, self healing ulcers at fairly regular intervals.[18] Although there are many causes of oral ulceration, recurrent oral ulceration has relatively few causes, most commonly aphthous stomatitis, but rarely Behçet's disease, erythema multiforme, ulceration associated with gastrointestinal disease,[11][18] and recurrent intra-oral herpes simplex infection. A systemic cause is more likely in adults who suddenly develop recurrent oral ulceration with no prior history.[14] Special investigations may be indicated to rule out other causes of oral ulceration. These include blood tests to exclude anemia, deficiencies of iron, folate or vitamin B12, or celiac disease.[7] However, the nutritional deficiencies may be latent and the peripheral blood picture may appear relatively normal.[7] Some suggest that screening for celiac disease should form part of the routine work up for individuals complaining of recurrent oral ulceration.[8] Many of the systemic diseases cause other symptoms apart from oral ulceration, which is in contrast to aphthous stomatitis where there is isolated oral ulceration. Patch testing may be indicated if allergies are suspected (e.g. a strong relationship between certain foods and episodes of ulceration). Several drugs can cause oral ulceration (e.g. nicorandil), and a trial substitution to an alternative drug may highlight a causal relationship.[2] Tissue biopsy is not usually required, unless to rule out other suspected conditions such as oral squamous cell carcinoma.[18] The histopathologic appearance is not pathognomonic (the microscopic appearance is not specific to the condition). Early lesions have a central zone of ulceration covered by a fibrinous membrane. In the connective tissue deep to the ulcer there is increased vascularity and a mixed inflammatory infiltrate composed of lymphocytes, histiocytes and polymorphonuclear leukocytes. The epithelium on the margins of the ulcer shows spongiosis and there are many mononuclear cells in the basal third. There are also lymphocytes and histiocytes in the connective tissue surrounding deeper blood vessels near to the ulcer, described histologically as "perivascular cuffing".[5][18] ### Classification[edit] Aphthous stomatitis has been classified as a type of non-infectious stomatitis (inflammation of the mouth).[18] One classification distinguishes "common simple aphthae", accounting for 95% of cases, with 3–6 attacks per year, rapid healing, minimal pain and restriction of ulceration to the mouth; and "complex aphthae", accounting for 5% of cases, where ulcers may be present on the genital mucosa in addition to mouth, healing is slower and pain is more severe.[4] A more common method of classifying aphthous stomatitis is into three variants, distinguished by the size, number and location of the lesions, the healing time of individual ulcers and whether a scar is left after healing (see below). #### Minor aphthous ulceration[edit] This is the most common type of aphthous stomatitis, accounting for about 80–85% of all cases.[7] This subtype is termed minor aphthous ulceration (MiAU),[2] or minor recurrent aphthous stomatitis (MiRAS). The lesions themselves may be referred to as minor aphthae or minor aphthous ulcers. These lesions are generally less than 10 mm in diameter (usually about 2–3 mm),[7] and affect non-keratinized mucosal surfaces (i.e. the labial and buccal mucosa, lateral borders of the tongue and the floor of the mouth). Usually several ulcers appear at the same time, but single ulcers are possible. Healing usually takes seven to ten days and leaves no scar. Between episodes of ulceration, there is usually an ulcer-free period of variable length.[6] #### Major aphthous ulceration[edit] This subtype makes up about 10% of all cases of aphthous stomatitis.[5] It is termed major aphthous ulceration (MaAU) or major recurrent aphthous stomatitis (MaRAS). Major aphthous ulcers (major aphthae) are similar to minor aphthous ulcers, but are more than 10 mm in diameter and the ulceration is deeper.[5][6] Because the lesions are larger, healing takes longer (about twenty to thirty days), and may leave scars. Each episode of ulceration usually produces a greater number of ulcers, and the time between attacks is less than seen in minor aphthous stomatitis.[5] Major aphthous ulceration usually affects non-keratinized mucosal surfaces, but less commonly keratinized mucosa may also be involved, such as the dorsum (top surface) of the tongue or the gingiva (gums).[8] The soft palate or the fauces (back of the throat) may also be involved,[8] the latter being part of the oropharynx rather than the oral cavity. Compared to minor aphthous ulceration, major aphthae tend to have an irregular outline.[7] #### Herpetiform ulceration[edit] Herpetiform ulcers,[6] (also termed stomatitis herpetiformis,[19] or herpes-like ulcerations) is a subtype of aphthous stomatitis so named because the lesions resemble a primary infection with herpes simplex virus (primary herpetic gingivostomatitis).[5] However, herpetiform ulceration is not caused by herpes viruses. As with all types of aphthous stomatitis, it is not contagious. Unlike true herpetic ulcers, herpetiforme ulcers are not preceded by vesicles (small, fluid-filled blisters).[8] Herpetiforme ulcers are less than 1 mm in diameter and occur in variably sized crops up to one hundred at a time. Adjacent ulcers may merge to form larger, continuous areas of ulceration. Healing occurs within fifteen days without scarring.[7] The ulceration may affect keratinized mucosal surfaces in addition to non keratinized. Herpetiform ulceration is often extremely painful, and the lesions recur more frequently than minor or major aphthous ulcers. Recurrence may be so frequent that ulceration is virtually continuous. It generally occurs in a slightly older age group than the other subtypes,[8] and females are affected slightly more frequently than males.[2] #### RAS type ulceration[edit] Recurrent oral ulceration associated with systemic conditions is termed "RAS-type ulceration", "RAS-like ulceration", or "aphthous-like ulcers".[2] Aphthous stomatitis occurs in individuals with no associated systemic disease.[6] Persons with certain systemic diseases may be prone to oral ulceration, but this is secondary to the underlying medical condition (see the systemic disease section).[6] This kind of ulceration is considered by some to be separate from true aphthous stomatitis.[6][13] However, this definition is not strictly applied. For example, many sources refer to oral ulceration caused by anemia and/or nutritional deficiencies as aphthous stomatitis, and some also consider Behçet's disease to be a variant.[5][7] ## Treatment[edit] The vast majority of people with aphthous stomatitis have minor symptoms and do not require any specific therapy. The pain is often tolerable with simple dietary modification during an episode of ulceration such as avoiding spicy and acidic foods and beverages.[3] Many different topical and systemic medications have been proposed (see table), sometimes showing little or no evidence of usefulness when formally investigated.[6] Some of the results of interventions for RAS may in truth represent a placebo effect.[14] No therapy is curative, with treatment aiming to relieve pain, promote healing and reduce the frequency of episodes of ulceration.[6] ### Medication[edit] The first line therapy for aphthous stomatitis is topical agents rather than systemic medication,[6] with topical corticosteroids being the mainstay treatment.[2][14] Systemic treatment is usually reserved for severe disease due to the risk of adverse side effects associated with many of these agents. A systematic review found that no single systemic intervention was found to be effective.[6] Good oral hygiene is important to prevent secondary infection of the ulcers.[2] Occasionally, in females where ulceration is correlated to the menstrual cycle or to birth control pills, progestogen or a change in birth control may be beneficial.[2] Use of nicotine replacement therapy for people who have developed oral ulceration after stopping smoking has also been reported.[8] Starting smoking again does not usually lessen the condition.[11] Trauma can be reduced by avoiding rough or sharp foodstuffs and by brushing teeth with care. If sodium lauryl sulfate is suspected to be the cause, avoidance of products containing this chemical may be useful and prevent recurrence in some individuals.[20] Similarly patch testing may indicate that food allergy is responsible, and the diet modified accordingly.[2] If investigations reveal deficiency states, correction of the deficiency may result in resolution of the ulceration. For example, there is some evidence that vitamin B12 supplementation may prevent recurrence in some individuals.[20] Medications Drug type Intended action Example(s) Topical covering agents / barriers Reduce pain Orabase (often combined with triamcinolone).[21] Topical analgesics / anesthetics / anti-inflammatory agents Reduce pain Benzydamine hydrochloride mouthwash or spray,[14] Amlexanox paste,[21][20] viscous lidocaine,[21] diclofenac in hyaluronan.[2] Topical antiseptics Fasten healing (prevent secondary infection) Doxycycline,[6] tetracycline,[6] minocycline,[21] chlorhexidine gluconate,[14] triclosan.[14] Topical mild potency corticosteroids Reduce inflammation Hydrocortisone sodium succinate.[2] Topical moderate potency corticosteroids Reduce inflammation Beclomethasone dipropionate aerosol,[2] fluocinonide,[14] clobetasol,[2] betamethasone sodium phosphate,[2] dexamethasone.[21] Systemic medications Various, mostly modulating immune response Prednisolone,[6] colchicine,[6] pentoxifylline,[6] azathioprine, thalidomide,[6] dapsone,[6] mycophenolate mofetil,[6] adalimumab,[14] vitamin B12,[6] Clofazimine,[6] Levamisole,[6][14] Montelukast,[6] Sulodexide,[6] ### Other[edit] Surgical excision of aphthous ulcers has been described, but it is an ineffective and inappropriate treatment.[5] Silver nitrate has also been used as a chemical cauterant.[14] Apart from the mainstream approaches detailed above, there are numerous treatments of unproven effectiveness, ranging from herbal remedies to otherwise alternative treatments, including Aloe vera, Myrtus communis, Rosa damascena, potassium alum, zinc sulfate, nicotine, polio virus vaccine and prostaglandin E2.[2] ## Prognosis[edit] By definition, there is no serious underlying medical condition, and most importantly, the ulcers do not represent oral cancer nor are they infectious. However, aphthae are capable of causing significant discomfort. There is a spectrum of severity, with symptoms ranging from a minor nuisance to disabling.[3] Due to pain during eating, weight loss may develop as a result of not eating in severe cases of aphthous stomatitis. Usually, the condition lasts for several years before spontaneously disappearing in later life.[2] ## Epidemiology[edit] Aphthous stomatitis affects between 5% and 66% of people, with about 20% of individuals in most populations having the condition to some degree.[5][7] This makes it the most common disease of the oral mucosa.[18] Aphthous stomatitis occurs worldwide, but is more common in developed countries.[2] Within nations, it is more common in higher socioeconomic groups.[2] Males and females are affected in an equal ratio, and the peak age of onset between 10 and 19 years.[6] About 80% of people with aphthous stomatitis first developed the condition before the age of 30.[5] There have been reports of ethnic variation. For example, in the United States, aphthous stomatitis may be three times more common in white-skinned people than black-skinned people.[14] ## History, society and culture[edit] "Aphthous affectations" and "aphthous ulcerations" of the mouth are mentioned several times in the treatise "Of the Epidemics" (part of the Hippocratic corpus, in the 4th century BC),[22] although it seems likely that this was oral ulceration as a manifestation of some infectious disease, since they are described as occurring in epidemic-like patterns, with concurrent symptoms such as fever. Aphthous stomatitis was once thought to be a form of recurrent herpes simplex virus infection, and some clinicians still refer to the condition as "herpes" despite this cause having been disproven.[23] The informal term "canker sore" is sometimes used, mainly in North America,[24] either to describe this condition generally, or to refer to the individual ulcers of this condition,[25] or mouth ulcers of any cause unrelated to this condition. The origin of the word "canker" is thought to have been influenced by Latin, Old English, Middle English and Old North French.[26] In Latin, cancer translates to "malignant tumor" or literally "crab" (related to the likening of sectioned tumors to the limbs of a crab). The closely related word in Middle English and Old North French, chancre, now more usually applied to syphilis, is also thought to be involved.[26] Despite this etymology, aphthous stomatitis is not a form of cancer but rather entirely benign. An aphtha (plural aphthae) is a non specific term that refers to an ulcer of the mouth. The word is derived from the Greek word aphtha meaning "eruption" or "ulcer".[8] The lesions of several other oral conditions are sometimes described as aphthae, including Bednar's aphthae (infected, traumatic ulcers on the hard palate in infants),[27] oral candidiasis, and foot-and-mouth disease. When used without qualification, aphthae commonly refers to lesions of recurrent aphthous stomatitis. Since the word aphtha is often taken to be synonymous with ulcer, it has been suggested that the term "aphthous ulcer" is redundant, but it remains in common use.[28] Stomatitis is also a non-specific term referring to any inflammatory process in the mouth, with or without oral ulceration.[29] It may describe many different conditions apart from aphthous stomatitis such as angular stomatitis. The current most widely used medical term is "recurrent aphthous stomatitis" or simply "aphthous stomatitis".[3] Historically, many different terms have been used to refer to recurrent aphthous stomatitis or its sub-types, and some are still in use. Mikulicz's aphthae is a synonym of minor RAS,[8] named after Jan Mikulicz-Radecki. Synonyms for major RAS include Sutton's ulcers (named after Richard Lightburn Sutton), Sutton's disease,[30] Sutton's syndrome and pariadenitis mucosa necrotica recurrens.[2][8] Synonyms for aphthous stomatitis as a whole include (recurrent) oral aphthae, (recurrent) aphthous ulceration and (oral) aphthosis.[5][13] In traditional Chinese medicine, claimed treatments for aphthae focus on clearing heat and nourishing Yin.[31] Rembrandt Gentle White toothpaste did not contain sodium lauryl sulfate, and was specifically marketed as being for the benefit of "canker sore sufferers". When the manufacturer Johnson & Johnson discontinued the product in 2014, it caused a backlash of anger from long-term customers, and the toothpaste began to sell for many times the original price on the auction website eBay.[32][33] ## See also[edit] * Acute necrotizing ulcerative gingivitis, also known as "trench mouth"—another painful, non-contagious mouth infection with similar symptoms ## References[edit] 1. ^ a b Bruch JM, Treister N (2009). Clinical Oral Medicine and Pathology. Springer Science & Business Media. p. 53. ISBN 9781603275200. 2. ^ 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 Scully C (2013). Oral and maxillofacial medicine: the basis of diagnosis and treatment (3rd ed.). Edinburgh: Churchill Livingstone. pp. 226–34. ISBN 978-0-7020-4948-4. 3. ^ a b c d e f Treister JM, Bruch NS (2010). Clinical oral medicine and pathology. New York: Humana Press. pp. 53–56. ISBN 978-1-60327-519-4. 4. ^ a b Altenburg A, Zouboulis CC (September 2008). "Current concepts in the treatment of recurrent aphthous stomatitis". Skin Therapy Letter. 13 (7): 1–4. PMID 18839042. 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 Neville BW, Damm DD, Allen CM, Bouquot JE (2008). Oral & maxillofacial pathology (3rd ed.). Philadelphia: W.B. Saunders. pp. 331–36. ISBN 978-1-4160-3435-3. 6. ^ 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 Brocklehurst P, Tickle M, Glenny AM, Lewis MA, Pemberton MN, Taylor J, Walsh T, Riley P, Yates JM (September 2012). "Systemic interventions for recurrent aphthous stomatitis (mouth ulcers)". The Cochrane Database of Systematic Reviews. 9 (9): CD005411. doi:10.1002/14651858.CD005411.pub2. PMID 22972085. 7. ^ a b c d e f g h i j k l m n Millet D, Welbury R (2004). Clinical problem solving in orthodontics and paediatric dentistry. Edinburgh: Churchill Livingstone. pp. 143–44. ISBN 978-0-443-07265-9. 8. ^ a b c d e f g h i j k l m n o p q r s t u Preeti L, Magesh K, Rajkumar K, Karthik R (September 2011). "Recurrent aphthous stomatitis". Journal of Oral and Maxillofacial Pathology. 15 (3): 252–6. doi:10.4103/0973-029X.86669. PMC 3227248. PMID 22144824. 9. ^ Souza PR, Duquia RP, Breunig JA, Almeida HL (September 2017). "Recurrent aphthous stomatitis in 18-year-old adolescents – Prevalence and associated factors: a population-based study". Anais Brasileiros de Dermatologia. 92 (5): 626–629. doi:10.1590/abd1806-4841.20174692. PMC 5674692. PMID 29166496. 10. ^ a b Slebioda Z, Szponar E, Kowalska A (June 2014). "Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review". Archivum Immunologiae et Therapiae Experimentalis. 62 (3): 205–15. doi:10.1007/s00005-013-0261-y. PMC 4024130. PMID 24217985. 11. ^ a b c Odell W (2010). Clinical problem solving in dentistry (3rd ed.). Edinburgh: Churchill Livingstone. pp. 87–90. ISBN 978-0-443-06784-6. 12. ^ a b "Canker sore". Mayo Foundation for Medical Education and Research. March 24, 2012. Retrieved July 7, 2014. 13. ^ a b c Riera Matute G, Riera Alonso E (September–October 2011). "[Recurrent aphthous stomatitis in Rheumatology]". Reumatologia Clinica. 7 (5): 323–8. doi:10.1016/j.reuma.2011.05.003. PMID 21925448. 14. ^ a b c d e f g h i j k l m n o p q Scully C, Porter S (April 2008). "Oral mucosal disease: recurrent aphthous stomatitis". The British Journal of Oral & Maxillofacial Surgery. 46 (3): 198–206. doi:10.1016/j.bjoms.2007.07.201. PMID 17850936. 15. ^ Dalvi SR, Yildirim R, Yazici Y (December 2012). "Behcet's Syndrome". Drugs. 72 (17): 2223–41. doi:10.2165/11641370-000000000-00000. PMID 23153327. S2CID 31095457. 16. ^ Baccaglini L, Lalla RV, Bruce AJ, Sartori-Valinotti JC, Latortue MC, Carrozzo M, Rogers RS (November 2011). "Urban legends: recurrent aphthous stomatitis". Oral Diseases. 17 (8): 755–70. doi:10.1111/j.1601-0825.2011.01840.x. PMC 3192917. PMID 21812866. 17. ^ Dorfman J, The Center for Special Dentistry 18. ^ a b c d e f Cawson RA, Odell EW, Porter S (2008). Cawson's essentials of oral pathology and oral medicine (8th ed.). Edinburgh: Churchill Livingstone. pp. 220–24. ISBN 978-0-443-10125-0. 19. ^ "International Classification of Diseases-10". World Health Organization. Retrieved February 16, 2013. 20. ^ a b c Bailey J, McCarthy C, Smith RF (October 2011). "Clinical inquiry. What is the most effective way to treat recurrent canker sores?". The Journal of Family Practice. 60 (10): 621–32. PMID 21977491. 21. ^ a b c d e McBride DR (July 2000). "Management of aphthous ulcers". American Family Physician. 62 (1): 149–54, 160. PMID 10905785. 22. ^ Wikisource:Of the Epidemics 23. ^ Greenberg MS, Glick M (2003). Burket's oral medicine diagnosis & treatment (10th ed.). Hamilton, Ont.: BC Decker. p. 63. ISBN 1-55009-186-7. 24. ^ "Canker". Oxford dictionaries. Retrieved July 12, 2014. 25. ^ "Aphthous stomatitis". Merriam-Webster, Incorporated. Retrieved July 12, 2014. 26. ^ a b "Chancre and Canker". Douglas Harper. Retrieved September 1, 2013. 27. ^ Tricarico A, Molteni G, Mattioli F, Guerra A, Mordini B, Presutti L, Iughetti L (November–December 2012). "Nipple trauma in infants? Bednar aphthae". American Journal of Otolaryngology. 33 (6): 756–7. doi:10.1016/j.amjoto.2012.06.009. PMID 22884485. 28. ^ Fischman SL (June 1994). "Oral ulcerations". Seminars in Dermatology. 13 (2): 74–7. PMID 8060829. 29. ^ Stewart MG, Selesnick S, eds. (January 1, 2011). Differential diagnosis in otolaryngology – head and neck surgery. New York: Thieme. ISBN 978-1-60406-279-3. 30. ^ Burruano F, Tortorici S (January–February 2000). "[Major aphthous stomatitis (Sutton's disease): etiopathogenesis, histological and clinical aspects]". Minerva Stomatologica. 49 (1–2): 41–50. PMID 10932907. 31. ^ Liu C, Tseng A, Yang S (2004). Chinese Herbal Medicine Modern Applications of Traditional Formulas. London: CRC Press. p. 533. ISBN 978-0-203-49389-2. 32. ^ Deardorff J (March 5, 2014). "Loss of canker sore toothpaste angers loyal users". Chicago Tribune. Retrieved April 12, 2014. 33. ^ Graedon J, Graedon T (2002). The people's pharmacy guide to home and herbal remedies. New York: St. Martin's Press. p. 122. ISBN 978-0-312-98139-6. ## External links[edit] Wikimedia Commons has media related to Aphthous ulcer. * Aphthous stomatitis at Curlie Classification D * ICD-10: K12.0 * ICD-9-CM: 528.2 * MeSH: D013281 External resources * MedlinePlus: 000998 * eMedicine: ent/700 derm/486 ped/2672 Wikiversity has learning resources about Oral ulceration * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Aphthous stomatitis

c0038363

wikipedia

https://en.wikipedia.org/wiki/Aphthous_stomatitis

{"gard": ["5834"], "mesh": ["D013281"], "umls": ["C0038363"], "wikidata": ["Q189956"]}

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600). Clinical Features Zhao et al. (2008) reported a 4-generation Chinese family in which 7 individuals had pure spastic paraplegia inherited in an autosomal dominant pattern. The average age at onset was 16.6 years, and all showed proximal muscle weakness of the lower extremities with hyperreflexia and spastic gait. The upper extremities showed normal tone with mild weakness of the small hand muscles. Four patients reported urinary urgency. There were no other neurologic signs, and cognition was normal. Mapping By genomewide linkage analysis of a Chinese family with autosomal dominant pure SPG, Zhao et al. (2008) identified an 18.88-cM region between markers D11S1324 and D11S1993 on chromosome 11p14.1-p11.2 (maximum 2-point lod score of 2.36 with several markers). INHERITANCE \- Autosomal dominant GENITOURINARY Bladder \- Urinary urgency MUSCLE, SOFT TISSUES \- Mild weakness of the small hand muscles NEUROLOGIC Central Nervous System \- Spastic paraplegia \- Spastic gait \- Lower limb muscle weakness, proximal \- Hyperreflexia MISCELLANEOUS \- Average age at onset 16.6 years \- One 4-generation Chinese family has been reported (as of 04/2010) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPASTIC PARAPLEGIA 41, AUTOSOMAL DOMINANT

c3888208

omim

https://www.omim.org/entry/613364

{"doid": ["0110793"], "omim": ["613364"], "orphanet": ["320355"], "synonyms": ["SPG41"]}

GRIN2B related syndrome is a genetic disorder that causes developmental delay and intellectual disability. Intellectual disability ranges from mild to severe. Other symptoms may include low muscle tone (hypotonia), seizures, behavior problems including autistic features, abnormal movements, a very small head (microcephaly), and developmental regression. Some children have brain malformations that can be seen in brain imaging exams. This disorder is caused by variations (mutations) in the GRIN2B gene, which plays a role in the transmission of signals in the brain. Inheritance is autosomal dominant. Treatment depends on the symptoms seen in each person. In some cases, the medication memantine was used with good results, but more studies are needed to know if it is broadly effective. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

GRIN2B related syndrome

c3151411

gard

https://rarediseases.info.nih.gov/diseases/12851/grin2b-related-syndrome

{"omim": ["613970"], "synonyms": ["GRIN2B-related intellectual disability", "Autosomal dominant intellectual disability-6", "GRIN2B encephalopathy", "Intellectual disability, autosomal dominant 6, with or without seizures", "GRIN2B-related neurodevelopmental disorder"]}

Barth syndrome is a metabolic and neuromuscular disorder, occurring almost exclusively in males, that primarily affects the heart, immune system, muscles, and growth. It typically becomes apparent during infancy or early childhood, but the age of onset, associated symptoms and findings, and disease course varies considerably among affected individuals. The main characteristics of the condition include abnormalities of heart and skeletal muscle (cardiomyopathy and skeletal myopathy); low levels of certain white blood cells called neutrophils that help to fight bacterial infections (neutropenia); and growth retardation, potentially leading to short stature. Other signs and symptoms may include increased levels of certain organic acids in the urine and blood (such as 3-methylglutaconic acid), and increased thickness of the left ventricle of the heart due to endocardial fibroelastosis, which can cause potential heart failure. Barth syndrome is caused by mutations in the TAZ gene and is inherited in an X-linked recessive manner. Treatment is directed toward the specific symptoms that are apparent in each individual. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Barth syndrome

c0574083

gard

https://rarediseases.info.nih.gov/diseases/5890/barth-syndrome

{"mesh": ["D056889"], "omim": ["302060"], "umls": ["C0574083"], "orphanet": ["111"], "synonyms": ["BTHS", "3-methylglutaconic aciduria type II", "MGA type II", "Cardioskeletal myopathy with neutropenia and abnormal mitochondria", "TAZ defect"]}

A very rare glial neoplasm of the central nervous system, most often with an intra-axial peripheral supratentorial location in one hemisphere of the frontal or parietal lobes and usually presenting in infants and young adults with symptoms of vomiting, loss of consciousness, epileptic seizures and headaches. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Astroblastoma

c0334587

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251679

{"gard": ["10635"], "mesh": ["D018302"], "umls": ["C0334587"], "icd-10": ["C71.9"]}

Timothy syndrome SpecialtyNeurology Timothy syndrome is a rare autosomal-dominant disorder characterized by physical malformations, as well as neurological and developmental defects, including heart QT-prolongation, heart arrhythmias, structural heart defects, syndactyly (webbing of fingers and toes), and autism spectrum disorders. Timothy syndrome often ends in early childhood death. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 History * 7 References * 8 External links ## Signs and symptoms[edit] The most striking sign of Timothy syndrome is the co-occurrence of both syndactyly (about 0.03% of births) and long QT syndrome (1% per year) in a single patient. Other common symptoms include cardiac arrhythmia (94%), heart malformations (59%), and autism or an autism spectrum disorder (80% who survive long enough for evaluation). Facial dysmorphologies such as flattened noses also occur in about half of patients. Children with this disorder have small teeth, which due to poor enamel coating, are prone to dental cavities and often require removal. The average age of death due to complications of these symptoms is 2.5 years.[1][2][3] Atypical Timothy syndrome has largely the same symptoms as the classical form. Differences in the atypical form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and atrial fibrillation. Patients with atypical Timothy syndrome also have more facial deformities, including protruding foreheads and tongues. Finally, one patient with atypical Timothy syndrome had a body development discrepancy wherein her upper body was normally developed (that of a 6-year-old) while her lower half resembled a 2- or 3-year-old.[4] Children with Timothy syndrome tend to be born via caesarean section due to fetal distress.[1][2] ## Pathophysiology[edit] Timothy syndrome has an autosomal-dominant pattern of inheritance. There are two recognized types of Timothy syndrome, classical (type-1) and atypical (type-2). They are both caused by mutations in CACNA1C, the gene encoding the calcium channel Cav1.2 α subunit. Timothy syndrome mutations in CACNA1C cause delayed channel closing, thus increased cellular excitability. Both classical and atypical Timothy syndromes are caused by mutations in CACNA1C. These mutations are in exon 8 (atypical form) and exon 8a (classical form), an alternatively spliced exon. Exon 8a is highly expressed in the heart, brain, gastrointestinal system, lungs, immune system, and smooth muscle. Exon 8 is also expressed in these regions and its level is roughly five-fold higher than exon 8a expression. One mutation is found in patients with classical Timothy syndrome, G406R, located just past the sixth membrane-spanning segment of domain 1 (D1S6). The conserved glycine at this position seems to be vital for proper voltage-dependent inactivation, as the mutant is lacking in this respect.[3] Atypical Timothy syndrome mutations are similar, one being the identical G406R mutation in the other splice form and the second mutation being G402S, located a few amino acids upstream. The effect of these mutations on channel function is identical to the G406R mutation in classical Timothy syndrome.[4] The lack of proper voltage-dependent inactivation in these mutants causes prolonged inward current and depolarization during cardiac action potentials. This leads to long QT syndrome and resultant arrhythmia. Because exon 8 has greater expression in the heart versus exon 8a, patients with atypical Timothy syndrome have worsened cardiac defects compared to those with the classical form. ## Diagnosis[edit] Syndactyly in a 2 1/2 year old girl with Timothy syndrome Syndactyly and other deformities are typically observed and diagnosed at birth. Long QT syndrome sometimes presents itself as a complication due to surgery to correct syndactyly. Other times, children collapse spontaneously while playing. In all cases, it is confirmed with ECG measurements. Sequencing of the CACNA1C gene further confirms the diagnosis. ## Treatment[edit] Surgery is typically used to correct structural heart defects and syndactyly. Propanolol or beta-adrenergic blockers are often prescribed, as well as insertion of a pacemaker to maintain proper heart rhythm. With the characterization of Timothy syndrome mutations indicating that they cause defects in calcium currents, calcium channel blockers may be effective as a therapeutic agent.[4] ## Prognosis[edit] The prognosis for patients diagnosed with Timothy syndrome is very poor. Of 17 children analyzed in one study, 10 died at an average age of 2.5 years. Of those that did survive, three were diagnosed with autism, one with an autism spectrum disorder, and the last had severe delays in language development.[3] One patient with atypical Timothy syndrome was largely normal with the exception of heart arrhythmia.[4] Likewise, the mother of two Timothy syndrome patients also carried the mutation, but lacked any obvious phenotype. In both of these cases, however, the lack of severity of the disorder was due to mosaicism. ## History[edit] Some of the abnormalities observed in Timothy syndrome were described in the 1990s. However, it was linked with calcium channel abnormalities in 2004, and the disorder was thence named "Timothy syndrome" in honor of Katherine W. Timothy, who was among the first to identify a case and performed much of the phenotypic analysis that revealed other abnormalities.[3] ## References[edit] 1. ^ a b Marks M, Whisler S, Clericuzio C, Keating M (1995). "A new form of long QT syndrome associated with syndactyly". J Am Coll Cardiol. 25 (1): 59–64. doi:10.1016/0735-1097(94)00318-K. PMID 7798527. 2. ^ a b Marks M, Trippel D, Keating M (1995). "Long QT syndrome associated with syndactyly identified in females". Am J Cardiol. 76 (10): 744–745. doi:10.1016/S0002-9149(99)80216-1. PMID 7572644. 3. ^ a b c d Splawski I, Timothy K, Sharpe L, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz P, Joseph R, Condouris K, Tager-Flusberg H, Priori S, Sanguinetti M, Keating M (2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. doi:10.1016/j.cell.2004.09.011. PMID 15454078. 4. ^ a b c d Splawski I, Timothy K, Decher N, Kumar P, Sachse F, Beggs A, Sanguinetti M, Keating M (2005). "Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations". Proc Natl Acad Sci USA. 102 (23): 8089–8096. Bibcode:2005PNAS..102.8089S. doi:10.1073/pnas.0502506102. PMC 1149428. PMID 15863612. ## External links[edit] Classification D * OMIM: 601005 * MeSH: C536962 C536962, C536962 * DiseasesDB: 34006 * GeneReview/NCBI/NIH/UW entry on Timothy 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 Diseases of ion channels Calcium channel Voltage-gated * CACNA1A * Familial hemiplegic migraine 1 * Episodic ataxia 2 * Spinocerebellar ataxia type-6 * CACNA1C * Timothy syndrome * Brugada syndrome 3 * Long QT syndrome 8 * CACNA1F * Ocular albinism 2 * CSNB2A * CACNA1S * Hypokalemic periodic paralysis 1 * Thyrotoxic periodic paralysis 1 * CACNB2 * Brugada syndrome 4 Ligand gated * RYR1 * Malignant hyperthermia * Central core disease * RYR2 * CPVT1 * ARVD2 Sodium channel Voltage-gated * SCN1A * Familial hemiplegic migraine 3 * GEFS+ 2 * Febrile seizure 3A * SCN1B * Brugada syndrome 6 * GEFS+ 1 * SCN4A * Hypokalemic periodic paralysis 2 * Hyperkalemic periodic paralysis * Paramyotonia congenita * Potassium-aggravated myotonia * SCN4B * Long QT syndrome 10 * SCN5A * Brugada syndrome 1 * Long QT syndrome 3 * SCN9A * Erythromelalgia * Febrile seizure 3B * Paroxysmal extreme pain disorder * Congenital insensitivity to pain Constitutively active * SCNN1B/SCNN1G * Liddle's syndrome * SCNN1A/SCNN1B/SCNN1G * Pseudohypoaldosteronism 1AR Potassium channel Voltage-gated * KCNA1 * Episodic ataxia 1 * KCNA5 * Familial atrial fibrillation 7 * KCNC3 * Spinocerebellar ataxia type-13 * KCNE1 * Jervell and Lange-Nielsen syndrome * Long QT syndrome 5 * KCNE2 * Long QT syndrome 6 * KCNE3 * Brugada syndrome 5 * KCNH2 * Short QT syndrome * KCNQ1 * Jervell and Lange-Nielsen syndrome * Romano–Ward syndrome * Short QT syndrome * Long QT syndrome 1 * Familial atrial fibrillation 3 * KCNQ2 * BFNS1 Inward-rectifier * KCNJ1 * Bartter syndrome 2 * KCNJ2 * Andersen–Tawil syndrome * Long QT syndrome 7 * Short QT syndrome * KCNJ11 * TNDM3 * KCNJ18 * Thyrotoxic periodic paralysis 2 Chloride channel * CFTR * Cystic fibrosis * Congenital absence of the vas deferens * CLCN1 * Thomsen disease * Myotonia congenita * CLCN5 * Dent's disease * CLCN7 * Osteopetrosis A2, B4 * BEST1 * Vitelliform macular dystrophy * CLCNKB * Bartter syndrome 3 TRP channel * TRPC6 * FSGS2 * TRPML1 * Mucolipidosis type IV Connexin * GJA1 * Oculodentodigital dysplasia * Hallermann–Streiff syndrome * Hypoplastic left heart syndrome * GJB1 * Charcot–Marie–Tooth disease X1 * GJB2 * Keratitis–ichthyosis–deafness syndrome * Ichthyosis hystrix * Bart–Pumphrey syndrome * Vohwinkel syndrome) * GJB3/GJB4 * Erythrokeratodermia variabilis * Progressive symmetric erythrokeratodermia * GJB6 * Clouston's hidrotic ectodermal dysplasia Porin * AQP2 * Nephrogenic diabetes insipidus 2 See also: ion channels *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Timothy syndrome

c1832916

wikipedia

https://en.wikipedia.org/wiki/Timothy_syndrome

{"gard": ["9294"], "mesh": ["C536962"], "umls": ["C1832916"], "orphanet": ["768", "65283"], "wikidata": ["Q3508705"]}

## Description The Ehlers-Danlos syndrome shows phenotypic and genetic heterogeneity; see 130000. Marked joint hyperextensibility without skeletal deformity dominates the clinical picture of hypermobility-type EDS. Skin manifestations are relatively inconspicuous. Differentiation from familial joint laxity (147900) is often uncertain. Clinical Features 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 serum deviations above population-based norms. Fourteen of 42 individuals with the classic form of EDS (see 130000) and 6 of 29 individuals with the hypermobile form 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. Castori et al. (2010) noted that there are more female than male patients with signs and symptoms of joint hypermobility. In a cohort of 38 well-characterized EDS hypermobility type index cases, 34 (89%) were female and 4 (11%) male. A positive family history was found for 9 probands, and among the affected relatives, 9 were female (69%) and 4 were male (31%), yielding a F:M sex ratio of 43 (84%): 8 (16%). Castori et al. (2010) postulated different mechanisms for the sex bias, including differential perception of muscle pain between men and women, greater joint stability in men, and hormonal changes in women. All of these biologic factors may work to explain the high gender bias in this disorder. Other Features Voermans et al. (2009) performed a cross-sectional study on the presence of neuromuscular symptoms among 40 patients with various forms of EDS. Ten patients each were analyzed with classic EDS (130000), vascular EDS (130050), hypermobility EDS, 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. Molecular Genetics Narcisi et al. (1994) reported a family in which multiple members with a connective tissue disorder answering to the description of either EDS III or familial joint instability syndrome (147900) had a mutation in the COL3A1 gene (G637S; 120180.0020). Abnormalities in type III collagen are characteristic of EDS IV (130050); no features of that disorder, such as thin skin, typical facial features, or vascular fragility, were found in affected members of the family. The disorder in this family is here classified as a nonvascular variant of EDS IV. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Mitral valve prolapse SKELETAL \- Joint hypermobility (large and small joints) \- Recurrent joint dislocations (shoulder, patella, temporomandibular joints) \- Osteoarthritis (onset 30-40 years) SKIN, NAILS, & HAIR Skin \- Soft skin \- Hyperextensible skin \- Sacral striae \- No scarring MISCELLANEOUS \- Joint laxity decreases with age \- One patient reported with COL3A1 mutation ( 120180.0020 ) MOLECULAR BASIS \- Caused by mutation in the tenascin XB gene (TNXB, 600985.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

EHLERS-DANLOS SYNDROME, HYPERMOBILITY TYPE

c0268337

omim

https://www.omim.org/entry/130020

{"doid": ["14757"], "mesh": ["C536196"], "omim": ["130020"], "orphanet": ["285"], "synonyms": ["Alternative titles", "EHLERS-DANLOS SYNDROME, TYPE III", "EDS III", "BENIGN HYPERMOBILITY SYNDROME"], "genereviews": ["NBK1279"]}

Cyclic vomiting syndrome is a disorder that causes recurrent episodes of nausea, vomiting, and tiredness (lethargy). This condition is diagnosed most often in young children, but it can affect people of any age. The episodes of nausea, vomiting, and lethargy last anywhere from an hour to 10 days. An affected person may vomit several times per hour, potentially leading to a dangerous loss of fluids (dehydration). Additional symptoms can include unusually pale skin (pallor), abdominal pain, diarrhea, headache, fever, and an increased sensitivity to light (photophobia) or to sound (phonophobia). In most affected people, the signs and symptoms of each attack are quite similar. These attacks can be debilitating, making it difficult for an affected person to go to work or school. Episodes of nausea, vomiting, and lethargy can occur regularly or apparently at random, or can be triggered by a variety of factors. The most common triggers are emotional excitement and infections. Other triggers can include periods without eating (fasting), temperature extremes, lack of sleep, overexertion, allergies, ingesting certain foods or alcohol, and menstruation. If the condition is not treated, episodes usually occur four to 12 times per year. Between attacks, vomiting is absent, and nausea is either absent or much reduced. However, many affected people experience other symptoms during and between episodes, including pain, lethargy, digestive disorders such as gastroesophageal reflux and irritable bowel syndrome, and fainting spells (syncope). People with cyclic vomiting syndrome are also more likely than people without the disorder to experience depression, anxiety, and panic disorder. It is unclear whether these health conditions are directly related to nausea and vomiting. Cyclic vomiting syndrome is often considered to be a variant of migraines, which are severe headaches often associated with pain, nausea, vomiting, and extreme sensitivity to light and sound. Cyclic vomiting syndrome is likely the same as or closely related to a condition called abdominal migraine, which is characterized by attacks of stomach pain and cramping. Attacks of nausea, vomiting, or abdominal pain in childhood may be replaced by migraine headaches as an affected person gets older. Many people with cyclic vomiting syndrome or abdominal migraine have a family history of migraines. Most people with cyclic vomiting syndrome have normal intelligence, although some affected people have developmental delay or intellectual disability. Autism spectrum disorder, which affects communication and social interaction, have also been associated with cyclic vomiting syndrome. Additionally, muscle weakness (myopathy) and seizures are possible. People with any of these additional features are said to have cyclic vomiting syndrome plus. ## Frequency The exact prevalence of cyclic vomiting syndrome is unknown; estimates range from 4 to 2,000 per 100,000 children. The condition is diagnosed less frequently in adults, although recent studies suggest that the condition may begin in adulthood as commonly as it begins in childhood. ## Causes Although the causes of cyclic vomiting syndrome have yet to be determined, researchers have proposed several factors that may contribute to the disorder. These factors include changes in brain function, hormonal abnormalities, and gastrointestinal problems. Many researchers believe that cyclic vomiting syndrome is a migraine-like condition, which suggests that it is related to changes in signaling between nerve cells (neurons) in certain areas of the brain. Many affected individuals have abnormalities of the autonomic nervous system, which controls involuntary body functions such as heart rate, blood pressure, and digestion. Based on these abnormalities, cyclic vomiting syndrome is often classified as a type of dysautonomia. Some cases of cyclic vomiting syndrome, particularly those that begin in childhood, may be related to changes in mitochondrial DNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). Several changes in mitochondrial DNA have been associated with cyclic vomiting syndrome. Some of these changes alter single DNA building blocks (nucleotides), whereas others rearrange larger segments of mitochondrial DNA. These changes likely impair the ability of mitochondria to produce energy. Researchers speculate that the impaired mitochondria may cause certain cells of the autonomic nervous system to malfunction, which could affect the digestive system. However, it remains unclear how changes in mitochondrial function could cause episodes of nausea, vomiting, and lethargy; abdominal pain; or migraines in people with this condition. ### Learn more about the chromosome associated with Cyclic vomiting syndrome * mitochondrial dna ## Inheritance Pattern In most cases of cyclic vomiting syndrome, affected people have no known history of the disorder in their family. However, many affected individuals have a family history of related conditions, such as migraines, irritable bowel syndrome, or depression, in their mothers and other maternal relatives. This family history suggests an inheritance pattern known as maternal inheritance or mitochondrial inheritance, which applies to genes contained in mtDNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children. Occasionally, people with cyclic vomiting syndrome have a family history of the disorder that does not follow maternal inheritance. In these cases, 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

Cyclic vomiting syndrome

c0152164

medlineplus

https://medlineplus.gov/genetics/condition/cyclic-vomiting-syndrome/

{"gard": ["6230"], "mesh": ["C536228"], "omim": ["500007"], "synonyms": []}

Hypermethioninemia is an excess of a particular protein building block (amino acid), called methionine, in the blood. This condition can occur when methionine is not broken down (metabolized) properly in the body. People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit intellectual disability and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage. Hypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula. ## Frequency Primary hypermethioninemia that is not caused by other disorders or excess methionine intake appears to be rare; only a small number of cases have been reported. The actual incidence is difficult to determine, however, since many individuals with hypermethioninemia have no symptoms. ## Causes Mutations in the AHCY, GNMT, and MAT1A genes cause hypermethioninemia. Inherited hypermethioninemia that is not associated with other metabolic disorders can be caused by shortages (deficiencies) in the enzymes that break down methionine. These enzymes are produced from the MAT1A, GNMT and AHCY genes. The reactions involved in metabolizing methionine help supply some of the amino acids needed for protein production. These reactions are also involved in transferring methyl groups, consisting of a carbon atom and three hydrogen atoms, from one molecule to another (transmethylation), which is important in many cellular processes. The MAT1A gene provides instructions for producing the enzyme methionine adenosyltransferase. This enzyme converts methionine into a compound called S-adenosylmethionine, also known as AdoMet or SAMe. The GNMT gene provides instructions for making the enzyme glycine N-methyltransferase. This enzyme starts the next step in the process, converting AdoMet to a compound called S-adenosyl homocysteine, or AdoHcy. The AHCY gene provides instructions for producing the enzyme S-adenosylhomocysteine hydrolase. This enzyme converts the AdoHcy into the compound homocysteine. Homocysteine may be converted back to methionine or into another amino acid, cysteine. A deficiency of any of these enzymes results in a buildup of methionine in the body, and may cause signs and symptoms related to hypermethioninemia. ### Learn more about the genes associated with Hypermethioninemia * AHCY * GNMT * MAT1A ## Inheritance Pattern Hypermethioninemia can have different inheritance patterns. This condition is usually inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition. Hypermethioninemia is occasionally inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In these cases, an affected person usually has one parent with the condition. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hypermethioninemia

c1847720

medlineplus

https://medlineplus.gov/genetics/condition/hypermethioninemia/

{"gard": ["10764", "13177", "8397"], "mesh": ["C564683"], "omim": ["606664", "613752", "250850"], "synonyms": []}

A rare, genetic disorder of urea cycle metabolism characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations in infancy, childhood or adulthood with chronic neurocognitive deficits, acute encephalopathy and/or coagulation defects or other chronic liver dysfunction. ## Epidemiology More than 100 cases have been reported in the literature to date. The prevalence in Northern Saskatchewan, Canada is especially high due to a founder effect and is estimated in this population at 1/1550 live births. ## Clinical description Age of onset can range from the neonatal period to adulthood and a wide phenotypic spectrum is noted. The neonatal presentation usually begins a few days after birth with lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. Onset of symptoms (ranging from mild to severe) in the majority of patients occurs in infancy, childhood and adulthood with episodes of confusion, forgetfulness, hyperammonemic coma, intellectual disability, developmental delay, spastic paraplegia, cerebellar ataxia, learning difficulties, unexplained seizures, liver dysfunction (rarely failure) and coagulopathy with factor VII-, IX- and X-deficiencies. An aversion to protein-rich foods before diagnosis is often reported. ## Etiology The syndrome is due to mutations in the SLC25A15 gene (13q14) encoding the mitochondrial ornithine transporter 1 (ORNT1) which plays a role in ornithine transport across the mitochondrial membrane and consecutively in mitochondrial protein synthesis, metabolism of arginine and lysine, and synthesis of polyamines. Mutations in this protein disrupt the urea cycle, resulting in hyperornithinemia, hyperammonemia and homocitrullinuria. Patients with a complete ORNT1 deficiency present in the neonatal period with severe hyperammonemia whereas those with a partial deficiency present later, between infancy to adulthood. ## Diagnostic methods Diagnosis is based on clinical findings and specific metabolic abnormalities. Laboratory tests usually reveal increased urinary excretion of orotic acid, homocitrulline and uracil, and a rise in the levels of plasma polyamines, ornithine, glutamine, alanine, and liver transaminases. Plasma ammonia levels are elevated episodically or postprandially and plasma ornithine is chronically elevated and is a hallmark of the disease as is the presence of homocitrulline in urine. Molecular genetic testing confirms diagnosis. ## Differential diagnosis Differential diagnosis includes other urea cycle disorders as well as lysinuric protein intolerance. Hyperinsulinism-hyperammonemia syndrome, pyruvate carboxylase deficiency and secondary causes of hyperammonemia should also be considered. ## Antenatal diagnosis Prenatal diagnosis is possible in families with a known disease causing mutation on both alleles. ## Genetic counseling The pattern of inheritance is autosomal recessive; where both parents are unaffected carriers, there is a 25% risk of inheriting the disease. ## Management and treatment Treatment involves the adherence to a low protein diet along with citrulline or arginine supplementation. In resistant cases, sodium benzoate and/or sodium or glycerol phenylbutyrate may be necessary for control of plasma ammonia levels. Patients should be monitored during times of stress (e.g. pregnancy, surgery, intercurrent infections) and when taking certain medications (i.e. corticosteroids) as they can trigger an episode of hyperammonemia. Hyperammonemic coma is treated in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration), ammonia scavenger therapy implemented, catabolism reversed (with glucose and lipid infusions) and special care taken to reduce the risk of neurological damage. ## Prognosis With early diagnosis and proper adherence to treatment protocol the prognosis is better than for most other urea cycle defects. However, patients remain at risk for metabolic decompensation throughout life and irreversible neurological complications can occur if treatment is delayed. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

c0268540

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=415

{"gard": ["2830"], "mesh": ["C538380"], "omim": ["238970"], "umls": ["C0268540"], "icd-10": ["E72.4"], "synonyms": ["HHH syndrome", "ORNT1 deficiency", "Ornithine carrier deficiency", "Ornithine translocase deficiency", "Triple H syndrome"]}

Arthus reaction SpecialtyEmergency medicine In immunology, the Arthus reaction (/ˌɑːrˈtjuːs/) is a type of local type III hypersensitivity reaction. Type III hypersensitivity reactions are immune complex-mediated, and involve the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium), and glomeruli. This reaction is usually encountered in experimental settings following the injection of antigens. ## Contents * 1 History * 2 Process * 3 See also * 4 References * 5 External links ## History[edit] The Arthus reaction was discovered by Nicolas Maurice Arthus in 1903.[1] Arthus repeatedly injected horse serum subcutaneously into rabbits. After four injections, he found that there was edema and that the serum was absorbed slowly. Further injections eventually led to gangrene.[citation needed] ## Process[edit] The Arthus reaction involves the in situ formation of antigen/antibody complexes after the intradermal injection of an antigen. If the animal/patient was previously sensitized (has circulating antibody), an Arthus reaction occurs. Typical of most mechanisms of the type III hypersensitivity, Arthus manifests as local vasculitis due to deposition of IgG-based immune complexes in dermal blood vessels. Activation of complement primarily results in cleavage of soluble complement proteins forming C5a and C3a, which activate recruitment of PMNs and local mast cell degranulation (requiring the binding of the immune complex onto FcγRIII[2]), resulting in an inflammatory response. Further aggregation of immune complex-related processes induce a local fibrinoid necrosis with ischemia-aggravating thrombosis in the tissue vessel walls.[3] The end result is a localized area of redness and induration that typically lasts a day or so. Arthus reactions have been infrequently reported after vaccinations containing diphtheria and tetanus toxoid. The CDC's description: > Arthus reactions (type III hypersensitivity reactions) are rarely reported after vaccination and can occur after tetanus toxoid–containing or diphtheria toxoid–containing vaccines. An Arthus reaction is a local vasculitis associated with deposition of immune complexes and activation of complement. Immune complexes form in the setting of high local concentration of vaccine antigens and high circulating antibody concentration. Arthus reactions are characterized by severe pain, swelling, induration, edema, hemorrhage, and occasionally by necrosis. These symptoms and signs usually occur 4–12 hours after vaccination. ACIP has recommended that persons who experienced an Arthus reaction after a dose of tetanus toxoid–containing vaccine should not receive Td more frequently than every 10 years, even for tetanus prophylaxis as part of wound management.[4] ## See also[edit] * Serum sickness ## References[edit] 1. ^ Injections répétées de serum du cheval chez le lapin, Comptes rendus des séances de la Société de biologie et de ses filiales, Paris, 55 (1903), 817–820. 2. ^ Parham, Peter (2009). "12". The Immune System (3rd ed.). New York, NY: Garland Science. p. 390. 3. ^ Kumar, Vinay; Abbas, A.K.; Fausto, N.; Aster, J.C. (2010). "6". In William Schmitt (ed.). Robbins and Cotran Pathologic Basis of Disease (8th ed.). Philadelphia: Saunders Elsevier. p. 205. 4. ^ Preventing Tetanus, Diphtheria, and Pertussis Among Adolescents: Use of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccines, K. R. Broder et al., MMWR Recommendations and Reports, March 24, 2006 / 55(RR03), 1–34, page 18. ## External links[edit] Classification D * ICD-10: T78.4 * ICD-9-CM: 995.21 * MeSH: D001183 * DiseasesDB: 33220 * v * t * e Consequences of external causes Temperature Elevated Hyperthermia Heat syncope Reduced Hypothermia Immersion foot syndromes Trench foot Tropical immersion foot Warm water immersion foot Chilblains Frostbite Aerosol burn Cold intolerance Acrocyanosis Erythrocyanosis crurum Radiation Radiation poisoning Radiation burn Chronic radiation keratosis Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy Radiation acne Radiation-induced cancer Radiation recall reaction Radiation-induced erythema multiforme Radiation-induced hypertrophic scar Radiation-induced keloid Radiation-induced morphea Air * Hypoxia/Asphyxia * Barotrauma * Aerosinusitis * Decompression sickness * High altitude * Altitude sickness * Chronic mountain sickness * Death zone * HAPE * HACE Food * Starvation Maltreatment * Physical abuse * Sexual abuse * Psychological abuse Travel * Motion sickness * Seasickness * Airsickness * Space adaptation syndrome Adverse effect * Hypersensitivity * Anaphylaxis * Angioedema * Allergy * Arthus reaction * Adverse drug reaction Other * Electrical injury * Drowning * Lightning injuries Ungrouped skin conditions resulting from physical factors * Dermatosis neglecta * Pinch mark * Pseudoverrucous papules and nodules * Sclerosing lymphangitis * Tropical anhidrotic asthenia * UV-sensitive syndrome environmental skin conditions Electrical burn frictional/traumatic/sports Black heel and palm Equestrian perniosis Jogger's nipple Pulling boat hands Runner's rump Surfer's knots Tennis toe Vibration white finger Weathering nodule of ear Wrestler's ear Coral cut Painful fat herniation Uranium dermatosis iv use Skin pop scar Skin track Slap mark Pseudoacanthosis nigricans Narcotic dermopathy * v * t * e Hypersensitivity and autoimmune diseases Type I/allergy/atopy (IgE) Foreign * Atopic eczema * Allergic urticaria * Allergic rhinitis (Hay fever) * Allergic asthma * Anaphylaxis * Food allergy * common allergies include: Milk * Egg * Peanut * Tree nut * Seafood * Soy * Wheat * Penicillin allergy Autoimmune * Eosinophilic esophagitis Type II/ADCC * * IgM * IgG Foreign * Hemolytic disease of the newborn Autoimmune Cytotoxic * Autoimmune hemolytic anemia * Immune thrombocytopenic purpura * Bullous pemphigoid * Pemphigus vulgaris * Rheumatic fever * Goodpasture syndrome * Guillain–Barré syndrome "Type V"/receptor * Graves' disease * Myasthenia gravis * Pernicious anemia Type III (Immune complex) Foreign * Henoch–Schönlein purpura * Hypersensitivity vasculitis * Reactive arthritis * Farmer's lung * Post-streptococcal glomerulonephritis * Serum sickness * Arthus reaction Autoimmune * Systemic lupus erythematosus * Subacute bacterial endocarditis * Rheumatoid arthritis Type IV/cell-mediated (T cells) Foreign * Allergic contact dermatitis * Mantoux test Autoimmune * Diabetes mellitus type 1 * Hashimoto's thyroiditis * Multiple sclerosis * Coeliac disease * Giant-cell arteritis * Postorgasmic illness syndrome * Reactive arthritis GVHD * Transfusion-associated graft versus host disease Unknown/ multiple Foreign * Hypersensitivity pneumonitis * Allergic bronchopulmonary aspergillosis * Transplant rejection * Latex allergy (I+IV) Autoimmune * Sjögren syndrome * Autoimmune hepatitis * Autoimmune polyendocrine syndrome * APS1 * APS2 * Autoimmune adrenalitis * Systemic autoimmune disease *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Arthus reaction

c0003907

wikipedia

https://en.wikipedia.org/wiki/Arthus_reaction

{"mesh": ["D001183"], "umls": ["C0003907"], "wikidata": ["Q712320"]}

Periventricular leukomalacia (PVL) is a brain injury disorder characterized by the death of the white matter of the brain due to softening of the brain tissue. It can affect fetuses or newborns, and premature babies are at the greatest risk of the disorder. PVL is caused by a lack of oxygen or blood flow to the area around the ventricles of the brain, which results in the death of brain tissue. Although babies with PVL generally have no apparent signs or symptoms of the disorder at delivery, they are at risk for motor disorders, cerebral palsy, delayed mental development, coordination problems, and vision and hearing impairments.There is no cure for PVL. Treatment is generally supportive. Prognosis is dependent on the extent of damage to the ventricles. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Periventricular leukomalacia

c0023529

gard

https://rarediseases.info.nih.gov/diseases/10285/periventricular-leukomalacia

{"mesh": ["D007969"], "umls": ["C0023529"], "orphanet": ["171676"], "synonyms": ["PVL"]}

A number sign (#) is used with this entry because Seckel syndrome-5 is caused by homozygous or compound heterozygous mutation in the CEP152 gene (613529) on chromosome 15q21. Description Seckel syndrome is an autosomal recessive disorder characterized by proportionate short stature, severe microcephaly, mental retardation, and a typical 'bird-head' facial appearance (summary by Kalay et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see 210600. Clinical Features Kalay et al. (2011) clinically evaluated 5 consanguineous families with Seckel syndrome originating from an isolated rural area in Turkey. The patients presented with microcephaly, sloping forehead, high nasal bridge, beaked nose, and retrognathia. Cranial magnetic resonance imaging in 2 patients showed simplified gyri. Inheritance Seckel syndrome-5 is an autosomal recessive disorder (Kalay et al., 2011). Mapping Using SNP array homozygosity mapping in 4 affected members of 3 Turkish families segregating Seckel syndrome, Kalay et al. (2011) obtained a lod score of 6.03 on chromosome 15q21.1-q21.2. Subsequent fine mapping confirmed shared homozygosity and a founder haplotype in a 3.4-Mb region between markers D15S123 and D15S1017. Molecular Genetics Kalay et al. (2011) sequenced the candidate gene CEP152 in affected members of 3 Turkish families segregating Seckel syndrome mapping to chromosome 15q21.1-q21.2 and identified a homozygous splice site mutation in intron 4 (613529.0003), which cosegregated with the founder haplotype. Through the use of an exome sequencing strategy, Kalay et al. (2011) identified the same mutation in an affected French individual of Turkish origin, who was born to consanguineous parents. By sequence analysis, Kalay et al. (2011) also identified compound heterozygous mutations in the CEP152 gene in affected Seckel syndrome patients of different ethnic origins (613529.0004-613529.0007). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly Face \- Sloping forehead \- Micrognathia \- Retrognathia Eyes \- Downslanting palpebral fissures (in some patients) \- Strabismus (in some patients) \- Blepharophimosis (in some patients) Nose \- Beaked nose \- High nasal bridge Mouth \- High-arched palate Teeth \- Hypodontia \- Oligodontia \- Enamel hypoplasia (in some patients) Selective tooth agenesis CHEST Ribs Sternum Clavicles & Scapulae \- 11 pairs of ribs (in some patients) GENITOURINARY External Genitalia (Female) \- Clitoromegaly (in some patients) Internal Genitalia (Male) \- Cryptorchidism (in some patients) SKELETAL \- Delayed bone age (in some patients) Hands \- Fifth finger clinodactyly Feet \- Pes planus (in some patients) NEUROLOGIC Central Nervous System \- Simplified gyri \- Mental retardation MOLECULAR BASIS \- Caused by mutation in the centrosomal protein, 152kD gene (CEP152, 613529.0003 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SECKEL SYNDROME 5

c0265202

omim

https://www.omim.org/entry/613823

{"doid": ["0070012"], "omim": ["613823"], "orphanet": ["808"]}

A number sign (#) is used with this entry because of evidence that familial hyperinsulinemic hypoglycemia-4 is (HHF4) is caused by homozygous mutation in the gene encoding 3-hydroxyacyl-CoA dehydrogenase (HADH; 601609) on chromosome 4q25. For a phenotypic description and discussion of genetic heterogeneity of familial hyperinsulinemic hypoglycemia, see HHF1 (256450). Clinical Features Gotlin and Silver (1970) reported a male infant who had profound hypoglycemia at birth, with abnormally high insulin/glucose ratios. Attempts to control his hypoglycemia with conventional dietary and drug management were only partially successful. At 10 months of age he had a prolonged hypoglycemic convulsion resulting in coma, at which time severe hyperinsulinism was confirmed. He underwent partial pancreatectomy; microscopically there was a marked decrease in the secretory granules of the beta cells and an absence of alpha cells. Vidnes (1976) was the first to document glucagon deficiency in a case of persistent hereditary neonatal hypoglycemia. Vidnes and Oyasaeter (1977) described an inbred Pakistani family in which 2 brothers and a sister appear to have had hypoglycemia due to isolated glucagon deficiency. Two of the 3 had died before the nature of the problem was identified. Treatment with glucagon replacement was successful. Molven et al. (2002) restudied the family described by Vidnes and Oyasaeter (1977). Another affected sib, a sister 19 years old at the time of the report, had hypoglycemia, but had been diagnosed with hyperinsulinism. Indeed, Molven et al. (2002) questioned the existence of congenital glucagon deficiency in this family. They concluded that the family had hereditary hyperinsulinism. Clayton et al. (2001) reported an Indian child who presented at age 4 months with a hypoglycemic convulsion. She continued to have frequent episodes of hypoketotic hypoglycemia associated with increased plasma insulin levels. Biochemical studies indicated increased blood acylcarnitine levels, suggesting a disorder of fatty acid oxidation. Molecular Genetics In a 4-month-old Indian girl with hyperinsulinemic hypoglycemia, Clayton et al. (2001) identified homozygosity for a mutation in the HADH gene (601609.0003); her apparently nonconsanguineous parents were heterozygous for the mutation. In 4 sibs with hyperinsulinemic hypoglycemia from a consanguineous Pakistani family originally reported by Vidnes and Oyasaeter (1977), Molven et al. (2004) identified homozygosity for a deletion in the HADH gene (601609.0004). The parents were heterozygous for the mutation. In 11 (10%) of 115 unrelated patients with diazoxide-responsive hyperinsulinemic hypoglycemia who were negative for mutation in the hyperinsulinemia-associated genes ABCC8 (600509), KCNJ11 (600937), GCK (138079), and HNF4A (600281), Flanagan et al. (2011) identified homozygous mutations in the HADH gene (see, e.g., 601609.0005 and 601609.0006). When DNA was available, carrier status was confirmed in the unaffected parents; none of the probands had an affected sib. Although screening tests were not complete in all patients, Flanagan et al. (2011) noted that none of them were reported to have abnormalities in plasma acylcarnitines or urine organic acids. In a Turkish proband with diazoxide-responsive hyperinsulinemic hypoglycemia mapping to chromosome 4q25, previously studied by Flanagan et al. (2011) and in whom no coding mutation in the HADH gene had been found but who showed a reduction in HADH activity in cultured skin fibroblasts, Flanagan et al. (2013) performed next-generation sequencing of the entire genomic region of HADH and identified homozygosity for a deep intronic splicing variant (636+471G-T; 601609.0007). Screening for the variant in an additional 56 consanguineous and/or Turkish diazoxide-responsive HHF probands revealed homozygosity for 636+471G-T in 8 more Turkish probands, including 2 patients previously studied by Flanagan et al. (2011). All 9 mutation-positive Turkish patients were also homozygous for an HADH SNP, 636+385A-G (rs732941), and 5 of the patients were known to share a 1.6-Mb haplotype at chromosome 4q25. Flanagan et al. (2013) stated that the 636+471G-T Turkish founder mutation was the most common HADH mutation in their cohort and accounted for 9 (32%) of 28 individuals with HADH mutations. INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Seizures, hypoglycemic \- Coma, hypoglycemic \- Mental retardation due to repeated episodes of hypoglycemia ENDOCRINE FEATURES \- Hyperinsulinemic hypoglycemia LABORATORY ABNORMALITIES \- Hypoglycemia \- Hyperinsulinemia \- Elevated blood spot hydroxybutyryl carnitine MISCELLANEOUS \- Genetic heterogeneity (see HHF1 256450 ) MOLECULAR BASIS \- Caused by mutation in the L-3-hydroxyacyl-CoA dehydrogenase gene (HADH, 601609.0003 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 4

c1291230

omim

https://www.omim.org/entry/609975

{"doid": ["0070215"], "mesh": ["C535310"], "omim": ["609975"], "orphanet": ["71212"], "genereviews": ["NBK1375"]}

## Clinical Features Neubauer et al. (2006) reported a 3-generation family from northern Germany in which 4 males had a disorder characterized by early-onset leukoencephalopathy associated with metaphyseal chondrodysplasia. Inheritance was consistent with an X-linked recessive pattern. The proband developed normally until age 2 to 3 years, when he developed slow gait and toe-walking. Broad knees and wrists were noted. In the following years, he developed a fine tremor and deteriorating vision. Examination at age 11 years showed spastic paraplegia, hyperreflexia with extensor plantar responses, action tremor, and an IQ of 65 to 70. He had a low nasal bridge, mild midface hypoplasia, and anteverted nares. A younger brother had a similar course. A 36-year-old maternal uncle developed spastic paraplegia, tremor, and thick knees at age 5 years. He also had horizontal nystagmus and almost complete loss of vision. He died at age 37 of aspiration pneumonia in a bilateral decorticate rigid state. An affected grandfather had a similar disease course and died at age 26 years. Brain MRI of the brothers and uncle showed homogeneous increased high signal intensities in the white matter. Plain radiographs showed areas of marked radiolucency in the distal metaphyses of the ulna and radius. Postmortem examination of the uncle showed cerebral atrophy, hypoplastic corpus callosum, thin optic nerves, and atrophic pyramidal tracts. Astrocytes were markedly increased. Bone mineralization was diffusely decreased. Neubauer et al. (2006) observed that the disorder in this family was slowly progressive and implicated demyelination. Mapping In the family reported by Neubauer et al. (2006), linkage analysis of the X chromosome identified a 14-cM candidate region on Xq25-q27 between DXS8093 and DXS1232. Two-point linkage analysis resulted in positive lod scores of 0.89 to 1.41, the latter of which was the maximum score obtainable for the family structure. The PLP1 gene (300401) and 23 other genes in the region were excluded. INHERITANCE \- X-linked recessive HEAD & NECK Face \- Mild midface hypoplasia Eyes \- Horizontal nystagmus \- Loss of vision Nose \- Low nasal bridge \- Anteverted nares SKELETAL \- Decreased bone mineralization Limbs \- Metaphyseal chondrodysplasia \- Broad knees \- Broad wrists NEUROLOGIC Central Nervous System \- Normal psychomotor development until age 2 to 3 years \- Mental retardation \- Abnormal gait \- Spastic paraplegia \- Fine tremor \- Hyperreflexia \- Extensor plantar responses \- Leukoencephalopathy \- White matter abnormalities \- Diffuse cerebral atrophy MISCELLANEOUS \- Onset in early childhood \- Slowly progressive ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

LEUKOENCEPHALOPATHY WITH METAPHYSEAL CHONDRODYSPLASIA

c1970840

omim

https://www.omim.org/entry/300660

{"mesh": ["C567065"], "omim": ["300660"], "orphanet": ["83629"]}

A pseudohallucination (from Ancient Greek: ψευδής (pseudḗs) "false, lying" + "hallucination") is an involuntary sensory experience vivid enough to be regarded as a hallucination, but considered by the person as subjective and unreal, unlike "true" hallucinations, which are considered real by patients with psychological disorders.[1] Unlike normal hallucinations, which occurs when one sees, hears, smells, tastes or feels something that is not there, with a compelling feeling or thought that it is real, pseudohallucinations are recognised by the person as unreal. In other words, it is a hallucination that is recognized as a hallucination, as opposed to a "normal" hallucination which would be perceived as real. The term "pseudohallucination" appears to have been coined by Friedrich Wilhelm Hagen.[2] Hagen published his 1868 book "Zur Theorie der Halluzination," to define them as "illusions or sensory errors".[2] The term "pseudohallucination" was then further explored by the Russian psychiatrist Victor Kandinsky (1849–1889).[2] In his work "On Pseudohallucinations" (Russian: "О псевдогаллюцинациях" [o psevdogalliutsinatsiakh]), he described his psychotic experience defining pseudohallucinations as "subjective perceptions similar to hallucinations, with respect to its character and vividness, but that differ from those because these do not have objective reality".[3][2] The term is not widely used in the psychiatric and medical fields, as it is considered ambiguous;[4] the term nonpsychotic hallucination is preferred.[5] Pseudohallucinations, then, are more likely to happen with a hallucinogenic drug. But "the current understanding of pseudohallucinations is mostly based on the work of Karl Jaspers".[6] A further distinction is sometimes made between pseudohallucinations and parahallucinations, the latter being a result of damage to the peripheral nervous system.[7] They are considered a possible symptom of conversion disorder in DSM-IV (2000).[8] In DSM-5 (2013), this definition has been removed.[2] Also, pseudohallucinations can occur in people with visual/hearing loss, with the typical such type being Charles Bonnet syndrome.[citation needed] ## See also[edit] * Anomalous experiences * Auditory hallucination * Illusion * Lucid dream * Phosphene ## References[edit] 1. ^ Lavretsky, H. (1998). "The Russian Concept of Schizophrenia: A Review of the Literature". Schizophrenia Bulletin. 24 (4): 537–557. doi:10.1093/oxfordjournals.schbul.a033348. ISSN 0586-7614. PMID 9853788. 2. ^ a b c d e Telles-Correia, Diogo; Moreira, Ana Lúcia; Gonçalves, João S. (2015). "Hallucinations and related concepts—their conceptual background". Frontiers in Psychology. 6: 991. doi:10.3389/fpsyg.2015.00991. ISSN 1664-1078. PMC 4515540. PMID 26283978. 3. ^ Kandinsky, V. (1885). Kritische und klinische Betrachtungen im Gebiete der Sinnestäuschungen. Berlin: Verlag von Friedlander and Sohn. p. 134 4. ^ Berrios, G. E.; Dening, T. R. (1996). "Pseudohallucinations: A conceptual history". Psychological Medicine. 26 (4): 753–63. doi:10.1017/S0033291700037776. PMID 8817710. 5. ^ van der Zwaard, Roy; Polak, Machiel A. (2001). "Pseudohallucinations: A pseudoconcept? A review of the validity of the concept, related to associate symptomatology". Comprehensive Psychiatry. 42 (1): 42–50. doi:10.1053/comp.2001.19752. PMID 11154715. 6. ^ Sanati, Abdi (2012). "Pseudohallucinations: a critical review" (PDF). Dialogues in Philosophy, Mental and Neuro Sciences. 5 (2): 42–47. 7. ^ El-Mallakh, Rif S.; Walker, Kristin L. (2010). "Hallucinations, pseudohallucinations, and parahallucinations". Psychiatry. 73 (1): 34–42. doi:10.1521/psyc.2010.73.1.34. PMID 20235616. 8. ^ First, Michael B.; Frances, Allen; Pincus, Harold Alan (2002). DSM-IV-TR Handbook of Differential Diagnosis. American Psychiatric Pub. p. 64. ## Bibliography[edit] * В. Х. Кандинский. О псевдогаллюцинациях (1890) (Victor Kandinsky On Pseudohallucinations) (in Russian) *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Pseudohallucination

c0233758

wikipedia

https://en.wikipedia.org/wiki/Pseudohallucination

{"umls": ["C0233758"], "icd-9": ["780.1"], "wikidata": ["Q2361468"]}

Infantile acropustulosis Other namesAcropustulosis of infancy[1]:483) SpecialtyDermatology Infantile acropustulosis is an intensely itchy vesicopustular eruption of the hands and feet.[2]:205 Involvement of scabies has been suggested.[3]infantile acropustulosis is characterized by itchy papules and vesicles that are similar to those found in scabies "mosquito like bites" but there is absence of the typical burrowing with S like burrows on the skin and can occur in small babies as opposed to scabies mostly found on children and young adults. ## See also[edit] * Acropustulosis * 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. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 3. ^ Mancini AJ, Frieden IJ, Paller AS (1998). "Infantile acropustulosis revisited: history of scabies and response to topical corticosteroids". Pediatr Dermatol. 15 (5): 337–41. doi:10.1046/j.1525-1470.1998.1998015337.x. PMID 9796580. ## External links[edit] Classification D External resources * eMedicine: article/909472 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

Infantile acropustulosis

c0406787

wikipedia

https://en.wikipedia.org/wiki/Infantile_acropustulosis

{"umls": ["C0406787"], "wikidata": ["Q6029033"]}

In the son of healthy, consanguineous Filipino parents, Marles and Chudley (1990) described congenital absence of the ulnars with oligodactyly and endocardial fibroelastosis. The baby showed hydrops fetalis and died soon after birth. Because of the presence of 2 major malformations and the parental consanguinity, Marles and Chudley (1990) suggested that this may represent a 'new' autosomal recessive malformation syndrome. Cardiac \- Endocardial fibroelastosis Limbs \- Absent ulnae \- Oligodactyly Misc \- Hydrops fetalis \- Neonatal death Inheritance \- ? Autosomal recessive ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ULNAR AGENESIS AND ENDOCARDIAL FIBROELASTOSIS

c1848649

omim

https://www.omim.org/entry/276822

{"mesh": ["C564756"], "omim": ["276822"]}

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: "Pseudoporphyria" – news · newspapers · books · scholar · JSTOR (December 2008) (Learn how and when to remove this template message) Pseudoporphyria Other namesPseudoporphyria cutanea tarda[1] Healing blisters on the hand of a woman using naproxen and tanning booth SpecialtyEndocrinology Pseudoporphyria is a bullous photosensitivity that clinically and histologically mimics porphyria cutanea tarda.[2]:524 The difference is that no abnormalities in urine or serum porphyrin is noted on laboratories. Pseudoporphyria has been reported in patients with chronic kidney failure treated with hemodialysis and in those with excessive exposure to ultraviolet A (UV-A) by tanning beds.[3] ## Contents * 1 Presentation * 1.1 Race * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 Frequency * 7 History * 8 References * 9 External links ## Presentation[edit] Pseudoporphyria is clinically characterized by increased skin fragility; erythema; and the appearance of tense bullae and erosions on sun-exposed skin, which are identical to those seen in patients with PCT. However, a clinical pearl that may prove helpful in differentiating between pseudoporphyria and PCT is that the classic features of hypertrichosis, hyperpigmentation, and sclerodermoid changes found with PCT are unusual with pseudoporphyria. A second clinical pattern of pseudoporphyria has a similar presentation to erythropoietic protoporphyria (EPP), an autosomal dominant porphyria resulting from a reduced activity of ferrochelatase.[citation needed] In contrast to PCT, EPP usually begins in childhood with a history of photosensitivity, often described as a burning sensation immediately after sunlight exposure. Clinically, EPP is characterized by erythema, edema, shallow scars, and waxy induration of the skin, particularly on the face. Pseudoporphyria that clinically mimics EPP has been described almost exclusively in children taking naproxen for juvenile rheumatoid arthritis. Naproxen-induced pseudoporphyria seems to have a dimorphic presentation with the PCT-like pattern more often seen in the adult population and the EPP-like pattern more commonly seen in children, although some overlap has been documented. ### Race[edit] Although pseudoporphyria has no predilection toward any one race, it has been shown that fair-skinned children who are highly prone to sunburn are more likely to develop naproxen-induced pseudoporphyria than those children with skin types III or higher. Wallace et al. demonstrated that even in the absence of a history of blistering, children with light skin and blue or green eyes are at an increased risk of developing shallow scars on the face while taking naproxen. ## Causes[edit] Pseudoporphyria can be induced by a wide range of medications, excessive UV-A exposure, and hemodialysis. One frequently reported drug is naproxen. A frequent source of UV-A exposure is tanning booths. As recognition of pseudoporphyria increases and the number of new medications expands, the list of etiologic agents associated with pseudoporphyria will most likely continue to grow. Agents associated with pseudoporphyria are as follows:[4] * Propionic acid derivatives (NSAIDs) - naproxen, diflunisal, ketoprofen, oxaprozin, mefenamic acid, rofecoxib * Ketone NSAID-nabumetone * Antibiotics \- nalidixic acid, tetracycline, oxytetracycline, ampicillin-sulbactam, cefepime, fluoroquinolones (M Poh, personal communication, June 1999) * Antifungals \- voriconazole * Diuretics \- furosemide, chlorthalidone, butamide, triamterene/hydrochlorothiazide * Antiarrhythmics \- amiodarone * Chemotherapy \- 5-fluorouracil * Immunosuppressants \- cyclosporine * Sulfones \- dapsone * Vitamins \- brewers' yeast, pyridoxine * Vitamin A derivatives - etretinate, isotretinoin * Muscle relaxants \- carisoprodol/aspirin * Nonsteroidal antiandrogens \- flutamide * Other - hemodialysis, excessive UV-A, cola, oral contraceptive pills (levonorgestrel and ethinylestradiol), narrowband UV-B phototherapy (rarely) ## Pathophysiology[edit] The precise pathophysiologic mechanism of pseudoporphyria is not fully understood. Some drugs, especially non steroidal anti-inflammatory drugs, can trigger pseudoporphyria in the presence of ultraviolet light. The pathophysiology of pseudoporphyria associated with hemodialysis has not been fully explained. Aluminum hydroxide has been implicated in hemodialysis-associated pseudoporphyria. Aluminum hydroxide is found in dialysis solution and has been shown to produce a porphyrialike disorder after long-term administration in rats. ## Diagnosis[edit] This section is empty. You can help by adding to it. (November 2017) ## Treatment[edit] Sun avoidance, avoidance of tanning booths, and usage of broad spectrum sunscreen that blocks both UVA and UVB. Identification and avoidance of the offending drug. ## Frequency[edit] Although fewer than 100 cases are documented in English language literature, pseudoporphyria is most likely underreported in the literature because it is only a symptom of some other affliction, e.g. side effect of medicine or symptom of liver problems. As the symptoms of pseudoporhphyra have other names, those symptoms are mentioned. The rarity of porphyria in modern times also makes the use of the term pseudoporphyria obscure. ## History[edit] A careful history is of utmost importance when the diagnosis of pseudoporphyria is being considered. A personal and family history of hepatitis, porphyria, or photosensitivity disorder must be sought. Although a genetic factor has not been considered in pseudoporphyria, one case of monozygotic twins developing pseudoporphyria after excessive UV-A exposure from long-term tanning bed use has been documented. The patient should be thoroughly questioned regarding any symptoms of connective tissue disorder, which may be the underlying pathology of the photosensitivity. Recent reports suggest that a connective tissue disorder may be a predisposing factor in patients using nonsteroidal anti-inflammatory drugs (NSAIDs) who develop pseudoporphyria. ## 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. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 3. ^ "Pseudoporphyria: Background, Pathophysiology, Etiology". February 2019. Cite journal requires `|journal=` (help) 4. ^ Suarez SM, Cohen PR, DeLeo VA. Bullous photosensitivity to naproxen: "pseudoporphyria". Arthritis Rheum. Jun 1990;33(6):903-8 ## External links[edit] Classification D * ICD-10: E80.2 (ILDS E80.250) * DiseasesDB: 31360 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Pseudoporphyria

c0521616

wikipedia

https://en.wikipedia.org/wiki/Pseudoporphyria

{"umls": ["C0521616"], "icd-10": ["E80.2"], "wikidata": ["Q2246688"]}

A number sign (#) is used with this entry because of evidence that peroxisomal fatty acyl-CoA reductase-1 disorder (PFCRD) is caused by homozygous or compound heterozygous mutation in the FAR1 gene (616107) on chromosome 11p15. Description Peroxisomal fatty acyl-CoA reductase-1 disorder is an autosomal recessive disorder characterized by onset in infancy of severely delayed psychomotor development, growth retardation with microcephaly, and seizures. Some patients may have congenital cataracts and develop spasticity later in childhood. Biochemical studies tend to show decreased plasmalogen, consistent with a peroxisomal defect. The disorder is reminiscent of rhizomelic chondrodysplasia punctata (see, e.g., RCDP1, 215100), although the characteristic skeletal abnormalities observed in RCDP are absent (Buchert et al., 2014). Nomenclature Baroy et al. (2015) considered the disorder described by Buchert et al. (2014) to be a form of rhizomelic chondrodysplasia punctata, which they called type 4 (RCDP4). Clinical Features Buchert et al. (2014) reported 3 patients from 2 families with a severe disorder comprising intellectual disability, growth retardation, and early-onset epilepsy. Two sibs, born of consanguineous Syrian parents, showed neonatal hypotonia, delayed psychomotor development, and onset of well-controlled seizures around age 13 months. At ages 5 and 3 years, both had significant microcephaly (-6.6 and -8.7 SD, respectively) and were small for their age. One sib had bilateral cataracts, developed spasticity of the upper and lower extremities, and showed a Dandy-Walker variant on brain imaging. One sib was reported to have mild dysmorphic facial features, including long philtrum, high-arched eyebrows, large ears, and flattened nasal root. The third patient, born of unrelated parents, had a complex medical and neurodevelopmental history. In infancy, he showed significant growth delay with microcephaly (-4 to -5 SD), nuclear cataracts, and generalized and complex seizures that were difficult to control. Dysmorphic facial features included hypertelorism, short nose, long and smooth philtrum, high-arched eyebrows, and thin upper lip. He later developed progressive spastic quadriparesis with contractures, had symmetric short stature, and never achieved independent walking or standing. At age 19 years, he was severely disabled and often drowsy. Brain imaging showed cerebellar atrophy with progressive multiple punctate white matter lesions throughout the cortical and subcortical regions. He had a coarse facial appearance with ptosis. None of the patients had rhizomelia or evidence of bone dysplasia. Inheritance The transmission pattern of peroxisomal fatty acyl-CoA reductase-1 disorder in the families reported by Buchert et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In 3 patients from 2 unrelated families with peroxisomal fatty acyl-CoA reductase-1 disorder, Buchert et al. (2014) identified biallelic mutations in the FAR1 gene (616107.0001-616107.0003). The mutations, which were found by exome sequencing, segregated with the disorder in the families. In vitro functional expression studies showed that all the mutations resulted in a complete loss of enzyme activity. Red blood cell plasmalogens of 1 patient were significantly decreased compared to controls, consistent with the functional studies. INHERITANCE \- Autosomal recessive GROWTH Other \- Growth retardation HEAD & NECK Head \- Microcephaly Face \- Dysmorphic facial features, mild \- Coarse facies \- Long philtrum Ears \- Large ears Eyes \- Cataracts \- High-arched eyebrows Nose \- Flattened nasal root Mouth \- Thin upper lip MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development, severe \- Mental retardation \- Spasticity \- Seizures \- Cerebellar atrophy (1 patient) \- Cerebral white matter lesions (1 patient) LABORATORY ABNORMALITIES \- Decreased plasmalogen MISCELLANEOUS \- Onset in early infancy \- Three patients from 2 families have been reported (last curated December 2014) MOLECULAR BASIS \- Caused by mutation in the fatty acyl CoA reductase 1 gene (FAR1, 616107.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

PEROXISOMAL FATTY ACYL-CoA REDUCTASE 1 DISORDER

c4015344

omim

https://www.omim.org/entry/616154

{"omim": ["616154"], "orphanet": ["438178"], "synonyms": ["Severe intellectual disability-epilepsy-cataract syndrome due to FAR1 deficiency", "Severe intellectual disability-epilepsy-cataract syndrome due to peroxisomal disorder"]}

A number sign (#) is used with this entry because mitochondrial DNA depletion syndrome-5 (MTDPS5) is caused by homozygous or compound heterozygous mutation in the beta subunit of the succinate-CoA ligase gene (SUCLA2; 603921) on chromosome 13q14. See MTDPS9 (245400) for a description of a similar disorder caused by mutation in the alpha subunit of the succinate-CoA ligase gene (SUCLG1; 611224). Description Mitochondrial DNA depletion syndrome-5 is an autosomal recessive disorder characterized by infantile onset of hypotonia, progressive neurologic deterioration, a hyperkinetic-dystonic movement disorder, external ophthalmoplegia, deafness, and variable renal tubular dysfunction. Laboratory studies often show mild methylmalonic aciduria (Carrozzo et al., 2007). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041). Clinical Features Elpeleg et al. (2005) reported a small Muslim pedigree with an autosomal recessive encephalomyopathy associated with mtDNA depletion. The proband showed irritability and inconsolable crying in early infancy. She had severely delayed psychomotor development with marked muscle hypotonia, impaired hearing, and generalized seizures. Brain MRI was suggestive of Leigh syndrome (256000). At age 7 years, she was severely retarded and had contractures of the knee and hip joints. An affected cousin had muscle hypotonia, lack of voluntary movements, bilateral hearing loss, generalized seizures, and severe psychomotor retardation. Liver and renal tests in both patients were normal. Urinary organic acid profiles were not reported. Ostergaard et al. (2007) reported 10 patients from the Faroe Islands with encephalomyopathic mtDNA depletion associated with mild methylmalonic aciduria. The clinical phenotype comprised infantile-onset hypotonia, muscle atrophy, hyperkinesias, severe hearing impairment, postnatal growth retardation, and lactic acidosis. Most patients had scoliosis or kyphosis, recurrent airway infections, and required tube feeding due to swallowing difficulties. Neuroimaging showed demyelination and central and cortical atrophy; some patients fulfilled the criteria for Leigh syndrome. Carrozzo et al. (2007) also reported 11 patients from 8 related families in the Faroe Islands with neonatal onset of encephalomyopathy. Ten of the patients were in the report of Ostergaard et al. (2007) (Chinnery, 2007). Affected patients had feeding problems since birth and showed failure to thrive. Other features included severe muscle hypotonia with progressive areflexia, profound motor developmental delay, and none learned to sit or stand without support. They had progressive neurologic deterioration from the age of 12 to 14 months, and developed a hyperkinetic-dystonic movement disorder with external ophthalmoplegia. All developed profound sensorineural deafness. One had seizures, 2 had polyneuropathy, 1 had mild cardiomyopathy, and 1 had renal tubular dysfunction. Six patients died as children due to infection. Brain MRI showed hyperintense lesions in the basal ganglia. Laboratory studies showed mild methylmalonic aciduria, methylglutaconic aciduria, increased urinary carnitine esters, increased lactic acid in blood and CSF, and combined deficiencies of mitochondrial respiratory chain enzymes. SUCLA2 activity and protein were decreased in patient muscle. Carrozzo et al. (2007) reported 3 additional patients from southern Italy with a similar phenotype, including infantile onset of hypotonia and severely delayed development associated with deafness and dystonic posturing. Jaberi et al. (2013) reported 2 Iranian cousins with early-onset encephalomyopathy. One was a 4-year-old girl with delayed motor milestones, failure to thrive due to poor feeding, severe hypotonia with an inability to walk, severe generalized dystonia, and hearing loss. The second child was a 10-year-old girl who first showed progressive problems in gait and dystonia around age 3 years. She also had hearing loss and severe bulbar dystonia. Brain MRI of both patients showed T2-weighted hyperintensities in the caudate and putamen. Laboratory studies in 1 patient showed increased lactate and succinylcarnitine, but methylmalonic acid levels were normal. Muscle tissue was not available for mtDNA analysis. Inheritance The transmission pattern of MTDPS5 in the family reported by Jaberi et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics Elpeleg et al. (2005) identified a homozygous mutation in the SUCLA2 gene (603921.0001) in 2 first cousins from a consanguineous Muslim family with encephalomyopathy and mitochondrial DNA depletion syndrome-5. Urinary organic acid profiles were not reported in the patients studied by Elpeleg et al. (2005). SUCLA2 encodes succinyl-CoA synthase, an enzyme in the Krebs cycle, that is also involved in the salvage pathway of deoxyribonucleotides during mtDNA synthesis. Elpeleg et al. (2005) hypothesized that mtDNA depletion was likely explained by decreased mitochondrial NDP kinase (NDPK; see 156491) activity, resulting from the inability of NDPK to form a complex with SUCLA2. In a total of 16 patients from the Faroe Islands with encephalomyopathic mitochondrial DNA depletion and mild methylmalonic aciduria, Ostergaard et al. (2007) and Carrozzo et al. (2007) independently identified a homozygous founder mutation in the SUCLA2 gene (603921.0002). Carrozzo et al. (2007) identified 2 additional SUCLA2 mutations (603921.0003; 603921.0004) in southern Italian patients with a similar disorder. In 2 Iranian cousins with encephalomyopathy, Jaberi et al. (2013) identified a homozygous mutation in the SUCLA2 gene (D251N; 603921.0005). The mutation was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder, and was not present in 200 ethnically matched control individuals. Molecular modeling suggested that the mutation may cause structural changes that affect protein function. Functional studies were not performed. Population Genetics Ostergaard et al. (2007) estimated the incidence of the encephalomyopathic form of mtDNA depletion syndrome with methylmalonic aciduria in the Faroe Islands to be 1 in 1,700. Carrozzo et al. (2007) estimated the carrier and disease frequencies in the Faroe Island population to be 2% and 1 in 2,500, respectively. INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Face \- Facial diplegia Ears \- Hearing loss, sensorineural Eyes \- Ophthalmoplegia \- Ptosis \- Strabismus RESPIRATORY \- Respiratory insufficiency due to muscle weakness ABDOMEN Gastrointestinal \- Poor feeding MUSCLE, SOFT TISSUES \- Hypotonia \- Muscle weakness \- Delayed motor skills \- Inability to walk \- Loss of ability to walk in early childhood \- Skeletal muscle tissue shows depletion of mitochondrial DNA (mtDNA) \- Decreased activities of mitochondrial-encoded respiratory chain complexes NEUROLOGIC Central Nervous System \- Encephalopathy, progressive \- Psychomotor delay, severe \- Mental retardation \- Dystonia \- Athetoid movements \- Hyperkinetic movements \- Spasticity \- Hyporeflexia \- Seizures \- Imaging shows signal abnormalities in basal ganglia \- Cerebral atrophy Peripheral Nervous System \- Peripheral neuropathy, axonal and demyelinating Behavioral Psychiatric Manifestations \- Crying, inconsolable \- Irritability METABOLIC FEATURES \- Lactic acidosis LABORATORY ABNORMALITIES \- Increased serum creatine kinase \- Increased serum and CSF lactate \- Methylmalonic aciduria, mild \- Methylglutaconic aciduria, mild \- Increased urinary carnitine esters \- Aminoaciduria, intermittent MISCELLANEOUS \- Onset in infancy \- Increased frequency in the Faroe Islands (carrier 1 in 25) MOLECULAR BASIS \- Caused by mutation in the succinate-CoA ligase ADP-forming beta-subunit gene (SUCLA2, 603921.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MITOCHONDRIAL DNA DEPLETION SYNDROME 5 (ENCEPHALOMYOPATHIC WITH OR WITHOUT METHYLMALONIC ACIDURIA)

c2749864

omim

https://www.omim.org/entry/612073

{"doid": ["0080124"], "omim": ["612073"], "orphanet": ["254803", "1933"], "synonyms": ["mtDNA depletion syndrome, encephalomyopathic form", "mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria", "MITOCHONDRIAL DNA DEPLETION SYNDROME, ENCEPHALOMYOPATHIC FORM, WITH OR WITHOUT METHYLMALONIC ACIDURIA, AUTOSOMAL RECESSIVE, SUCLA2-RELATED", "Alternative titles", "Mitochondrial encephalomyopathy-aminoacidopathy syndrome", "Booth-Haworth-Dilling syndrome"], "genereviews": ["NBK6803"]}

A number sign (#) is used with this entry because of evidence that hypotrichosis-13 (HYPT13) is caused by heterozygous mutation in the KRT71 gene (608245) on chromosome 12q13. One such family has been reported. For a discussion of genetic heterogeneity of hypotrichosis, see HYPT1 (605389). Clinical Features Fujimoto et al. (2012) reported a 3-generation Japanese family with woolly hair/hypotrichosis. The proband was a 5-year-old girl who had had tightly curled scalp hair since birth. The scalp hairs were short and stopped growing at a few inches, although there was no apparent hair shaft fragility; no follicular papules were present. The proband also showed reduced density of scalp hairs, eyebrows, and eyelashes. There were no dysmorphic features, and teeth, nails, and sweating were normal. Her father and paternal grandfather also had woolly hair and hypotrichosis; however, their symptoms gradually improved with age, resulting in only woolly hair with almost normal hair density. Under scanning electron microscopy, the proband's hair shafts frequently showed longitudinal grooves that were not seen in age-matched Japanese control hairs, suggesting abnormal hair growth. Molecular Genetics In a 3-generation Japanese family segregating autosomal dominant woolly hair/hypotrichosis, Fujimoto et al. (2012) sequenced 7 genes associated with nonsyndromic forms of woolly hair or autosomal dominant forms of hypotrichosis but identified no mutations. Subsequent analysis of 3 genes expressed in the inner root sheath revealed a heterozygous missense mutation in KRT71 (F141C; 608245.0001) that segregated with disease in the family and was not found in 200 Japanese controls. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Hair \- Tightly curled ('woolly') scalp hair \- Scalp hair stops growing at a few inches \- Hypotrichosis \- Reduced density of scalp hair \- Longitudinal grooves in hair shafts \- Reduced density of eyebrows \- Reduced density of eyelashes MISCELLANEOUS \- Symptoms improve with age, resulting in woolly hair with almost normal hair density \- Based on the report of 1 Japanese family (last curated July 2014) MOLECULAR BASIS \- Caused by mutation in the keratin-71 gene (KRT71, 608245.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

HYPOTRICHOSIS 13

c0343073

omim

https://www.omim.org/entry/615896

{"doid": ["0110710"], "omim": ["615896"], "orphanet": ["170"], "synonyms": ["Alternative titles", "HYPOTRICHOSIS WITH WOOLLY HAIR"]}

This article is about the replitilian disease. For other diseases, see Charcot disease. Spinal osteoarthropathy (also known as Charcot's disease) is a rare disease affecting reptiles (including snakes[1] and lizards) which causes abnormal bone growth on vertebrae, giving the reptile a lumpy appearance. The growth of animals with this disease is limited (a python may only grow 2 feet (61 cm) long), and their life spans are greatly shortened. The movement of reptiles with this ailment appears jittery and wooden, and the head movement will be greatly restricted. The condition worsens as the patient ages; the end result is a reptile fused together by its own bones. They are usually euthanized well before this stage, but in general these animals can live their short lives comfortably with little pain. Spinal osteoarthropathy can also occur in humans.[2][dead link] ## Contents * 1 Causes * 2 Housing * 3 Feeding * 4 Handling * 5 References * 6 External links ## Causes[edit] Fully-grown corn snake (two feet long) with spinal osteoarthropathy Spinal osteoarthropathy is genetic, carried by parents and passed onto their offspring. Another known cause of this disease is a vitamin B12 deficiency in the reptile, which can be treated by injecting its food with a vitamin supplement. ## Housing[edit] A reptile with spinal osteoarthropathy does not require a large vivarium. Like all vivaria it needs to be heated according to the particular reptile's needs, with a dark hiding area (e.g. a log or dark box), normal substrate and clean water for the reptile to access. It is advisable not to have anything too high for them to climb because the reptile's ability to hold onto branches (for example) is restricted; floor space is more important. It is best not to keep them with a tank-mate (especially a healthy one), since bullying may occur. ## Feeding[edit] Burmese python with spinal osteoarthropathy (note spinal bone growths) Reptiles with this condition are usually fed small rodents (e.g. mice) which are small, easy to swallow and easily injectable with vitamin supplements. Animals with this condition find it more difficult to eat (especially snakes, whose bony growths compromise their ability to manipulate food down their throat). ## Handling[edit] Handling may be painful and stressful because of their poor body movement and how the bones have grown. Due to the stress, handling should be kept to a minimum. ## References[edit] 1. ^ Spinal Osteoarthropathy in two Southern Copperheads 2. ^ Human Spinal osteoarthropathy ## External links[edit] * Review of the literature and report on two cases *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Spinal osteoarthropathy

None

wikipedia

https://en.wikipedia.org/wiki/Spinal_osteoarthropathy

{"wikidata": ["Q7577471"]}

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (MTDPS9) affects the brain, nervous system, and muscles. Symptoms are different from person to person. They may include muscle weakness, hearing loss, and difficulty feeding and breathing. Other symptoms may include severe low muscle tone, developmental delay, and cognitive impairment. Symptoms usually begin in early infancy and get worse over time, often leading to death in infancy. MTDPS9 is caused by genetic variants in the SUCLG1 gene (also known as the SUCLA1 gene) and is inherited in an autosomal recessive pattern. Diagnosis is based on the symptoms, clinical exam, imaging studies, and the removal of a small piece of muscle for examination (muscle biopsy). The diagnosis may also be confirmed by the results of genetic testing. Treatment is focused on managing the symptoms and providing support. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria

c2749864

gard

https://rarediseases.info.nih.gov/diseases/3681/mitochondrial-dna-depletion-syndrome-encephalomyopathic-form-with-methylmalonic-aciduria

{"omim": ["245400"], "umls": ["C2749864"], "synonyms": ["Mitochondrial encephalomyopathy aminoacidopathy", "Mitochondrial dna depletion syndrome, encephalomyopathic form with methylmalonic aciduria, autosomal recessive", "Booth-Haworth-Dilling syndrome", "mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria", "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria", "Mitochondrial DNA depletion syndrome 9"]}

Scalp–ear–nipple syndrome Other namesFinlay-Marks syndrome Scalp–ear–nipple syndrome is inherited in an autosomal dominant manner[1] Scalp–ear–nipple syndrome (also known as "Finlay–Marks syndrome") is a condition associated with aplasia cutis congenita.[2] ## Contents * 1 Presentation * 2 Genetics * 2.1 Inheritance * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 Etymology * 7 See also * 8 References * 9 External links ## Presentation[edit] The key affected features of this condition[3] are described in its name. Scalp: There are raised nodules over the posterior aspect of the scalp, covered by scarred non-hair bearing skin. Ears: The shape of the pinnae is abnormal, with the superior edge of the pinna being turned over more than usual. The size of the tragus, antitragus and lobule may be small. Nipples: The nipples are absent or rudimentary. The breasts may be small or virtually absent. Other features of the condition[4] include: Dental abnormalities: missing or widely spaced teeth[5] Syndactyly: toes or fingers may be partially joined proximally [3][4][5][6] Renal abnormalities: renal hypoplasia,[7][8] pyeloureteral duplication [9] Eye abnormalities: Cataract,[7] coloboma of the iris and asymmetric pupils.[4] ## Genetics[edit] Candidate genes were identified for the Finlay-Marks Syndrome by probing gene expression databases using simple descriptors of the main organs affected.[10] Scalp-Ear Nipple Syndrome is caused by potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations.[11] Evaluation of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.[11] ### Inheritance[edit] It is likely that this syndrome is inherited in an autosomal dominant fashion,[5][12] however there may be a recessive form with hypotonia and developmental delay.[13] ## Diagnosis[edit] This section is empty. You can help by adding to it. (May 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (May 2017) ## Epidemiology[edit] The original report was of a family in Cardiff, United Kingdom.[3] There are subsequent reports of patients from the USA,[4][12][14][15][16] France,[7][8][9] Australia,[5] UAE,[13] India[17] and from Cuba.[18] ## Etymology[edit] The syndrome was first described by Finlay and Marks as “An hereditary syndrome of lumpy scalp, odd ears and absent nipples”.[3] It was termed "The Finlay-Marks (S.E.N.) Syndrome" by Aase in 1987,[19] “the Finlay Syndrome” by Le Merrer in 1991,[8] the “Scalp-Ear-Nipple Syndrome” by Edwards in 1994,[5] and “Finlay-Marks Syndrome” by Plessis in 1991.[7] The OMIM number OMIM 181270 was assigned in 1987 by Victor A McKusick with the name “Scalp-Ear-Nipple Syndrome” and alternative names “Finlay-Marks Syndrome” and “SEN Syndrome”.[20] ## See also[edit] * Say syndrome * List of cutaneous conditions ## References[edit] 1. ^ RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Scalp ear nipple syndrome". www.orpha.net. Retrieved 24 August 2017. 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 892. ISBN 978-1-4160-2999-1. 3. ^ a b c d Finlay AY, Marks R (Oct 1978). "An hereditary syndrome of lumpy scalp, odd ears and rudimentary nipples". Br J Dermatol. 99 (4): 423–30. doi:10.1111/j.1365-2133.1978.tb06182.x. PMID 708615. S2CID 1373499. 4. ^ a b c d Sobreira NL, Brunoni D, Cernach MC, Perez AB. Finlay-Marks (SEN) syndrome: a sporadic case and the delineation of the syndrome. Am J Med Genet A 2006 Feb 1;140(3):300-2. 5. ^ a b c d e Edwards MJ, McDonald D, Moore P, Rae J (Apr 1994). "Scalp-ear-nipple syndrome: additional manifestations". Am J Med Genet. 50 (3): 247–50. doi:10.1002/ajmg.1320500307. PMID 8042668. 6. ^ Baris H, Tan WH, Kimonis VE (Apr 2005). "Hypothelia, syndactyly, and ear malformation--a variant of the scalp-ear-nipple syndrome?: Case report and review of the literature". Am J Med Genet A. 134A (2): 220–2. doi:10.1002/ajmg.a.30612. PMID 15712197. S2CID 25330094. Erratum in: Am J Med Genet A 2005 Jul 1;136(1):114-5. 7. ^ a b c d Plessis G, Le Treust M, Le Merrer M (Oct 1997). "Scalp defect, absence of nipples, ear anomalies, renal hypoplasia: another case of Finlay-Marks syndrome". Clin Genet. 52 (4): 231–4. doi:10.1111/j.1399-0004.1997.tb02553.x. PMID 9383029. S2CID 34423125. 8. ^ a b c Le Merrer M, Renier D, Briard ML (1991). "Scalp defect, nipples absence and ears abnormalities: an other case of Finlay syndrome". Genet Couns. 2 (4): 233–6. PMID 1799422. 9. ^ a b Picard C, Couderc S, Skojaei T, Salomon R, de Lonlay P, Le Merrer M, Munnich A, Lyonnet S, Amiel J (Aug 1999). "Scalp-ear-nipple (Finlay-Marks) syndrome: a familial case with renal involvement". Clin Genet. 56 (2): 170–2. doi:10.1034/j.1399-0004.1999.560216.x. PMID 10517259. S2CID 26396675. 10. ^ Van Steensel MA, Celli J, van Bokhoven JH, Brunner HG (Dec 1999). "Probing the gene expression database for candidate genes". Eur J Hum Genet. 7 (8): 910–9. doi:10.1038/sj.ejhg.5200405. PMID 10602367. 11. ^ a b Marneros AG, et al. (2013). "Mutations in KCTD1 Cause Scalp-Ear-Nipple Syndrome". The American Journal of Human Genetics. 92 (4): 621–6. doi:10.1016/j.ajhg.2013.03.002. PMC 3617379. PMID 23541344. 12. ^ a b Baris H, Tan WH, Hypothelia Kimonis VE (Jul 2005). "Am J Med Genet A 2005 Apr 15;134A(2) 220-2. Review. Erratum". Am J Med Genet A. 136 (1): 114–5. doi:10.1002/ajmg.a.30781. S2CID 85250132. 13. ^ a b Al-Gazali L, Nath R, Iram D, Al Malik H (Apr 2007). "Hypotonia, developmental delay and features of scalp-ear-nipple syndrome in an inbred Arab family". Clin Dysmorphol. 16 (2): 105–7. doi:10.1097/mcd.0b013e3280147217. PMID 17351354. S2CID 32112570. 14. ^ Steinberg RD, Ethington J, Esterly NB (Nov 1990). "Lumpy scalp syndrome". Int J Dermatol. 29 (9): 657–8. doi:10.1111/j.1365-4362.1990.tb02591.x. PMID 2272740. S2CID 43359312. 15. ^ Taniai H, Chen H, Ursin S (Jun 2004). "Finlay-Marks syndrome: another sporadic case and additional manifestations". Pediatr Int. 46 (3): 353–5. doi:10.1111/j.1442-200x.2004.01905.x. PMID 15151556. S2CID 12987593. 16. ^ Paik YS, Chang CW (Jun 2010). "Stahl ear deformity associated with Finlay-Marks syndrome". Ear Nose Throat J. 89 (6): 256–7. doi:10.1177/014556131008900606. PMID 20556735. 17. ^ Naik P, Kini P, Chopra D, Gupta Y (Jul 2012). "Finlay-Marks syndrome: report of two siblings and review of literature". Am J Med Genet A. 158A (7): 1696–701. doi:10.1002/ajmg.a.35389. PMID 22639454. S2CID 21388969. 18. ^ Morales-Perelta E, Andres V, Campillo Betancourt D (2014). "Scalp-ear-nipple syndrome: a case report". Case Rep Med. 2014: 785916. doi:10.1155/2014/785916. PMC 3934383. PMID 24660003. 19. ^ Aase JM (1987). "The Finlay-Marks (S.E.N.) Syndrome: report of a new case and review of the literature". Proceedings of the Greenwood Genetic Center. 7: 177–8. 20. ^ OMIM. Online Mendelian Inheritance in Man. http://www.omim.org/ Accessed 26 August 2012. ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 181270 * MeSH: C536623 * DiseasesDB: 33575 External resources * Orphanet: 2036 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Scalp–ear–nipple syndrome

c1867020

wikipedia

https://en.wikipedia.org/wiki/Scalp%E2%80%93ear%E2%80%93nipple_syndrome

{"gard": ["159"], "mesh": ["C536623"], "umls": ["C1867020"], "orphanet": ["2036"], "wikidata": ["Q7429841"]}

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-56 (MRD56) is caused by heterozygous mutation in the CLTC gene (118955) on chromosome 17q23. Clinical Features DeMari et al. (2016) reported a 3.5-year-old girl, conceived through in vitro fertilization, with global developmental delay, intellectual disability, absent language, hypotonia, and inability to walk. Her neonatal period was notable for hypoglycemia, apnea, bradycardia, hyperbilirubinemia, subdural hematoma, laryngomalacia, and feeding difficulties requiring admission to the NICU for a month. She also had hydrocephalus, hypothyroidism, and vitamin K-dependent clotting factor deficiency, and she developed a mediastinal ganglioneuroblastoma. Dysmorphic features included low-set ears, depressed nasal bridge, anteverted nares, and widely spaced and inverted nipples. She did not have seizures; brain imaging and EEG were normal. At age 3.5 years, she was socially alert and interactive and was making some developmental progress. Hamdan et al. (2017) reported 12 unrelated patients with MRD56. The patients ranged in age from 3 to 30 years. All had global developmental delay of varying degree and intellectual disability that ranged from borderline to severe. Most had hypotonia, delayed walking, poor fine motor skills, clumsiness, and poor or absent speech. Several patients were able to attend special schools, whereas a few patients had more significant disability, never achieving ambulation or speech. Several patients had nonspecific and variable dysmorphic features, such as upslanting palpebral fissures, long philtrum, thin upper lip, open mouth, high-arched palate, and prominent ears. Four patients had seizures with onset in the first years of life, and a fifth patient had 1 seizure at age 14 years without recurrence. Two patients had had pharmacoresistant epilepsy with a preponderance of myoclonic and generalized tonic-clonic seizures, whereas 2 had seizures that could be controlled. Other more variable features included ataxia, spasticity, paraparesis, acquired microcephaly, oral and motor apraxia, and behavioral abnormalities, such as impulsivity and attention deficits. Brain imaging was normal in most patients, but showed nonspecific abnormalities in others, including pontocerebellar atrophy, thin corpus callosum, delayed myelination, and abnormal T2-weighed signals. Molecular Genetics In a 3.5-year-old girl, conceived by in vitro fertilization, with MRD56, DeMari et al. (2016) identified a de novo heterozygous frameshift mutation in the CLTC gene (118955.0001). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated haploinsufficiency of CLTC as the pathogenetic mechanism. DeMari et al. (2016) noted that CLTC is highly expressed in the brain and plays a role in neuronal transmission by facilitating the recycling and/or release of vesicles at the presynaptic termini of neurons. In 12 unrelated patients with MRD56, Hamdan et al. (2017) identified de novo heterozygous missense mutations in the CLTC gene (see, e.g., 118955.0002-118955.0006). The mutations were found by whole-exome or whole-genome sequencing of several cohorts of patients with developmental delay and epilepsy. There were 5 truncating mutations, 2 small in-frame deletions, 1 splice site mutation, and 3 missense mutations, 1 of which was recurrent and found in 3 unrelated patients. Individuals with refractory epilepsy were found to carry variants in the first section of the clathrin light chain-binding domain, whereas truncating mutations affecting the C terminus tended to be associated with hypotonia, global developmental delay, and intellectual disability. Studies of patient cells and functional studies of the variants were not performed. Hamdan et al. (2017) noted that CLTC is involved in endocytosis, intracellular trafficking, and synaptic recycling. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly, acquired Face \- Dysmorphic features, nonspecific, variable (in some patients) \- Long philtrum Ears \- Prominent ears Eyes \- Upslanting palpebral fissures Mouth \- High-arched palate \- Open mouth \- Thin upper lip \- Oral apraxia MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Intellectual disability \- Seizures (in some patients) \- Ataxia \- Spasticity \- Paraparesis \- Brain abnormalities, nonspecific and variable (in some patients) Behavioral Psychiatric Manifestations \- Impulsivity \- Attention deficit MISCELLANEOUS \- Onset in infancy or first years of life \- Highly variable severity \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the clathrin heavy polypeptide gene (CLTC, 118955.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MENTAL RETARDATION, AUTOSOMAL DOMINANT 56

c4693389

omim

https://www.omim.org/entry/617854

{"doid": ["0080226"], "omim": ["617854"], "orphanet": ["178469", "442835"], "synonyms": ["Undetermined EOEE"]}

Typical hemolytic-uremic syndrome (typical HUS) is a thrombotic microangiopathy characterized by mechanical hemolytic anemia, thrombocytopenia, and renal dysfunction that is usually associated with prodromal enteritis caused by Shigella dysentriae type 1 or E. Coli. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Shiga toxin-associated hemolytic uremic syndrome

c1856143

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90038

{"omim": ["235400"], "icd-10": ["D58.8"], "synonyms": ["D+ HUS", "EHEC-HUS", "Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli", "Hemolytic uremic syndrome with diarrhea", "STEC-HUS", "Shiga-like toxin-associated HUS", "Stx-HUS", "Typical HUS", "Typical hemolytic uremic syndrome"]}

A number sign (#) is used with this entry because variation in the NPSR1 gene (608595) has been implicated in susceptibility to asthma-related traits linked to the 7p15-p14 region. Description Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing, and dyspnea; bronchial hyperresponsiveness (BHR) as assessed by methacholine challenge test; serum IgE levels; atopy; and atopic dermatitis (Laitinen et al., 2001; Illig and Wjst, 2002). For a general phenotypic description and a discussion of genetic heterogeneity of asthma, see 600807. Mapping Laitinen et al. (2001) conducted a genomewide scan for susceptibility loci in asthma in the population of the Kainuu province in eastern central Finland. The population of 100,000 represented the expansion from a population of 2,000 four hundred years ago. A twin family study had supported a strong genetic component for asthma in Finland (Laitinen et al., 1998). Laitinen et al. (2001) identified 2 regions of suggestive linkage and studied them further with higher-density mapping. They obtained evidence for linkage in a 20-cM region of 7p15-p14 for 3 phenotypes: asthma, a high level of IgE, and the combination of the phenotypes. The strongest linkage was seen for high serum IgE. They also observed linkage between this locus and asthma or atopy in 2 independent data sets. Polvi et al. (2002) used 4 highly polymorphic microsatellite markers spanning 169 kb across the TCRG locus (see 186970) on 7p15-p14 in linkage and association studies in 2 independent Finnish family sets segregating asthma-related traits. They found no strong association of TCRG with asthma or elevated IgE serum levels and concluded that TCRG was unlikely to be a major susceptibility gene in the 7p15-p14 region. Molecular Genetics To identify asthma susceptibility genes on chromosome 7p, Laitinen et al. (2004) adopted a hierarchical genotyping design. Laitinen et al. (2004) identified a 133-kb risk-conferring segment containing 2 genes. One of these genes encodes an orphan G protein-coupled receptor, which they called GPRA (NPSR1). (The other gene, AAA1 (608596), lies on the opposite DNA strand from GPRA.) GPRA expression was much higher in the ciliated cells of the respiratory epithelium from asthma patients compared with those from normal controls. Asthmatic smooth muscle stained strongly positive for GPRA isoform B, in contrast to the negative finding in controls. A higher level of GPRA expression was also found in mRNA from lungs of sensitized versus control mice after inhaled ovalbumin challenge. In 3 cohorts from Finland and Canada, SNP-tagged haplotypes were associated with high serum IgE or asthma. The murine ortholog of GPRA is upregulated in a mouse model of ovalbumin-induced inflammation. Laitinen et al. (2004) found that 5 microsatellite markers and 13 SNPs implicated a 47-kb haplotype pattern involving 10 markers between NM51 and SNP563704. They identified a coding polymorphism, SNP591694 (608595.0001), in the asthma susceptibility haplotype. Laitinen et al. (2004) concluded that their data implicate GPRA in the pathogenesis of atopy and asthma. Orsmark-Pietras et al. (2008) identified tenascin C (TNC; 187380) as a downstream target gene of NPS-NPSR1 signaling pathway in transfected HEK-293H cells and in a human lung epithelial cell line. Both the TNC and NPSR1 proteins showed increased expression in the bronchial epithelium of patients with asthma compared to controls. By genotyping SNPs within and 3-prime to the TNC gene in 3,113 Western European children with asthma-related disorders, Orsmark-Pietras et al. (2008) found significant associations between several SNPs and haplotypes in the TNC gene on chromosome 9q33 (ASRT8; 613207). Further analysis showed evidence of an epistatic interaction between TNC and NPSR1 variants. The TNC variant rs2104772 (L1677I), in combination with NPSR1 SNPs rs323922 and rs324384, showed significant interactions for atopic sensitization or doctor's diagnosis for asthma (p values ranging from 0.009 to 0.037). Bruce et al. (2009) presented evidence that SNPs in the NPSR1 gene may play a role in the observed protective effect of exposure to farm animals on childhood allergies. Timing of initiation of farm animal contact also appeared to be significant. These observations were strengthened by the finding that exposure to the endotoxin lipopolysaccharide upregulated NPSR1A levels in monocytes. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 2

c1837811

omim

https://www.omim.org/entry/608584

{"omim": ["608584"], "synonyms": ["Alternative titles", "ASRT2"]}

This article is about the contagious skin disease. For the change in state from liquid to gas, see Boiling. For other uses, see Boil (disambiguation). Boils Furuncle SpecialtyDermatology General surgery SymptomsPainful, small, rough skin growth Causesbacteria Ingrown hair A boil, also called a furuncle, is a deep folliculitis, infection of the hair follicle. It is most commonly caused by infection by the bacterium Staphylococcus aureus, resulting in a painful swollen area on the skin caused by an accumulation of pus and dead tissue.[1] Boils which are expanded are basically pus-filled nodules.[2][verification needed] Individual boils clustered together are called carbuncles.[3] Most human infections are caused by coagulase-positive S. aureus strains, notable for the bacteria's ability to produce coagulase, an enzyme that can clot blood. Almost any organ system can be infected by S. aureus. ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Causes * 2.1 Bacteria * 2.2 Family history * 2.3 Other * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Boils are bumpy, red, pus-filled lumps around a hair follicle that are tender, warm, and painful. They range from pea-sized to golf ball-sized. A yellow or white point at the center of the lump can be seen when the boil is ready to drain or discharge pus. In a severe infection, an individual may experience fever, swollen lymph nodes, and fatigue. A recurring boil is called chronic furunculosis.[1][4][5][6] Skin infections tend to be recurrent in many patients and often spread to other family members. Systemic factors that lower resistance commonly are detectable, including: diabetes, obesity, and hematologic disorders.[7] Boils can be caused by other skin conditions that cause the person to scratch and damage the skin. Boils may appear on the buttocks or near the anus, the back, the neck, the stomach, the chest, the arms or legs, or even in the ear canal.[8] Boils may also appear around the eye, where they are called styes.[9] A boil on the gum is called intraoral dental sinus, or more commonly, a gumboil. ### Complications[edit] The most common complications of boils are scarring and infection or abscess of the skin, spinal cord, brain, kidneys, or other organs. Infections may also spread to the bloodstream (bacteremia) and become life-threatening.[5][6] S. aureus strains first infect the skin and its structures (for example, sebaceous glands, hair follicles) or invade damaged skin (cuts, abrasions). Sometimes the infections are relatively limited (such as a stye, boil, furuncle, or carbuncle), but other times they may spread to other skin areas (causing cellulitis, folliculitis, or impetigo). Unfortunately, these bacteria can reach the bloodstream (bacteremia) and end up in many different body sites, causing infections (wound infections, abscesses, osteomyelitis, endocarditis, pneumonia)[10] that may severely harm or kill the infected person. S. aureus strains also produce enzymes and exotoxins that likely cause or increase the severity of certain diseases. Such diseases include food poisoning, septic shock, toxic shock syndrome, and scalded skin syndrome.[11] Almost any organ system can be infected by S. aureus. Squeezing or cutting boils in the danger triangle of the face can be particularly dangerous if done outside a medical setting, as blood vessels in this area drain into the brain and can carry serious infections there. When burst, a seemingly solid, whitish colored pus initially appears then the pus and some blood follows. ## Causes[edit] ### Bacteria[edit] Naturally the cause is bacteria such as staphylococci that are present on the skin. Bacterial colonisation begins in the hair follicles and can cause local cellulitis and inflammation.[1][5][6] Myiasis caused by the tumbu fly in Africa usually presents with cutaneous furuncles.[12] Risk factors for furunculosis include bacterial carriage in the nostrils, diabetes mellitus, obesity, lymphoproliferative neoplasms, malnutrition, and use of immunosuppressive drugs.[13] ### Family history[edit] People with recurrent boils are as well more likely to have a positive family history, take antibiotics, and to have been hospitalised, anemic, or diabetic; they are also more likely to have associated skin diseases and multiple lesions.[14] ### Other[edit] Other causes include poor immune system function such as from HIV/AIDS, diabetes, malnutrition, or alcoholism.[15] Poor hygiene and obesity have also been linked.[15] It may occur following antibiotic use due to the development of resistance to the antibiotics used.[16] An associated skin disease favors recurrence. This may be attributed to the persistent colonization of abnormal skin with S. aureus strains, such as is the case in persons with atopic dermatitis.[16] Boils which recur under the arm, breast or in the groin area may be associated with hidradenitis suppurativa (HS).[17] ## Diagnosis[edit] Diagnosis is made through clinical evaluation by a physician, which may include culturing of the lesion.[18] ## Treatment[edit] A boil may clear up on its own without bursting, but more often it will need to be opened and drained. This will usually happen spontaneously within two weeks. Regular application of a warm moist compress, both before and after a boil opens, can help speed healing. The area must be kept clean, hands washed after touching it, and any dressings disposed of carefully, in order to avoid spreading the bacteria. A doctor may cut open or "lance" a boil to allow it to drain, but squeezing or cutting should not be attempted at home, as this may further spread the infection. Antibiotic therapy may be recommended for large or recurrent boils or those that occur in sensitive areas (such as the groin, breasts, armpits, around or in the nostrils, or in the ear).[1][4][5][6] Antibiotics should not be used for longer than one month, with at least two months (preferably longer) between uses, otherwise it will lose its effectiveness.[19] If the patient has chronic (more than two years) boils, removal by plastic surgery may be indicated. Furuncles at risk of leading to serious complications should be incised and drained if antibiotics or steroid injections are not effective. These include furuncles that are unusually large, last longer than two weeks, or occur in the middle of the face or near the spine.[1][6] Fever and chills are signs of sepsis and indicate immediate treatment is needed.[20] Staphylococcus aureus has the ability to acquire antimicrobial resistance easily, making treatment difficult. Knowledge of the antimicrobial resistance of S. aureus is important in the selection of antimicrobials for treatment.[21] ## See also[edit] * Nodule (medicine) * Cutaneous condition ## References[edit] 1. ^ a b c d e MedlinePlus Encyclopedia: Furuncle 2. ^ "Causes and Cures of Skin". Healthguidance.org. Retrieved 26 July 2014. 3. ^ MedlinePlus Encyclopedia: Carbuncle 4. ^ a b Blume JE, Levine EG, Heymann WR (2003). "Bacterial diseases". In Bolognia JL, Jorizzo JL, Rapini RP (eds.). Dermatology. Mosby. p. 1126. ISBN 0-323-02409-2. 5. ^ a b c d Habif, TP (2004). "Furuncles and carbuncles". Clinical Dermatology: A Color Guide to Diagnosis and Therapy (4th ed.). Philadelphia PA: Mosby. 6. ^ a b c d e Wolf K; et al. (2005). "Section 22. Bacterial infections involving the skin". Fitzpatrick's Color Atlas & Synopsis of Clinical Dermatology (5th ed.). McGraw-Hill. 7. ^ Steele RW, Laner SA, Graves MH (February 1980). "Recurrent staphylococcal infection in families". Arch Dermatol. 116 (2): 189–90. doi:10.1001/archderm.1980.01640260065016. PMID 7356349. 8. ^ "Boils, Carbuncles and Furunculosis". Patient.info. Retrieved 26 July 2014. 9. ^ "Boils, Kidshealth". Retrieved 26 July 2014. 10. ^ Lina G, Piémont Y, Godail-Gamot F, Bes M, Peter MO, Gauduchon V, Vandenesch F, Etienne J (November 1999). "Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia". Clin Infect Dis. 29 (5): 1128–32. doi:10.1086/313461. PMID 10524952. 11. ^ "Staph Infection Causes, Symptoms, Treatment – Staph Infection Diagnosis". eMedicineHealth. 12. ^ Tamir J, Haik J, Schwartz E (2003). "Myiasis with Lund's fly (Cordylobia rodhaini) in travellers". J Travel Med. 10 (5): 293–95. doi:10.2310/7060.2003.2732. PMID 14531984. 13. ^ Scheinfeld NS (2007). "Furunculosis". Consultant. 47 (2). 14. ^ El-Gilany AH, Fathy H (January 2009). "Risk factors of recurrent furunculosis". Dermatol Online J. 15 (1): 16. PMID 19281721. 15. ^ a b Demos, M; McLeod, MP; Nouri, K (October 2012). "Recurrent furunculosis: a review of the literature". The British Journal of Dermatology. 167 (4): 725–32. doi:10.1111/j.1365-2133.2012.11151.x. PMID 22803835. 16. ^ a b Laube S, Farrell M (2002). "Bacterial skin infection in the elderly: diagnosis and treatment". Drugs & Aging. 19 (5): 331–42. doi:10.2165/00002512-200219050-00002. PMID 12093320. 17. ^ "What is this boil like abscess under your arm, breast or groin". The Hidradenitis Suppurativa Trust. Archived from the original on 29 September 2015. Retrieved 28 September 2015. 18. ^ "Furuncles and Carbuncles". Merck Manuals. August 2017. Retrieved 29 April 2018. 19. ^ Mayo Clinic Archived 15 August 2012 at the Wayback Machine 20. ^ "Archived copy". Archived from the original on 15 August 2012. Retrieved 14 August 2012.CS1 maint: archived copy as title (link) 21. ^ Nagaraju U, Bhat G, Kuruvila M, Pai GS, Babu RP (2004). "Methicillin-resistant staphylococcus aureus in community-acquired pyoderma". Int J Dermatol. 43 (6): 412–14. doi:10.1111/j.1365-4632.2004.02138.x. PMID 15186220. ## External links[edit] Classification D * ICD-10: L02 * ICD-9-CM: 680.9 * MeSH: D005667 * DiseasesDB: 29434 * SNOMED CT: 416675009 External resources * MedlinePlus: 001474 Wikimedia Commons has media related to Furuncles. * DermAtlas 1817374494 * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Bacterial skin disease Gram +ve Firmicutes * Staphylococcus * Staphylococcal scalded skin syndrome * Impetigo * Toxic shock syndrome * Streptococcus * Impetigo * Cutaneous group B streptococcal infection * Streptococcal intertrigo * Cutaneous Streptococcus iniae infection * Erysipelas / Chronic recurrent erysipelas * Scarlet fever * Corynebacterium * Erythrasma * Listeriosis * Clostridium * Gas gangrene * Dermatitis gangrenosa * Mycoplasma * Erysipeloid of Rosenbach Actinobacteria * Mycobacterium-related: Aquarium granuloma * Borderline lepromatous leprosy * Borderline leprosy * Borderline tuberculoid leprosy * Buruli ulcer * Erythema induratum * Histoid leprosy * Lepromatous leprosy * Leprosy * Lichen scrofulosorum * Lupus vulgaris * Miliary tuberculosis * Mycobacterium avium-intracellulare complex infection * Mycobacterium haemophilum infection * Mycobacterium kansasii infection * Papulonecrotic tuberculid * Primary inoculation tuberculosis * Rapid growing mycobacterium infection * Scrofuloderma * Tuberculosis cutis orificialis * Tuberculosis verrucosa cutis * Tuberculous cellulitis * Tuberculous gumma * Tuberculoid leprosy * Cutaneous actinomycosis * Nocardiosis * Cutaneous diphtheria infection * Arcanobacterium haemolyticum infection * Group JK corynebacterium sepsis Gram -ve Proteobacteria * α: Endemic typhus * Epidemic typhus * Scrub typhus * North Asian tick typhus * Queensland tick typhus * Flying squirrel typhus * Trench fever * Bacillary angiomatosis * African tick bite fever * American tick bite fever * Rickettsia aeschlimannii infection * Rickettsialpox * Rocky Mountain spotted fever * Human granulocytotropic anaplasmosis * Human monocytotropic ehrlichiosis * Flea-borne spotted fever * Japanese spotted fever * Mediterranean spotted fever * Flinders Island spotted fever * Verruga peruana * Brill–Zinsser disease * Brucellosis * Cat-scratch disease * Oroya fever * Ehrlichiosis ewingii infection * β: Gonococcemia/Gonorrhea/Primary gonococcal dermatitis * Melioidosis * Cutaneous Pasteurella hemolytica infection * Meningococcemia * Glanders * Chromobacteriosis infection * γ: Pasteurellosis * Tularemia * Vibrio vulnificus * Rhinoscleroma * Haemophilus influenzae cellulitis * Pseudomonal pyoderma / Pseudomonas hot-foot syndrome / Hot tub folliculitis / Ecthyma gangrenosum / Green nail syndrome * Q fever * Salmonellosis * Shigellosis * Plague * Granuloma inguinale * Chancroid * Aeromonas infection * ε: Helicobacter cellulitis Other * Syphilid * Syphilis * Chancre * Yaws * Pinta * Bejel * Chlamydia infection * Leptospirosis * Rat-bite fever * Lyme disease * Lymphogranuloma venereum Unspecified pathogen * Abscess * Periapical abscess * Boil/furuncle * Hospital furunculosis * Carbuncle * Cellulitis * Paronychia / Pyogenic paronychia * Perianal cellulitis * Acute lymphadenitis * Pilonidal cyst * Pyoderma * Folliculitis * Superficial pustular folliculitis * Sycosis vulgaris * Pimple * Ecthyma * Pitted keratolysis * Trichomycosis axillaris * Necrotizing fascitis * Gangrene * Chronic undermining burrowing ulcers * Fournier gangrene * Elephantiasis nostras * Blistering distal dactylitis * Botryomycosis * Malakoplakia * Gram-negative folliculitis * Gram-negative toe web infection * Pyomyositis * Blastomycosis-like pyoderma * Bullous impetigo * Chronic lymphangitis * Recurrent toxin-mediated perineal erythema * Tick-borne lymphadenopathy * Tropical ulcer *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Boil

c0242301

wikipedia

https://en.wikipedia.org/wiki/Boil

{"mesh": ["D005667"], "icd-9": ["680.9"], "icd-10": ["L02"], "wikidata": ["Q193918"]}

A number sign (#) is used with this entry because of evidence that retinal dystrophy and iris coloboma with or without congenital cataract (RDICC) is caused by heterozygous mutation in the MIR204 gene (610942) on chromosome 9q21. One such family has been reported. Clinical Features Conte et al. (2015) reported a 5-generation British family segregating autosomal dominant nonsyndromic retinal dystrophy with iris coloboma. The proband was an 18-year-old male who was diagnosed with retinal dystrophy and bilateral iris coloboma in early childhood. Examination revealed reduced visual acuity (less than 20/100 bilaterally), significantly reduced color vision, and bilateral iris colobomata with iridolenticular adhesions. Funduscopy showed scattered mottling of the retinal pigment epithelium with retinal atrophy and attenuation of the retinal vasculature. Optical coherence tomography was consistent with severe photoreceptor loss. Electroretinography (ERG) revealed bilaterally extinguished responses to all conditions except a minimal residual light-adapted 30-Hz flicker response; the authors noted that an ERG 4 years earlier had shown less-attenuated light-adapted responses. The proband's 42-year-old mother was diagnosed in infancy with bilateral iris colobomata and progressive retinopathy. She underwent bilateral cataract surgery at 30 years of age, and was registered as blind. Examination showed hand movement vision in the right eye and no light perception in the left eye. Four additional family members were registered blind, including the proband's maternal grandmother and maternal great-uncle; all had bilateral iris coloboma and a slowly progressive retinal dystrophy leading to marked loss of vision by late childhood or early adult life. The maternal great-uncle also had congenital cataracts and underwent surgery at 7 years of age. Mapping In a 5-generation British family segregating autosomal dominant nonsyndromic retinal dystrophy with iris coloboma, Conte et al. (2015) performed linkage analysis and identified 4 regions over 5 Mb with lod scores between -2 and 1.81. Molecular Genetics In a 5-generation British family segregating autosomal dominant nonsyndromic retinal dystrophy and iris coloboma with or without congenital cataract, Conte et al. (2015) performed exome sequencing to detect possible causal variants within potential linked regions, and identified a point mutation in the MIR204 gene that was present in the 6 affected family members tested. The mutation was not found in 2 unaffected family members or in the Exome Variant Server or 1000 Genomes Project databases. Screening of the MIR204 gene in an additional 21 cases of retinal dystrophy with microphthalmia and coloboma, as well as in a cohort of 457 patients with isolated microphthalmia/anophthalmia and coloboma and 672 patients with autosomal dominant retinal degeneration, did not reveal any mutations. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Decreased visual acuity \- Decreased color vision \- Iris colobomata, bilateral \- Iridolenticular adhesions \- Mottling of retinal pigment epithelium \- Retinal atrophy \- Attenuation of retinal vasculature \- Severe photoreceptor loss on optical coherence tomography \- Extinguished responses to almost all stimuli on electroretinography \- Congenital cataract (in some patients) MISCELLANEOUS \- Based on report of one 5-generation family (last curated December 2015) MOLECULAR BASIS \- Caused by mutation in the micro RNA-204 gene (MIR204, 615147.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

RETINAL DYSTROPHY AND IRIS COLOBOMA WITH OR WITHOUT CONGENITAL CATARACT

c4225233

omim

https://www.omim.org/entry/616722

{"omim": ["616722"], "orphanet": ["488197"], "synonyms": []}

A rare, systemic amyloidosis characterized by slowly progressive renal disease presenting with proteinuria, hypertension and decreased glomerular filtration rate leading to progressive renal failure. Histology reveals amyloid deposits of leukocyte chemotactic factor-2 protein in the renal cortical interstitium, tubular basement membranes, glomeruli and the vessel walls. Extra-renal deposits can be seen in the liver, lungs, spleen and adrenal glands. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ALECT2 amyloidosis

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=439224

{"icd-10": ["E85.8"], "synonyms": ["Leukocyte chemotactic factor-2 amyloidosis"]}

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: "Pregnancy over age 50" – news · newspapers · books · scholar · JSTOR (April 2018) Italian singer Gianna Nannini was 56 years old when she gave birth in 2010 Pregnancy over the age of 50 has, over recent years, become possible for more women, and more easily achieved for many, due to recent advances in assisted reproductive technology, in particular egg donation. Typically, a woman's fecundity ends with menopause, which, by definition, is 12 consecutive months without having had any menstrual flow at all. During perimenopause, the menstrual cycle and the periods become irregular and eventually stop altogether, but even when periods are still regular, the egg quality of women in their forties is lower than in younger women, making the likelihood of conceiving a healthy baby also reduced, particularly after age 42.[1] The female biological clock can vary greatly from woman to woman. A woman's individual level of fertility can be tested through a variety of methods.[2] Men also experience a decline in fertility as they age. Male fertility drops gradually and steadily; the average time to pregnancy if both partners are under 25 is just over 4.5 months but nearly two years if a man is over 40 (and the woman is under 25).[3] The risk of genetic defects is greatly increased due to the paternal age effect. Children with fathers aged 40 or older are more than five times as likely to have an autism spectrum disorder than children fathered by men aged under 30.[4] Researchers estimate that compared to a male fathering a child in his early 20s, there is double the chance of the child getting schizophrenia when the father is age 40, and triple the risk of schizophrenia when the father is age 50 (though, for most people this means the risk goes from approximately 1 in 121 when a man is 29, to 1 in 47 when a man is age 50 to 54).[5] The volume and fecundity of a man's semen quality and sperm motility (the ability of sperm to move towards an egg) decrease continually between the ages of 20 and 80.[4] The incidence of dwarfism[6] and miscarriage also increases as men age.[4][7] In the United States, between 1997 and 1999, 539 births were reported among mothers over age 50 (four per 100,000 births), with 194 being over 55.[8] The oldest recorded mother to date to conceive was 74 years, and the youngest mother was 5 years old. According to statistics from the Human Fertilisation and Embryology Authority, in the UK more than 20 babies are born to women over age 50 per year through in-vitro fertilization with the use of donor oocytes (eggs).[9] Maria del Carmen Bousada de Lara is the oldest verified mother; she was aged 66 years 358 days when she gave birth to twins; she was 130 days older than Adriana Iliescu, who gave birth in 2005 to a baby girl. In both cases the children were conceived through IVF with donor eggs.[10] The oldest verified mother to conceive naturally (listed currently as of 26 January 2017[update] in the Guinness Records[11]) is Dawn Brooke (Guernsey); she conceived a son at the age of 59 years in 1997.[12] Erramatti Mangamma currently holds the record for being the oldest living mother at the age of 74 after conceiving through the process of in-vitro fertilisation via caesarean in Guntur town of Hyderabad. She delivered twin baby girls. In fact, she also became the oldest mother to give birth to twins.[13] The previous record for being the oldest living mother was held by Mrs Daljinder Kaur Gill from Amritsar, Punjab, India who gave birth to a baby boy in her 70s, after 46 years of marriage. She took treatment at a Fertility Clinic for 2 years after which she conceived with IVF. ## Contents * 1 Medical considerations * 2 Cases of pregnancy over age 50 * 3 Debate * 4 See also * 5 References ## Medical considerations[edit] The risk of pregnancy complications increases as the mother's age increases. Risks associated with childbearing over the age of 50 include an increased incidence of gestational diabetes, hypertension, delivery by caesarean section, miscarriage, preeclampsia, and placenta previa.[8][14][unreliable medical source?] In comparison to mothers between 20 and 29 years of age, mothers over 50 are at almost three times the risk of low birth weight, premature birth, and extremely premature birth; their risk of extremely low birth weight, small size for gestational age, and fetal mortality was almost double.[15] ## Cases of pregnancy over age 50[edit] Age of mother Date Mother Father Nature of conception Country Notes 50 years 1865 Ann Barlow Unidentified Mitchell (her husband) Natural conception United Kingdom According to family records - Gave birth to Mary Mitchell at the age of 50 in 1865.[16] 50 years 1847 Christina Potts Moore William Moore (her husband) Natural conception United States According to family records - Gave birth to Samuel Hensell Moore at the age of 50 in 1847.[citation needed] 50 years 1858 Catherine Elizabeth Rowe Dibble Isaac Dibble, her husband Natural conception United States According to birth certificates, Catherine Elizabeth Rowe Dibble, the daughter of German Andrew Raue, gave birth to Julia Rowe at age 50, in Greensburg, PA.[citation needed] 50 years 1960 Mrs. L. Her husband Natural conception USSR The 'Book of Records of Ukraine. Man and Society. In the world of science and technology' by Matsenko G.O., reports, at page 18, the case of Mrs. L., a resident of Pidvolochysk, Ternopil oblast, south-east of the country, happy to have had a baby at age 50.[17] 50 years July 1996 Judy Bershak David Cook, her 31-year-old husband, General Attorney Assistant of California IVF with oocytes donation United States Judy Bershak of Los Angeles, California, gave birth to her first child, daughter Sarah, in 1996 at the age of 50. Bershak got married at the age of 44, and after failing in conceiving naturally and adopting, she went through IVF treatment with oocyte donation and became pregnant after first attempt.[18] 50 years February 1997 Cheryl Fillippini Robert Fillippini, her 49-year-old husband IVF United States Cheryl Fillippini of Lompoc, California, gave birth to quadruplets, three girls, Rebecca, Amanda, and Sydney, and a boy, Robert, on February 20, 1997, by Caesarean section, in Santa Barbara, at the age of 50, after IVF treatment. Fillippini and her husband had 10 children altogether from their previous marriages, but wanted to have a child together.[19] 50 years April 2001 Tsuya Otake Hisatoshi Shiraishi, her husband Natural conception United States Tsuya Otake gave birth to a daughter, Ashima Shiraishi, who would become a world class rock climber.[20] 50 years May 2010 Heather Elizabeth Parisi Umberto Maria Anzolin, her 42-year-old third husband, contractor Natural conception Italy Heather Elizabeth Parisi, Italian-American singer and actress, already mother of two daughters of her previous unions, Rebecca Jewel Manenti, 16, and Jacqueline Lune di Giacomo, 10, gave birth on May 22, 2010, in Vicenza, Italy, to twins, a girl and a boy, Elizabeth Jaden and Dylan Maria, naturally conceived with her 42-year-old third husband contractor, Umberto Maria Anzolin.[21] 50 years June 2010 Svetlana Krupenik Her 62-year-old husband IVF Ukraine Svetlana Krupenik gave birth to a girl in Kyiv, Ukraine, in June 2010, at the age of 50, after IVF treatment. She and her 62-year-old husband were trying to conceive for 30 years.[22] 50 years August 2010 Aggie Ezekiel Wilson Brown, her son-in-law (gestational surrogate) Post-menopausal IVF Canada Aggie Ezekiel of Edmonton, Alberta, already a mother of three adult daughters with her husband Johnny Ezekiel, gave birth in August 2010 to her own granddaughter Clare at the age of 50 years and 9 months. She chose to act as a surrogate mother for her daughter, Tinna (age 28), who happened to be born without a uterus and had one of her ovaries removed at the age of 21. Aggie had been premenopausal for two years and could not produce the child herself, so she had to undergo fertilization hormone to boost her menstrual cycles so that the matrix can accommodate two to seven eggs retrieved by her daughter and fertilized in vitro with the sperm from her daughter's partner, Wilson Brown. One of the two implanted embryos happened to appear in a lateral position in Aggie's uterus as a result of which she delivered her granddaughter through caesarean section. The girl weighed 8.69 lb (3.94 kg) and did not breathe on her own. As a result, she was placed on an oxygen machine for an hour to clear her lungs.[23] Tinna and Wilson separated shortly before the birth of their daughter. The young biological mother decided to bring the child to Fort McMurray, 330 km north-east of Edmonton with her husband, Sean Noseworthy. 50 years January 2011 Seiko Noda Her partner IVF Japan Japanese politician Seiko Noda gave birth to a boy in Tokyo conceived through in vitro fertilization. After years of unsuccessful fertility treatments and several miscarriages, Noda decided to receive assistance from an American egg donor.[24] 50 years June 2011 Anthea Nicholas Peter Byrnes, her 54-year-old husband Natural conception Australia Anthea Nicholas, from Gold Coast, Queensland, Australia, is believed to be the oldest primigravida having naturally conceived in Australia. Anthea and her husband Peter were told in 2006 that they could not have children. As a result of a medical concern, in 2010, Peter researched and developed a personal diet and health regime which enabled him to return to perfect health and subsequently corrected a sperm imperfection, which, within months of his recovery, resulted in the completely unexpected pregnancy of Anthea, while she presented then clinical signs of menopause. Anthea gave birth to her son, Nicholas Jay, on June 15, 2011.[25][26][27] 50 years December 2013 Tina Malone Paul Chase, her husband IVF United Kingdom English actress Tina Malone gave birth to a baby girl in December 2013 at the age of 50, after IVF treatment.[28] 50 years July 2015 Sophie B. Hawkins Unknown IVF United States American singer Sophie B. Hawkins gave birth to a baby girl named Esther Ballantine Hawkins on July 7, 2015, at the age of 50, after IVF treatment.[29] 50 years January 2017 Janet Jackson Wissam Al Mana, her husband Natural conception United States [30] 50 years April 2018 Tammy Duckworth Bryan Bowlsbey, her husband IVF United States American politician Tammy Duckworth gave birth to her second child, a girl named Maile, in April 2018, at the age of 50, after IVF treatment.[31][32] 50 years August 2018 Rachael Harris Christian Hebel, her husband Natural conception United States [33] 50 years October 2018 Tracey Britten Steven, her husband IVF United Kingdom Tracey Britten, 50, gave birth to twin girls, another baby girl and a boy via caesarean section in October 2018, after IVF treatment, becoming Britain's oldest mother of quadruplets.[34] 50 years December 2018 Michele Hall Jerry Hall, her husband Natural conception United States Michele Hall of Golden Gate, Florida, already a mother of 4, gave birth in December 2018 to a baby boy, Grayson Matthew, at the age of 50.[35] 51 years 1988 Irina Her husband Natural conception Russia Irina had an accident at the age of 25 and was told by the doctors that she was unable to have children. Later she married, and after many years of marriage eventually became pregnant and gave birth to her only son at the age of 51 in 1988.[36] 51 years 1991 Edith Jones Her son-in-law (gestational surrogate) IVF with her daughter's oocytes (gestational surrogate) United Kingdom Edith Jones gave birth to her granddaughter in 1991, at the age of 51, acting as a surrogate mother for her daughter Suzanne Langston, who was born without a womb.[37] 51 years March 1997 Adrienne Barbeau Billy Van Zandt, her husband Natural conception United States American actress Adrienne Barbeau gave birth to twin sons, Walker Steven and William Dalton, on March 17, 1997, at the age of 51. After marrying Billy Van Zandt in 1992 she started trying to have a child, tried in vitro fertilization unsuccessfully, but later became pregnant naturally.[38] 51 years 2000 Elizabeth Edwards John Edwards, her husband, former U.S. Senator and Vice Presential nominee IVF with oocytes donation supposed United States Elizabeth Edwards, wife of the former U.S. Senator and Vice Presidential nominee John Edwards, gave birth to son Jack in 2000 at the age of 51. The couple decided to have more children after one of their two children—a 16-year-old son—was killed in a car accident in 1996. Mrs. Edwards had also had a daughter, Emma Claire, at the age of 49. Some fertility experts believe she used donor's oocytes; Elizabeth Edwards remained silent on this question.[39] 51 years July 2001 Unidentified Her second husband IVF with oocytes donation Ukraine 51-year-old woman gave birth to twins, a boy and a girl, in Kyiv, Ukraine in July 2001, after IVF treatment with oocytes donation. She decided to have children at such a late age after getting married for the second time.[40] 51 years November 2020 Julie Loving Her son-in-law (gestational surrogate) IVF with her daughter's oocytes (gestational surrogate) United States Julie Loving decided to step in and become a gestational surrogate for her daughter Breanna Lockwood, who is infertile.[41] 51 years August 2001 Morgan Zantua Georges Zantua, her 57-year-old second husband Natural conception United States Morgan Zantua, of Tacoma, Washington, gave birth to her first child, daughter Auriel, on August 1, 2001, in Los Angeles, at the age of 51. She was married a second time at age 44, had a miscarriage and decided not to try to have children, and then unexpectedly found out she was pregnant at age 51.[18] 51 years December 2006 Sarajean Grainson David Grainson, her second husband, former priest IVF with oocytes donation United States Sarajean Grainson of Long Island, New York, gave birth to a son, Luke, in December 2006 at the age of 51, after IVF treatment with oocytes donation. Grainson and her second husband David, former priest, had twins, Matthew and David, in June 2008. Sarajean Grainson also had three adult children from her first marriage.[42] 51 years September 2007 Rosinete Palmeira Serrão Her son-in-law (gestational surrogate) IVF with her daughter's oocytes (gestational surrogate) Brazil Rosinete Palmeira Serrão gave birth to her own twin grandsons, Antonio Bento and Vitor Gabriel, at a hospital in Recife, Brazil, on September 28, 2007 at the age of 51, after choosing to act as a gestational surrogate for her 27-year-old daughter, Claudia Michelle Serrão Pereira, who had tried to become pregnant for four years. Under Brazilian law, a surrogate mother is required to be one's close relative, so Serrao volunteered because Claudia had no sisters. The children were conceived through artificial insemination using Claudia's eggs and her husband's sperm.[43][44][45] 51 years December 2009 Anita Makhtur Her husband, Indian origin as her IVF with her own unfrozen oocytes India Anita Makhtur, previously childless Indian woman, gave birth to twin boys in December 2009, at the age of 51, after IVF treatment. She was unable to get pregnant for 23 years because of fibroma uteri and had two unsuccessful IVF tries. She is probably the oldest woman who had IVF using her own unfrozen oocytes.[46] 51 years October 2012 Naomi Gryn Pete, her partner IVF United Kingdom English writer and filmmaker Naomi Gryn, daughter of British Reform rabbi and broadcaster Hugo Gryn, gave birth to her first child, a daughter Sadie Inez Liberty Joy, at UCLH on October 31, 2012, at the age of 51, after IVF treatment.[47] 51 years 2013 Rashmi Verma Her husband, Mr. A. K. Verma IVF India Mrs (Dr.) Rashmi Verma gave birth to a daughter (Lalli) in Delhi India in 2013 at the age of 51. Mrs. Rashmi Verma and her husband decided to go through fertility treatment after accidental death of their only child Amritanshu Verma.[48] 51 years 2015 Sebastiana Maria da Conceicao Her husband Natural conception Brazil Sebastiana Maria da Conceicao, gave birth to her 21st child in the city of Aracaju, Brazil in May 2015, at the age of 51. The little boy joined the family of 10 brothers and 10 sisters, of whom 18 were alive. "I had my first son when I was 13, I was still a child, I didn’t know much. But after, at an older age, I started to have one after the other," Sebastiana said.[49] 51 years June 2018 Julia Zhabyko Evgenij Zhabyko, her 53-year-old husband IVF Russia Julia Zhabyko, gave birth to triplets, two sons and a daughter, in Vladivostok, Russia in June 2018, at the age of 51, after IVF treatment.[50] 52 years November 1999 Helen Schermerhorn Morris Martin Scorsese, her husband Natural conception United States Helen Morris was 52 when she gave birth to her daughter Francesca in November 1999.[51] 52 years October 2001 Annie Leibovitz Anonymous sperm donor Natural conception United States American portrait photographer Annie Leibovitz was 52 when she gave birth to her daughter Sarah in October 2001.[52] 52 years August 2003 Lyudmila Belyavskaya Aleksandr Belyavsky, her husband, Russian actor Natural conception Russia Lyudmila Belyavskaya, second wife of Russian actor Aleksandr Belyavsky, gave birth to her first child, daughter Alexandra, in Moscow, Russia, on August 28, 2003, at the age of 52, after a natural conception.[53][54] 52 years May 2007 Unidentified Her son-in-law (gestational surrogate) IVF with oocytes donation (gestational surrogate) Greece 52-year-old woman gave birth to her own twin grandchildren in Greece in May 2007, after choosing to act as a gestational surrogate, by IVF with oocytes donation, for her infertile daughter. Under the laws of Greece, a surrogate mother is required to be under 50, but in this case an exception was made.[55] 52 years June 2008 Karen Johnston Roger Johnston, her 53-year-old husband IVF United Kingdom Karen Johnston of Bicester, England, gave birth to a girl, Willow, in June 2008, at the age of 52, after undergoing IVF treatment in Czech Republic. She was already a mother of 7, always alternating boy and girl also —Daniel (33), Jemma (28), Scott (27), Amy (26), Aiden (17), Bethany (14), Joseph (13), and had a set of twins — Imogen and Asa — in July 2010 also after IVF treatment in the same Czech clinic.[56] 52 years January 2011 Catherine Colonges Alain Colonges, her 51-year-old husband Natural conception France Catherine Colonges, French woman from Togo, of Limogne-en-Quercy, Lot, France, gave birth to triplets, a girl Léonore, and two boys, Elian and Alexis, in Toulouse, France, at the age of 52, after conceiving naturally with her husband Alain. Mrs Colonges already has a 30-year-old and a 27-year-old son, a 15-year-old daughter and three grandchildren.[57] 52 years October 2012 Shakuntala Devi Ramjit Raghav, her 96-year-old husband Natural conception India Shakuntala Devi from India gave birth to her second son at the age of 52, after conceiving naturally with her husband Ramjit Raghav, aged 96. She gave birth to her first child in 2010 at the age of 50.[58][59] 52 years July 2019 Lilian Chan Lai-lai Brian Wong Chak-fung [zh], her 52-year-old husband Natural conception Hong Kong [60] 52 years, 4 months June 1757 Julienne Despeignes Blouin Pierre Blouin, her 61-year-old husband Natural conception France Julienne Despeignes wife Blouin, French woman from Ercé-en-Lamée, in Brittany, 35 km south Rennes, France, born on February 13, 1705, gave birth to her last daughter, Magdelaine, on June 11, 1757, at the age of 52 years and almost 4 months, after conceiving naturally with her husband Pierre. Mrs Blouin born Despeignes had already had 12 children, of which, at 44 years, in February 1749, before having two others, at 45 and 49 years, two twins of opposite sex, as she herself had a twin brother.[61] 53 years November 1992 Mary Shearing Don Shearing, her 32-year-old second husband IVF with oocytes donation United States Mary Shearing, a 53-year-old Californian woman, former amateur body builder, became pregnant with the help of medical technology in New York, New York, after marrying 7 years earlier Don Shearing, a 21 years younger man. She gave birth on November 10, 1992 to about 12 weeks premature twin girls, at Martin Luther Hospital. The first baby, Amy Leigh, born naturally, was 2 pounds, 2 ounces. Her sister, Kelly Ann, born by Caesarean section, weighed 2 pounds, 12.5 ounces.[62] 53 years December 1992 Geraldine Wesolowski Her son (gestational surrogate) IVF with her daughter-in-law's oocytes (gestational surrogate) United States Geraldine Wesolowski of New York, New York, gave birth to her own grandson Matthew on December 28, 1992 at the age of 53, after IVF treatment in Christian Fertility Institute in Easton, Pennsylvania, in order to act as a gestational surrogate for her 31-year-old son Mark Wesolowski and his 32-year-old wife, Susan Cooper Wesolowski, who underwent hysterectomy at age 21 after the birth of her first son died at 2, and was not able to have children. It was believed that Geraldine Wesolowski, who was postmenopausal, was then the oldest woman in the United States to give birth through in vitro fertilization. That led to appearances on the Oprah Winfrey and Montel Williams television shows, according to Dr. Ida M. Campagna, the Amherst-based obstetrician who delivered Matthew.[63] Matthew died in February 2010 due to injuries sustained in a car accident.[64] 53 years September 2005 Annie Casserley Her son-in-law (gestational surrogate) IVF with her daughter's genetically selected oocytes (gestational surrogate) United Kingdom Annie Casserley gave birth to her own granddaughter Annie Trinity Hattersley in United Kingdom in September 2005, at the age of 53, after choosing to act as a gestational surrogate for her 35-year-old daughter, Emma Hattersley, who has a rare cancer-like condition, Histiocytosis X, making her unable to withstand pregnancy.[65] 53 years June 2008 Sarajean Grainson David Grainson, her second husband, former priest IVF with oocytes donation United States Sarajean Grainson of Long Island, New York, gave birth to twin sons, Matthew and David, in June 2008 at the age of 53, after IVF treatment with oocytes donation. Grainson and her second husband David, former priest, already had a son Luke in December 2006. Sarajean Grainson also had three adult children from her first marriage.[42] 53 years December 2008 Adele Dramis Her husband IVF with oocytes donation Italy Adele Dramis, an Italian woman of Greek origin, gave birth to twins, a boy, Vicenzo, and a girl, Rosa, in Naples, Italy, in late December 2008, at the age of 53. She had been trying to get pregnant since she got married at age 45, and after years of trying she decided to receive IVF treatment.[66] 53 years June 2011 Anna Fehér Her husband IVF Hungary Hungarian actress Anna Fehér gave birth to her first child, a son, László Barnabás, on June 4, 2011, at the age of 53. She has been trying to conceive for ten years.[67] 53 years June 2011 Debbie Hughes Paul Clarke, her 47-year-old partner Natural conception United Kingdom Debbie Hughes of Daventry, gave birth naturally to her son Kyle at Northampton General Hospital in June 2011 at the age of 53, after a natural conception. She had no plans to become a mother again when she became pregnant, as she had been taking contraceptive pills.[68] 54 years 2000 Galina Shevchenko Her husband Postmenopausal IVF treatment with oocytes donation Russia Galina Shevchenko gave birth to twin sons in Russia in 2000 at the age of 54. Shevchenko and her husband decided to go through fertility treatment after accidental death of their only son. It was the first case of successful case of IVF treatment of a postmenopausal woman in Russia.[69] 54 years 2001 Viven Morris Mark Westrop, her son-in-law (gestational surrogate) IVF with her daughter's oocytes (gestational surrogate) United Kingdom Vivien Morris gave birth to her granddaughte Maisie in 2001, at the age of 54, acting as a surrogate mother for her 29-year-old daughter Laura Westrop, who was unable to carry a baby after cancer treatment, and her husband Mark.[37] 54 years January 2007 Unidentified Her husband IVF with oocytes donation Czech Republic 54-year-old woman gave birth to a daughter in Prague in "U Apolináře" clinic in January 2007, after IVF treatment with oocytes donation.[70] 54 years November 2009 Unidentified Her 71-year-old husband, previously childless IVF with oocytes donation supposed Israel 54-year-old woman gave birth to twins, boy and girl, in Bnei Brak, Israel, in November 2009. Her 71-year-old husband became a first-time father, while she had adult children from a previous marriage.[71] 54 years July 2010 Karen Johnston Roger Johnston, her 55-year-old husband IVF United Kingdom Karen Johnston of Bicester, England, gave birth to twins, a boy, Asa, and a girl, Imogen, in July 2010, at the age of 54, after undergoing IVF treatment in Czech Republic. She was already a mother of 8, always alternating boy and girl also —Daniel (♂) 33, Jemma (♀) 28, Scott (♂) 27, Amy (♀) 26, Aiden (♂) 17, Bethany (♀) 14, Joseph (♂) 13, Willow (♀) 2—. Her eighth child was born in June 2008 also after IVF treatment in the same Czech clinic.[56] 54 years October 2010 Giovanna Ciardi Bruno Paoli, her partner Natural conception Italy Giovanna Ciardi of Camaiore, Province of Lucca, already mother of two, gave birth to her third child, a daughter, named Adria, on October 11, 2010, at the age of 54, after a natural conception.[72] 54 years August 2011 Solange Couto dos Santos Jamerson de Andrade, her second husband Natural conception Brazil Brazilian actress Solange Couto dos Santos, already mother of a son, Márcio Felipe, and a daughter, Morena Mariah, of her previous marriage, gave birth to her third child, a son, named Benjamin, on August 15, 2011, at the age of 54, after a natural conception.[73] 54 years June 2018 Brigitte Nielsen Mattia Dessi, her husband Natural conception Denmark [74] 54 years October 2019 Unidentified Unknown Natural conception Russia 54-year-old woman from Tomsk Oblast, Russia gave birth to her fifth child in November 2019 after natural conception.[75] 54 years, 1 month February 1916 Elizabeth Pearce Her husband Natural conception United Kingdom Mrs Elizabeth Pearce of Biterne, Southampton, England, gave birth to her youngest child on February 10, 1916, when she was 54 years and 40 days old.[76][77] 54 years, 10 months January 2000 Aracelia Garcia Her husband Natural conception United States Aracelia Garcia of Sunnyside, Washington, astounded doctors when she naturally conceived (without hormonal treatment) all-female triplets in 1999 at the age of 54. She delivered by Caesarean section in early January 2000 three healthy girls, named Arianna, Brianna and Cecelia, to play on initials A, B, C.[78][79][80] 54 years, 11 months April 1847 Barbara Christman Her husband Natural conception United States Barbara "Barbary" Christman (née Klientop) of Pennsylvania, gave birth 3 days shy of her 55th birthday, to William Christman on April 30, 1847. Her husband, Daniel Christman of Chestnut Hill, PA, was 62. William was the seventh of Daniel and Barbara's seven children. 55 years 1998 Unidentified Anonymous sperm donor IVF with ICSI India 55-year-old Bodo woman, from states of the far north-eastern India, bordering Tibet and Bhutan, gave birth after IVF treatment with intra cytoplasmic sperm injection (ICSI).[81] 55 years April 1998 Merryl Fudel Anonymous sperm single donor IVF United States Merryl Fudel, a five-time divorcee from San Diego, gave birth to quadruplets, three girls and a boy, on April 18, 1998, at the age of 55, after IVF treatment. She is probably the oldest woman who gave birth to quadruplets. Three girls and one boy were born at 27 weeks, the smallest of them weighted only 10 oz at birth.[82] One of the girls died 8 days later. Fudel surrendered two other girls for adoption, so only the boy remained with mother.[83] 55 years February 2000 Marilyn McReavy Nolen Randy Nolen, her 48-year-old husband IVF with oocytes donation United States Marilyn Nolen (born McReavy), former Olympic athlete and volleyball coach at St. Louis University, gave birth to twin sons, Travis and Ryan, on February 22, 2000, at the age of 55. She married her husband Randy Nolen in 1988, and since that were trying to have a child, and after 10 years with no success they decided in 1998 to go through IVF.[84] 55 years December 2004 Tina Cade Jason Hammond, her 29-year-old son-in-law (gestational surrogate) IVF with her daughter's oocytes (gestational surrogate) United States Tina Cade, from Virginia, gave birth to her own triplet grandchildren, two boys, Aaron and Kai, and a girl, Simone, in December 2004, at the age of 55, acting as a surrogate mother for her 29-year-old daughter Camille Hammond and her husband Jason. Camille suffers from endometriosis and had tried six attempts of IVF, but had been unsuccessful each time, and then Ms Cade has offered her help.[85] 55 years July 2007 Veronica Mensah Atsu Dikenou, a fellow Ghanaian IVF United States Veronica Mensah of Lithonia, Georgia, gave birth to twins, boy and girl, Daniel Atsu and Diana Atsupui, in July 2007, at the age of 55. The children are named Dikenou after their genitor. She had been trying to have children since she was 25, and after 30 years she decided to try through IVF, which was done in her native Ghana.[86] 55 years August 2007 "Brinda" "Alagappan", her 57-year-old husband IVF with oocytes donation and ICSI India Indian woman named "Brinda" from Bhadravathi, Karnataka, gave birth to twin sons, Akash and Rishikesh, on August 27, 2007, in Chennai, at the age of 55. She and her husband "Alagappan" were childless for 28 years due to lack of sufficient number of his sperms (oligospermia), so they decided to go through in vitro fertilization (IVF) with oocytes donation and intra cytoplasmic sperm injection (ICSI).[81] 55 years 2008 Unidentified Unknown IVF South Korea A 55-year-old Korean gave birth at Seoul, South Korea, in 2008 (date not sure), with the help of the team of Dr. Kim Ahm who followed, after, "Park", the 57-year-old woman become a mother at Seoul in late September 2012.[87] 55 years November 2008 Unidentified Anonymous sperm single donor IVF Austria 55-year-old single woman gave birth to twin girls in Graz, Austria on November 21, 2008, by Caesarian section. She became pregnant after IVF abroad. The father is anonymous.[88] 55 years March 2016 Sharon Cutts Stuart Reynolds, her 40-year-old partner IVF United Kingdom Sharon Cutts of Lincolnshire, England, already a mother of 4, gave birth to triplets, sons Mason and Ryan and a daughter Lily, in March 2016, at the age of 55, after undergoing IVF treatment in Cyprus.[89] 55 years September 2017 Muazzez Çınar Her 55-year-old partner IVF Turkey Muazzez Çınar of Uşak, Turkey, gave birth to twin boys in September 2017, at the age of 55, after IVF treatment. They named one of the boys after their son, Hüseyin, who drowned in the sea in northern Rize.[90] 55 years January 2019 Emma Miles Adam Smith, her son-in-law (gestational surrogate) IVF with her daughter's oocytes (gestational surrogate) United Kingdom Emma Miles gave birth to her granddaughter Evie on January 16, 2019, at the age of 55, acting as a surrogate mother for her 31-year-old daughter Tracey Smith, who was born without a womb, and her husband Adam Smith.[91] 55 years, 3 days 1936 Winifred Wilson Her husband Natural conception United Kingdom Winifred Wilson, from Eccles, west of Manchester, England, who gave birth to her 10th child at the age of 55 years and 3 days in 1936, was the oldest British mother until September 1987, when Kathleen Campbell, from Nottingham, England, gave birth at 55 years and 141 days.[92][93] 55 years, 2 months, 10 days March 1931 Mary Higgins Her husband Natural conception Ireland Mrs Mary Higgins of Cork City, Ireland, born on January 7, 1876, gave birth to her first child when she was 55 years and 69 days old, on March 17, 1931, St-Patrick Day, Irish National Day. The case was reported on July 5, 1932.[77][94] 55 years, 4 months, 19 days September 1987 Kathleen Campbell Sydney Campbell, her 65-year-old husband Natural conception United Kingdom Kathleen Campbell of Kimberley, Nottinghamshire, England, born on April 21, 1932, and already grandmother by one of her six elder children ages 16 to 22, gave birth by Caesarean section to her 7th child, a 6 lb 7 oz (2.920 kg) son named Isaac Joby, on September 9, 1987, at the age of 55 years and 141 days, having conceived naturally.[92][93] 55 years, 11 months (also 51 years) March 1999 Pauline Lyon David Lyon, her 54-year-old second husband IVF United Kingdom Pauline Lyon, born in late March 1943, gave birth to a son, Brodie, at Hinchingbrooke Hospital, Huntingdon, Cambridgeshire, England, on March 22, 1999, at the age of 55 years and 11 months, after IVF treatment. She had also given birth to a girl at age 51 after the same treatment, and Lyon and her second husband wanted their daughter to have a sibling. Lyon also had an adult daughter from her first marriage.[95] 56 years May 2001 Lynn Bezant Derek Bezant, her husband IVF with oocytes donation United Kingdom Lynn Bezant of Croughton, Northamptonshire gave birth to twins, girl and boy, Susan and David, by Caesarean section, on May 24, 2001, at the age of 56, after receiving fertility treatment. Bezant, who already had three adult children with her husband Derek, received donor eggs which had been fertilised with her husband's sperm. The couple had always wanted a larger family but had failed after Bezant gave birth to stillborn twins and then suffered a miscarriage.[96] 56 years 2006 Unidentified Unknown IVF with oocytes donation Australia A 56-year-old woman, from Queensland, Australia, gave birth to a baby, in 2006, after IVF treatment with oocytes donation.[97] 56 years June 1911 Úrsula Guardiola Román Rafael Picorelli, her 36-year-old husband. Natural Puerto Rico A 56-year-old woman from Dorado, Puerto Rico, gave birth to her sixth and last daughter, Lucía Picorelli. 56 years January 2008 Raisa Akhmadeeva Rachid Akhmadeev, her husband Natural conception supposed Russia Raisa Akhmadeeva gave birth to her first child, a boy, in Ulyanovsk, Russia on January 10, 2008, at the age of 56. Her husband Rachid has already three children from his previous marriage, but they always wanted to have a child together.[98] 56 years October 2008 Jacilyn Dalenberg Joe Coseno, her son-in-law (gestational surrogate) IVF with her daughter's oocytes (gestational surrogate) United States Jacilyn Dalenberg (former Wooster) of Mansfield, Ashland, Ohio, gave birth to her own triplet granddaughters, Elisabeth Jacilyn, and twins Carmina Ann and Gabriella Claire, on October 11, 2008, at the age of 56, acting as a surrogate mother for her daughter Kim Wooster Coseno and her husband Joe Coseno. Already mother of two children, a girl, Brittni (Wilkinson) and a boy, Colin (Anderson), of her two previous companions, Kim Wooster became sterile after giving birth to her son.[99] 56 years May 2010 Gabriella De Ambrosis Luigi De Ambrosis, her 69-year-old husband IVF with oocytes donation Italy Gabriella De Ambrosis gave birth to her first child, daughter Viola, on May 26, 2010 in Italy, at the age of 56, after IVF treatment abroad. Gabriella married her husband Luigi in 1990. They tried for many years to conceive naturally, and also had two requests for adoption turned down. In September 2011 an Italian court has ordered their daughter to be taken into care after ruling that librarian Gabriella, 57, and her retired husband, 70, were too old.[100] 56 years November 2010 Gianna Nannini Her partner Natural conception, on hormone replacement therapy (HRT) Italy On November 26, 2010, 56-year-old Italian singer Gianna Nannini gave birth to her first child, a girl named Penelope, having conceived naturally following fertility treatments.[101] 56 years November 2014 "Tessa" Anonymous sperm donor Postmenopausal IVF treatment with oocytes donation Canada "Tessa", a 56-year-old Toronto lawyer, gave birth to a baby boy on November 25, 2014, after IVF treatment with oocytes donation. She was single and had three adult children from her provious marriage.[102] 56 years December 2014 Lisa Swinton McLaughlin Michael McLaughlin, her husband IVF United States Lisa Swinton McLaughlin, the medical director for the American Red Cross in Baltimore, gave birth to premature twin boys on December 27, 2014, at the age of 56, after more than 10 years of fertility treatment attempts. She was discharged from hospital on December 31, but was still suffering from the stomach pain, and died at home of a bowel obstruction on January 4, 2015, while her sons were still in the hospital.[103] 56 years February 2018 Irina Vitorgan Emmanuil Vitorgan, her husband IVF Russia Irina Vitorgan, third wife of Russian actor Emmanuil Vitorgan, gave birth to a baby girl named Ethel on February 26, 2018, at the age of 56, after IVF treatment.[104][105] 56 years, 11 months, 27 days November 2004 Aleta St. James Two anonymous sperm donors IVF with oocytes donation United States Aleta St. James, born on November 12, 1947, gave birth to twins, a boy and a girl, Francesca and Gian, at Mount Sinai Hospital in New York, New York on November 9, 2004, just three days before her 57th birthday, after having undergone IVF treatment using donor eggs.[14] 57 years March 1996 Natalya Surkova Her second husband Natural conception, on hormone replacement therapy (HRT) Russia Natalya Surkova became the oldest mother in Russia after giving birth to her daughter Sasha on March 14, 1996, at the age of 57. She became pregnant after 1.5 years of hormonal treatment, having been established in premenopausal. Surkova, a divorced mother of two adult children, decided to have one more child because her new partner was childless.[106] 57 years December 1998 Judith Cates Carl M. Cates Jr, her 48-year-old husband IVF United States Judith Cates of Evansville, Indiana gave birth to twin girls, Margaret Jan Marie (Maggi) and Carli Sue Morgan (Carli), on December 12, 1998, at the age of 57. She got pregnant after IVF treatment, and she has said that she and her husband, Carl, are often mistaken for grandparents.[107] 57 years April 2005 Rosie Swain Jay Swain, her husband Postmenopausal IVF treatment with oocytes donation United States Rosie Swain naturally gave birth to twins, girl and boy, Diana and Christian, in USA on April 20, 2005, at the age of 57. Swain and her husband Jay, who already were six times grandparents and four times great-grandparents, by her six eldests, decided to go through IVF in order to give their last child, 6-year-old son Jimmy, a sibling close in age.[108] 57 years March 2008 Susan Tollefsen Nick Mayer, her 46-year-old partner IVF with oocytes donation United Kingdom Susan Tollefsen, English woman Norway native, of Laindon, Essex, England, gave birth to her first child, daughter Freya, on March 28, 2008, at the age of 57, after IVF treatment with oocytes donation. She was refused to be treated in Britain due to her age, so she went to Russia and Poland to receive IVF. Two years later she was willing to have one more child, this time she was accepted at London Women's Clinic, and became the oldest woman in Britain who was offered this kind of treatment, but later she decided not to risk her health.[109] 57 years July 2008 "Vera" Her husband Natural conception Ukraine 57-year-old woman gave birth to a son, Andrei, in Kiev, Ukraine by Caesarean section on June 13, 2008 at the age of 57. Her first son died at age 20, later she gave birth to twin boys, but they died after 10 days, so she and her husband decided to try once again.[110] 57 years 2010 Unidentified Unknown IVF with oocytes donation Australia A 57-year-old woman gave birth to a baby in 2010, in Perth, Western Australia, after IVF treatment with oocytes donation.[97] 57 years August 2010 Pamela Butler Her son-in-law (gestational surrogate) IVF with her daughter's oocytes (gestational surrogate) United Kingdom 57-year-old Pamela Butler, of Blackwood, Wales, gave birth to a boy, Josef, in August 2010 via surrogacy. Her 35-year-old daughter, Nichola, had tried to have a baby on her own and failed. Pamela Butler became Britain's oldest surrogate mother.[111] 57 years November 2010 Unidentified Anonymous Indian sperm donor IVF Australia 57-year-old Indian woman gave birth to a girl in Melbourne, Australia, in November 2010, after IVF with sperm donated from India, setting a record to become the oldest mother in Australia.[112] 57 years September 2011 Silvana Sofia Her 70-year-old husband IVF with oocytes donation Italy Silvana Sofia, 57-year-old woman doctor, gave birth to female twins, Karola Pia and Adriana Cristina, in Salerno, Italy in September 2011. Her husband was 70 years old at that time.[113] 57 years September 2012 "Park" Her 60-year-old husband Postmenopausal IVF treatment with oocytes donation South Korea A 57-year-old Korean (born in 1955), nicknamed "Park", gave birth by caesarean section performed at 36 weeks, to two girls, fraternal twins, weighing, respectively, 2.230 kg and 2.630 kg, on September 26, 2012, at the Obstetric Asan Medical Center, at Seoul, South Korea. After 27 years to try unsuccessfully to conceive naturally with her husband, because of the obstruction of her fallopian tubes, the menopause had occurred when she was 45 years old, twelve years before. She therefore had to resort to IVF with donated oocytes, fertilized by the sperm of her 60-year-old husband.[87] 57 years, 4 months (also 52 and 55 years) November 1972 Anna Martin Raymond Martin, her 55-year-old husband Natural conception United States Anna Martin, of Broken Arrow, near Tulsa, Oklahoma, already mother of six children, the eldest, Louis, was then 25, gave birth by Caesarean section to a daughter, Mary-Jane, on November 24, 1972, at the age of 57 years and 4 months. She already had her previous children, a daughter, in summer 1967, at the age of 52, then a son, Donnie-Ray, in summer 1970, at the age of 55.[114] 57 years, 4 months, 7 days October 1956 Ruth Alice Kistler Her husband Natural conception, on hormone replacement therapy (HRT) United States Ruth Alice Kistler of Portland, Oregon, gave birth to a daughter, Susan, in Los Angeles, California, on October 18, 1956, at the age of 57 years and 129 days. The birth predated the advent of in-vitro fertilization (IVF) making Kistler one of the oldest women known to have conceived naturally.[115][116] Born in June 1899, she died in 1982, at the age of 82 or 83, while her daughter was 25 or 26. 58 years December 1818 Mrs George Saunders Her husband Natural conception United Kingdom The Royal Cornwall Gazette of January 2, 1819, reporting the birth of twins, on previous Christmas Eve (December 24, 1818), to Mrs George Saunders, wife of a London shoemaker, in the 59th year of her age. Her last previous child had been born 35 years before that.[77] 58 years 1995 Emilia Bacco Her husband Postmenopausal IVF treatment with oocytes donation Italy Emilia Bacco, 58-year-old Italian woman from Salerno, Italy, gave birth to twin boys in 1995, after IVF treatment with oocytes donation fertilized by her husband's sperm.[117] 58 years June 2001 "Pragna" Her husband Postmenopausal IVF treatment with oocytes donation India "Pragna", 58-year-old Indian woman, from Mumbai, Maharashtra, gave birth to a son, by Caesarean section, in June 2001.[118] 58 years September 2002 Janet Bosher Donated embryos' genitor Postmenopausal IVF with embryos donation United Kingdom Janet Bosher gave birth to her twins children Sarah and James in London in September 2002, at the age of 58, after IVF treatment with donated embryos, her partner Martin Maslin, also apparently sterile, at the Professor Ian Craft's private clinic. In January 2003, Martin Maslin died from a heart attack at age 64, four months after the twins' birth. After his death the wisdom of a couple close to retirement age having fertility treatment was debated.[119] 58 years March 2003 Samira Ellis Her companion Postmenopausal IVF with oocytes donation Sweden Samira Ellis, an Israeli native, gave birth to twins, boy, Elias, and girl, Solva, in Sweden on March 8, 2003, at the age of 58.[120] 58 years December 2006 Ann Stopler Ayal Chomsky, her son-in-law (gestational surrogate) Postmenopausal IVF with her daughter's oocytes (gestational surrogate) United States Ann Stolper, of Delray Beach, Florida, gave birth to her own twin granddaughters, Itai & Maya, in USA on December 1, 2006, at the age of 58, acting as a surrogate mother for her daughter Caryn Stopler Chomsky and her husband Ayal Chomsky. Caryn Chomsky had had a hysterectomy at age 25 as she had been diagnosed with cervical cancer, and was not able to have children the traditional way.[121] 58 years May 2010 "Cicly" Her husband Postmenopausal IVF treatment with oocytes donation India An Indian woman named Cicly of Muvattupuzha, Ernakulam district gave birth to a boy in St George Hospital on May 31, 2010, at the age of 58, after IVF treamment, with her own eggs supposedly. Cicly's first son had died many years ago at the age of three and her second son died at the age of 16 in an accident in 2008. She and her husband then decided to try to have one more child.[122] 58 years May 2010 Unidentified Her husband Postmenopausal IVF treatment with oocytes donation Italy 58-year-old woman of Turin, Italy, gave birth to a daughter in May 2010, after IVF treatment with oocytes donation.[123] 58 years December 2010 Carole Hobson Anonymous Scandinavian sperm donor Postmenopausal IVF treatment with oocytes donation United Kingdom Carole Hobson of Kent, South East England, gave birth to twins, a boy and a girl, in December 2010, at the age of 58, following IVF treatment at a clinic in India.[124] 58 years September 2011 Unidentified Her 65 or 72-year-old husband Postmenopausal IVF treatment with oocytes donation Italy A 58-year-old woman gave birth to twins, a boy and a girl, in Milan, Italy, in September 2011, after IVF treatment abroad with donor eggs. The woman and her 65-year-old (72 yo according another source) husband, mechanic, were trying to conceive naturally for 27 years.[113] 58 years May 2012 Maria Addolorata Montuori Salvatore Manzo, her 59-year-old husband Postmenopausal IVF treatment with oocytes donation Italy Maria Addolorata Montuori, a 58-year-old woman from Boscoreale, near Naples, Campania, Italia, gave birth to triplets, one girl, Giovanna, and two boys, Alessandro and Adriano, on May 9, 2012, at the General Hospital of aples, after postmenopausal IVF treatment, with oocytes donation fertilized by sperm of her husband, Salvatore Manzo, 59 years.[125] 58 years, 4 months December 2004 Lauren Cohen Frank Garcia, her 39-year-old second husband Postmenopausal IVF treatment with oocytes donation United States Lauren Cohen of Paramus, New Jersey, born on August 11, 1946, already mother of a 26-year-old daughter, Renee, of her first marriage, gave birth to a daughter, Raquel, in New York, New York, in December 2004, at the age of 58 years and 4 months. Lauren Cohen and her husband, Frank Garcia, will still have twins together through IVF in May 2006, using the husband's sperm and oocytes from a donor. The couple, faced with either giving away the embryos left over from the first IVF treatment or letting them be destroyed, decided to try again. As to why she chose to have children at such a late age, with a husband approximately 20 years her junior, Lauren Cohen stated, "I just thought it would be unfair to Frank for him to marry me and never have the opportunity to have a child. He never asked me to have a child, but I knew it would make him happy".[126] 58 years, 5 months December 2007 Türkan Katicelik Selim Katicelik, her 64-year-old husband IVF with anonymous 25-year-old donor's ovocytes Germany Türkan Katicelik, a Turkish woman living in Aschaffenburg, Germany gave birth to a daughter, Karya, in December 2007. The child weighed 2.1 kg, was 46 cm tall and was delivered by caesarean section. She had had several miscarriages before she gave birth to her first child. She used IVF with an anonymous 25-year-old donor's oocytes. In 2008, she announced she was a bit younger than had previously been reported, due to a mistake in the official registration. She would be 60 in July, 2009, meaning she had been about 58 ½ at the birth.[127][128] 58 years, 6 months 1998 Lin Fu-mei Her husband[citation needed] Natural conception, on HRT[citation needed] Republic Of China Lin Fu-mei, of Republic of China (Taiwan), whose age was reported between 58 and 59, gave birth to twin daughters in 1998.[129] 59 years December 1993 Jennifer F. Her 45-year-old husband IVF with oocytes donation United Kingdom Jennifer F. (not released name), millionnaire British businesswoman, gave birth to twin boys in a London hospital on December 25, 1993, at the age of 59, after undergoing IVF treatment in Rome, Italy, with the help of Dr. Severino Antinori. The oocytes from an Italian 22-year-old donor and the sperm of Jennifer's 45-year-old husband were used. This case produced much ethical debate in UK.[130] 59 years August 1997 Dawn Brooke Raymond Brooke, her 64-year-old husband Natural conception, on hormone replacement therapy (HRT) United Kingdom Dawn Brooke of Guernsey, Channel Islands, gave birth to a son by Caesarian section on August 20, 1997, at the age of 59. She became pregnant unexpectedly, initially mistaking the symptoms she experienced for cancer, and is the oldest mother currently known to have conceived naturally. It has been speculated that the hormone replacement therapy which she had may have contributed to her ability to ovulate past menopause.[131][132] 59 years (also 57 years) October 2004 Sandra Lennon Michaël Lennon, her second husband Postmenopausal IVF treatment with oocytes donation United Kingdom Sandra Lennon of Byfleet, Surrey, who already had two adult children from her first marriage, gave birth to her son Alex in October 2004, at the age of 59. It was her second child born after IVF treatment, the first of them, son Joshua, had been born in the beginning of 2003.[133] 59 years 2005 Svetlana Glazyrina Ilgizar Glazyrin, her 50-year-old husband Postmenopausal IVF treatment with oocytes donation Russia Svetlana Glazyrina, of Sochi, Russia, gave birth to her first child, a boy, Camille Rinat, weighing 3.8 kg and 54 cm tall, on September 13, 2005, at the age of 59. She had been trying to have children since her marriage at age 44. After seven unsuccessful pregnancies she decided to go through IVF treatment.[134] 59 years, 9 months, 11 days May 2006 Lauren Cohen Frank Garcia, her 40-year-old second husband Postmenopausal IVF treatment with oocytes donation United States Lauren Cohen of Paramus, New Jersey, born on August 11, 1946, already mother of a 27-year-old daughter, Renee, of her first marriage, gave birth to twins, a boy and a girl, Giselle & Gregory, in New York, New York, on May 22, 2006, at the age of 59 years, 9 months, and 11 days. Lauren Cohen and her husband, Frank Garcia, had previously had a daughter, Raquel, together through IVF in December 2004, using the husband's sperm and an egg from a donor. The couple, faced with either giving away the embryos left over from the first IVF treatment or letting them be destroyed, decided to try again. As to why she chose to have children at such a late age, with a husband approximately 20 years her junior, Lauren Cohen stated, "I just thought it would be unfair to Frank for him to marry me and never have the opportunity to have a child. He never asked me to have a child, but I knew it would make him happy".[126] 59 years 2008 Unidentified Her 71-year-old husband Postmenopausal IVF treatment with oocytes donation United Kingdom 59-year-old British Indian woman gave birth in the English Midlands to twin girls conceived by IVF in India. The woman's husband was 72 years old at the moment of birth.[135] 59 years September 2008 Unidentified Her husband Postmenopausal IVF treatment with Vietnamese donor's oocytes France 59-year-old Frenchwoman of Vietnamese origin gave birth by Caesarian section to two boys and a girl on September 6, 2008. The woman is thought to have resorted to a private Vietnamese clinic willing to overlook the age limit for egg donation and IVF, set at 45 in Vietnam. Egg donations are authorised in France, but most fertility clinics set a maximum age limit of 42 for would-be mothers.[136] 59 years June 2017 Akosua Budu Amoako Isaiah Somuah Anim, her 59-year-old husband Postmenopausal IVF treatment with oocytes donation USA Akosua Budu Amoako, aged 59, gave birth to a son, Isaiah Somuah Anim, on June 15 at Bellevue Woman's Center in Niskayuna, New York, after IVF treatment using her husband's sperm and a donor egg.[137] 60 years 1996 Haristoula Karioti Her husband Pre-menopausal IVF treatment Greece Haristoula Karioti from Rhodes, Greece, gave birth to twin sons at the age of 60, after IVF treatment in Athens, Greece. She was pregnant with triplets, but the doctors later decided to reduce the number of fetuses by one. She entered menopause years after the birth of her children - her mother, too, had entered menopause at a very late age.[138] 60 years November 1997 Elizabeth Ann "Liz" Jeffrey Buttle Her boyfriend Postmenopausal IVF treatment with oocytes donation United Kingdom Elizabeth Ann Jeffrey "Liz" Buttle, of Wales, already mother of a 41-year-old daughter, Belinda, she had at the age of 19, gave birth to a son, Joe, in November 1997, at the age of 60, after she had informed doctors that she was 49, although she was 59 actually, in order to be eligible for IVF.[citation needed] Buttle's husband died of a heart attack several years earlier; she started a new relationship and was desperate to have another child.[139] Her only previous child, daughter Belinda, was born in 1956, when Liz was 19, so she is probably the woman with the longest interval between two births.[140] As of September 2006, Buttle was still alive.[139] 60 years July 2001 Unidentified Her husband Postmenopausal IVF treatment with oocytes donation Japan 60-year-old Japanese woman became the oldest mother in Tokyo, Japan when gave birth to her first child in July 2001, after IVF treatment received in the US using her husband's sperm and oocytes donated by an Asian woman.[141] 60 years August 2001 "Aruna" Her husband Postmenopausal IVF treatment with oocytes donation India "Aruna", a 60-year-old Indian woman, from Mumbai, Maharashtra, India, gave birth to a son in August 2001, conceived by IVF treatment with oocytes donation. She and her husband married 29 years earlier, remained childless, after 3 abortions of previa pregnancies.[118] 60 years May 2007 Frieda Birnbaum Ken Birnbaum, her 63-year-old husband Postmenopausal IVF treatment with oocytes donation United States Dr Frieda Birnbaum of Saddle River, New Jersey, gave birth to twin sons, Jake and Jared, on May 22, 2007, at the age of 60. The babies weighed 4 lb 11 oz (2.12 kg) each and were delivered by Caesarean section. Frieda Birnbaum underwent IVF at a South African fertility clinic specializing in older women. She and her husband, who have a 6-year-old son and two adult children, a 33-year-old son and a 29-year-old daughter, said that they wanted their younger son to have siblings close in age. Hospital officials believe Dr Frieda Birnbaum may be the oldest woman to give birth to twins in the United States.[142] 60 years February 2009 Ranjit Hayer Jagir Hayer, her 60-year-old husband Postmenopausal IVF treatment with oocytes donation Canada Ranjit Hayer of Calgary, Alberta, gave birth to twin boys, in February 2009, at the age of 60, became pregnant through fertility treatments and IVF practiced in India, after several miscarriages in several years.[143] 60 years May 2010 Wu Cheng Wu Jingzhou, her husband Postmenopausal IVF treatment with oocytes donation China Wu Cheng, 60-year-old Chinese woman, gave birth to twin girls prematurely via Caesarean section in Hefei on May 25, 2010. The woman and her husband decided to go through IVF treatment after the death of their 28-year-old daughter Tingting and son-in-law. The woman has said: "The girls give me and my husband the courage to live on. Despite the fact that we are old, we have the confidence to bring them up."[144] 60 years September 2010 Unidentified Her son-in-law (gestational surrogate) Postmenopausal IVF treatment with her daughter's oocytes (gestational surrogate) Brazil 60-year-old Brazilian woman from Rio de Janeiro gave birth to her own granddaughter Alice on September 28, 2010, after choosing to act as a gestational surrogate for her 32-year-old daughter, who is infertile. Under Brazilian law, a surrogate mother is required to be one's close relative.[145] 60 years January 2012 Raju Ben Hawa Singh, her 68-year-old husband Postmenopausal IVF treatment with oocytes donation India Raju Ben of gave birth to a son in Jaipur in January 2012, at the age of 60.[146] Married for 40 years, she suffered with four miscarriages in the past and had multiple surgeries on her tubes & uterus because of tuberculosis, ovarian cysts, etc., thus making her impossible to conceive, so she and her husband decided to try IVF.[146] 60 years May 2015 Punjiben Patel Ranchhod Patel, her 65-year-old husband Postmenopausal IVF treatment with oocytes donation India Punjiben Patel of Vond village of Bhachau in Kutch district, Gujarat, gave birth to a son in May 2015, at the age of 60. Married in 1982, she and her husband failed to conceive naturally. Patel became pregnant after the first attempt of IVF.[147] 60 years June 2017 Atifa Nokić Her 68-year-old husband Postmenopausal IVF treatment with oocytes donation Serbia Atifa Nokić of Novi Pazar, Serbia, gave birth on 20 June 2017, at the age of 60. Nokić and her 68-year-old husband Šerif became fifth time parents with the help of IVF treatment.[148] 60 years, 10 months, 19 days January 2010 Lia Georgia Triff Prince Paul-Philippe von Hohenzollern al Romania, her 62-year-old husband Postmenopausal IVF treatment with allegedly one of her frozen oocytes Romania Princess Lia Georgia Triff, wife of Prince Paul-Philippe Hohenzollern of Romania, gave birth in Romania to the Prince Carol Ferdinand Hohenzollern on January 11, 2010 ; born on February 23, 1949, she was then 60 years, 10 months, and 19 days. She previously had a daughter born in 1973 from her first union. Later, Lia Triff alleged that she used her own frozen eggs.[149] 61 years January 1988 Cecilia Tuaileva Her husband Postmenopausal IVF treatment with oocytes donation Australia Cecilia Tuaileva, Australian woman, gave birth to a son on January 16, 1988, at the age of 61. She has used IVF with oocytes donation fertilized by her husband's sperm.[150] 61 years July 1992 Liliana Cantadori Her husband Postmenopausal IVF treatment with oocytes donation Italy Liliana Cantadori gave birth to a son in Modena, Italy on July 27, 1992, at the age of 61. She used IVF with oocytes donation fertilized by her husband's sperm.[151] 61 years December 2002 Unidentified Her husband Postmenopausal IVF treatment with oocytes donation Austria An unnamed Austrian woman gave birth to her second child, a daughter weighing 6 lb (2.72 kg), on December 15, 2002 at the age of 61 in Graz. She also gave birth to another child, a boy, in early March 2007 at the age of 66. Her oldest child, a daughter, was then 25. Both pregnancies over 60 were made possible by IVF. The second will overseen by Severino Antinori. This may be the only known case in the world of two pregnancies and births at over age 60.[152][153] 61 years February 2007 Unidentified Her husband Postmenopausal IVF treatment with oocytes donation Denmark 61-year-old woman, from Vanlose, Copenhague, Denmark, gave birth to a daughter on February 19, 2007, in Copenhague, conceived by IVF treatment practiced in England, with oocytes donation.[154] 61 years 2007 Unidentified Her husband Postmenopausal IVF treatment with oocytes donation Switzerland 61-year-old woman became first-time mother in Switzerland in 2007, after becoming pregnant abroad by IVF treatment with oocytes donation, a procedure which is banned in the Helvetic Confederation. Another woman gave birth the same year in the country to twin boys at the age of 61 years.[155] 61 years February 2009 Unidentified Her son-in-law (gestational surrogate) Postmenopausal IVF treatment with her daughter's oocytes (gestational surrogate) Japan 61-year-old woman gave birth to her own grandson in Nagano, northwestern Tokyo, Japan, on February 10, 2009, after choosing to act as a gestational surrogate for her daughter, who has no uterus and could not become pregnant herself. She would be the oldest surrogate mother recorded in Japan.[156] 61 years February 2011 Kristine Casey Her 42-year-old son-in-law (gestational surrogate) Postmenopausal IVF treatment with her daughter's oocytes (gestational surrogate) United States Kristine Casey gave birth to her own grandson Finnean Lee on February 13, 2011, at Prentice Women's Hospital in Chicago, Illinois, at the age of 61. She chose to act as a surrogate for her 36-year-old daughter Sara Connell, who is infertile. Kidney complications affecting the surrogate mother shortly after birth were quickly resolved.[157] 61 years October 2012 Antônia Letícia Asti Her 55-year-old husband, José César Asti Postmenopausal IVF treatment with her own frozen oocytes Brazil Antônia Letícia Asti, a Brazilian woman from Santos, 40 km south-east São Paulo, State of São Paulo, gave birth, two months before term, to twins, Sofia and Roberto, weighing 900 g (less than 2 lb) each, on October 26, 2012, one week after her a 61st birthday, after a postmenopausal IVF treatment using her own frozen oocytes fertilized by her husband (age 55 at the twins birth) remaining after their three previous unsuccessful attempts since 1992.[158] 61 years March 2019 Cecile Eledge Her son (gestational surrogate) Postmenopausal IVF treatment with son-in-law's sister's oocytes donation (gestational surrogate) United States Cecile Eledge, a woman living in Nebraska, gave birth to her own granddaughter Uma on March 25, 2019, at the age of 61. She chose to be a gestational surrogate for her son and his husband and used IVF with oocytes donated from her son-in-law's sister and fertilized with her son's sperm.[159] 61 years, 9 months 2007 Unidentified Her husband Postmenopausal IVF treatment with oocytes donation Switzerland Swiss woman became first-time mother in 2007, giving birth to twins, at the age of 61 years and 9 months. She became pregnant abroad at the age of 61 after IVF treatment with oocytes donation, a procedure which is banned in Switzerland. A fellow woman, became pregnant by the same means at 60, still abroad, gave birth to a son at 61 the same year.[155] 62 years August 1992 Concetta Ditessa her 53-year-old husband Postmenopausal IVF treatment with oocyte donation Italy Concetta Ditessa, a housewife from a Calabrian village in southern Italy, was due to give birth to a boy in August 1992. She was impregnated with an egg from a 30-year-old woman that was fertilized with sperm from Ditessa's husband, who is 53. There is no trace of an article about her childbirth, but her pregnancy referred to around 6 months of gestation, she probably has not had a miscarriage at this stage.[160] 62 years May 2001 Jeanine Salomone Robert Salomone, her 52-year-old brother Postmenopausal IVF treatment with oocyte donation France Jeanine Salomone, French retired teacher, gave birth to a son, Benoît-David, on May 14, 2001, in Fréjus, Var, France, at the age of 62. It is against the law in France for post-menopausal women to receive IVF so she went to the US for treatment. The case caused some ethical debate because the two eggs donated to Jeanine by a Californian woman were inseminated with sperm from Jeanine's brother, Robert: one was brought to term by Jeanine, the other by the donor as surrogate, who will give birth the week after, on May 22, 2001, to Marie-Cécile, her biological daughter promised to Jeanine. Their doctor was not informed that Jeanine and Robert were sister and brother; he thought that they were a married couple. The infants were reportedly born into a fraught family atmosphere in which Jeanine and Robert hate each other and are wrangling over a family inheritance.[161] Jeanine Salomone died on June 18, 2015, aged 75.[162] 62 years April 2004 Amma Bhavani Anonymous sperm donor Postmenopausal IVF treatment with oocytes donation India Amma Bhavani, of Thiruvananthapuram, southern India, gave birth to a son by Caesarean section on April 12, 2004, at the age of 62, after an IVF treatment with oocytes donation fertilized by sperm taken from the sperm bank.[163] The boy named Kannan drowned in a bucket in 2006, and in 2008 Bhavani, aged 66, was preparing for the second IVF attempt.[164] 62 years (also 59 years) February 2006 Janise Wulf Scott Wulf, her 48-year-old second husband Postmenopausal IVF treatment with oocytes donation United States Janise Wulf of Redding, California, gave birth to a boy, Adam Charles, her 12th child, on February 19, 2006, at the age of 62. The baby was delivered by Caesarean section, weighing 6 lb 10 oz (3.00 kg), and was conceived through in-vitro fertilization (IVF). Her doctor stated that, for women over 35, giving birth can have risks, but he agreed to oversee the procedure because Janise Wulf was in good health. She and her second husband, Scott, said that they decided to have children together because Scott had not had any children in his previous marriage, and because they did not want their other son, Ian, born late 2002, also conceived through IVF, to grow up an only child. Of the 10 children Janise Wulf had previously, before Ian, the oldest was 40 at the time of the birth, and the youngest was 24. Janise Wulf also has 20 grandchildren and 3 great-grandchildren.[165][166] 62 years July 2006 Patricia "Patti" Rashbrook Farrant John Farrant, her 60-year-old husband, until then childless Postmenopausal IVF treatment with oocytes donation United Kingdom Patricia Rashbrook, already mother of 3 adults children, ages 26, 22, and 18, from her first union, gave birth to a son, Jude, in Brighton, England on July 5, 2006, at the age of 62. She and her husband, John Farrant, received, in Russia, IVF treatment from the same Italian fertility expert who the Della Cortes had consulted, Severino Antinori. The birth of the baby, which was born by Caesarean section and weighed 6 lb 10.5 oz (3.02 kg), sparked debate over the ethics of late motherhood in the U.K.[167][168] 62 years July 2007 Mileva Radulovic Sreten Radulovic, her 69-year-old husband Postmenopausal IVF treatment with oocytes donation Montenegro Mileva Radulovic of Danilovgrad, northwest of Podgorica, Montenegro, gave birth in July 2007, at the age of 62. Radulovic and her 69-year-old husband Sreten became first time parent after 35 years of marriage with the help of IVF treatment.[169] As of March 2015, Mileva was a widow and her son, Savo, was a schoolboy.[170] 62 years May 2010 Krasimira Dimitrova Anonymous sperm donor Postmenopausal IVF treatment with oocytes donation Bulgaria Bulgarian psychiatrist Krasimira Dimitrova, from Ruse, Bulgaria, gave birth on May 5, 2010 to female twins, Mary and Jacqueline, weighing only 0.5 and 0.9 kg, after IVF treatment, at the age of 62. She decided to become pregnant after she was refused the option of adoption because of her age. Jacqueline died on June 13, 2010.[171] Dimitrova was initially impregnated with triplets, but later doctors decided to remove one of the foetuses. She is only the second known woman aged over 60 that has given birth to twins.[172] As of April 2018 Dimitrova was still alive and Mary was in the second grade.[173] 62 years February 2015 Galina Shubenina Her husband Postmenopausal IVF treatment with oocytes donation Russia Galina Shubenina of Moscow gave birth to a daughter in February 2015, at the age of 62. She wanted to have a child after the death of her son from previous marriage.[174] 62 years, 6 months 1887 Unidentified Her husband Natural conception England The Lancet Medical Journal reported in 1887 the case of an English woman who had given birth, at the age of 62 years and 6 months, to three boys, real triplets, her 11th, 12th, and 13th children with her husband.[175] 62 years, 9 months July 1994 Rosanna Della Corte Mauro Della Corte, her husband Postmenopausal IVF treatment with oocytes donation Italy Rosanna Della Corte of Canino, Italy gave birth to a son, Riccardo, on July 18, 1994, at the age of 62. After their first son was killed when a car crashed into his motorcycle in 1991, Rosanna Della Corte and her husband, Mauro, decided to attempt to have a second child. The couple tried to adopt, but were unable to, as under Italian law an adoptive parent could be no more than 40 years older than their potential child. Mauro read in the newspaper about an Italian doctor, Severino Antinori, who had helped a woman in her late 50s have a child. With Dr. Antinori's help, the Della Cortes conceived through IVF with oocytes donation and Mauro's sperm. Rosanna, 60, became pregnant on the first attempt, but miscarried after 40 days, and it took 6 more attempts before there was success. She was then just 62.[176] 63 years April 1997 Unidentified Her 60-year-old husband Postmenopausal IVF treatment with oocytes donation United States An anonymous menopausal 63-year-old woman, remained childless, who had claimed to doctors to be only 55 to be eligible for the program of artificial insemination, gave birth to a 6 lb 4 oz baby girl, on April 23, 1997, at the Hospital of the University of Southern California's School of Medicine, in Los Angeles, after IVF with a young anonymous donor's oocyte fertilized by her 60-year-old husband's sperm, and frozen embryo transfer.[177][178] 63 years March 2011 Tineke Geessink Anonymous sperm donor Postmenopausal IVF treatment with oocytes donation Netherlands Tineke Geessink of Harlingen, Netherlands, gave birth to daughter Meagan on March 22, 2011, at the age of 63. Single mother Tineke Geessink, currently the oldest woman in the Netherlands to ever give birth, explained to press that she had always longed for a child and chose to do so "whatever way she could". She was treated by the famous Italian doctor Severino Antinori, who implanted a donated oocyte fertilized with donated sperm; the Dutch limit for such treatments is at age 45.[179] The announcement of Geessink's pregnancy sparked a debate about the ethics of late motherhood in the Netherlands. Geessink died on June 25 2020, leaving behind her, then, 9-year-old daughter.[180] 63 years August 2016 Unidentified Unidentified Donor IVF Australia A woman in Australia successfully gave birth at 63 in Melbourne, Victoria, according to newspapers and current affairs. The woman and the father formally requested to remain unidentifiable. She received an embryo implantation overseas. She is Australia's oldest first mother. Father is an unidentified 78-year-old. The child was born prematurely, at 34 weeks gestation, both mother and child are healthy. She is a Tasmanian. 63 years, 9 months November 1996 Arceli Keh Isagani Keh, her 57-year-old husband Postmenopausal IVF treatment with oocytes donation United States Arceli Keh of Highland, California, gave birth to a daughter, Cynthia, on November 7, 1996, at the age of 63 years and 9 months. She and her husband, Isagani, had been married for 16 years when they decided to try to have a child. In order to gain admission to a fertility program that had an upper age limit of 55, Kehs told doctors that she was 50, although she was in fact 10 years older at the time. Five IVF transfer cycles were required before Arceli Keh successfully became pregnant. The ovum came from a donor and was fertilized with sperm from Arceli's husband.[14][181] 64 years February 2004 Papathiammal Subramaniam Her 74-year-old husband, without son Postmenopausal IVF treatment with her 30-year-old cousin's oocyte, and selected her husband's Y sperm India Papathiammal Subramaniam gave birth to a son in Erode, Tamil Nadu, India on February 23, 2004, at the age of 64. The baby was delivered by Caesarean section and weighed 1.75 kg (3.8 lb). He was conceived through IVF, with an ovum donated by a 30-year-old Papathiammal's cousin and the sperm of Papathiammal's husband, a 74-year-old farmer until then remained without son.[182] 64 years June 2004 Unidentified Anonymous sperm donor Postmenopausal IVF treatment with oocytes donation Israel 64-year-old Israeli woman gave birth to a son in June 2004 in Tel Aviv after receiving a postmenopausal IVF with oocytes and sperm donations.[183][184] 64 years October 2006 Memnune Tiryaki Omer Tiryaki, her 62-year-old husband Postmenopausal IVF treatment with oocytes donation Turkey Memnune Tiryaki gave birth to her first child, son Yasin, in Istanbul, Turkey, on October 9, 2006, at the age of 64, after IVF treatment with oocytes donation, practiced in Turkish occupied section of Cyprus. Tiryaki and her 62-year-old husband were trying to have children for 35 years.[185] 64 years July 2010 Dominique C. Daniel C., her 60-year-old husband Postmenopausal IVF treatment with oocytes donation Switzerland 64-year-old Swiss woman, from Oberlunkhofen, Canton of Argovie, western Zurich, Switzerland, whose husband was 60, gave birth to their first child, daughter Katerina, in July 2010, after IVF treatment with oocyte(s) donation. She went to Russia for IVF using donor eggs, after a miscarriage at the age of 61, because egg donation is illegal in Switzerland.[186] 65 years April 2003 Satyabhama Mahapatra Her husband Krishnachandra's niece's husband Postmenopausal IVF treatment using her husband's niece Veenarani's oocyte India Satyabhama Mahapatra of Nayagarh, Odisha, India gave birth to a son on April 9, 2003, in Raipur, at the age of 65. The baby, weighing 6 lb 8 oz (2.95 kg) was born by Caesarean section. Mahapatra became pregnant through the help of IVF using an ovum donated by 26-year-old niece Veenarani Mahapatra (of her husband Krishnachandra Mahapatra) and spermatozoons from the husband of the latter. Krishnachandra could not fertilize his niece's oocyte himself. This was their first child after 50 years of marriage. Doctors had attempted to persuade the couple not have IVF. Satyabhama Mahapatra was also hospitalized for the last trimester of her pregnancy.[187] 65 years May 2015 Haya Shahar Shmuel, her 67-year-old husband Postmenopausal IVF treatment with oocytes donation Israel Haya Shahar, of Bnei Brak, Israel, who was unable to have a baby during her 46-year marriage with Shmuel, gave birth to a son in May 2015 at Meir Medical Center in Kfar Saba. She became the oldest woman in Israel to give birth. The IVF was performed abroad since it is illegal in Israel to perform IVF on a woman over 54.[188] 65 years May 2015 Annegret Raunigk Unknown sperm donor Postmenopausal IVF treatment with oocytes donation Germany Annegret Raunigk, a Berliner, age 55 years and 9 months, professor of English and Russian, already the mother of 12 children (5 girls and 7 boys) ages 34 to 13 years – Antje (♀) 34, Ellen (♀) 31, Bjarne (♂) 30, Torben (♂) 27, Lieven (♂) 25, Tjard (♂) 24, Inken (♀) 23, Svea (♀) 20, Lennart (♂) 19, Velten (♂) 18, Ingvar (♂) 17, and Auda (♀) 13, all with Nordic names to be distinct from those of her students, born of five different fathers, and grandmother of six grandchildren ages 16 years to 6 months, gave birth, in late October 2005, in Berlin, Germany, to a daughter, Lelia, her 13th child, conceived naturally. Shortly before this last delivery, she had to flee with her six cadets children still living at home, in Hungary, where is born her last grandson.[189][190] In May 2015, Raunigk gave birth to quadruplets at age 65 after IVF with donated eggs.[191] 65 years October 2019 Xinju Tian (田新菊) Weiping Huang (黄维平) her 68-year-old husband Natural conception China [192] Tian's age was previously reported as 67, but it was later corrected to 65. The couple has two children before this one. Their oldest grandchild is now 18 years old.[193] 66 years April 1999 Harriet Stole Ross Stoll, her son (gestational surrogate) Postmenopausal IVF treatment with her daughter-in-law's oocytes (gestational surrogate) United Kingdom Harriet Stole of Southgate, North London gave birth to a son, Henry Thomas, in April 1999 at age 66 after agreeing to be a surrogate mother for her infertile daughter in-law (Lucy Handerson Stole). Lucy and her husband- Harriet's son (Ross Stole) had an egg fertilized and later implanted into the womb of Harriet. The child was born prematurely at 8 months, weighing 4 pounds 5 oz, but survived and is healthy.[194] 66 years March 2007 Unidentified Her husband Postmenopausal IVF treatment with oocytes donation Austria An unnamed Austrian woman gave birth to her third child in early March 2007 at the age of 66 in Graz. She had previously given birth to another child, a girl weighing 6 lb (2.72 kg), in the middle of December 2002 at the age of 61. Her oldest child- a daughter, is 30. Both pregnancies over 60 were made possible by IVF with oocytes donation. The second was overseen by Severino Antinori. This may be the only known case in the world of two pregnancies and births at over age 60.[152] 66 years May 2009 Elizabeth Adeney Ukrainian anonymous sperm donor Postmenopausal IVF treatment with oocytes donation United Kingdom Elizabeth "Lizzie" Adeney, aged 66, gave birth to a 5 lb 3oz son, Jolyon, in Addenbrooke's Hospital, Cambridge, England, on May 28, 2009, becoming Britain's oldest mother. The child, who was conceived through IVF treatment in Ukraine from oocyte and sperm donations, was delivered by Caesarean section.[195] 66 years February 2011 Valentyna Pidverbna Anonymous sperm donor Postmenopausal IVF treatment with oocytes donation Ukraine Valentyna Pidverbna, unmarried woman, aged 66, gave birth to her first child, a girl weighing 3.3 kg and being 54 cm height in Chernihiv, Ukraine in February 2011. She underwent three cycles of IVF treatment to achieve positive results.[196] 66 years March 2012 Unidentified Anonymous Ukrainian sperm single donor Postmenopausal IVF treatment with oocytes donation Switzerland 66-year-old Swiss Protestant pastor living in Grüsh, near Coire, in the eastern canton of Graubuenden gave birth to two boys, Michael & Joshua by Caesarean section on March 3, 2012 after receiving IVF treatment with eggs and sperm donor in Ukraine.[197] 66 years June 2010 Bhateri Devi Singh Deva Singh, her 64-year-old husband Postmenopausal IVF treatment with oocytes donation India Bhateri Devi, previously childless Indian woman, gave birth to triplets, two boys and a girl, in Alewa, Haryana, North of Delhi, at the age of 66, after IVF treatment with oocytes donation. One of the triplets died some days after the birth.[198] As of October 2014, Devi was still alive.[199] 66 years, 7 months, 16 days January 2005 Adriana Iliescu Anonymous sperm single donor Postmenopausal IVF treatment with oocytes donation Romania Adriana Iliescu, born on May 31, 1938, gave birth to a daughter Eliza Maria at a hospital in Bucharest, Romania by Caesarean section on January 16, 2005 at the age of 66 years, 7 months and 16 days. After undergoing IVF using donated eggs, Iliescu initially became pregnant with triplets, but one of the fetuses died in utero. The other two were delivered by caesarean section, but one of them was stillborn. New York Daily News said that she was the oldest recorded woman to deliver a child until 2008 when Omkari Panwar gave birth to twins.[200] 66 years, 11 months, 24 days December 2006 Maria del Carmen Bousada de Lara Two sperm donors selected from a catalog Postmenopausal IVF treatment with oocytes donation Spain Maria del Carmen Bousada de Lara called Carmela Bousada (b. January 5, 1940, d. July 11, 2009, age 69), from Cadix, Spain, gave birth to twin sons, Pau and Christian, at Sant Pau Hospital in Barcelona, Spain, on December 29, 2006, at the age of 66 years, 11 months, and 24 days — one week before her 67th birthday. The babies were delivered prematurely by Caesarean section and weighed 3.5 lb (1.6 kg) each. M.C. Bousada became pregnant after receiving IVF treatment with oocytes donation and two sperm donors selected from a catalog from a fertility clinic in Los Angeles, California, which claims that Bousada informed them that she was 55 (their maximum age for IVF treatment). Her family was unaware that she had gone to the United States to undergo fertility treatment prior to the births, and thought she was joking when she told them she was pregnant. Manuel Bousada de Lara, Maria del Carmen's older brother, criticized her decision, expressing concern over whether she would be able to raise children at her age. In response to such concerns, Bousada stated, "My mum lived to be 101 and there's no reason I couldn't do the same".[201] Maria died on July 11, 2009 from stomach cancer, which she developed soon after giving birth to her twins; her sons were only 2 ½ years old then.[202] 68 years April 2020 Margaret Adenuga Noah Adenuga, her 77-year-old husband Postmenopausal IVF treatment with oocytes donation Nigeria Margaret Adenuga went through three previous IVF procedures before finally having twins. The babies were delivered via caesarian section at 37 weeks at the Lagos University Teaching Hospital (LUTH) but the hospital only recently made the news public to give the first-time mother time to recuperate.[203] 70 years June 2008 Omkari Panwar Charan Singh Panwar, her 77-year-old husband Postmenopausal IVF treatment with oocytes donation India Omkari Panwar gave birth to twins, a boy and a girl, in Muzaffarnagar, Uttar Pradesh, via emergency Caesarean section, on June 27, 2008, at the age of 70. The babies weighed 2 pounds each. Omkari became pregnant through IVF treatment with a single oocytes donor, process which she and her husband pursued in order to produce a male heir. Omkari has two adult daughters and five grandchildren. However, Omkari does not have a birth certificate, her age has been estimated by her claim that she was 9 years old when the British Raj left India in 1947. In response to hearing that she had possibly broken the record for world's oldest mother, Omkari stated, "If I am the world's oldest mother it means nothing to me. I just want to see my new babies and care for them while I am still able."[200] 70 years November 2008 Rajo Devi Lohan Baba Ral "Ballo" Lohan, her 71-year-old husband Postmenopausal IVF treatment with oocytes donation India Rajo Devi Lohan gave birth to a daughter, Naveen, at the age of 70.[204][205] Lohan's health soon deteriorated and nearly died due to complications following childbirth. As of October 2014, Lohan and her husband were still alive.[199] 72 years April 2016 Daljinder Kaur Mohinder Singh Gill, her 79-year-old husband Postmenopausal IVF treatment with oocytes donation India Daljinder Kaur gave birth to a son, Arman, on April 19, 2016, after nearly five decades of marriage and two unsuccessful IVF tries. Kaur stated her age as 70 at the time of birth, but the clinic where she had IVF treatments stated she was 72.[206] 74 years September 2019 Mangayamma Yaramati Sitarama Rajarao, her 82-year-old husband Postmenopausal IVF treatment with oocytes donation India [207] ## Debate[edit] Pregnancies among older women have been a subject of controversy and debate. Some argue against motherhood late in life on the basis of the health risks involved, or out of concern that an older mother might not be able to give proper care for a child as she ages, while others contend that having a child is a fundamental right and that it is commitment to a child's wellbeing, not the parents' ages, that matters.[208][209][210] A survey of attitudes towards pregnancy over age 50 among Australians found that 54.6% believed it was acceptable for a postmenopausal woman to have her own eggs transferred and that 37.9% believed it was acceptable for a postmenopausal woman to receive donated ova or embryos.[211] Governments have sometimes taken actions to regulate or restrict later-in-life childbearing. In the 1990s, France approved a bill which prohibited postmenopausal pregnancy, which the French Minister of Health at the time, Philippe Douste-Blazy, said was "... immoral as well as dangerous to the health of mother and child". In Italy, the Association of Medical Practitioners and Dentists prevented its members from providing women aged 50 and over with fertility treatment. Britain's then-Secretary of State for Health, Virginia Bottomley, stated, "Women do not have the right to have a child; the child has a right to a suitable home".[210] However, in 2005, age restrictions on IVF in the United Kingdom were officially withdrawn.[212] Legal restrictions are only one of the barriers confronting women seeking IVF, as many fertility clinics and hospitals set age limits of their own.[201] ## See also[edit] * List of oldest birth fathers * List of oldest birth mothers * List of people with the most children * List of multiple births * List of youngest birth fathers * List of youngest birth mothers * Mother * Pregnancy * Sarah and her son Isaac * Sexuality in older age ## References[edit] 1. ^ Advanced Fertility Center of Chicago, Female Age, Fertility and Infertility [1] 2. ^ "Fertility tests for women". 3. ^ A man’s age matters https://yourfertility.org.au/for-men/age/ Archived 2018-03-29 at the Wayback Machine 4. ^ a b c "How Age Matters For Your Fertility | Your Fertility". 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Archivio – la Repubblica.it. 118. ^ a b "Sixty-year-old woman gives birth to baby". The Times of India. 119. ^ "Oldest mum of twins 'goes against nature'". 120. ^ "Oldest Parents of Twins Archived 2010-12-01 at the Wayback Machine". 121. ^ "I Gave Birth to My Grandkids". 122. ^ "Woman gives birth to boy at 58". 123. ^ "Donna di 58 anni partorisce una bambina al Sant'Anna di Torino". Archived from the original on 2013-11-02. 124. ^ "UK mom, 58, gives birth to IVF twins | General center | SteadyHealth.com". ic.steadyhealth.com. 125. ^ "Napoli, a 58 anni diventa mamma di tre gemelli Archived 2013-11-02 at the Wayback Machine" Retrieved October 27, 2012 126. ^ a b "59-Year-Old Woman Delivers Twins." People. Retrieved November 2, 2010. 127. ^ Benöhr-Laqueur, Susanne "Sollten Frauen jenseits der Menopause Mütter werden können? - Eine rechtspolitische Analyse Archived 2012-03-22 at the Wayback Machine" DIE HEBAMME, 2008, Heft 21, S. 150 ff 128. ^ "Deutschland Älteste Gebärende ist doch etwas jünger"Welt. Retrieved December 1, 2008. 129. ^ "Mom, 56, Shows Off New Twins". 130. ^ "Birth to 59-Year-Old Briton Raises Ethical Storm". 131. ^ Basnett, Guy, & Calvert, Gemma. (n.d.) "The World's Oldest Natural Mum at 58." News of the World. Retrieved September 28, 2007. 132. ^ Farmer, Ben. (August 20, 2007). "UK woman, 59, world's oldest natural mother." The Telegraph. Retrieved September 28, 2007. 133. ^ "Woman, 59, has second test-tube baby". 134. ^ (in Russian) "Жительница Сочи родила первенца в 59 лет" 135. ^ "The fertility tourists". 136. ^ France: Woman, 59, is oldest mother of triplets 137. ^ "59-year-old woman gives birth after trying for decades". 138. ^ "She gave birth at 60, she was raising 10-year old twins at 70, and she is happy with them at 83". 139. ^ a b "I gave birth at 60". IOL. 140. ^ "Examples Of Unusual Relationships And Genealogical Rareties". 141. ^ "Japanese Woman Gives Birth at 60". 142. ^ "60-Year-Old Woman Gives Birth To Twins." (May 24, 2007). CBS News. Retrieved May 25, 2007. 143. ^ "60-year-old Calgary woman gives birth to twins" 144. ^ "Chinese woman, 60, gives birth to twins". Telegraph.co.uk. 27 May 2010. 145. ^ "Шестидесятилетняя бразильянка стала суррогатной матерью своей внучки | В мире | Лента новостей "РИА Новости"". Rian.ru. 2010-09-28. Retrieved 2012-08-13. 146. ^ a b "Medical Miracle: 60 years old woman delivers a healthy child". Archived from the original on 2016-01-20. 147. ^ "Age is no worry for miracle mom-at-60, saya God has a plan". Archived from the original on 2015-12-14. Retrieved 2016-02-05. 148. ^ "MAJKA U 60. GODINI Ona je druga najstarija porodilja u ISTORIJI SRBIJE i evo šta o tome IMA DA KAŽE " 149. ^ "Stiri – stiri online, stiri TV, stiri video, stiri mobil – REALITATEA.NET". REALITATEA.NET. 6 April 2016. Archived from the original on 1 August 2010. 150. ^ "Family Records". www.nealirc.org. 151. ^ "Turning Back the Clock". 152. ^ a b "Austria: 66-year-old woman gives birth to healthy baby." (March 28, 2007). International Herald Tribune. Retrieved April 18, 2007. 153. ^ (in German) "Die Geheimnisse der späten Mutter." (n.d.). Österreich. Retrieved June 23, 2007. 154. ^ "61-årig føder pige på Riget". 28 February 2007. 155. ^ a b "Switzerland records first over-60 mothers". 156. ^ "61-Year-Old Gave Birth To Her Grandchild". 157. ^ "Grandmother, 61, gives birth to daughter's baby". 158. ^ "Antônia Letícia Asti, 61 Year-Old Brazilian Woman, Gives Birth To Twins". 159. ^ "To help gay son, 61-year-old woman gives birth to own grandchild". NBC News. 160. ^ "Stories of Pregnancy and Birth over 40 years old: 03/2012 – 04/2012". Pregnancyover44.com. Retrieved 2012-08-13. 161. ^ "BBC News – EUROPE – Doctor hits back in IVF row". 2001-06-21. 162. ^ "Espace souvenirs de Jeanine SALOMONE - Dans Nos Coeurs". 163. ^ Reporter, Our Staff (May 5, 2004). "62-year-old woman gives birth to baby boy" – via www.thehindu.com. 164. ^ "At 66, her quest for motherhood is still on". Sify. 165. ^ "Great-Grandmother Gives Birth at 62." (February 19, 2006). ABC News. Retrieved March 4, 2003. 166. ^ Goldenberg, Suzanne. (February 23, 2006). "Woman, 62, gives birth to 12th child." The Guardian. Retrieved March 4, 2007. 167. ^ "62-year-old British woman gives birth." (July 10, 2006). CTV.ca. Retrieved March 4, 2007. 168. ^ "Briton becomes new mother at 62." (July 8, 2006). BBC News. Retrieved March 4, 2007. 169. ^ "Montenegro woman has first child at 62 Archived 2011-07-22 at the Wayback Machine". 170. ^ Radojević, Vesna (29 March 2015). ""Majka hrabrost" koja je rodila u 62-oj, danas sama podiže sina: Nikada se ne predajem". 171. ^ "Почина едно от близначетата на 62-годишната Красимира | Dnes.bg". www.dnes.bg. 172. ^ "Bulgarian Psychiatrist Becomes Mother at 62." 173. ^ Най-възрастната родилка спря да излиза 174. ^ "Родившая в 62 года жительница Москвы назвала дочь Клеопатрой » Информинг. Информируем о главном". informing.ru. 175. ^ Russell, Alan; McWhirter, Norris D. (1987). The Guinness book of records 1988. ISBN 9780851128689. 176. ^ D'Emilio, Frances. (July 22, 1997). "A child to relieve her grief Archived 2004-11-09 at the Wayback Machine." SouthCoast Today. Retrieved March 4, 2007. 177. ^ "Becoming a 63-Year-Old Mom : Is it Ethical?" 178. ^ "MIRACLE MOM ?" 179. ^ "Mother Geessink (63): Young mothers are not always better". 180. ^ "Tineke Geessink, die op haar 63e moeder werd, overleden" [Tineke Geessink, who became mother at 63, passed away]. NOS.nl (in Dutch). NOS. Retrieved July 11, 2020. 181. ^ "18 Ways to Make a Baby: Student Handout." (2001). NOVA Online . Retrieved March 7, 2007. 182. ^ "64-year-old woman delivers baby." (February 23, 2004). BBC News. Retrieved March 4, 2007. 183. ^ "Woman Gives Birth in Tel HaShomer at the Age of 64 – Latest News Briefs – Arutz Sheva". Arutz Sheva. 184. ^ "Bahrain News Agency – 64-Year-old Israeli woman gives birth". 185. ^ "Turkish woman gives birth at the age of 64 Archived 2011-07-16 at the Wayback Machine". 186. ^ "When I’m 64 – I’ll have my first child". 187. ^ "Indian 'is world's oldest mother'." (April 9, 2003). BBC News. Retrieved March 4, 2007. 188. ^ "At 65, hassidic woman from Bnei Brak becomes oldest in Israel to give birth". The Jerusalem Post – JPost.com. 189. ^ "Späte Mutter? Blödsinn!". derStandard.at. 190. ^ "schon gelesen? schaut mal!!! | Forenarchiv | Alle Antworten für Eltern". www.rund-ums-baby.de. 191. ^ Jethro Mullen, CNN (24 May 2015). "Report: German woman, 65, gives birth to quadruplets". CNN. 192. ^ 观察者网 (October 25, 2019). "山东枣庄67岁孕妇自然受孕产女 68岁丈夫：天赐的". 193. ^ 祖一飞 (November 1, 2019). "六旬夫妇高龄产女之后". 194. ^ "Penn Medical Ethics and Health Policy | Home". medicalethicshealthpolicy.med.upenn.edu. 195. ^ Oppenheimer, Jeni (June 2, 2009). "Britain's oldest mother Elizabeth Adeney takes son home" – via www.telegraph.co.uk. 196. ^ "66-YEAR-OLD UKRAINIAN WOMAN GAVE BIRTH TO A HEALTHY GIRL". www.ukrainiansurrogates.com. 197. ^ "Swiss Woman, 66, Has Twins After IVF Treatment In Ukraine". RadioFreeEurope/RadioLiberty. 198. ^ Chinki Sinha (July 2, 2010). "Bhateri's child dies, other 2 still at child care centre". Indian Express. 199. ^ a b "The older Indian women having children". BBC News. 200. ^ a b Daily News Staff (July 4, 2008). "70-year-old woman becomes world's oldest mother with birth of twins". Retrieved November 30, 2014. 201. ^ a b Appel, Jacob M. Motherhood: Is It Ever Too Late? July 15, 2009. 202. ^ Spanish Maria del Carmen Bousada de Lara World's oldest mother dies at 69 Archived 2011-10-02 at the Wayback Machine, Barcelona Reporter July 15, 2009 203. ^ Nigerian woman, 68, gives birth to twins after four IVF attempts 204. ^ "Woman who gave birth at 70 sparks motherhood debate". thestar.com. 6 November 2010. 205. ^ Randeep Ramesh. "Randeep Ramesh meets Rajo Devi Lohan, the world's oldest mother". the Guardian. 206. ^ Arshad R. Zargar; Ashley Welch (12 May 2016). "Woman in her 70s may be oldest ever to give birth". CBS News. Retrieved 12 May 2016. 207. ^ "74-year-old woman gives birth to twins". Washington Post. 208. ^ "Motherhood At Mid-Life—A Medical and Ethical Dilema Archived 2013-09-29 at Archive.today." (July 1997). St. Louis Times. Retrieved March 4, 2007. 209. ^ Hinman, Lawrence M. (April 30, 1997). "What Counts in Parenthood? Archived 2007-07-30 at Archive.today." San Diego Union-Tribune. Retrieved March 4, 2007. 210. ^ a b Hinman, Lawrence M. Are Some Parents Too Old? Archived 2003-02-10 at Archive.today. Retrieved March 4, 2007. 211. ^ Bowman, M. C., & Saunders, D. M. (1994). Community attitudes to maternal age and pregnancy after assisted reproductive technology: too old at 50 years?. Human Reproduction, 9 (1), 167-171. Retrieved March 4, 2007. 212. ^ Gray, Louise. (November 3, 2005). "Couples any age to be allowed to apply for fertility treatment." The Scotsman. Retrieved March 4, 2007. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Pregnancy over age 50

None

wikipedia

https://en.wikipedia.org/wiki/Pregnancy_over_age_50

{"wikidata": ["Q2372105"]}

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: "Throat irritation" – news · newspapers · books · scholar · JSTOR (September 2018) Throat irritation can refer to a dry cough, a scratchy feeling at the back of the throat, a sensation of a lumpy feeling, something stuck at the back of the throat, or possibly a feeling of dust in the throat. The symptoms are unpleasant and usually temporary, but occasionally signifies a more serious health issue, such as laryngitis. ## Contents * 1 Common cold * 2 Coronavirus disease 2019 * 3 Allergy * 4 Laryngitis * 5 Pharyngitis * 6 Epiglottitis * 7 Post-nasal drip * 8 Strep throat * 9 Acid reflux * 10 Post-viral cough * 11 Cancer * 12 Diagnosis * 13 Treatment * 14 References ## Common cold[edit] Main article: Common cold ## Coronavirus disease 2019[edit] Main article: Coronavirus disease 2019 ## Allergy[edit] See also: Allergy During the summer months, allergies are a common cause of throat irritation. Many individuals have allergies to pet dander, dust, mites, pollen and molds that can trigger an allergic reaction which present with runny nose, red eyes, congested nose and throat irritation. Often a dry cough may also be present.[1] ## Laryngitis[edit] See also: Laryngitis It is inflammation of the voice box which can occur from overuse, irritation or an infection. Laryngitis can be a short term illness or a prolonged problem. The majority of cases of laryngitis are due to viral infections which only last a few days. Laryngitis is often a common complaint in individuals who sing. Opera singers or those who yell at sporting events strain the throat muscles and develop a case of laryngitis. ## Pharyngitis[edit] See also: Pharyngitis Viruses are common causes of the common cold. Less often, bacteria may also cause pharyngitis. Both of these organisms enter the body via the nose or mouth as aerosolized particles when someone sneezes or coughs. Because many germs are contagious, one can even acquire them from touching utensils, toys, personal care products or door knobs. The most common viruses that causes throat irritation include the common cold virus, influenza, infectious mononucleosis, measles and croup. Most bacteria and viruses usually induce throat irritation during the winter or autumn.[2] ## Epiglottitis[edit] See also: Epiglottitis It is a very serious disorder of the back of the throat near the windpipe. The most common cause of epiglottitis is an infection by the bacteria, H influenza. The condition may present all of a sudden with high fever, severe sore throat, difficult and painful swallowing, drooling saliva, hoarse voice, difficulty breathing and malaise. The condition is life-threatening and needs immediate hospitalization. Epiglottitis is treated with antibiotics. Routine vaccination has made epiglottitis very rare but it still does present in some children. Prompt diagnosis and treatment can be life saving. ## Post-nasal drip[edit] Also called rhinorrhea, is a very common medical disorder that occurs when the nasal tissues are congested and the excess fluid runs either at the back of the throat or out of the nose. Post-nasal drip can be caused by the common cold, allergies to dust, smoking, or pet dander. Even spicy foods can sometimes cause post-nasal drip. Runny nose is not life-threatening but can be uncomfortable and socially unacceptable.[3] ## Strep throat[edit] See also: Streptococcal pharyngitis It is caused by bacteria which if untreated can lead to many other problems in the body. Strep throat is most common in childhood but can affect people of all ages. It may present with throat pain, difficulty swallowing, painful and swollen tonsils, fever, headache, skin rash and flu. The diagnosis of strep throat is straight forward and the treatment requires a course of penicillin. However, if the treatment is not adequate, rheumatic fever can occur with resultant damage to the heart valves.[4] ## Acid reflux[edit] See also: Gastroesophageal reflux disease This affliction is a common cause of throat irritation. Normally the stomach produces acid in the stomach which is neutralized in the small intestine. To prevent acid from flowing backwards, the lower part of the swallowing tube (esophagus) has a valve which closes after food passes through. In some individuals, this valve becomes incompetent and acid goes up into the esophagus. Reflux episodes often occur at night and one may develop a bitter taste in the mouth. The throat can be severely irritated when acid touches the vocal cords and can lead to spasms of coughing. To prevent throat irritation from reflux, one should lose weight, stop smoking, avoid coffee beverages and sleep with the head elevated.[5] ## Post-viral cough[edit] A post-viral cough is a lingering cough that follows a viral respiratory tract infection, such as a common cold or flu and lasting up to eight weeks. Post-viral cough is a clinically recognized condition represented within the European medical literature. Patients usually experience repeated episodes of post-viral cough. The heightened sensitivity in the respiratory tract is demonstrated by inhalation cough challenge ## Cancer[edit] Rarely persistent throat irritation and hoarseness may also be from a more serious disorder like cancer. ## Diagnosis[edit] The diagnosis of a throat irritation include a physical exam and throat culture. ## Treatment[edit] The majority of cases of throat irritation usually go away without any treatment. There is no real treatment for throat irritation from a virus. If you have difficulty swallowing then you should drink liquids, suck on lozenges, ice chips or mix salt with warm water to gargle. Bacterial infections generally require antibiotics. Home remedies for throat irritation include gargling with warm water twice a day, sipping honey and lemon mixture or sucking on medicated lozenges. If the cause is dry air, then one should humidify the home. Since smoke irritates the throat, stop smoking and avoid all fumes from chemicals, paints and volatile liquids. Rest your voice if you have been screaming or singing. If you have pharyngitis, avoid infecting others by covering your mouth when coughing and wear a mask.[6] ## References[edit] 1. ^ Allergic Reaction Emedicine Health. Retrieved on 2010-02-05 2. ^ Pharyngitis Analysis American Academy of Family Physicians. Retrieved on 2010-02-05 3. ^ What is Post Nasal Drip Sinus Professionals Online Portal. Retrieved on 2010-02-05 4. ^ Strep Throat Mayo Clinic. Retrieved on 2010-02-05 5. ^ Gastro-oesophageal reflux NetDoctor Portal. Retrieved on 2010-02-05 6. ^ Sore Throat or Pharyngitis MedicineNet. Retrieved on 2010-02-05 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Throat irritation

c0700184

wikipedia

https://en.wikipedia.org/wiki/Throat_irritation

{"umls": ["C0700184"], "wikidata": ["Q7798315"]}

Uremic pericarditis Pericarditis fibrinosa SpecialtyUrology Uremic pericarditis is a form of pericarditis. It causes fibrinous pericarditis.[1] The main cause of the disease is poorly understood.[2] ## Contents * 1 Signs and symptoms * 2 Pathology * 3 Treatment * 4 References * 5 External links ## Signs and symptoms[edit] Fibrinous pericarditis is an exudative inflammation. The pericardium is infiltrated by the fibrinous exudate. This consists of fibrin strands and leukocytes. Fibrin describes an amorphous, eosinophilic (pink) network. Leukocytes (white blood cells; mainly neutrophils) are found within the fibrin deposits and intrapericardic. Vascular congestion is also present. Inflammatory cells do not penetrate the myocardium (as is seen with other presentations of pericarditis), and as a result, this particular variant does not present with diffuse ST elevation on ECG (a classic sign of pericarditis known as stage I ECG changes which are seen with other causes)[1] because the inflammatory cells do not penetrate the myocardium. To naked eye examination, this pathology is referred to as having a "Bread and Butter Appearance". ## Pathology[edit] Uremic pericarditis is associated with azotemia, and occurs in about 6-10% of kidney failure patients. BUN is normally >60 mg/dL (normal is 7–20 mg/dL). However, the degree of pericarditis does not correlate with the degree of serum BUN or creatinine elevation. The pathogenesis is poorly understood.[2] ## Treatment[edit] Uremic pericarditis is effectively treated with hemodialysis and can resolve the symptoms and decrease the size of any pericardial effusion, if present.[3] ## References[edit] 1. ^ a b "CIN'2003. Agarwal: UREMIC PERICARDITIS". Retrieved 2009-03-14. 2. ^ a b Black, R. 2011. 0. <http://www.uptodate.com/contents/pericarditis-in-renal-failure>. 3. ^ Gunukula, SR; Spodick, DH (January 2001). "Pericardial disease in renal patients". Seminars in Nephrology. 21 (1): 52–6. doi:10.1053/snep.2001.18378. PMID 11172559. ## External links[edit] Classification D * ICD-10: N18.8 * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Uremic pericarditis

c0265152

wikipedia

https://en.wikipedia.org/wiki/Uremic_pericarditis

{"icd-10": ["N18.8"], "wikidata": ["Q7900393"]}

Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood, is a rare form of neurodegeneration with brain iron accumulation (NBIA) characterized by early-onset developmental delay and further neurological deterioration in early adulthood. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Beta-propeller protein-associated neurodegeneration

c3550973

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=329284

{"gard": ["12570"], "omim": ["300894"], "icd-10": ["G23.0"], "synonyms": ["BPAN", "NBIA5", "Neurodegeneration with brain iron accumulation type 5", "SENDA", "Static encephalopathy of childhood with neurodegeneration in adulthood"]}

Ocular albinism SpecialtyEndocrinology Ocular albinism is a form of albinism which, in contrast to oculocutaneous albinism, presents primarily in the eyes.[1] There are multiple forms of ocular albinism, which are clinically similar.[2]:865 Both known genes are on the X chromosome. When the term "autosomal recessive ocular albinism" ("AROA") is used, it usually refers to mild variants of oculocutaneous albinism rather than ocular albinism, which is X-linked.[3] ## Types[edit] Name OMIM Gene Description Ocular albinism, type 1 (OA1) 300500 GPR143 Also known as Nettleship–Falls syndrome,[4][5][6] is the most common variety of ocular albinism. OA1 is usually associated with nystagmus, and difficult to otherwise detect in females; males show more readily observable symptoms. Ocular albinism, type 2 (OA2) 300600 CACNA1F[7] Also known as Forsius–Eriksson syndrome[8][9] or "Åland Island eye disease", mostly affects males, though females are often carriers and can sometimes be symptomatic; it is frequently linked with protanopic dichromacy (a form of color blindness) and with night blindness (nyctalopia). Ocular albinism with sensorineural deafness (OASD) 300650 ? (Xp22.3) Is, as its name implies, associated with loss of hearing. May be the same as OA1.[10] ## References[edit] 1. ^ "Ocular albinism - Genetics Home Reference". 2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 3. ^ Hutton SM, Spritz RA (March 2008). "A comprehensive genetic study of autosomal recessive ocular albinism in Caucasian patients". Invest. Ophthalmol. Vis. Sci. 49 (3): 868–72. doi:10.1167/iovs.07-0791. PMID 18326704. Archived from the original on 2019-12-15. Retrieved 2008-06-02. 4. ^ synd/990 at Who Named It? 5. ^ E. Nettleship. On some hereditary diseases of the eye. Transactions of the Ophthalmological Societies of the United Kingdom, 1908-1909, 29: 57-198. 6. ^ H. F. Falls. Sex-linked ocular albinism displaying typical fundal changes in the female heterozygote. American Journal of Ophthalmology, Chicago, 1951, 34: 41-50. 7. ^ Jalkanen R, Bech-Hansen NT, Tobias R, et al. (June 2007). "A novel CACNA1F gene mutation causes Aland Island eye disease". Invest. Ophthalmol. Vis. Sci. 48 (6): 2498–502. doi:10.1167/iovs.06-1103. PMID 17525176. Archived from the original on 2019-12-15. Retrieved 2008-06-02. 8. ^ synd/1336 at Who Named It? 9. ^ Forsius H, Eriksson AW (April 1964). "[A new eye syndrome with X-chromosomal transmission. a family clan with fundus albinism, fovea hypoplasia, nystagmus, myopia, astigmatism and dyschromatopsia.]". Klin Monatsbl Augenheilkd (in German). 144: 447–57. PMID 14230113. 10. ^ Winship IM, Babaya M, Ramesar RS (November 1993). "X-linked ocular albinism and sensorineural deafness: linkage to Xp22.3". Genomics. 18 (2): 444–5. doi:10.1006/geno.1993.1495. PMID 8288253. ## External links[edit] Classification D * ICD-10: E70.3 * ICD-10-CM: E70.31 * ICD-9-CM: 270.2 * MeSH: D016117 External resources * Orphanet: 284804 * GeneReviews/NCBI/NIH/UW entry on Ocular Albinism, X-Linked * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria * v * t * e Pigmentation disorders/Dyschromia Hypo-/ leucism Loss of melanocytes Vitiligo * Quadrichrome vitiligo * Vitiligo ponctué Syndromic * Alezzandrini syndrome * Vogt–Koyanagi–Harada syndrome Melanocyte development * Piebaldism * Waardenburg syndrome * Tietz syndrome Loss of melanin/ amelanism Albinism * Oculocutaneous albinism * Ocular albinism Melanosome transfer * Hermansky–Pudlak syndrome * Chédiak–Higashi syndrome * Griscelli syndrome * Elejalde syndrome * Griscelli syndrome type 2 * Griscelli syndrome type 3 Other * Cross syndrome * ABCD syndrome * Albinism–deafness syndrome * Idiopathic guttate hypomelanosis * Phylloid hypomelanosis * Progressive macular hypomelanosis Leukoderma w/o hypomelanosis * Vasospastic macule * Woronoff's ring * Nevus anemicus Ungrouped * Nevus depigmentosus * Postinflammatory hypopigmentation * Pityriasis alba * Vagabond's leukomelanoderma * Yemenite deaf-blind hypopigmentation syndrome * Wende–Bauckus syndrome Hyper- Melanin/ Melanosis/ Melanism Reticulated * Dermatopathia pigmentosa reticularis * Pigmentatio reticularis faciei et colli * Reticulate acropigmentation of Kitamura * Reticular pigmented anomaly of the flexures * Naegeli–Franceschetti–Jadassohn syndrome * Dyskeratosis congenita * X-linked reticulate pigmentary disorder * Galli–Galli disease * Revesz syndrome Diffuse/ circumscribed * Lentigo/Lentiginosis: Lentigo simplex * Liver spot * Centrofacial lentiginosis * Generalized lentiginosis * Inherited patterned lentiginosis in black persons * Ink spot lentigo * Lentigo maligna * Mucosal lentigines * Partial unilateral lentiginosis * PUVA lentigines * Melasma * Erythema dyschromicum perstans * Lichen planus pigmentosus * Café au lait spot * Poikiloderma (Poikiloderma of Civatte * Poikiloderma vasculare atrophicans) * Riehl melanosis Linear * Incontinentia pigmenti * Scratch dermatitis * Shiitake mushroom dermatitis Other/ ungrouped * Acanthosis nigricans * Freckle * Familial progressive hyperpigmentation * Pallister–Killian syndrome * Periorbital hyperpigmentation * Photoleukomelanodermatitis of Kobori * Postinflammatory hyperpigmentation * Transient neonatal pustular melanosis Other pigments Iron * Hemochromatosis * Iron metallic discoloration * Pigmented purpuric dermatosis * Schamberg disease * Majocchi's disease * Gougerot–Blum syndrome * Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis * Lichen aureus * Angioma serpiginosum * Hemosiderin hyperpigmentation Other metals * Argyria * Chrysiasis * Arsenic poisoning * Lead poisoning * Titanium metallic discoloration Other * Carotenosis * Tar melanosis Dyschromia * Dyschromatosis symmetrica hereditaria * Dyschromatosis universalis hereditaria See also * Skin color * Skin whitening * Tanning * Sunless * Tattoo * removal * Depigmentation * v * t * e X-linked disorders X-linked recessive Immune * Chronic granulomatous disease (CYBB) * Wiskott–Aldrich syndrome * X-linked severe combined immunodeficiency * X-linked agammaglobulinemia * Hyper-IgM syndrome type 1 * IPEX * X-linked lymphoproliferative disease * Properdin deficiency Hematologic * Haemophilia A * Haemophilia B * X-linked sideroblastic anemia Endocrine * Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy * KAL1 Kallmann syndrome * X-linked adrenal hypoplasia congenita Metabolic * Amino acid: Ornithine transcarbamylase deficiency * Oculocerebrorenal syndrome * Dyslipidemia: Adrenoleukodystrophy * Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency * Pyruvate dehydrogenase deficiency * Danon disease/glycogen storage disease Type IIb * Lipid storage disorder: Fabry's disease * Mucopolysaccharidosis: Hunter syndrome * Purine–pyrimidine metabolism: Lesch–Nyhan syndrome * Mineral: Menkes disease/Occipital horn syndrome Nervous system * X-linked intellectual disability: Coffin–Lowry syndrome * MASA syndrome * Alpha-thalassemia mental retardation syndrome * Siderius X-linked mental retardation syndrome * Eye disorders: Color blindness (red and green, but not blue) * Ocular albinism (1) * Norrie disease * Choroideremia * Other: Charcot–Marie–Tooth disease (CMTX2-3) * Pelizaeus–Merzbacher disease * SMAX2 Skin and related tissue * Dyskeratosis congenita * Hypohidrotic ectodermal dysplasia (EDA) * X-linked ichthyosis * X-linked endothelial corneal dystrophy Neuromuscular * Becker's muscular dystrophy/Duchenne * Centronuclear myopathy (MTM1) * Conradi–Hünermann syndrome * Emery–Dreifuss muscular dystrophy 1 Urologic * Alport syndrome * Dent's disease * X-linked nephrogenic diabetes insipidus Bone/tooth * AMELX Amelogenesis imperfecta No primary system * Barth syndrome * McLeod syndrome * Smith–Fineman–Myers syndrome * Simpson–Golabi–Behmel syndrome * Mohr–Tranebjærg syndrome * Nasodigitoacoustic syndrome X-linked dominant * X-linked hypophosphatemia * Focal dermal hypoplasia * Fragile X syndrome * Aicardi syndrome * Incontinentia pigmenti * Rett syndrome * CHILD syndrome * Lujan–Fryns syndrome * Orofaciodigital syndrome 1 * Craniofrontonasal dysplasia * v * t * e Diseases of ion channels Calcium channel Voltage-gated * CACNA1A * Familial hemiplegic migraine 1 * Episodic ataxia 2 * Spinocerebellar ataxia type-6 * CACNA1C * Timothy syndrome * Brugada syndrome 3 * Long QT syndrome 8 * CACNA1F * Ocular albinism 2 * CSNB2A * CACNA1S * Hypokalemic periodic paralysis 1 * Thyrotoxic periodic paralysis 1 * CACNB2 * Brugada syndrome 4 Ligand gated * RYR1 * Malignant hyperthermia * Central core disease * RYR2 * CPVT1 * ARVD2 Sodium channel Voltage-gated * SCN1A * Familial hemiplegic migraine 3 * GEFS+ 2 * Febrile seizure 3A * SCN1B * Brugada syndrome 6 * GEFS+ 1 * SCN4A * Hypokalemic periodic paralysis 2 * Hyperkalemic periodic paralysis * Paramyotonia congenita * Potassium-aggravated myotonia * SCN4B * Long QT syndrome 10 * SCN5A * Brugada syndrome 1 * Long QT syndrome 3 * SCN9A * Erythromelalgia * Febrile seizure 3B * Paroxysmal extreme pain disorder * Congenital insensitivity to pain Constitutively active * SCNN1B/SCNN1G * Liddle's syndrome * SCNN1A/SCNN1B/SCNN1G * Pseudohypoaldosteronism 1AR Potassium channel Voltage-gated * KCNA1 * Episodic ataxia 1 * KCNA5 * Familial atrial fibrillation 7 * KCNC3 * Spinocerebellar ataxia type-13 * KCNE1 * Jervell and Lange-Nielsen syndrome * Long QT syndrome 5 * KCNE2 * Long QT syndrome 6 * KCNE3 * Brugada syndrome 5 * KCNH2 * Short QT syndrome * KCNQ1 * Jervell and Lange-Nielsen syndrome * Romano–Ward syndrome * Short QT syndrome * Long QT syndrome 1 * Familial atrial fibrillation 3 * KCNQ2 * BFNS1 Inward-rectifier * KCNJ1 * Bartter syndrome 2 * KCNJ2 * Andersen–Tawil syndrome * Long QT syndrome 7 * Short QT syndrome * KCNJ11 * TNDM3 * KCNJ18 * Thyrotoxic periodic paralysis 2 Chloride channel * CFTR * Cystic fibrosis * Congenital absence of the vas deferens * CLCN1 * Thomsen disease * Myotonia congenita * CLCN5 * Dent's disease * CLCN7 * Osteopetrosis A2, B4 * BEST1 * Vitelliform macular dystrophy * CLCNKB * Bartter syndrome 3 TRP channel * TRPC6 * FSGS2 * TRPML1 * Mucolipidosis type IV Connexin * GJA1 * Oculodentodigital dysplasia * Hallermann–Streiff syndrome * Hypoplastic left heart syndrome * GJB1 * Charcot–Marie–Tooth disease X1 * GJB2 * Keratitis–ichthyosis–deafness syndrome * Ichthyosis hystrix * Bart–Pumphrey syndrome * Vohwinkel syndrome) * GJB3/GJB4 * Erythrokeratodermia variabilis * Progressive symmetric erythrokeratodermia * GJB6 * Clouston's hidrotic ectodermal dysplasia Porin * AQP2 * Nephrogenic diabetes insipidus 2 See also: ion channels *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Ocular albinism

c0078917

wikipedia

https://en.wikipedia.org/wiki/Ocular_albinism

{"mesh": ["D016117"], "icd-9": ["270.2"], "icd-10": ["E70.3"], "orphanet": ["284804"], "wikidata": ["Q2831905"]}

Yunis et al. (1980) described a Colombian family in which 10 males in 3 generations, in a typical X-linked recessive pedigree pattern, had the Dyggve-Melchior-Clausen syndrome. The affected males varied in age from 13 to 15 years. Normal intelligence was another difference from the autosomal recessive form. The authors cited some reported families that are equally consistent with X-linked or autosomal recessive inheritance (223800). Spranger (1981) suggested that the disorder described by Yunis et al. (1980) was in fact X-linked SED tarda (313400). INHERITANCE \- X-linked recessive GROWTH Height \- Short stature, disproportionate (short trunk) HEAD & NECK Head \- Brachycephaly \- Normal head circumference Face \- Coarse face \- Prognathism Neck \- Short neck CHEST External Features \- Barrel chest Ribs Sternum Clavicles & Scapulae \- Sternal protrusion SKELETAL \- Restricted joint mobility (shoulders, elbows, hips) \- Spondyloepimetaphyseal dysplasia Skull \- Calvarial thickening (parietal and occipital area) \- Marked pneumatization of paranasal sinuses Spine \- Scoliosis \- Pronounced lumbar lordosis \- Thoracic kyphosis \- Platyspondyly \- Hypoplastic sacrum Pelvis \- Small pelvis \- Small ilium \- Hypoplastic ischii \- Short femoral neck \- Irregular iliac crest \- Coxa vara \- Coxa plana Limbs \- Genu valgum \- Narrow joint spaces \- Hypoplastic distal ulna Hands \- Small carpals \- Short metacarpals \- Cone-shaped epiphyses Feet \- Hallux valgus NEUROLOGIC Central Nervous System \- Normal intelligence MISCELLANEOUS \- See also Dyggve-Melchior-Clausen disease ( 223800 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

DYGGVE-MELCHIOR-CLAUSEN SYNDROME, X-LINKED

c0265286

omim

https://www.omim.org/entry/304950

{"mesh": ["C535726"], "omim": ["304950"], "orphanet": ["239"]}

A number sign (#) is used with this entry because of evidence that hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (HIDEA) is caused by homozygous or compound heterozygous mutation in the P4HTM gene (614584) on chromosome 3p21. Description Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (HIDEA) is an autosomal recessive neurodevelopmental syndrome characterized by global developmental delay, poor or absent speech, hypotonia, variable ocular movement and visual abnormalities, and respiratory difficulties, including hypoventilation, and sleep apnea. Patients may have significant breathing problems during respiratory infections that may lead to early death (summary by Rahikkala et al., 2019). Clinical Features Kaasinen et al. (2014) reported a large Finnish kindred in which 6 individuals had a similar intellectual developmental disorder. The patients lived in the same village, and extensive genealogic work showed a common distant ancestor from the 17th century. The patients, who ranged in age from 14 to 59 years, had delayed walking at about 3.5 to 5 years, although a few never achieved independent walking. The patients were nonverbal, although 1 could speak in simple sentences. All had profoundly impaired intellectual development corresponding to the level of infancy. From early on, the patients were noted to have abnormal eye movements, including rotary pendular nystagmus, exotropia, and strabismus, as well as other ocular anomalies, including poor visual fixation, myopia, hyperopia, astigmatism, and pale retinal pigmentation. Three patients had infantile seizures, and 1 was diagnosed with epilepsy at age 22 years; the other 2 patients had a sleep behavior disorder. Skeletal features included scoliosis, kyphosis, pes planovalgus, mild elbow contractures, hip and knee flexion while walking, and valgus knee deformities. They also had coarse facial features, such as low nasal bridge, prominent forehead and chin, thick lips, and thick hair, as well as a tendency to obesity. Several other presumably affected deceased individuals were noted in the family, but not described in detail. Rahikkala et al. (2019) reported 7 patients from 4 unrelated families with HIDEA syndrome and reviewed the large Finnish family reported by Kaasinen et al. (2014). The families were Finnish, American, Turkish, and Syrian. Four patients died between 7 months and 8 years of age, whereas 3 were alive between 3 and 18 years of age. One patient from the family reported by Kaasinen et al. (2014) died at 61 years of age. The patients had global developmental delay, hypotonia, delayed walking or inability to walk, severe to profound intellectual disability, and poor or absent speech. Those who could walk had a wide-based unsteady gait. Most had seizures associated with EEG abnormalities, mainly multifocal spikes; 1 patient did not have overt seizures, but did have EEG abnormalities. The patients had common respiratory difficulties, including bradypnea and hypoventilation, and obstructive or restrictive sleep apnea, often requiring BiPAP at night. Most patients had recurrent pneumonia, usually associated with significant respiratory distress and sometimes resulting in death. Eye abnormalities included rotary nystagmus, myopia, hyperopia, astigmatism, strabismus, exotropia, achromic fundi, cortical blindness, and optic atrophy. A few patients had evidence of autonomic dysfunction, including hypo- or hyperthermia and constipation. Muscle biopsy from 4 patients was suggestive of defects in mitochondrial function. None of the patients had renal anomalies. Inheritance The transmission pattern of HIDEA in the families reported by Rahikkala et al. (2019) was consistent with autosomal recessive inheritance. Molecular Genetics In 6 patients from a large Finnish kindred with HIDEA, Kaasinen et al. (2014) identified 3 potentially damaging homozygous variants in 3 different genes within the candidate interval at chromosome 3p22-p21 that was identified by linkage analysis. The variants, which occurred in the P4HTM, TKT (606781), and USP4 (603486) genes, all segregated with the disorder in the kindred. In a follow-up report of this family and of 4 other families with a similar disorder, Rahikkala et al. (2019) confirmed that the pathogenic variant responsible for the phenotype was in the P4HTM gene. Five different homozygous or compound heterozygous mutations were found in affected members from the 5 families (614584.0001-614584.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression studies of 3 of the P4HTM variants showed that they caused a significant decrease in the amount of soluble protein compared to wildtype. These findings suggested that the mutations caused structural abnormalities and improper folding of the protein, resulting in a loss of function. Animal Model Leinonen et al. (2016) found that P4htm -/- mice were fertile and had normal life span. Lack of P4htm stabilized Hif1-alpha in cortical neurons under normoxia, whereas in hypoxia it increased expression of certain HIF target genes in tissues with high endogenous P4htm expression levels. Morphologic analysis of P4htm -/- kidneys revealed that, from the age of about 10 months, renal erythropoietin levels increased, leading to accumulation of lipid-containing lamellar bodies in kidney tubuli, inflammation and fibrosis, and after the age of 1 year, glomerular sclerosis and albuminuria. Lack of P4htm resulted in age-related retinal thinning, rosette-like infoldings, and drusen-like structure accumulation in RPE, characteristic of age-related macular degeneration (AMD; see 603075). P4htm -/- mice showed compromised photoreceptor recycling, and electroretinogram analysis revealed impaired cone pathway in adult mice and cone and rod deficiency in middle-aged mice. Leinonen et al. (2016) concluded that P4HTM is required for normal vision and is a candidate for AMD. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (in some patients) Weight \- Obesity (in some patients) HEAD & NECK Head \- Small head circumference (in some patients) Face \- Coarse facial features (in some patients) \- Prominent forehead \- Prominent chin Eyes \- Poor visual fixation \- Strabismus \- Exotropia \- Amblyopia \- Hyperopia \- Myopia \- Astigmatism \- Rotating eye movements \- Pendular nystagmus \- Optic atrophy \- Achromic fundi \- Abnormal eye movements \- Cortical blindness Nose \- Low nasal bridge Mouth \- Thick lips RESPIRATORY \- Hypoventilation \- Bradypnea \- Sleep apnea \- BiPAP at night \- Pneumonia, recurrent ABDOMEN Gastrointestinal \- Constipation SKELETAL Spine \- Scoliosis \- Kyphosis Pelvis \- Hip flexion Limbs \- Knee deformities \- Elbow contractures Hands \- Finger joint hypermobility Feet \- Planovalgus deformities SKIN, NAILS, & HAIR Hair \- Thick coarse hair MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Delayed walking \- Unsteady gait \- Inability to walk \- Intellectual disability, severe to profound \- Poor or absent speech \- Seizures \- EEG abnormalities \- Multifocal spikes \- Slowed background activity Behavioral Psychiatric Manifestations \- Abnormal sleep behavior METABOLIC FEATURES \- Poor temperature regulation \- Hyperthermia \- Hypothermia MISCELLANEOUS \- Onset in infancy \- Death due to respiratory insufficiency may occur MOLECULAR BASIS \- Caused by mutation in the prolyl 4-hydroxylase, transmembrane gene (P4HTM, 614584.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

HYPOTONIA, HYPOVENTILATION, IMPAIRED INTELLECTUAL DEVELOPMENT, DYSAUTONOMIA, EPILEPSY, AND EYE ABNORMALITIES

None

omim

https://www.omim.org/entry/618493

{"omim": ["618493"]}

## Summary ### Clinical characteristics. Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. The first manifestation is progressive gait imbalance (mean age of onset: 4.3 years; range: 2-10 years), followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. All affected individuals have generalized areflexia followed by a peripheral neuropathy and quadriplegia with loss of ambulation about seven to ten years after onset. Hands and feet are short and atrophic. Chorea and upper-limb dystonia are common. Intellect remains normal in some individuals; in others, different degrees of cognitive impairment have been observed. ### Diagnosis/testing. The diagnosis of AOA1 is based on clinical findings (including family history) and exclusion of the diagnosis of ataxia-telangiectasia. Cerebellar atrophy is visible on MRI in all affected individuals. EMG reveals axonal neuropathy in 100% of individuals with AOA1. APTX is the only gene known to be associated with AOA1. ### Management. Treatment of manifestations: May include physical therapy, particularly for disabilities resulting from peripheral neuropathy; a wheelchair for mobility, usually by age 15-20 years; educational support for difficulties with speaking, reading, and writing. Prevention of secondary complications: High-protein diet to prevent edema by restoring serum albumin concentration; low-cholesterol diet. Surveillance: Routine follow up with a neurologist. ### Genetic counseling. AOA1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if both pathogenic variants in a family have been identified. ## Diagnosis ### Suggestive Findings Diagnosis of ataxia with oculomotor apraxia type 1 (AOA1) should be suspected in individuals with the following combination of clinical features and test results. Clinical features * Cerebellar ataxia, oculomotor apraxia, and areflexia followed by signs of severe peripheral neuropathy * Childhood onset * Slow progression leading to severe motor handicap * Long survival [Barbot et al 2001] * Absence of extraneurologic findings common in ataxia-telangiectasia (telangiectasias and immunodeficiency). * Family history consistent with autosomal recessive inheritance Test results * MRI. Cerebellar atrophy is present in all affected individuals. A very few individuals also have brain stem atrophy. * EMG. Signs of axonal neuropathy are found in 100% of individuals with AOA1. Note: Normal EMG results may be observed only in those investigated in the very early stages of the disease. * Laboratory findings that can be used to confirm the diagnosis of AOA1 in a symptomatic person include [Barbot et al 2001, Le Ber et al 2003]: * Serum concentration of albumin. Serum concentration of albumin is decreased (<3.8 g/L) in 83% of individuals with disease duration of more than ten to 15 years. * Serum concentration of total cholesterol. Serum concentration of total cholesterol is increased (>5.6 mmol) in 68% of individuals with disease duration of more than ten to 15 years. * Normal serum concentration of alpha-fetoprotein * Neuropathology. Nerve biopsy confirms axonal neuropathy. ### Establishing the Diagnosis The diagnosis of AOA1 is established in a proband with the detection of biallelic pathogenic variants in APTX (see Table 1). One genetic testing strategy is sequence analysis of APTX. If only one or no pathogenic variant is found, perform deletion/duplication analysis. An alternative genetic testing strategy is use of a multigene panel that includes APTX and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ### Table 1. Molecular Genetic Testing Used in AOA1 View in own window Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method APTXSequence analysis 2Unknown 3 Deletion/duplication analysis 4Unknown 5 Unknown 6NA 1\. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants. 2\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 3\. All Portuguese families with AOA1 share the same pathogenic variant (p.Trp279Ter), while Japanese families first described by Uekawa et al [1992] shared another pathogenic variant (c.689dupT). 4\. Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 5\. Deletion of the entire gene APTX has been reported [Amouri et al 2004]. The frequency of alleles with partial- or whole-gene deletions is not known. 6\. Scanning for pathogenic variants identified variants diagnostic for either AOA1 or AOA2 in only 20 of the 43 (46.5%) individuals with the ataxia with oculomotor apraxia phenotype. In other words, almost half of Portuguese families with AOA do not appear to have AOA1 or AOA2 using scanning for pathogenic variants; thus, pathogenic variants in other genes or pathogenic variants not detectable by this test method (e.g., exon or whole-gene deletions) may be causative [Bras et al 2015]. ## Clinical Characteristics ### Clinical Description Ataxia is the main cause of disability in ataxia with oculomotor apraxia type 1 in the first stages of the disease. Later, peripheral axonal motor neuropathy dominates the clinical picture. Cerebellar ataxia. Symptoms are first noticed between ages two and ten years (mean: 4.3 years). In about 50% of affected individuals, onset is before age seven years. Two Italian adults with cerebellar ataxia were reported having disease onset at ages 28 and 29 years [Criscuolo et al 2004]. After initial normal motor development, all individuals develop cerebellar ataxia. The first manifestations of AOA1 are slowly progressive gait imbalance followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Oculomotor apraxia. Oculomotor apraxia is present in all individuals with AOA1. It is usually noticed a few years after the onset of ataxia. Oculomotor apraxia is the most striking feature in this disorder, but can be missed on routine neurologic examination. Individuals with oculomotor apraxia do not fixate normally on objects. When asked to look to one side, they turn their heads first, with eye contraversion, after which their eyes follow to the same side in several slow saccades with head thrusts. Blinking is exaggerated in most individuals. Ocular movements on command are usually slightly limited; the eyes stop before reaching extreme positions of gaze. These slow eye movements appear equally on lateral and vertical gaze. When the head is immobilized, movement of the eyes is impossible. Oculocephalic reflexes are spared until advanced stages of the disease. When standing and turning their heads, affected individuals lose their balance and tend to move the whole body to compensate. Ocular pursuit movements remain normal during the first years after the appearance of oculomotor apraxia. Later, oculomotor apraxia is followed by progressive external ophthalmoplegia (beginning with upward gaze). Neuropathy. All individuals with AOA1 have an axonal peripheral neuropathy, with early areflexia that dominates the clinical picture in advanced phases of the disease and is the major cause of motor disability with severe weakness and wasting. Loss of independent walking happens about seven to ten years after onset; most individuals become wheelchair bound by adolescence. Hands and feet are short and atrophic. Pes cavus is present in 30% of individuals and scoliosis in a few. Vibration and postural sense are impaired only in older individuals with very long disease duration. Pain and light touch sensation are preserved. Chorea. About 45% of affected individuals have chorea even after a long disease duration (≤51 years) [Shimazaki et al 2002, Le Ber et al 2003, Sekijima et al 2003, Tranchant et al 2003, Criscuolo et al 2004, Habeck et al 2004]. At onset, the percentage may be as high as 80%, but in almost 50% of affected individuals, chorea disappears over the course of the disease [Le Ber et al 2003]. Dystonia. Upper-limb dystonia occurs in about 50% of individuals and may in some cases be sufficiently pronounced to justify diagnostic consideration of extrapyramidal disorders. Intellect. Different degrees of cognitive impairment are observed, largely independent of ethnic origin [Tachi et al 2000, Moreira et al 2001a, Shimazaki et al 2002, Le Ber et al 2003, Sekijima et al 2003, Criscuolo et al 2004, Quinzii et al 2005]. Severe cognitive disability was reported in a single family [Moreira et al 2001b]. Life span. In the Portuguese kindreds, the age at last examination ranged from 17 to 68 years, corresponding to a disease duration of 12 to 58 years (mean: 27.5 years); two individuals died, one of an unknown cause and the other, a girl age 11 years with AOA1 who had been symptomatic for eight years, from a thalamic tumor. One Japanese individual died at age 71 years. In the cohort reported by Le Ber et al [2003], disease duration was 51 years. Other. No signs of extraneurologic involvement are evident. ### Genotype-Phenotype Correlations APTX pathogenic missense variants may be associated with a later onset (age ~9 years). All other individuals with AOA1 with homozygous truncating variants (nonsense or frameshift) had onset ranging between ages two and 12 years (mean: 4.6 years) [Moreira et al 2001b, Shimazaki et al 2002, Le Ber et al 2003, Sekijima et al 2003, Amouri et al 2004, Habeck et al 2004, Quinzii et al 2005]. Cognitive impairment was reported in several families of different ethnic origins who had a range of variant types, including nonsense, frameshift, splice site, and missense [Tachi et al 2000, Barbot et al 2001, Moreira et al 2001a, Shimazaki et al 2002, Le Ber et al 2003, Sekijima et al 2003, Criscuolo et al 2004, Quinzii et al 2005]. * The p.Trp279Ter nonsense variant can be associated with cognitive impairment [Le Ber et al 2003] or normal cognitive development [Moreira et al 2001a, Le Ber et al 2003, Tranchant et al 2003]. * The presence of severe cognitive impairment in p.[Glu232GlyfsTer38]+[Pro206Leu] compound heterozygotes and the presence of mild cognitive impairment/borderline intelligence in the respective homozygotes is unexplained. Two compound heterozygotes for the p.Arg199His missense variant and an unidentified second pathogenic variant had an atypical presentation with marked dystonia and mask-like faces in addition to the AOA1 clinical picture. The pathogenic variant p.Ala198Val is associated with predominant, more severe and persistent chorea [Le Ber et al 2003]. In two Italian adults, homozygous p.Pro206Leu and p.His201Gln pathogenic variants were associated with late-onset AOA1 (ages 28 and 29 years). In contrast, in Japanese individuals with AOA1, the p.Pro206Leu pathogenic variant is associated with earlier onset (age 10 years). The pathogenic missense variant p.Pro206Leu is associated with a later onset [Date et al 2001] and the pathogenic variants p.Val263Gly and p.Lys197Gln with even later onset: age 15 years [Tranchant et al 2003] and 25 years [Date et al 2001] respectively. To the authors' knowledge, no correlation exists between a specific pathogenic variant and the affected individual's survival. ### Nomenclature In Japan, AOA1 is called early-onset ataxia with oculomotor apraxia and hypoalbuminemia [Date et al 2001, Shimazaki et al 2002, Sekijima et al 2003]. ### Prevalence Through a systematic population-based survey of hereditary ataxias being conducted in Portugal since 1993 [Silva et al 1997], Friedreich ataxia (as expected) was found to be the most frequent autosomal recessive ataxia (32.8%), followed by AOA (12.6%). In Portugal there are now 42 individuals with AOA in 20 different families (AOA1= 3.6% of all autosomal recessive ataxias; AOA2= 3.3%). AOA prevalence in Portugal is estimated at 0.41 per 100,000 inhabitants. However, 20 of these individuals with AOA from 13 different families do not have either AOA1 or AOA2, illustrating AOA genetic heterogeneity [Bras et al 2015]. In Japan, AOA1 appears to be the most frequent cause of autosomal recessive ataxia [Uekawa et al 1992, Fukuhara et al 1995, Hanihara et al 1995, Kubota et al 1995, Sekijima et al 1998, Tachi et al 2000, Moreira et al 2001a, Shimazaki et al 2002, Sekijima et al 2003]. In the entire cohort studied by Le Ber et al [2003] mostly individuals of French origin with progressive cerebellar ataxia in whom Friedreich ataxia had been excluded — the frequency of AOA1 was 5.7%; among the subset of individuals with onset before age 25 years, the frequency of AOA1 was 9.1%. Affected individuals with pathogenic variants in APTX have been identified worldwide: thirteen individuals from three unrelated Tunisian families [Amouri et al 2004]; two unrelated individuals from Germany [Habeck et al 2004]; three unrelated Italian individuals [Criscuolo et al 2004]; two American children [Tsao & Paulson 2005]; and four individuals of northern European heritage with ataxia and CoQ10 deficiency [Quinzii et al 2005]. ## Differential Diagnosis The diagnosis of AOA1 is ruled out whenever the clinical picture includes non-progressive ataxia, microcephaly, or seizures. The differential diagnosis varies by age group. Ataxia with oculomotor apraxia type 2 (AOA2), the disorder most likely to be confused with AOA1, is characterized by onset between age three and 30 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of alpha-fetoprotein (AFP). See Table 2. AOA2 is associated with pathogenic variants of SETX, the gene that encodes the protein senataxin [Moreira et al 2004]. In one study, AOA2 accounted for 8% of all autosomal recessive cerebellar ataxia, making it second only to Friedreich ataxia in prevalence among adults with autosomal recessive ataxia [Le Ber et al 2004]. Ataxia with oculomotor apraxia type 3 (AOA3) (OMIM 615217) was described in a Saudi family in association with a pathogenic missense variant in PIK3R5. The disorder is most likely to be clinically and biochemically confused with AOA2 [Al Tassan et al 2012]. Ataxia with oculomotor apraxia type 4 (AOA4) was recently described in a cohort of nine Portuguese families associated with pathogenic variants in PNKP. Age of onset and clinical presentation, with marked extrapyramidal manifestations and rapid progression resembles AOA1 except for cognitive impairment. AOA4 is the most frequent form of AOA in the Portuguese population [Bras et al 2015]. ### Table 2. Comparison of AOA1, AOA2, AOA3 and AOA4 View in own window AOA TypeAOA1AOA2AOA3AOA4 Mean age at onset (range)4.3 yrs (2-10)13 yrs (10-14)15.6 yrs (14-18)4.3 yrs (1-9) EvolutionMore severeMore benignMore benignMore severe Oculomotor apraxiaEarly & severeMild to moderateLate & severeEarly & severe DystoniaMarked, early in the disease, disappearing w/ageLess markedNot mentionedMarked, early in the disease NeuropathyEarly & severeLess severe & beginning later in the diseaseSevereEarly & severe Cognitive impairmentNot presentNot presentNot mentionedOften present Biochemical findingsLate-onset low serum albumin & high cholesterol; normal alpha-fetoprotein at all stagesEarly elevation of alpha-fetoproteinEarly elevation of alpha-fetoproteinVariable levels of serum albumin, cholesterol, & alpha-fetoprotein Early childhood. The diagnosis of AOA1 can be difficult to establish in very young children because all features of the disorder are not yet apparent. * When oculomotor apraxia is present, ataxia-telangiectasia can be excluded. * Joubert syndrome is a rare, autosomal recessive disorder that affects the cerebellum and brain stem. It is characterized by the presence of a distinct respiratory pattern and profound tachypnea in the newborn period. Nonspecific features such as hypotonia, ataxia, developmental delay, and oculomotor apraxia can occur. The diagnosis of Joubert syndrome is based on the presence of these characteristic clinical features and is confirmed with cranial magnetic resonance imaging (MRI), which reveals the "molar tooth sign" resulting from hypoplasia of the cerebellar vermis and accompanying brain stem abnormalities [Maria et al 1999, Merritt 2003]. Adolescence * Friedreich ataxia (FRDA) can be excluded on clinical grounds. In FRDA, oculomotor apraxia is not observed and the cerebellum is normal on MRI. Molecular genetic testing of FRDA detects pathogenic variants in almost 100% of affected individuals. * Ataxia with vitamin E deficiency (AVED) and coenzyme Q10 deficiency should be considered because they are treatable disorders [Musumeci et al 2001, Quinzii et al 2005]. * Peripheral neuropathy with areflexia and pes cavus may be confused with Charcot-Marie-Tooth syndrome. See Charcot-Marie-Tooth Hereditary Neuropathy Overview. Adulthood. In apparent simplex cases (individuals with no family history of AOA1), SCA2, which also associates cerebellar ataxia with slow eye movements, can be excluded by molecular genetic testing of ATXN2, the gene in which mutation causes SCA2 [Pulst et al 1996]. See also Ataxia Overview. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ataxia with oculomotor apraxia type 1 (AOA1), the following evaluations are recommended: * Examination of cognitive function * Examination of cranial nerve function * Extended neurologic examination of the limbs: initial inspection, tone, strength testing, reflexes, coordination, sensory testing * Ophthalmologic examination * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Physical therapy may be helpful, particularly for disabilities resulting from peripheral neuropathy. A wheelchair is usually necessary for mobility by age 15-20 years. Educational support should be provided to compensate for difficulties in speaking (dysarthria), in reading (oculomotor apraxia), and in writing (upper-limb ataxia and weakness). ### Prevention of Secondary Complications High-protein diet to restore serum albumin concentration is indicated to prevent edema secondary to hypoalbuminemia. Low-cholesterol diet is advised. ### Surveillance Routine visits to the neurologist are appropriate. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Ataxia with Oculomotor Apraxia Type 1

c1859598

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK1456/

{"mesh": ["C538013"], "synonyms": ["AOA1"]}

Small patella syndrome (SPS) is a rare syndrome that mainly affects the way certain bones are formed (developed). A person with SPS usually has very small kneecaps (hypoplastic patella) or may have no kneecaps at all (aplastic). The hip (pelvic) bones may be weak, and the bones of the feet may not have formed correctly. Occasionally, bones in the face may also be affected. Small patella syndrome is caused by a change (pathogenic variant or mutation) in the TBX4 gene. The syndrome is inherited in an autosomal dominant manner. Diagnosis of the syndrome is suspected based on features that can be seen in a physical exam and on imaging tests such as X-rays. Diagnosis of SPS can be confirmed with genetic testing. Treatment of SPS may include pain management with medications, physical and occupational therapies, and surgical treatments. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Small patella syndrome

c1840061

gard

https://rarediseases.info.nih.gov/diseases/3030/small-patella-syndrome

{"mesh": ["C535540"], "omim": ["147891"], "umls": ["C1840061"], "orphanet": ["1509"], "synonyms": ["Scott-Taor syndrome", "Coxo-podo-patellar syndrome", "Ischiopatellar dysplasia", "Patella aplasia, coxa vara, tarsal synostosis", "Congenital coxa vara, patella aplasia and tarsal synostosis", "ischiocoxopodopatellar syndrome"]}

A rare, malignant splenic B-cell lymphoma/leukemia characterized by circulating abnormal lymphocytes with intermediate morphology between prolymphocytes and hairy cells with positive expression of CD11c and negative expression of CD25, CD123 and the BRAFV600E mutation. Manifestations include splenomegaly, elevated white blood cell (WBC) count, hyper-cellular bone marrow and anemia/thrombocytopenia, but no monocytopenia. ## Epidemiology Hairy cell leukemia variant (HCL-V) constitutes about 10% to 20% of patients with hairy cell leukemia (HCL) and 0.4% of all lymphoid malignancies. There is a slight male predominance (male/female: 1.6). ## Clinical description HCL-V onset is in adulthood, most frequently in the elderly population (median age: 71 years). Initial manifestations are typically of abdominal discomfort or distension, usually related to splenomegaly, hepatomegaly and manifestations derived from cytopenias such as anemia, bleeding and/or infections. HCL-V is more aggressive and resistant to therapy than classical HCL (HCL-C). A disease closely resembling HCL-V has been described in Japan and has been called the HCL Japanese variant (HCL-Jv). ## Etiology The etiology is unknown but there is no evidence of an association between exposure to carcinogens, radiation or viral infections. P53 dysfunction, due to either monosomy, monoallelic deletion or a TP53 mutation (17p13.1), has been reported in many patients (estimate 30% of patients) as well as mutations in the gene MAP2K1 (15q22.31) (estimate 50%). The VH gene family, IGHV4-34, appears to be over-expressed, but is also found in other B-cell malignancies. HCL-V is not considered to be biologically related to HCL-C, and HCL-V patients are negative for the BRAF-V600E mutation. ## Diagnostic methods Diagnosis is suspected on physical examination, bone marrow biopsy, and abdominal computed tomography (CT) scan, as well as laboratory tests which show raised white blood cell count (>10×109/l). HCL-V cells do not demonstrate reactivity to annexin A1 and are either weakly positive or negative for tartrate-resistant acid phosphatase (TRAP). HCL-V cells are negative for BRAFV600E mutation. The diagnosis of HCL-V is confirmed by flow cytometry immunophenotyping (positive for CD11C, and negative for CD123 and CD25 with variable expression of CD103, CD19, CD20, and CD22). ## Differential diagnosis Differential diagnosis includes splenic marginal zone lymphoma, splenic diffuse red pulp lymphoma (SRPL), HCL-C, mantle-cell lymphoma, and B-cell prolymphocytic leukemia (B-PLL). ## Management and treatment Asymptomatic patients with moderate splenomegaly and no cytopenias may be managed with close monitoring. Therapy is indicated for symptomatic disease (progressive splenomegaly and/or elevated lymphocyte counts with cytopenias). There are no formal guidelines for management and treatment, and information on the efficacy of the various agents is derived from the results on small series of patients or single case reports with limited follow-up. Splenectomy has been utilized in some patients resulting in improvement in anemia and thrombocytopenia; however, the response eventually results in progressive disease. A combination of purine analog (cladribine) and a monoclonal anti-CD20 antibody has resulted in complete remission in patients treated (although follow-up is limited). Immunotherapy alone may be considered and include rituximab (successful treatment in several case reports), and anti-CD22 recombinant immunotoxins (response observed in a limited number of patients but relapse reported). Treatment with interferon alpha and purine analogs alone is unsatisfactory and fails to achieve a durable, high complete remission rate. ## Prognosis HCL-V is an aggressive disorder with a chronic clinical course. The reported survival at five years is approximately 60%; however, complete remission has been reported, in particular with combined purine analog and rituximab treatment or immunotherapy alone. In general, significant anemia, older age, and mutations in TP53 are associated with a worse prognosis. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hairy cell leukemia variant

c0349633

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=300878

{"umls": ["C0349633"], "icd-10": ["C91.4"], "synonyms": ["HCL-v", "Leukemic reticuloendotheliosis variant", "Prolymphocytic variant of HCL", "Prolymphocytic variant of hairy cell leukemia"]}

This article is about the wrist fracture. For the vertebral fracture, see Smith fracture. Smith's fracture Other namesReverse Colles' fracture, Goyrand-Smith's Smith's fracture SpecialtyOrthopedics A Smith's fracture, is a fracture of the distal radius.[1] It is caused by a direct blow to the dorsal forearm[2] or falling onto flexed wrists, as opposed to a Colles' fracture which occurs as a result of falling onto wrists in extension. Smith's fractures are less common than Colles' fractures. The distal fracture fragment is displaced volarly (ventrally), as opposed to a Colles' fracture which the fragment is displaced dorsally. Depending on the severity of the impact, there may be one or many fragments and it may or may not involve the articular surface of the wrist joint. ## Contents * 1 Classification * 2 Presentation * 2.1 Complications * 3 Diagnosis * 3.1 Physical examination * 3.2 Investigation * 4 Treatment * 5 Eponym * 6 References * 7 External links ## Classification[edit] A commonly used classification of distal radial fractures is the Frykman Classification:[3] * Type I: Extra-articular * Type II: Type I, with fracture of distal ulna * Type III: Radiocarpal joint involvement * Type IV: Type III with fracture of distal ulna * Type V: Distal radioulnar joint involved. * Type VI: Type V with fracture of distal ulna * Type VII: Radiocarpal and distal radioulnar joint both involved. * Type VIII: Type VII with fracture of distal ulna. ## Presentation[edit] ### Complications[edit] The biggest concern is malunion of the wrist due to poor reduction or shortening of the distal radius. This can result in a permanent "garden-spade deformity". There are also higher risks of carpal tunnel syndrome and osteoarthritis in patients with a previous Smith fractures. Entrapment of the extensor pollicus longus can also occur in cases of non-union, and can result in late rupture of this tendon. Complex regional pain syndrome can be reported in up to 40% of fractures.[4] ## Diagnosis[edit] ### Physical examination[edit] Classic physical examination findings of a Smith's fracture is palmar displacement of the wrist that results in a "garden-spade deformity". ### Investigation[edit] Two views should be obtained: AP and lateral. PA radiography will look very similar to a Colles' fracture, with a fracture along the distal metaphysis of the radius (can be shortened or comminuted). Lateral radiography will demonstrate volar angulation / displacement of the fracture.[5] ## Treatment[edit] Treatment of this fracture depends on the severity of the fracture. An undisplaced fracture may be treated with a cast alone. A fracture with mild angulation and displacement may require closed reduction (putting into place without surgery). Significant angulation and deformity may require an open reduction and internal fixation. An open fracture will always require surgical intervention. Indications for operative management include dorsal or volar comminution, intra-articular involvement, instability post-reduction, angulation greater than 20 degrees, surface step-off over 2mm or shortening of the radius greater than 5mm.[4] For a closed reduction, the approach is the opposite of reductions completed for Colle's fractures. In the case of a Smith's fracture, the wrist must be reduced and splinted in extension.[4] ## Eponym[edit] This fracture is named after the orthopedic surgeon, Robert William Smith (1807–1873) in his book A Treatise on Fractures in the Vicinity of Joints, and on certain forms of Accidents and Congenital Dislocations published in 1847.[6] ## References[edit] 1. ^ Thomas CL (1993). Taber's Cyclopedic Medical Dictionary (18th ed.). F.A. Davis. ISBN 0-8036-0194-8. 2. ^ Stead LG, Stead SM, Kaufman MS (2006). First Aid: Emergency Medicine (2nd ed.). McGraw-Hill. ISBN 0-07-144873-X. 3. ^ Shehovych A, Salar O, Meyer C, Ford DJ (November 2016). "Adult distal radius fractures classification systems: essential clinical knowledge or abstract memory testing?". Annals of the Royal College of Surgeons of England. 98 (8): 525–531. doi:10.1308/rcsann.2016.0237. PMC 5392888. PMID 27513789. 4. ^ a b c Schroeder JD, Varacallo M (2019). "Smith's Fracture Review". StatPearls. StatPearls Publishing. PMID 31613494. Retrieved 2019-11-20. 5. ^ Patel Y (2005-01-01). "Emergency Medicine Manual, (6th): By O. John Ma, David M. Cline, Judith E. Tintinalli, Gabor D. Kelen, and J Stephan Stapczynski. New York: McGraw-Hill Medical Publishing Division, 2004, 977 pages, $45.00 (softcover)". Academic Emergency Medicine. 12 (1): 95–96. doi:10.1197/j.aem.2004.07.019. 6. ^ synd/2150 at Who Named It? ## External links[edit] * Radiograph of Smith's fracture Classification D * ICD-10: S52.5 * MeSH: 68011885 External resources * AO Foundation: 23-A2.3 * 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

Smith's fracture

c0347795

wikipedia

https://en.wikipedia.org/wiki/Smith%27s_fracture

{"umls": ["C0347795"], "icd-9": ["813.41"], "icd-10": ["S52.5"], "wikidata": ["Q3752481"]}

Atypical Rett syndrome is a neurodevelopmental disorder that is diagnosed when a child has some of the symptoms of Rett syndrome but does not meet all the diagnostic criteria. Like the classic form of Rett syndrome, atypical Rett syndrome mostly affects girls. Children with atypical Rett syndrome can have symptoms that are either milder or more severe than those seen in Rett syndrome. Several subtypes of atypical Rett syndrome have been defined: * The early-onset seizure type is characterized by seizures in the first months of life with later development of Rett features (including developmental problems, loss of language skills, and repeated hand wringing or hand washing movements). It is frequently caused by mutations in the X-linked CDKL5 gene (Xp22). * The congenital variant is the most severe form of atypical Rett syndrome, with onset of classic Rett features during the first three months of life. This variant is generally caused by mutations in the FOXG1 gene (14q11-q13). * The forme fruste is a milder variant with onset in early childhood and an incomplete and prolonged course. * The late childhood regression form is characterized by a normal head circumference and by a more gradual and later onset (late childhood) regression of language and motor skills. * The preserved speech variant is marked by recovery of some verbal and manual skills and is caused in at least some cases by mutations in the MECP2 (Xq28) gene, which is also responsible for the majority of cases of classic Rett syndrome. Diagnosis relies on clinical evaluation using the diagnostic criteria for atypical Rett syndrome which was defined by Hagberg in 1994. Molecular genetic testing may confirm the diagnosis. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Atypical Rett syndrome

c2748910

gard

https://rarediseases.info.nih.gov/diseases/4694/atypical-rett-syndrome

{"mesh": ["C567576"], "umls": ["C2748910"], "orphanet": ["3095"], "synonyms": ["Rett like syndrome", "Rett syndrome variant"]}

Apraxia Apraxia is characterized by loss of the ability to execute or carry out learned purposeful movements SpecialtyNeurology, Psychiatry TreatmentPhysical therapy Apraxia is a motor disorder caused by damage to the brain (specifically the posterior parietal cortex or corpus callosum[1]) in which the individual has difficulty with the motor planning to perform tasks or movements when asked, provided that the request or command is understood and the individual is willing to perform the task. The nature of the brain damage determines the severity, and the absence of sensory loss or paralysis helps to explain the level of difficulty.[2] Some children may be born with apraxia although the cause is unknown. Symptoms are usually noticed in the early stages of life as the child develops. Apraxia that results from a brain injury or a neurodegenerative illness is known as acquired apraxia. Acquired apraxia is typically caused by a traumatic brain injury, stroke, dementia, Alzheimer's disease, brain tumor, and other neurodegenerative disorders.[3] There are multiple types of apraxia and are categorized by what specific ability or body part is affected. The term comes from the Greek ἀ- a- ("without") and πρᾶξις praxis ("action").[4] ## Contents * 1 Types * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 See also * 7 References * 8 Further reading * 9 External links ## Types[edit] There are several types of apraxia including: * Apraxia of speech (AOS): Difficulty planning and coordinating the movements necessary for speech (e.g. Potato=Totapo, Topato).[5] AOS can independently occur without issues in areas such as verbal comprehension, reading comprehension, writing, articulation or prosody.[6] * Buccofacial or orofacial apraxia: This is the most common type of apraxia and is the inability to carry out facial movements on demand. For example, an inability to lick one's lips, wink, or whistle when requested to do so. This suggests an inability to carry out volitional movements of the tongue, cheeks, lips, pharynx, or larynx on command.[7][8] * Constructional apraxia: The inability to draw, construct, or copy simple configurations, such as intersecting shapes. These patients have difficulty copying a simple diagram or drawing basic shapes.[7] * Gait apraxia: The loss of ability to have normal function of the lower limbs such as walking. This is not due to loss of motor or sensory functions.[9] * Ideational/conceptual apraxia: Patients have an inability to conceptualize a task and impaired ability to complete multistep actions. This form of apraxia consists of an inability to select and carry out an appropriate motor program. For example, the patient may complete actions in incorrect orders, such as buttering bread before putting it in the toaster, or putting on shoes before putting on socks. There is also a loss of ability to voluntarily perform a learned task when given the necessary objects or tools. For instance, if given a screwdriver, the patient may try to write with it as if it were a pen, or try to comb their hair with a toothbrush.[10][11] * Ideomotor apraxia: These patients have deficits in their ability to plan or complete motor actions that rely on semantic memory. They are able to explain how to perform an action, but unable to "imagine" or act out a movement such as "pretend to brush your teeth" or "pucker as though you bit into a sour lemon." However, when the ability to perform an action automatically when cued remains intact, this is known as automatic-voluntary dissociation. For example, they may not be able to pick up a phone when asked to do so, but can perform the action without thinking when the phone rings.[10][11] * Limb-kinetic apraxia: The inability to perform precise, voluntary movements of extremities. For example, a person affected by limb apraxia may have difficulty waving hello, tying their shoes, or typing on a computer.[12][8] This type is common in patients who have experienced a stroke, some type of brain trauma, or have Alzheimer disease.[13] * Oculomotor apraxia: Difficulty moving the eye on command, especially with saccade movements that direct the gaze to targets. This is one of the 3 major components of Balint's syndrome.[8] ## Causes[edit] Apraxia is most often due to a lesion located in the dominant (usually left) hemisphere of the brain, typically in the frontal and parietal lobes. Lesions may be due to stroke, acquired brain injuries, or neurodegenerative diseases such as Alzheimer's disease or other dementias, Parkinson's disease, or Huntington's disease. It is also possible for apraxia to be caused by lesions in other areas of the brain.[11] Ideomotor apraxia is typically due to a decrease in blood flow to the dominant hemisphere of the brain and particularly the parietal and premotor areas. It is frequently seen in patients with corticobasal degeneration.[11] Ideational apraxia has been observed in patients with lesions in the dominant hemisphere near areas associated with aphasia; however, more research is needed on ideational apraxia due to brain lesions. The localization of lesions in areas of the frontal and temporal lobes would provide explanation for the difficulty in motor planning seen in ideational apraxia as well as its difficulty to distinguish it from certain aphasias.[14] Constructional apraxia is often caused by lesions of the inferior non-dominant parietal lobe, and can be caused by brain injury, illness, tumor or other condition that can result in a brain lesion.[14] ## Diagnosis[edit] Although qualitative and quantitative studies exist, there is little consensus on the proper method to assess for apraxia. The criticisms of past methods include failure to meet standard psychometric properties as well as research-specific designs that translate poorly to non-research use.[15] The Test to Measure Upper Limb Apraxia (TULIA) is one method of determining upper limb apraxia through the qualitative and quantitative assessment of gesture production. In contrast to previous publications on apraxic assessment, the reliability and validity of TULIA was thoroughly investigated.[16] The TULIA consists of subtests for the imitation and pantomime of non-symbolic (“put your index finger on top of your nose”), intransitive (“wave goodbye”) and transitive (“show me how to use a hammer”) gestures.[15] Discrimination (differentiating between well- and poorly performed tasks) and recognition (indicating which object corresponds to a pantomimed gesture) tasks are also often tested for a full apraxia evaluation. However, there may not be a strong correlation between formal test results and actual performance in everyday functioning or activities of daily living (ADLs). A comprehensive assessment of apraxia should include formal testing, standardized measurements of ADLs, observation of daily routines, self-report questionnaires and targeted interviews with the patients and their relatives.[15] As stated above, apraxia should not be confused with aphasia (the inability to understand language); however, they frequently occur together. It has been stated that apraxia is so often accompanied by aphasia that many believe that if a person displays AOS then it should be assumed that the patient also has some level of aphasia.[17] ## Treatment[edit] Treatment for individuals with apraxia includes speech therapy, occupational therapy, and physical therapy.[18] Currently there are no medications indicated for the treatment of apraxia, only therapy treatments.[19] Generally, treatments for apraxia have received little attention for several reasons, including the tendency for the condition to resolve spontaneously in acute cases. Additionally, the very nature of the automatic-voluntary dissociation of motor abilities that defines apraxia means that patients may still be able to automatically perform activities if cued to do so in daily life. Nevertheless, research shows that patients experiencing apraxia have less functional independence in their daily lives,[20] and that evidence for the treatment of apraxia is scarce.[21] However, a literature review of apraxia treatment to date reveals that although the field is in its early stages of treatment design, certain aspects can be included to treat apraxia.[22] One method is through rehabilitative treatment, which has been found to positively impact apraxia, as well as activities of daily living.[22] In this review, rehabilitative treatment consisted of 12 different contextual cues, which were used in order to teach patients how to produce the same gesture under different contextual situations.[22] Additional studies have also recommended varying forms of gesture therapy, whereby the patient is instructed to make gestures (either using objects or symbolically meaningful and non-meaningful gestures) with progressively less cuing from the therapist.[23] It may be necessary for patients with apraxia to use a form of alternative and augmentative communication depending on the severity of the disorder. In addition to using gestures as mentioned, patients can also use communication boards or more sophisticated electronic devices if needed.[24] No single type of therapy or approach has been proven as the best way to treat a patient with apraxia, since each patient's case varies. However, one-on-one sessions usually work the best, with the support of family members and friends. Since everyone responds to therapy differently, some patients will make significant improvements, while others will make less progress.[25] The overall goal for treatment of apraxia is to treat the motor plans for speech, not treating at the phoneme (sound) level. Research suggests that individuals with apraxia of speech should receive treatment that focuses on the repetition of target words and rate of speech. Research rerouted that the overall goal for treatment of apraxia should be to improve speech intelligibility, rate of speech and articulation of targeted words.[26] ## Prognosis[edit] The prognosis for individuals with apraxia varies. With therapy, some patients improve significantly, while others may show very little improvement. Some individuals with apraxia may benefit from the use of a communication aid. However, many people with apraxia are no longer able to be independent. Those with limb-kinetic and/or gait apraxia should avoid activities in which they might injure themselves or others. Occupational therapy, physical therapy, and play therapy may be considered as other references to support patients with apraxia. These team members could work along with the SLP to provide the best therapy for people with apraxia. However, because people with limb apraxia may have trouble directing their motor movements, occupational therapy for stroke or other brain injury can be difficult. No medication has been shown useful for treating apraxia. ## See also[edit] * Praxis (process) * Aging movement control * Developmental coordination disorder * Lists of language disorders ## References[edit] 1. ^ Zeidman, Lawrence A. (2020). Brain Science Under the Swastika: Ethical Violations, Resistance, and Victimization of Neuroscientists in Nazi Europe. Oxford University Press. p. 36. ISBN 978-0-19-872863-4. 2. ^ ASHA 3. ^ "Apraxia: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2019-08-07. 4. ^ "Definition of APRAXIA". www.merriam-webster.com. Retrieved 2017-05-02. 5. ^ Heilman KM, Watson RT, Gonzalez-Rothi LJ. Praxis. In: Goetz CG. Goetz: Textbook of Clinical Neurology. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2007:chap 4. 6. ^ Duffy, Joseph R. (2013). Motor Speech Disorders: Substrates, Differential Diagnosis, and Management. St. Louis, MO: Elsevier. p. 269. ISBN 978-0-323-07200-7. 7. ^ a b "Apraxia". NORD (National Organization for Rare Disorders). Retrieved 2019-08-02. 8. ^ a b c "Apraxia Information Page | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. 2019. Retrieved 2019-08-01. 9. ^ Nadeau SE (2007). "Gait apraxia: further clues to localization". Eur. Neurol. 58 (3): 142–5. doi:10.1159/000104714. PMID 17622719. S2CID 40700537. 10. ^ a b Sathian, K; et al. (Jun 2011). "Neurological and rehabilitation of action disorders: common clinical deficits". Neurorehabilitation and Neural Repair. 25 (5): 21S–32S. doi:10.1177/1545968311410941. PMC 4139495. PMID 21613535. 11. ^ a b c d Gross, RG; Grossman, M. (Nov 2008). "Update on apraxia". Current Neurology and Neuroscience Reports. 8 (6): 490–496. doi:10.1007/s11910-008-0078-y. PMC 2696397. PMID 18957186. 12. ^ Treatment Resource Manual for Speech Pathology 5th edition 13. ^ Foundas, Anne L. (2013-01-01), Barnes, Michael P.; Good, David C. (eds.), "Chapter 28 - Apraxia: neural mechanisms and functional recovery", Handbook of Clinical Neurology, Neurological Rehabilitation, Elsevier, 110, pp. 335–345, retrieved 2019-08-07 14. ^ a b Tonkonogy, Joseph & Puente, Antonio (2009). Localization of clinical syndromes in neuropsychology and neuroscience. Springer Publishing Company. pp. 291–323. ISBN 978-0826119674. 15. ^ a b c Vanbellingen, T.; Bohlhalter, S. (2011). "Apraxia in neurorehabilitation: Classification, assessment and treatment". NeuroRehabilitation. 28 (2): 91–98. doi:10.3233/NRE-2011-0637. PMID 21447909. 16. ^ Vanbellingen, T.; Kersten, B.; Van Hemelrijk, B.; Van de Winckel, A.L.J.; Bertschi, M.; Muri, R.; De Weerdt, W.; Bohlhalter, S. (2010). "Comprehensive assessment of gesture production: a new test to measure upper limb apraxia". European Journal of Neurology. 17 (1): 59–66. doi:10.1111/j.1468-1331.2009.02741.x. PMID 19614961. 17. ^ (Manasco, 2014) 18. ^ "NINDS Apraxia Information Page". Retrieved 8 March 2012. 19. ^ Worthington, Andrew (2016). "Treatments and technologies in the rehabilitation of apraxia and action disorganisation syndrome: A review". NeuroRehabilitation. 39 (1): 163–174. doi:10.3233/NRE-161348. ISSN 1053-8135. PMC 4942853. PMID 27314872. 20. ^ Hanna-Pladdy, B; Heilman, K.M.; Foundas, A.L. (Feb 2003). "Ecological implications of ideomotor apraxia: evidence from physical activities of daily living". Neurology. 60 (3): 487–490. doi:10.1212/wnl.60.3.487. PMID 12578932. S2CID 23836106. 21. ^ West, C; Bowen, A.; Hesketh, A.; Vail, A. (Jan 2008). "Interventions for motor apraxia following stroke". Cochrane Database of Systematic Reviews. 23 (1): CD004132. doi:10.1002/14651858.CD004132.pub2. PMC 6464830. PMID 18254038. 22. ^ a b c Buxbaum LJ, Haaland KY, Hallett M, et al. (February 2008). "Treatment of limb apraxia: moving forward to improved action" (PDF). Am J Phys Med Rehabil. 87 (2): 149–61. doi:10.1097/PHM.0b013e31815e6727. PMID 18209511. 23. ^ Smania, N; et al. (Dec 2006). "Rehabilitation of limb apraxia improves daily life activities in patients with stroke". Neurology. 67 (11): 2050–2052. doi:10.1212/01.wnl.0000247279.63483.1f. PMID 17159119. S2CID 4456810. 24. ^ "ASHA, Apraxia of Speech in Adults". 25. ^ Dovern, A.; Fink, GR.; Weiss, PH. (Jul 2012). "Diagnosis and treatment of upper limb apraxia". J Neurol. 259 (7): 1269–83. doi:10.1007/s00415-011-6336-y. PMC 3390701. PMID 22215235. 26. ^ Wambaugh, JL; Nessler, C; Cameron, R; Mauszycki, SC (2012). "Acquired apraxia of speech: the effects of repeated practice and rate/rhythm control treatments on sound production accuracy". American Journal of Speech-Language Pathology. 21 (2): S5–S27. doi:10.1044/1058-0360(2011/11-0102). PMID 22230177. ## Further reading[edit] * Fish, Margaret; "Here's How to Treat Childhood Apraxia of Speech, Second Edition". San Diego: Plural Publishing, Inc., 2015. * Kasper, D.L.; Braunwald, E.; Fauci, A.S.; Hauser, S.L.; Longo, D.L.; Jameson, J.L.. Harrison's Principles of Internal Medicine. New York: McGraw-Hill, 2005. ISBN 0-07-139140-1. * Manasco, H. (2014). Introduction to Neurogenic Communication Disorders. Jones & Bartlett Publishers. ## External links[edit] Classification D * ICD-10: R48.2 * ICD-9-CM: 438.81, 784.69 * MeSH: D001072 * DiseasesDB: 31600 * SNOMED CT: 68345001 External resources * MedlinePlus: 007472 * eMedicine: neuro/438 * Patient UK: Apraxia * Acquired Apraxia of Speech: A Treatment Overview * Apraxia: Symptoms, Causes, Tests, Treatments * ApraxiaKids * GettingTheWordOutOnApraxia.com: A Community for Parents of Children with Apraxia Authority control * NDL: 00570969 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Apraxia

c3495144

wikipedia

https://en.wikipedia.org/wiki/Apraxia

{"gard": ["5838"], "mesh": ["D001072"], "icd-9": ["784.69", "438.81"], "icd-10": ["R48.2"], "wikidata": ["Q498916"]}

## Clinical Features Teebi et al. (1988) described an Arabic family with normal consanguineous parents and 5 children (3 males and 2 females) with some features of Aarskog syndrome (see 305400) in addition to unusual hair changes. The hair was coarse, dry, and relatively hypopigmented with widow's peak trait (194000). The hands were small and broad with mild interdigital webbing, fifth finger clinodactyly, and hyperextensible joints. The feet were small with metatarsus varus and stubby toes. Hypertelorism and, in the males, shawl-like scrotum completed the similarities to Aarskog syndrome. In the same Kuwaiti Bedouin tribe from which the first family came, Teebi and Al Awadi (1991) observed another sibship with 2 affected males who were double first cousins to the first reported cases. Moreover, they observed 3 other distantly related sibships with 9 affected members who all could be traced to a common ancestor. The consistent features were a triangular or elongated face, telecanthus or mild hypertelorism, wide palpebral fissures without ptosis, short stubby nose with anteverted nostrils, high arched and narrow palate, long, deep philtrum, wide mouth with protruding lower lip, posteriorly rotated ears with minor ear anomalies, long neck with sloping shoulders, small, broad hands with mild interdigital webbing and fifth finger clinodactyly, hyperextensible hand joints, and shawl scrotum. Short stature was confirmed in 10 cases, while the heights of the other 6 were between the 10th and 25th percentile for age. None of the 16 cases showed physical disability or mental retardation. Xu et al. (2010) reported a Chinese family in which 10 of 29 members had a disorder suggestive of Aarskog syndrome but with different limb anomalies and additional features. Characteristic manifestations of Aarskog syndrome included short stature, hypertelorism, long philtrum, and shawl scrotum, and less common manifestations of the syndrome included widow's peak, high-arched palate, abnormal teeth, retarded bone age, 4-finger flexion creases, adducted thumbs, vertebral malformations, pectus excavatum, broad feet with bulbous toes, phimosis, cryptorchidism, and mental retardation. Hyperextension of the proximal interphalangeal joints, one of the most characteristic features in the hands in Aarskog syndrome, was absent, but fifth finger clinodactyly, broad hands with interdigital webbing, and hyperextensible elbows were present. Additional features included central facial paralysis, trismus, hearing impairment, congenital absent 12th ribs, and frequent micturition. Inheritance Consanguinity and affected sibs in the families with an Aarskog-like syndrome reported by Teebi et al. (1988) and Teebi and Al Awadi (1991) suggested autosomal recessive inheritance. In a Chinese family with an Aarskog-like syndrome, Xu et al. (2010) excluded the FGD1 gene (300546), which is mutated in X-linked Aarskog syndrome, as a candidate for the disorder by linkage and sequence analysis. The occurrence of male-to-male transmission suggested autosomal dominant inheritance (see 100050), but autosomal recessive inheritance could not be excluded because affected members were born to consanguineous parents; in addition, because the family originated from a small geographic area, it was possible that seemingly unrelated parents were carriers due to a founder effect. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, proportionate HEAD & NECK Head \- Brachycephaly Face \- Triangular face \- Long, deep philtrum Ears \- Posteriorly rotated ears \- Small ears \- Abnormal auricles \- Hearing loss (rare) Eyes \- Wide palpebral fissures \- Downslanting palpebral fissures \- Hypertelorism Nose \- High nasal bridge \- Short, stubby nose \- Anteverted nostrils Mouth \- Wide mouth \- Pouting lower lip \- High-arched palate \- Narrow palate Teeth \- Malocclusion \- Abnormal teeth Neck \- Long neck CHEST External Features \- Sloping shoulders Ribs Sternum Clavicles & Scapulae \- Pectus excavatum \- Absent 12th rib (rare) GENITOURINARY External Genitalia (Male) \- Shawl scrotum \- Inguinal hernia Internal Genitalia (Male) \- Cryptorchidism Bladder \- Frequent urination (rare) SKELETAL Spine \- Vertebral fusion (rare) Hands \- Small, broad hands \- Fifth finger clinodactyly \- Mild syndactyly \- Hyperextensible hand joints \- Camptodactyly \- Interdigital webbing Feet \- Bulbous toes \- Small feet \- Metatarsus varus SKIN, NAILS, & HAIR Hair \- Coarse, dry scalp hair \- Hypopigmented scalp hair \- Widow's peak NEUROLOGIC Central Nervous System \- Normal intelligence \- Mental retardation (rare) \- Central facial nerve paralysis (rare) \- Trismus (rare) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

FACIODIGITOGENITAL SYNDROME, AUTOSOMAL RECESSIVE

c1856871

omim

https://www.omim.org/entry/227330

{"mesh": ["C535331"], "omim": ["227330"], "orphanet": ["1974"], "synonyms": ["Alternative titles", "AARSKOG-LIKE SYNDROME", "KUWAIT TYPE FACIODIGITOGENITAL SYNDROME"]}

A rare neoplastic disease characterized by the presence of ten or more hepatocellular adenomas in a background of normal appearing hepatic parenchyma. The majority of reported cases are female. There is no association with steroid use. The condition is considered benign, although the risk of complications (such as malignant transformation or spontaneous rupture with intraperitoneal hemorrhage) is much higher than in isolated hepatic adenoma. Hepatocellular carcinoma develops in less than 10% of cases. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Liver adenomatosis

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=566841

{"synonyms": ["Hepatic adenomatosis"]}

Whitehouse et al. (1988) studied the family of the fourth human example of anti-LKE (originally called Luke) and excluded close linkage to MNS, Rh, HLA, PI, Gm, and C6. They also showed that LKE is genetically independent of P1, K, Xg, Au, Se, and C3. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

BLOOD GROUP--LKE

c1862216

omim

https://www.omim.org/entry/111130

{"omim": ["111130"], "synonyms": ["Alternative titles", "BLOOD GROUP--LUKE, FORMERLY"]}

Prevalence of AIDS in Nigeria from 1991–2010. Includes predictions up to 2018. HIV/AIDS in Nigeria was a concern in the 2000s, when an estimated seven million people had HIV/AIDS. In 2008, the HIV prevalence rate among adults aged between 15 and 49 was 3.9 percent, in 2018 the rate among adults aged between 15 and 65 was 1.5 percent. As elsewhere in Africa, women are statistically more likely to have HIV/AIDS. The Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS) was the world's largest and presented statistics which showed the overall numbers were lower than expected. Antiretroviral treatment is available, but people prefer to take the therapy secretly, since there is still noticeable discrimination against people with HIV/AIDS. ## Contents * 1 Background * 2 Treatment * 3 See also * 4 References ## Background[edit] Nigeria is emerging from a period of military rule that accounted for almost 28 of the 47 years since independence in 1960. The President's Emergency Plan for AIDS Relief judged that the policy environment is not fully democratized, since civil society was weak during the military era, and its role in advocacy and lobbying remains weak. The size of the population and the nation pose logistical and political challenges particularly due to the political determination of the Nigerian Government to achieve health care equity across geopolitical zones. The necessity to coordinate programs simultaneously at the federal, state and local levels introduces complexity into planning. The large private sector is largely unregulated and, more importantly, has no formal connection to the public health system where most HIV/AIDS interventions are delivered. Training and human resource development is severely limited in all sectors and will hamper program implementation at all levels. Care and support is limited due to the fact that existing staff are overstretched and most have insufficient training in key technical areas to provide complete HIV services.[1] ## Treatment[edit] The Nigerian Government created the National AIDS Control and Prevention Program within the Federal Ministry of Health in 1987, a Presidential AIDS Commission composed of ministers from all sectors in 1999 and the National Action Committee on AIDS based in the Office of the Presidency in 2000. The HIV/AIDS Emergency Action Plan developed in 2001, and revised in 2004, serves as the national action framework.[1] Seven million people (almost 6 percent of the population] had HIV/AIDS in 2004.[2] In 2008, the HIV prevalence rate among adults aged between 15 and 49 was 3.9 percent.[1] Nigeria has the third-largest number of people living with HIV. The HIV epidemic in Nigeria is complex and varies widely by region. In some states, the epidemic is more concentrated and driven by high-risk behaviors, while other states have more generalized epidemics that are sustained primarily by multiple sexual partnerships in the general population. Youth and young adults in Nigeria are particularly vulnerable to HIV, with young women at higher risk than young men. There are many risk factors that contribute to the spread of HIV, including prostitution, high-risk practices among itinerant workers, high prevalence of sexually transmitted infections, clandestine high-risk heterosexual and homosexual practices, international trafficking of women, and irregular blood screening.[1] It was estimated that 3.4 million people were living with HIV/AIDS, leading the USA to spend $400 million annually and the Global Fund to Fight AIDS, Tuberculosis and Malaria $110 million supporting local initiatives.[3] As of 2018, the HIV/AIDS prevalence rate among adults aged between 15 and 64 was 1.5 percent. This was a lower figure than expected, but the National Agency for the Control of AIDS (NACA) had instituted a new and more accurate statistics program in 2016. Called the Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS), it was the world's biggest HIV/AIDS survey. It cost $91million and almost 100,000 households were called upon at random, with 250,000 interviewees aged between 15 and 64 years, plus 32,555 children. South South (Nigeria) was the zone with the highest prevalence, namely 3.1 percent.[3] Overall, the prevalence amongst women aged between 15 and 64 was 1.9 percent as compared to 1.1 percent for men.[3] The Joint United Nations Programme on HIV/AIDS had noted in 2004 that from all Africans aged between 15 and 49 who were HIV-positive, 57 percent were female, and from all Africans aged between 15 and 24, 75 percent were female.[4] Activist Yinka Jegede-Ekpe founded the Nigerian Community of Women Living With HIV/AIDS in 2001 and serves on the National Action Committee on AIDS. She commented in 2004 that HIV/AIDS would not be eradicated until men and women were treated equally.[2] As of 2007, the President's Emergency Plan for AIDS Relief estimated there were 126,400 people receiving antiretroviral treatment. It had provided 4,704,000 condoms for safe sex between 2004 and 2007.[1] A 2006 ethnographic study of how antiretroviral therapy interacted with marriage and sexual reproduction in southeast Nigeria determined that many people taking the drugs were doing so secretly. Whilst there were support groups available, there was still a stigma attached to being HIV-positive and noticeable discrimination against people with HIV/AIDS.[5] When Bisi Alimi announced on a national television show in and later on the BBC World Service that he was gay and HIV-positive, he was arrested and beaten up.[6] ## See also[edit] * AIDS pandemic * Health care in Nigeria * HIV/AIDS in Africa ## References[edit] 1. ^ a b c d e "2008 Country Profile: Nigeria". U.S. Department of State. 2008. Archived from the original on 16 August 2008. Retrieved 25 August 2008. This article incorporates text from this source, which is in the public domain. 2. ^ a b "Human rights award winner speaks at SPH". Harvard Gazette. 18 March 2004. Retrieved 5 May 2020. 3. ^ a b c "Results of NAIIS – the largest HIV survey ever done are in: Nigeria not doing as badly as we thought!". Nigeria Health Watch. 14 March 2019. Retrieved 5 May 2020. 4. ^ Fleshman, Michael (October 2004). "Women: the face of AIDS in Africa". Africa Renewal. United Nations. Retrieved 5 May 2020. 5. ^ Mbakwem, Benjamin C.; Smith, Daniel Jordan (2006). "Love, Marriage and Positive Living" (PDF). Sexuality in Africa. Lagos: Africa Regional Sexuality Resource Centre (ARSRC). ISSN 0189-7667. 6. ^ Staff (13 September 2011). "Persecuted for being gay". The Guardian. Retrieved 5 May 2020. * v * t * e HIV/AIDS in Africa Sovereign states * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde (Cabo Verde) * Central African Republic * Chad * Comoros * Democratic Republic of the Congo * Republic of the Congo * Djibouti * Egypt * Equatorial Guinea * Eritrea * Eswatini (Swaziland) * Ethiopia * Gabon * The Gambia * Ghana * Guinea * Guinea-Bissau * Ivory Coast (Côte d'Ivoire) * Kenya * Lesotho * Liberia * Libya * Madagascar * Malawi * Mali * Mauritania * Mauritius * Morocco * Mozambique * Namibia * Niger * Nigeria * Rwanda * São Tomé and Príncipe * Senegal * Seychelles * Sierra Leone * Somalia * South Africa * South Sudan * Sudan * Tanzania * Togo * Tunisia * Uganda * Zambia * Zimbabwe States with limited recognition * Sahrawi Arab Democratic Republic * Somaliland Dependencies and other territories * Canary Islands / Ceuta / Melilla (Spain) * Madeira (Portugal) * Mayotte / Réunion (France) * Saint Helena / Ascension Island / Tristan da Cunha (United Kingdom) * 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

HIV/AIDS in Nigeria

None

wikipedia

https://en.wikipedia.org/wiki/HIV/AIDS_in_Nigeria

{"wikidata": ["Q5629871"]}

Charcot-Marie-Tooth disease, type 2B2 (CMT2B2, also referred to as CMT4C3) is an axonal CMT peripheral sensorimotor polyneuropathy that has been described in a large consanguineous Costa Rican family of Spanish ancestry. ## Clinical description Onset occurs in adulthood (between 26 and 42 years of age) with symmetric moderate to severe weakness of the distal muscles, predominantly affecting the lower extremities. Marked sensory deficits were also reported. ## Etiology CMT2B2 is transmitted in an autosomal recessive manner and the disease-causing gene was mapped to chromosome 19q13.3 (MED25). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Charcot-Marie-Tooth disease type 2B2

c1854150

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=101101

{"gard": ["1249"], "mesh": ["C537991"], "omim": ["605589"], "umls": ["C1854150"], "icd-10": ["G60.0"], "synonyms": ["AR-CMT2B2", "Autosomal recessive axonal CMT4C3", "Autosomal recessive axonal Charcot-Marie-Tooth disease type 2B2"]}

Waldmann disease Other namesWaldmann's disease, Primary intestinal lymphangiectasia Waldmann disease is a rare disease[1] characterized by enlargement of the lymph vessels supplying the lamina propria of the small intestine.[2] Although its prevalence is unknown, it being classified as a "rare disease" means that less than 200,000 of the population of the United States are affected by this condition and its subtypes.[1][3] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Management * 5 History * 6 References * 7 External links ## Signs and symptoms[edit] Signs and symptoms of the disease include diarrhea, nausea, swelling of the legs, protein-losing enteropathy, immunodeficiency and loss of lymphatic fluid into the intestines.[2][4] It is usually diagnosed before the patient is 3 years old, but it is sometimes diagnosed in adults.[3] ## Pathophysiology[edit] The illness is usually caused by lymphatic vessels that were misshaped at birth, causing obstruction and subsequent enlargement. The condition can also be a result of other illnesses such as constrictive pericarditis and pancreatitis.[citation needed] ## Diagnosis[edit] The disease is diagnosed by doing a biopsy of the affected area. Severity of the disease is then determined by measuring alpha1-antitrypsin proteins in a stool sample.[4] ## Management[edit] Once the main cause of the disease is treated, a diet of low-fat and high-protein aliments, supplemental calcium and certain vitamins has been shown to reduce symptom effects.[4] This diet, however, is not a cure. If the diet is stopped, the symptoms will eventually reappear.[3] ## History[edit] The disease was first reported in 1961 by T.A. Waldmann. He described 18 cases of patients having a low level 131I-albumin. Biopsies of the small intestine were examined under the microscope and found various levels of dilatation of the lymph vessels.[5] ## References[edit] 1. ^ a b "Waldmann disease". Retrieved 2009-06-11. 2. ^ a b Boursier, V.; Vignes, S. (May 2004). "Limb lymphedema as a first manifestation of primary intestinal lymphangiectasia (Waldmann's disease)". Journal des Maladies Vasculaires. 29 (2): 103–106. doi:10.1016/S0398-0499(04)96722-4. ISSN 0398-0499. PMID 15229406. 3. ^ a b c Vignes, S.; Bellanger, J. (Feb 2008). "Primary intestinal lymphangiectasia (Waldmann's disease)". Orphanet Journal of Rare Diseases (Free full text). 3: 5. doi:10.1186/1750-1172-3-5. PMC 2288596. PMID 18294365. 4. ^ a b c Ruiz, Atenodoro R. "Intestinal Lymphangiectasia". Merck. Retrieved 2009-06-11. 5. ^ Vignes, S.; Bellanger, J. (Mar 2007). "Intérêt de l'entéroscopie par vidéocapsule dans le diagnostic des lymphangiectasies intestinales primitives" [Videocapsule endoscopy as a useful tool to diagnose primary intestinal lymphangiectasia]. La Revue de Médecine Interne (in French). 28 (3): 173–175. doi:10.1016/j.revmed.2006.11.019. ISSN 0248-8663. PMID 17229491. ## External links[edit] Classification D * ICD-10: I89.0 * ICD-9-CM: 457.1 * MeSH: C536567 * DiseasesDB: 12214 * v * t * e Lymphatic disease: organ and vessel diseases Thymus * Abscess * Hyperplasia * Hypoplasia * DiGeorge syndrome * Ectopic thymus * Thymoma * Thymic carcinoma Spleen * Asplenia * Asplenia with cardiovascular anomalies * Accessory spleen * Polysplenia * Wandering spleen * Splenomegaly * Banti's syndrome * Splenic infarction * Splenic tumor Lymph node * Lymphadenopathy * Generalized lymphadenopathy * Castleman's disease * Intranodal palisaded myofibroblastoma * Kikuchi disease * Tonsils * see Template:Respiratory pathology Lymphatic vessels * Lymphangitis * Lymphangiectasia * Lymphedema * Primary lymphedema * Congenital lymphedema * Lymphedema praecox * Lymphedema tarda * Lymphedema–distichiasis syndrome * Milroy's disease * Secondary lymphedema * Bullous lymphedema * Factitial lymphedema * Postinflammatory lymphedema * Postmastectomy lymphangiosarcoma * Waldmann disease *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Waldmann disease

c2931241

wikipedia

https://en.wikipedia.org/wiki/Waldmann_disease

{"gard": ["7873"], "mesh": ["C536567"], "umls": ["C2931241", "C0267372"], "icd-9": ["457.1"], "icd-10": ["I89.0"], "orphanet": ["90362"], "wikidata": ["Q7961531"]}

Inverse Marcus-Gunn phenomenon is a rare congenital synkinesis where jaw opening by the pterygoid muscle (during eating or yawning) causes eyelid drooping from inhibition of the oculomotor nerve to the levator palpebrae superioris. Familial occurrence has been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Inverse Marcus-Gunn phenomenon

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98951

{"icd-10": ["Q07.8"]}

Distal myopathy refers to a group of muscle diseases which share the clinical pattern of predominant weakness and atrophy beginning in the feet and/or hands. ## Epidemiology The estimated prevalence of distal myopathy in the northern region of England is 1/300,000. Some forms have been identified with greater frequency in certain populations. For example, tibial muscular dystrophy is frequent in Finland with a prevalence of 1/5,000 and Welander distal myopathy occurs with greater frequency in Sweden. ## Clinical description Distal myopathy is characterized by progressive muscular weakness and atrophy beginning in the distal parts of upper and lower limbs with an extremely variable age of onset. Distal myopathy is a genetically heterogeneous group (currently comprising more than 20 genetic types) which affects different regions of the distal extremities and is classified according to clinical features, inheritance pattern, histopathological criteria, and molecular genetics. The main autosomal dominant forms of distal myopathy are Welander distal myopathy (weakness in the distal upper extremities which later progresses to distal lower extremity), tibial muscular dystrophy (mainly affects the front of the lower leg), distal myotilinopathy (progressive distal muscle weakness and peripheral neuropathy with hyporeflexia), late-onset distal myopathy, Markesbery-Griggs type (ZASP-related myofibrillar myopathy), Laing early-onset distal myopathy, distal myopathy with posterior leg and anterior hand involvement (distal ABD-filaminopathy), and adult-onset distal myopathy due to VCP mutation. The genetically confirmed autosomal recessive forms are distal myopathy, Nonaka type (GNE-myopathy, weakness in the anterior distal legs), Miyoshi myopathy (weakness in the distal lower extremity posterior compartment), nebulin-related early-onset distal myopathy and distal anoctaminopathy. The age at onset is extremely variable and for recessive varieties of distal myopathy, symptoms usually develop in early adult life whereas in the dominant Welander and tibial muscular dystrophy, the onset is usually later. However, in some disorders (i.e. Laing early-onset distal myopathy and nebulin-related early-onset distal myopathy) the onset may be during childhood, and even in infancy. ## Etiology Distal myopathy is caused by defect or lack of specific proteins that play an essential role in the proper function and health of muscle cells. 15 causative genes have to date been associated with distal myopathy: ANO5 (11p15.1), CRYAB (11q22.3-q23.1), DES (2q35), DYSF (2p13.3), FLNC (7q32-q35), GNE (9p13.1), KLHL9 (9p22), LDB3 (10q22.3-q23.2), MATR3 (5q31.3), MYH7 (14q11.2-q13), MYOT (5q31.2), NEB (2q22), TIA1 (2p13), TTN (2q31) and VCP (9p13.3). ## Genetic counseling Distal myopathy can be inherited as an autosomal dominant or as an autosomal recessive trait. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Distal myopathy

c0751336

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=599

{"mesh": ["D049310"], "umls": ["C0751336"], "icd-10": ["G71.0"], "synonyms": ["Distal muscular dystrophy"]}

3q29 microdeletion syndrome is a rare chromosome disorder. Symptoms may include delay reaching some developmental milestones such as sitting, walking or talking, frequent ear and respiratory infections, and a small head size (microcephaly). Some babies with this condition are born with a cleft lip or cleft palate, and a few have been reported to have heart defects. As children with this condition get older, they may develop behavioral difficulties such as autism, and they may have symptoms of mental illness. The severity of symptoms can vary, and some people with 3q29 microdeletion syndrome may have very mild symptoms or may not even know they are affected. 3q29 microdeletion syndrome is caused by the loss of a small piece of DNA in one copy of chromosome 3, one of the 23 pairs of chromosomes in each cell in our bodies. Most cases of 3q29 microdeletion syndrome are de novo, which means the deletion was not passed down from either parent. Some cases may be inherited from a parent who is only mildly affected by the condition. Diagnosis of 3q29 microdeletion syndrome may be suspected by symptoms but is confirmed by genetic testing. Treatment is based on signs and symptoms of each person and may include surgeries to repair any physical abnormalities, speech therapy, behavior therapy and special education. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

3q29 microdeletion syndrome

c2674949

gard

https://rarediseases.info.nih.gov/diseases/11974/3q29-microdeletion-syndrome

{"mesh": ["C567184"], "omim": ["609425"], "orphanet": ["65286"], "synonyms": ["3qter deletion", "Del(3)(q29)", "Monosomy 3qter", "Chromosome 3q29 microdeletion syndrome", "3q subtelomere deletion syndrome", "3q29 deletion", "Monosomy 3q29", "3q29 deletion syndrome"]}

Cochleosaccular degeneration-cataract syndrome is characterised by progressive sensorineural hearing loss due to severe cochleosaccular degeneration and cataract. So far, it has been reported in two families. Transmission is autosomal dominant. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Cochleosaccular degeneration-cataract syndrome

c1861512

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3233

{"gard": ["9418"], "mesh": ["C536432"], "omim": ["120040"]}

A number sign (#) is used with this entry because of evidence that Cohen-Gibson syndrome (COGIS) is caused by heterozygous mutation in the EED gene (605984) on chromosome 11q14. Description Cohen-Gibson syndrome is an overgrowth disorder characterized by increased somatic parameters apparent from birth and associated with variable intellectual disability. Affected individuals have dysmorphic facial features, advanced bone age, and skeletal abnormalities, including flaring of the metaphyses of the long bones, large hands with long fingers and camptodactyly, and often scoliosis or cervical spine anomalies. Other features may include hypotonia, difficulty walking due to skeletal anomalies, and umbilical hernia (summary by Cooney et al., 2017). Clinical Features Cohen et al. (2015) reported a 27-year-old man, born of unrelated Turkish parents, with an overgrowth syndrome associated with intellectual disability. At birth, he had only mildly increased length and weight, and thereafter showed delayed psychomotor development with speech delay and poor fine motor skills. He developed seizures at 4.5 years of age. Dysmorphic features included macrocephaly, large ears, hypertelorism, downslanting palpebral fissures, and retrognathia with a prominent crease between the lower lip and the chin. Brain imaging was normal. At age 8 years, he was very tall (+4.6 SD), but his height leveled out in adulthood (+1.85). Additional features included myopia, cataracts, umbilical hernia, cryptorchidism, posttraumatic patellar dislocation, widely spaced nipples, pigmented nevi, and large hands with camptodactyly. Radiographic studies showed advanced bone age, scoliosis, abnormal flaring of the distal clavicles, distal ribs, and metaphyses of the distal radius, distal ulna, distal femur, and proximal tibia, as well as a flattened left acetabulum and femoral head. Cohen and Gibson (2016) reported a second male patient, born of unrelated Caucasian parents, with COGIS. Somatic overgrowth was observed on prenatal ultrasound, and he had respiratory distress and mild jaundice soon after birth. He showed developmental delay in infancy, with walking at 24 months and poor speech acquisition; he also had an umbilical hernia. Throughout childhood and adulthood, he had hypotonia, stiffness of the joints and tendons, and biomechanical variations of the feet and knees, resulting in balance, coordination, and walking difficulties. Radiographic studies showed advanced bone age and scoliosis. Dysmorphic features included asymmetric skull, macrocephaly, round face, abnormal bite, retrognathia with a prominent crease between the lower lip and chin, deep-set eyes, almond-shaped palpebral fissures, large low-set ears, prominent nasal root and nasal bridge with bulbous nasal tip, and bifid uvula. He also had large hands with long slender fingers, large slender feet, numerous pigmented nevi, and C1-C2 spinal instability resulting in traumatic spinal cord compression. His growth slowed with age: at age 22 years, his height was above the 97th percentile and head circumference was above the 90th percentile. His stance remained slightly forward, with hips and knees flexed and restricted range of movement of certain large joints of the upper and lower limbs. Cooney et al. (2017) reported a 16-year-old girl, born of unrelated Hispanic parents, with COGIS. She had increased birth weight (+4.2 SD), length (+2.6), and head circumference (+2.2). Dysmorphic features noted at birth included cleft palate, posterior ear pits, capillary hemangioma of the back, and umbilical hernia. She had hypotonia, poor feeding, and global developmental delay with moderate intellectual disability. She had multiple additional congenital anomalies, including nephromegaly, tracheomalacia, patent ductus arteriosus requiring coil occlusion, atrial septal defect, mitral regurgitation, and inguinal and femoral hernias. Brain imaging at age 2 years showed substantial white matter volume loss, particularly in the frontal lobe, and moderate to severe thinning of the corpus callosum. Skeletal anomalies included advanced bone age, cervical spine stenosis, small iliac wings, coxa valga, wide metaphyses, osteopenia, Achilles tendon and hamstring contractures, chondromalacia, recurrent dislocation and subluxation of the patellae, pes planovalgus, and camptodactyly. She had an abnormal gait due to her contractures. At age 16, her growth parameters were above the 95th percentile, and she had dysmorphic facial features, including broad face with short forehead, depression of the supraorbital ridges, long and low-set ears, thick eyebrows, hypertelorism, downslanting and almond-shaped palpebral fissures, wide and depressed nasal bridge, and broad neck. She also had visual disturbances due to exotropia, hyperopic astigmatism, and ptosis. Distal skeletal abnormalities included long, broad palms, long fingers, broad thumbs, camptodactyly, small nails, and joint laxity of the small joints of the hands. Imagawa et al. (2017) reported a 5-year-old Japanese boy with COGIS. He had increased birth weight (+3.1 SD), length (+2.2 SD), and head circumference (+1.4 SD). Characteristic craniofacial features included macrocephaly, round face, broad forehead, hypertelorism, prominent long philtrum, retrognathia, low nasal bridge, large ears, and epicanthus. Brain imaging was normal. He had delayed psychomotor development, with walking at 23 months, speech delay, and low IQ (57 to 65). He had multiple skeletal abnormalities, including advanced bone age, flexion disorder of the metacarpophalangeal joints of the first and fifth fingers, and wide metaphyses of the femoral and tibial bones. He also had an umbilical hernia. At age 5.4 years, his height, weight, and head circumference were +4.5 SD, +3.8 SD, and +2.6 SD, respectively. Molecular Genetics In a 27-year-old man, born of unrelated Turkish parents, with COGIS, Cohen et al. (2015) identified a de novo heterozygous missense mutation in the EED gene (R302S; 605984.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. In a 22-year-old man, born of unrelated Caucasian parents, with COGIS, Cohen and Gibson (2016) identified a de novo heterozygous missense mutation in the EED gene (H258Y; 605984.0002). The mutation was found by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. In a 16-year-old girl, born of unrelated Hispanic parents, with COGIS, Cooney et al. (2017) identified a heterozygous missense mutation in the EED gene (R302G; 605984.0003). The mutation, which was found by whole-exome sequencing, was not present in the mother; the father was unavailable for testing. Functional studies of the variant and studies of patient cells were not performed. In a 5-year-old Japanese boy with COGIS, Imagawa et al. (2017) identified a de novo heterozygous missense mutation in the EED gene (R236T; 605984.0004). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the R236T and R302S mutant proteins were associated with decreased levels of H3K27me3 compared to wildtype, and Western blot analysis of patient cells with the R236T mutation also showed loss of H3K27me3, consistent with loss of PRC2 activity and a loss of function. INHERITANCE \- Autosomal dominant GROWTH Height \- Increased birth length \- Tall stature Weight \- Increased birth weight \- Increased weight Other \- Excessive postnatal growth HEAD & NECK Head \- Macrocephaly Face \- Round face \- Broad forehead \- Short forehead \- Retrognathia \- Crease between the mouth and the chin Ears \- Large ears \- Long ears \- Low-set ears Eyes \- Hypertelorism \- Downslanting palpebral fissures \- Almond-shaped eyes \- Ptosis \- Epicanthal folds \- Cataracts \- Myopia Nose \- Wide nasal bridge \- Depressed nasal bridge CARDIOVASCULAR Heart \- Patent ductus arteriosus (in some patients) \- Septal defect (in some patients) CHEST Ribs Sternum Clavicles & Scapulae \- Flaring of the clavicles ABDOMEN External Features \- Umbilical hernia SKELETAL \- Advanced bone age \- Joint contractures \- Chondromalacia \- Osteopenia Spine \- Cervical spine stenosis \- Scoliosis Pelvis \- Flattened acetabulum and femoral head \- Small iliac wings Limbs \- Flared metaphyses \- Subluxation of the patellae \- Coxa valga Hands \- Large hands \- Long hands \- Long fingers \- Broad thumbs \- Camptodactyly \- Joint laxity of the small joints of the hand Feet \- Large feet \- Pes planovalgus SKIN, NAILS, & HAIR Skin \- Pigmented nevi Nails \- Small nails \- Thin nails MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Intellectual disability \- Delayed speech \- Abnormal gait \- Poor coordination MISCELLANEOUS \- Onset at birth \- Variable phenotype \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the homolog of the mouse embryonic ectoderm development protein gene (EED, 605984.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

COHEN-GIBSON SYNDROME

c4479654

omim

https://www.omim.org/entry/617561

{"omim": ["617561"], "genereviews": ["NBK540017"]}

## Summary ### Clinical characteristics. Kindler syndrome (KS), a rare subtype of inherited epidermolysis bullosa, is characterized by skin fragility and acral blister formation beginning at birth, diffuse cutaneous atrophy, photosensitivity (which is most prominent during childhood and usually decreases after adolescence), poikiloderma, diffuse palmoplantar hyperkeratosis, and pseudosyndactyly. Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings can include ectropion, esophageal strictures/stenosis, anal stenosis, colitis, urethral stenosis/strictures, and severe phimosis. Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas. Manifestations can range from mild to severe. ### Diagnosis/testing. The diagnosis of Kindler syndrome is established in a proband with characteristic clinical findings and identification of either biallelic FERMT1 pathogenic variants on molecular genetic testing or suggestive histologic findings and/or immunolabeling on skin biopsy. ### Management. Treatment of manifestations: When possible, children with KS should be managed by a multidisciplinary team (dermatologist, pediatrician, ophthalmologist, dentist, gastroenterologist, urologist, nurse specialist, and dietitian) in a center experienced in caring for children with skin fragility. Skin care includes standard blister care, use of moisturizers, and protection from trauma and the sun. Mucosal involvement can require lubrication of the cornea, regular dental care to ensure optimal oral hygiene to reduce periodontal disease, management of GI complications (esophageal strictures/stenosis, anal stenosis, colitis) and urethral complications (meatal stenosis/strictures). Prevention of secondary complications: Monitoring for iron-deficiency anemia in those with colitis and esophageal strictures. Surveillance: Screening for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeated annually. Agents/circumstances to avoid: Sun exposure. Pregnancy management: Planning for potential complications at delivery (e.g., vaginal stenosis, labial synechiae) ### Genetic counseling. KS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FERMT1 pathogenic variants have been identified in an affected family member, carrier testing is possible and prenatal testing or preimplantation genetic diagnosis for a pregnancy at increased risk may be an option that a couple may wish to consider. ## Diagnosis ### Suggestive Findings Kindler syndrome should be suspected in individuals with the following clinical findings (in order of their specificity and importance for clinical diagnosis) [Lai-Cheong & McGrath 2010, Sybert 2010]. Skin fragility with trauma-induced blistering. Blisters, the most common clinical manifestation of KS, result from cutaneous trauma and/or exposure to sunlight. Blisters are present at birth. Skin atrophy, characterized by thin, wrinkled (cigarette-paper) skin, develops early in life, particularly on the dorsa of the hands and feet. It usually becomes generalized by adolescence and is often present on the abdomen, thighs, knees, and elbows (Figure 1a, 1f, 1g) [Jobard et al 2003]. #### Figure 1. Characteristic clinical features of Kindler syndrome a. Child age nine years: atrophy of skin on the dorsum of the hands and poikiloderma on the neck and axillary area Some individuals have nail dystrophy. The plate of the nails is thin, with atrophy and onycholysis (Figure 1a, 1e, 1f, 1g) [Jobard et al 2003]. Photosensitivity, characterized by erythema and burning after sun exposure, tends to improve with age; however, some degree of photosensitivity usually persists (e.g., facial erythema after minimal sun exposure) [Ashton et al 2004]. Note: Affected individuals can develop redness within minutes of sun exposure. Poikiloderma, characterized by reticular telangiectasia and mottled hypo- and hyperpigmentation of the skin, frequently appears between ages two and three years. Generalized poikiloderma (in both sun-exposed and non-sun-exposed areas) eventually develops and persists throughout adult life in most affected individuals. Axillary freckling may be observed in some (Figure 1a) [Jobard et al 2003, Siegel et al 2003]. Hyperkeratosis of the palms and soles with fissuring observed in about 65% of affected individuals. Palmar hyperkeratosis often has a waxy appearance, occasionally leading to the loss of the dermal ridges (i.e., fingerprints). Dermatoglyphics can be flattened or lost. Some individuals may have ridged, ribbed hyperkeratosis of the lateral and anterior ankles reminiscent of epidermolytic hyperkeratosis. Pseudosyndactyly (i.e., partial fusion of the third and fourth and fourth and fifth toes) may be the result of repeated blistering and scarring in infancy (Figure 1g). Mucosal involvement can include the following [Jobard et al 2003, Penagos et al 2004]: * Eyes. Conjunctivitis, conjunctival scarring, corneal erosion, and ectropion of the lower eyelids [Lelli 2010, Martinez & Siegel 2011, Signes-Soler et al 2013] * Mouth and periodontium. Severe periodontal disease (e.g., hemorrhagic mucositis, gingivitis, periodontitis, premature loss of teeth, and labial leukokeratosis), usually beginning in early adolescence [Lai-Cheong & McGrath 2010] * Gastrointestinal tract. Esophageal stenosis, severe colitis, bloody diarrhea, constipation, and rectal mucosal fissures and stenosis. Also, there are reports of affected children born with an imperforate anus that required surgical repair [Lai-Cheong & McGrath 2010]. * Vagina. Vaginal stenosis and labial synechiae * Urethra. In some individuals, urethral meatal stenosis and urethral strictures * Phimosis ### Establishing the Diagnosis The diagnosis of Kindler syndrome is established in a proband with characteristic clinical findings and identification of EITHER of the following: * Biallelic FERMT1 pathogenic variants on molecular genetic testing (see Table 1) * Suggestive histologic findings and/or immunolabeling on skin biopsy #### Molecular Genetic Testing Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing. * Single-gene testing. Sequence analysis of FERMT1 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. * A multigene panel that includes FERMT1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. * More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes FERMT1) fails to confirm a diagnosis in an individual with features of Kindler syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Kindler Syndrome View in own window Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method FERMT1Sequence analysis 3~ 95% 4 Gene-targeted deletion/duplication analysis 5~ 3% 6 UnknownNot determined 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Ashton et al [2004], Has et al [2011] 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Has et al [2006], Has et al [2008], Zhou et al [2009], Piccinni et al [2013], Fuchs-Telem et al [2014] 7\. Although there is no proof of a second locus for Kindler syndrome, several pedigrees showing consanguinity have been reported with either no evidence of homozygosity at FERMT1 or no pathogenic variant detected, indicating that some pathogenic variants may not be readily detectable by these methods [Siegel et al 2003, Youssefian et al 2015]. #### Skin Biopsy Histopathologic examination shows hyperkeratosis, nonspecific epidermal atrophy, dermal edema, incontinence of pigment with or without cytoid bodies, loss of rete ridges, and focal vacuolization of the basal layer of the epidermis and pigmentary incontinence in the upper dermis, consistent with poikiloderma [Shimizu et al 1997]. A characteristic feature is a split within the basement membrane zone at different levels. However, the most frequently encountered cleavage plane is through the lowermost portion of the basal layer of the epidermis. Extensive reduplication of the basement membrane and associated collagen deposition within the clefts are unique ultrastructural and histopathologic findings in KS. Electron microscopy. The level of cleavage of blisters can be variable; intradermal, junctional, and dermal cleavage planes have been reported in a single biopsy from one individual. Transmission electron microscopy of non-blistered skin demonstrates marked disorganization of the dermo-epidermal basement membrane with reduplication of the basal lamina, focal interruptions of the lamina densa, and cleavage at or close to the dermo-epidermal junction. Desmosomes, hemidesosomes, tonofilaments, anchoring filaments, and anchoring fibrils appear normal [Shimizu et al 1997, Lanschuetzer et al 2003]. Immunofluorescence staining. Antigen mapping analysis revealed that the major diagnostic criterion for Kindler syndrome is intense, broad, reticulate, and branching staining pattern with antibodies directed against laminin-332 and type IV and type VII collagen. Although anti-kindlin-1 immunostaining is also applied as a diagnostic test for KS, the final confirmation is made by FERMT1 molecular genetic testing [Lanschuetzer et al 2003, Barzegar et al 2015]. ## Clinical Characteristics ### Clinical Description Kindler syndrome (KS), a rare subtype of epidermolysis bullosa, is characterized by skin fragility and acral blister formation beginning at birth or in early infancy, diffuse cutaneous atrophy, photosensitivity (which is most prominent during childhood and usually decreases after adolescence), poikiloderma, palmoplantar hyperkeratosis, and pseudosyndactyly. Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings include ectropion, urethral stenosis, and severe phimosis. Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas. See the reviews by Lai-Cheong & McGrath [2010] and Has et al [2011], which are the basis of much of the following discussion. The phenotypic spectrum ranges from mild to severe based on age of onset, organs involved, and severity of manifestations. The mild end of the spectrum is characterized by minimal skin involvement (such as that observed in adults with KS), with or without other mild manifestations. Some individuals with mild manifestations are not diagnosed until late in life; for example, two individuals diagnosed by molecular genetic testing in their 60s and 70s after early-stage cutaneous precancerous lesions and epithelial skin cancer were identified and treated in their 50s [Has et al 2010]. In contrast, the severe end of the spectrum is characterized by such findings as severe mucosal involvement, severe esophageal stenosis, pseudo-ainhum, anemia, and/or malignancies. Blisters observed in childhood are mainly localized to extremities. The number of blisters decreases by age ten to 12 years [Siegel et al 2003, Penagos et al 2004]. Pyogenic skin infections can be a complication of blistering. Skin atrophy, initially primarily localized to hands and feet, becomes generalized by adolescence [Jobard et al 2003]. Poikiloderma, which is not present at birth, appears first on sun-exposed areas, progressing with age to non-sun-exposed areas. Hyperkeratosis of the palms and soles has been reported as fissured or punctate [Penagos et al 2004]. Pseudosyndactyly. Typically, interdigital webbing develops (Figure 1f), but without the scarring or milia noted in other forms of epidermolysis bullosa (EB) [Jobard et al 2003, Siegel et al 2003]. Constricting bands of pseudoainhum type have also been reported (Figure 1e, 1g) [Penagos et al 2004]. Fragility of mucosal surfaces can include [Jobard et al 2003, Penagos et al 2004]: * Gums resulting in severe periodontal disease; * Esophagus, anus, urethra, and vagina resulting stenosis and strictures (Figure 1c); * Colitis; * Conjunctiva resulting in ectropion. An increased risk for malignancies has been reported: * Squamous cell carcinomas in acral skin and the mouth (lip and hard palate) [Lotem et al 2001, Emanuel et al 2006] * Transitional cell carcinomas of the bladder [Alper et al 1978] Other findings that may be present: * Xerosis, eczema, and dermatitis * Variable hypermobility of the thumb, fingers, knees, and elbows without skin hyperextensibility [Penagos et al 2004] * Nail dystrophy (Figure 1e) Morbidity and mortality mostly result from mucosal strictures and associated complications, secondary infections or cutaneous bullae, and cancer. ### Genotype-Phenotype Correlations Most FERMT1 variants associated with Kindler syndrome are null variants. It has been proposed that FERMT1 pathogenic missense variants and in-frame deletions are associated with milder disease manifestations and later onset of complications [Maier et al 2016]. Also, environmental factors and as-yet unknown modifiers likely influence the course of the disease [Has et al 2010, Has et al 2011]. ### Nomenclature Kindler syndrome (KS) was first described by Theresa Kindler [Kindler 1954]. In May 2007, 18 leading authorities on epidermolysis bullosa (EB) revised the EB classification to include KS based on its biologic and clinical findings [Fine et al 2008, Fine et al 2014]. ### Prevalence Since the first description of Kindler syndrome in 1954 [Kindler 1954], about 250 affected individuals have been reported worldwide. Persons of any race can be affected and there is no sex predilection [Penagos et al 2004, Has et al 2011, Youssefian et al 2015]. A cluster of 26 Panamanian affected individuals and 24 Iranian affected individuals with the syndrome have been identified [Penagos et al 2004, Youssefian et al 2015]. ## Differential Diagnosis The differential diagnosis of Kindler syndrome (KS) includes the following disorders, which can exhibit features of poikiloderma but are distinguishable by other clinical features. The clinical features of KS overlap with those of other inherited blistering skin disorders (e.g., dystrophic, junctional, and simplex epidermolysis bullosa) and congenital poikilodermas (e.g., Rothmund-Thomson syndrome). Before the onset of the photosensitivity and poikiloderma in the first few years of life, KS is frequently confused with other variants of epidermolysis bullosa; however, acral skin atrophy is indicative of KS. Furthermore, in contrast to blistering in other types of epidermolysis bullosa, the blistering in KS significantly improves with age. The designation Weary-Kindler syndrome (WKS) has been used for a disorder with features that overlap with Kindler syndrome including vesicopustules, eczema, poikiloderma, and acral keratotic papules in infancy. In WKS the bullae are not congenital and photosensitivity and mucosal involvement are not observed [Weary et al 1971, Larrègue et al 1981, Lai-Cheong et al 2009]. WKS is inherited in an autosomal dominant manner; the associated gene(s) have not been identified. Several authors have noted the similarity of the findings in these patients to those in the original case described by Theresa Kindler, and some believe that Weary and Kindler syndromes are aspects of the same disorder [Lee et al 2012]. Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. Poikiloderma and nail dystrophy occur in late childhood. Individuals with DC are at increased risk for progressive bone marrow failure, myelodysplastic syndrome or acute myelogenous leukemia, solid tumors, and pulmonary fibrosis. Pathogenic variants in CTC1, DKC1, TERC, TERT, TINF2, NHP2, NOP10, and WRAP53 have been identified in approximately half of individuals who meet clinical diagnostic criteria for DC. DC is inherited in an X-linked, autosomal dominant, or autosomal recessive manner depending on the involved gene. Mendes da Costa syndrome, also referred to as hereditary bullous dystrophy, macular type (OMIM 302000), is characterized by microcephaly, short stature, mild intellectual disability, cone-shaped fingers, and poikiloderma. The disorder has been described in Dutch and Italian families [Sybert 2010]. Mendes da Costa syndrome is linked to the Xq27.3-qter region; the associated gene(s) are unknown. Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma; sparse hair, eyelashes, and/or eyebrows; small stature; skeletal and dental abnormalities; cataracts; and an increased risk for cancer, especially osteosarcoma. The skin is typically normal at birth; the rash of RTS develops between age three and six months as erythema, swelling, and blistering on the face and subsequently spreads to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, punctate atrophy, and telangiectases, collectively known as poikiloderma. To date, RECQL4 is the only gene in which mutation is known to cause RTS. RTS is inherited in an autosomal recessive manner. Poikiloderma with neutropenia (poikiloderma with neutropenia, Clericuzio-type) is characterized by post-inflammatory poikiloderma and permanent (noncyclic) moderate to severe neutropenia. Findings include poikiloderma, moderate neutropenia, defective neutrophil oxidative burst, anemia, thrombocytopenia, and recurrent sinopulmonary and skin infections. Myelodysplastic syndrome has been seen in adults. Poikiloderma with neutropenia is caused by mutation of USB1 and inherited in an autosomal recessive manner. Xeroderma pigmentosum (XP) is characterized by sun sensitivity, ocular involvement, and greatly increased risk of cutaneous neoplasms. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. XP is caused by mutation of XPA, ERCC1, ERCC3, XPC, ERCC2, DDB2, ERCC4, ERCC5, or POLH and is inherited in autosomal recessive manner. XP typically does not have acral bullae whereas in KS acral bullae are observed in childhood. Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, highly characteristic sparseness of subcutaneous fat tissue throughout infancy and early childhood, and short stature throughout postnatal life that in most affected individuals is accompanied by an erythematous and sun-sensitive skin lesion of the face (but not true poikiloderma). Gastroesophageal reflux (GER) is common and very possibly responsible for infections of the upper respiratory tract, the middle ear, and the lung that occur repeatedly in most persons with BSyn. Although most affected individuals have normal intellectual capability, many exhibit a poorly defined (and little studied) learning disability. Serious medical complications that are much more common than in the general population and that also appear at unusually early ages are chronic obstructive pulmonary disease, diabetes mellitus resembling the adult-onset type, and cancer of a wide variety of types and anatomic sites. BSyn is caused by mutation of BLM and inherited in an autosomal recessive manner. Hereditary sclerosing poikiloderma (OMIM 173700) is characterized by progressive poikiloderma in flexural areas (manifest as hyper- and hypopigmentation without telangiectasia or atrophy), sclerotic bands, poor dentition, and, occasionally, calcinosis cutis [Weary et al 1969]. A later-onset complication is stenosis of cardiac valves. Absence of bullae and photosensitivity distinguish hereditary sclerosing poikiloderma from KS. Hereditary sclerosing poikiloderma is inherited in an autosomal dominant manner. Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is characterized by the skin findings of poikiloderma (typically beginning in the first six months and mainly localized to the face), hypohidrosis with heat intolerance, mild lymphedema of the extremities, chronic erythematous and scaly skin lesions on the extremities, sclerosis of the digits, and mild palmoplantar keratoderma. Typically scalp hair, eyelashes, and/or eyebrows are sparse; nail dysplasia may be associated. Muscle contractures are usually seen in childhood and can be present as early as age two years. The majority of affected individuals develop progressive weakness of the proximal and distal muscles of all four limbs. Some adults develop progressive interstitial pulmonary fibrosis which can be life threatening within three to four years after respiratory symptoms appear. Other features are exocrine pancreatic insufficiency, liver impairment, hematologic abnormalities, relative short stature, and cataract. POIKTMP is caused by mutation of FAM111B and inherited in an autosomal dominant manner. ## Management ### Evaluation Following Initial Diagnosis To establish the extent of the disease and needs in an individual diagnosed with Kindler syndrome (KS), the following are recommended: * Evaluation by a dermatologist for management of skin fragility, blistering, photosensitivity, and risk for squamous cell carcinoma * Evaluation for mucosal involvement of the eyes (ophthalmologic consultation), mouth (dental consultation) GI tract (gastroenterology consultation), urethra, foreskin (in males) (urology consultation), and vagina (in females) (gynecology consultation) * Evaluation of nutritional status, diet, and oral intake * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations No established treatment for Kindler syndrome exists. The goals of care are to treat manifestations and prevent complications. When possible, children with KS should be managed by a multidisciplinary team in a center experienced in caring for children with skin fragility. When possible, the team should include a dermatologist, pediatrician, ophthalmologist, dentist, gastroenterologist, urologist, nurse specialist, and dietitian. Skin. The following are recommended: * Standard blister care in childhood. If a blister is not painful, it should be kept intact. Otherwise alleviate blister-related pain by draining the fluid using a sterile needle, leaving the overlying skin in place. Apply an ointment to the blister and cover it with nonstick gauze bandage. Antibiotics may be used to treat an infected blister. * Protection from trauma, for example, by use of soft and protective clothing and avoiding contact sports to prevent physical trauma * Use of moisturizers for dry, pruritic skin * Sun-safety education, including use of high sun protective factor (>30 SPF) sunscreens, use of sun-protective clothing (hats and long-sleeve shirts) and avoidance of sun exposure as much as possible Pseudosyndactyly is usually relatively mild and does not require surgical treatment. Mucosal involvement • Eyes. Lubrication of the cornea by artificial tears and eye drops and prevention of infections by use of local antibiotics; surgical correction of corneal scarring as needed by an ophthalmologist • Mouth and periodontium. Regular dental care to ensure optimal oral hygiene to reduce periodontal disease * Gastrointestinal tract * Esophageal dilatation may be indicated for those with dysphagia. * Esophageal strictures and stenosis may require fluoroscopically guided balloon dilations [Sadler et al 2006]. * Temporary parenteral nutrition may be necessary when esophageal dysfunction is severe. * Anal stenosis and bleeding requires regular laxatives. * Severe colitis may require surgical bowel resection in some cases. * Urethra. Meatal stenosis may require dilatation. Strictures may require stenting and/ or surgical intervention. * Phimosis. Most males require circumcision [Penagos et al 2004]. ### Prevention of Secondary Complications Monitor for secondary iron-deficiency anemia. ### Surveillance Screen for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeat annually. ### Agents/Circumstances to Avoid Avoid sun exposure by using sunscreen (SFP >30) and sun-protective clothing. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Although the cutaneous manifestations of KS are not exacerbated by pregnancy, vaginal stenosis and labial synechiae have been reported; thus, obstetric planning, such as consideration of delivery by elective cesarean section, warrants consideration [Mansur et al 2007]. Of note, specialized perioperative cesarean section management is needed to protect vulnerable skin and mucosa. Breast-feeding is not advised because of the risk of blistering the breasts [Hayashi et al 2007]. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Kindler Syndrome

c0406557

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK349072/

{"mesh": ["C536321"], "synonyms": ["Congenital Bullous Poikiloderma"]}

A number sign (#) is used with this entry because of evidence that spastic paraplegia-6 (SPG6) is caused by heterozygous mutation in the NIPA1 gene (608145) on chromosome 15q11. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600). Clinical Features Fink et al. (1995) reported a family in which hereditary spastic paraplegia had been diagnosed in 31 living subjects. The disorder developed insidiously with progressive gait disturbance at age 12 to 35 years. The unimodal distribution of age at onset of symptoms (mean 22.0 +/- 5.3 years) was similar to that of type I familial spastic paraplegia reported by Harding (1981), who found a mean age at onset of 20.5 +/- 17.9 years. Neurologic examination of affected subjects revealed hyperreflexia and spasticity in the lower limbs, weakness of hip flexion and ankle dorsiflexion, extensor plantar responses, diminished vibratory sense in the feet, and pes cavus. Muscle atrophy, when present, was noted only in the shins. Bladder disturbance was present in 3 affected subjects. Reed et al. (2005) reported a large British family in which 14 members had spastic paraplegia inherited in an autosomal dominant pattern. The mean age at onset was 16.5 years (range 9 to 23), and most developed marked lower limb spasticity with hyperreflexia and extensor plantar responses. Mild bladder disturbances were also found, and most patients had pes cavus. Five affected individuals had generalized tonic-clonic seizures, and 3 developed a postural tremor in the upper limbs in their thirties. Mapping In a large kindred extensively affected with autosomal dominant, uncomplicated familial spastic paraplegia, Fink et al. (1995) demonstrated linkage to a group of markers on chromosome 15q (maximum 2-point lod score = 9.70 at theta = 0.05); this locus was designate SPG6. Previous physical mapping of the microsatellite markers allowed Fink et al. (1995) to assign the SPG6 locus to 15q11.1. In this same family, Fink et al. (1996) observed obligate recombinants for polymorphisms immediately adjacent to the genes encoding the alpha-5 subunit of the GABA receptor (137142) and the beta-3 subunit of the GABA receptor (137192), excluding these as possible candidates. Dube et al. (1997) referred to the chromosome 15-linked form of hereditary spastic paraplegia as SPG4a. Molecular Genetics Rainier et al. (2003) analyzed a large kindred in which autosomal dominant hereditary spastic paraplegia mapped to the SPG6 locus (Fink et al., 1995) and found no evidence of genetic imprinting. Therefore, they analyzed as SPG6 candidates the 4 unique, nonimprinted, and highly evolutionarily conserved genes mapped proximal to the imprinted domain and within the pericentromeric region of 15q (Chai et al., 2003). In 28 SPG6 patients, Rainier et al. (2003) identified a mutation in the NIPA1 (608145.0001). In affected members of a large British family with SPG6, Reed et al. (2005) identified a heterozygous mutation in the NIPA1 gene (608145.0004). INHERITANCE \- Autosomal dominant GENITOURINARY Bladder \- Urinary urgency \- Urinary incontinence \- Sphincter disturbances SKELETAL Feet \- Pes cavus NEUROLOGIC Central Nervous System \- Lower limb spasticity \- Lower limb weakness \- Spastic gait \- Hyperreflexia \- Clonus \- Extensor plantar responses \- Weakness of hip and ankle flexion \- Decreased vibratory sense in the lower limbs \- Degeneration of lateral corticospinal tracts \- Seizures (reported in 1 family) \- Tremor, postural, upper limb, onset in fourth decade (reported in 1 family) MISCELLANEOUS \- Mean age at onset 16.5 years (range 9 to 35 years) \- Insidious onset \- Progressive disorder \- Variable severity \- Genetic heterogeneity, see SPG3A ( 182600 ) MOLECULAR BASIS \- Caused by mutation in the nonimprinted gene in Prader-Willi syndrome/Angelman syndrome chromosome region-1 (NIPA1, 608145.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPASTIC PARAPLEGIA 6, AUTOSOMAL DOMINANT

c1838192

omim

https://www.omim.org/entry/600363

{"doid": ["0110811"], "mesh": ["C536866"], "omim": ["600363"], "orphanet": ["100988"], "synonyms": ["Alternative titles", "FAMILIAL SPASTIC PARAPLEGIA, AUTOSOMAL DOMINANT, 3"]}

A number sign (#) is used with this entry because of evidence that an intellectual developmental disorder with autism and speech delay (IDDAS) is caused by heterozygous mutation in the TBR1 gene (604616) on chromosome 2q. Description IDDAS is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, autism spectrum disorder, and language deficits (Deriziotis et al., 2014; den Hoed et al., 2018). Clinical Features Deriziotis et al. (2014) reported 4 unrelated patients with sporadic occurrence of autism and mutation in TBR1. Clinical details were somewhat limited, but 3 were noted to have delayed intellectual development and language delay. One was nonverbal at age 7 years, another had phrase speech at age 8, and the third was verbally fluent at age 7. Deriziotis et al. (2014) also reported 4 patients with autism with mutation in TBR1 inherited from an unaffected parent. Cognitive functioning in these patients ranged from average to intellectually disabled; 3 patients were verbally fluent and 1 was nonverbal. Language delay was reported in all of these patients. Den Hoed et al. (2018) reported 2 unrelated patients diagnosed with autism spectrum disorder, both of whom also had delayed intellectual development. One of the patients was nonverbal and unable to understand simple commands. The parents were unaffected. McDermott et al. (2018) reported a patient, born of unrelated Caucasian parents, with IDDAS. In the first months of life, she was noted to have global developmental delay, which was followed by delayed walking (age 23 months) and delayed speech. In childhood, she had joint hypermobility, poor expressive language, stereotypic behaviors, and impaired social interaction. Her parents were unaffected. A second unrelated child had a similar phenotype. Vegas et al. (2018) reported 2 unrelated boys with IDDAS and evidence of cortical migration defects on brain imaging. The patients presented in the first year of life with global developmental delay and hypotonia. At age 7 years, 1 of the patients could walk with help, but was nonverbal and showed stereotypic movements. At age 5 years, the other patient was unable to walk or speak. Brain imaging of both patients showed irregularity of the cortical gray-white matter junction, evidence of pachygyria, and a thick cortex; 1 patient also had a thin corpus callosum. The findings expanded the phenotype associated with IDDAS. Mapping Buxbaum et al. (2001) reported linkage evidence for a susceptibility gene for autism on chromosome 2. They found a maximum multipoint heterogeneity lod score (hlod) of 1.96 and a maximum multipoint nonparametric linkage (NPL) score of 2.39 on 2q in an analysis of 95 affected-relative-pair families. By genomewide linkage analysis of 152 autistic sib pairs, the International Molecular Genetic Study of Autism Consortium (2001) (IMGSAC) identified a locus on chromosome 2q (maximum multipoint lod score of 3.74 at marker D2S2188). The lod score increased to 4.80 when stricter diagnostic criteria for autism were used. ### Autism-Related Phrase Speech Delay In an attempt to increase the power for identifying susceptibility genes by decreasing sample heterogeneity, Buxbaum et al. (2001) studied autism-affected relative pairs with delayed onset (at age greater than 36 months) of phrase speech (PSD, for phrase speech delay). In an analysis of 49 families with 2 or more individuals having a narrow diagnosis of autism and PSD, they found a maximal multipoint heterogeneity lod score of 2.99 and a nonparametric linkage score of 3.32 for linkage to 2q. Like Buxbaum et al. (2001), Shao et al. (2002) classified their data set of 82 sib pairs with autism, identifying 45 families with autism and phrase speech delay. Analysis of the latter subset increased support for linkage to 2q (MLS = 2.86 and hlod = 2.12 for marker D2S116). Cytogenetics Newbury et al. (2009) reported 2 unrelated girls with developmental delay and language impairment who had 2 different but overlapping deletions of chromosome 2q. The first girl, who had mild developmental delay particularly affecting her speech and language but not fulfilling the criteria for autism spectrum disorder, had a 3.6-Mb deletion spanning chromosome 2q23.3-q24.1 and containing 6 genes. The second girl, who had pervasive developmental disorder, attention deficit difficulties, obsessive traits, and bipolar disorder, had a 4.5-Mb deletion spanning 2q24.1-q24.2 and containing 14 genes. Both had interruption of the KCNJ3 gene (601534); however, a mutation screen of the gene in 47 autistic probands indicated that coding variants are unlikely to underlie the linkage between autism and chromosome 2q. Molecular Genetics In 4 unrelated patients with impaired intellectual development with autism and speech delay, Deriziotis et al. (2014) identified 4 different de novo heterozygous mutations in the TBR1 gene (604616.0001-604616.0004). There were 2 frameshift mutations, resulting in premature termination, and 2 missense mutations at highly conserved residues in the T-box domain. In vitro functional expression studies using cellular transfection models (HEK293 cells and SHSY5Y neuroblastoma cells) showed that the frameshift mutations resulted in nonfunctional proteins that lost nuclear localization, lost interaction with CASK (300172) and FOXP2 (605317), and had deficient transcriptional repression activity compared to wildtype. Furthermore, these mutations may have resulted in nonsense-mediated mRNA decay, but patient tissue was not available for study. The findings related to these mutations were consistent with haploinsufficiency. Similar in vitro studies of the missense variants showed that they retained some transcriptional repression activity, suggesting that DNA-binding activity was not completely abolished, although they were unable to interact with FOXP2. These variants were able to interact with CASK and homodimerize with wildtype TBR1 to form abnormal aggregates in the nucleus. The findings related to these mutations suggested a dominant-negative effect. The patients carrying loss-of-function mutations had more severe cognitive impairment than those with missense mutations. Several additional missense variants were found in patients that had been inherited from unaffected parents. Functional studies of the inherited variants showed that they had little or no impact on TBR1 function, suggesting that inherited TBR1 mutations do not have a role in autism, although minor contributions in conjunction with additional unidentified variants in other genes could not be excluded. The study also suggested that disruption of TBR1-FOXP2 interactions, caused by mutations in either gene, result in speech and language deficits, thus providing a mechanistic bridge between neurodevelopmental disorders. In 2 unrelated patients with IDDAS, den Hoed et al. (2018) identified de novo heterozygous mutations in the TBR1 gene that affected conserved residues in the T-box domain (604616.0005 and 604616.0006). In vitro functional expression studies in HEK293 cells showed that these mutant proteins retained the ability to repress luciferase activity, self-associate and interact with wildtype TBR1, and colocalize with CASK, but formed abnormal aggregates in the nucleus, suggesting a dominant-negative effect. The mutations abolished the TBR1-FOXP2 interaction. In 2 unrelated patients with IDDAS, McDermott et al. (2018) identified de novo heterozygous mutations in the TBR1 gene (G316X and L311P). Functional studies of the variants were not performed. In 2 unrelated boys with IDDAS, Vegas et al. (2018) identified the same de novo heterozygous frameshift mutation in the TBR1 gene (604616.0007). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors suggested that the mutation may lead to disruption of the downstream reelin pathway (see RELN, 600514). Both patients had malformations of cortical development, including pachygyria, on brain imaging, thus expanding the phenotype associated with TBR1 mutations. Animal Model Hevner et al. (2001) developed mice with targeted disruption of the Tbr1 gene. Mutant mice died shortly after birth in the absence of hand feeding. The cortex of neonatal mutants was approximately normal size, but early-born neurons, which guide early neuronal migrations and axonal projections, showed molecular and functional defects. Early-born cells formed a preplate but did not express markers of Cajal-Retzius, subplate, or layer 6 neurons. Cajal-Retzius cells expressed decreased levels of reelin (600514), resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. Markers of later-born cortical layers were relatively normal, and other properties of cortical neurons, such as neurotransmitter expression, cell death, and neuronal morphology, were mostly unaffected. Huang et al. (2014) showed that haploinsufficiency of Tbr1 in mice resulted in features of autism, including impaired social interaction, impaired vocalization, and impaired cognition and memory. Examination of brains from Tbr1 +/- mice showed defective axonal projection of neurons in the amygdala. Tbr-null mice had severely impaired neuronal migration in the cerebral cortex. INHERITANCE \- Autosomal dominant SKELETAL \- Joint laxity (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Impaired intellectual development \- Delayed walking \- Inability to walk \- Delayed speech \- Absence of speech \- Thick cortex (in some patients) \- Pachygyria (in some patients) Behavioral Psychiatric Manifestations \- Autism spectrum disorder \- Impaired social interaction \- Stereotypic behaviors MISCELLANEOUS \- Onset in first year of life \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the T-box, brain, 1 gene (TBR1, 604616.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISM AND SPEECH DELAY

c1853755

omim

https://www.omim.org/entry/606053

{"omim": ["606053"], "synonyms": ["Alternative titles", "PHRASE SPEECH DELAY, AUTISM-RELATED", "AUTISM-RELATED SPEECH DELAY", "AUTISM, SUSCEPTIBILITY TO, 5, FORMERLY"]}

In 3 brothers and a sister out of 9 sibs of nonconsanguineous parents, Richieri-Costa et al. (1984) described a progressive disorder with onset usually at a mean age of 5.7 years and including myotonia, progressive impairment of gait, alterations in the thorax and vertebral column, short stature, and mild to moderate mental retardation. The 15-year-old proband had 'painful spasms' in his legs and a progressively rigid gait. He showed pectus carinatum and generalized muscular hypertrophy with a firm consistency. Both spontaneous and elicited myotonia was found. A wedge deformity of the first and second lumbar vertebra was demonstrated. The articular surfaces of the acetabulum and the femoral epiphyses were also irregular. His 13-year-old brother also had 'painful spasms,' pectus carinatum, pronounced muscular hypertrophy and firm consistency of muscles, and kyphoscoliosis. Their affected 20-year-old brother was only 139 cm tall. Wedge vertebra at the first and/or second lumbar level seemed to be a consistent feature. Richieri-Costa et al. (1984) pointed to the lack of blepharophimosis and small mouth and the presence of mental retardation as some of the features distinguishing this disorder from Schwartz-Jampel syndrome (255800). Furthermore, they pointed out that the Schwartz-Jampel syndrome usually starts in the first 2 years of life, whereas the initial manifestations were later in this disorder. (For some reason, however, they referred to the disorder as 'late infantile autosomal recessive myotonia' in the title of their article.) INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature CHEST External Features \- Bell-shaped chest Ribs Sternum Clavicles & Scapulae \- Pectus carinatum SKELETAL Spine \- Kyphoscoliosis \- Short vertebrae (thoracolumbar) \- Wedge-shaped vertebrae Limbs \- Irregular femoral epiphyses \- Genu valgum MUSCLE, SOFT TISSUES \- Muscular hypertrophy \- Firm muscles NEUROLOGIC Central Nervous System \- Mental retardation, mild-moderate \- Myotonia \- Rigid gait \- Progressive impairment of gait MISCELLANEOUS \- Onset 5-7 years ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MYOTONIA WITH SKELETAL ABNORMALITIES AND MENTAL RETARDATION

c2930978

omim

https://www.omim.org/entry/255710

{"mesh": ["C535675"], "omim": ["255710"], "orphanet": ["3101"]}

Norrie disease SpecialtyMedical genetics Norrie disease is a rare disease and genetic disorder that primarily affects the eyes and almost always leads to blindness. It is caused by mutations in the Norrin cystine knot growth factor (NDP) gene, which is located on the X chromosome.[1][2] In addition to the congenital ocular symptoms, the majority of patients suffer from a progressive hearing loss starting mostly in their 2nd decade of life, and some may have learning difficulties among other additional characteristics. Patients with Norrie disease may develop cataracts, leukocoria (where the pupils appear white when light is shone on them), along with other developmental issues in the eye, such as shrinking of the globe and the wasting away of the iris.[2] Around 30 to 50% of them will also have developmental delay/learning difficulties, psychotic-like features, incoordination of movements or behavioral abnormalities.[2] Most patients are born with normal hearing; however, the onset of hearing loss is very common in early adolescence.[3] About 15% of patients are estimated to develop all the features of the disease.[4] Due to the X-linked recessive pattern of inheritance, Norrie disease affects almost entirely males. Only in very rare cases, females have been diagnosed with Norrie disease; cases of symptomatic female carriers have been reported.[5][6] It is a very rare disorder that is not associated with any specific ethnic or racial groups, with cases reported worldwide (including cases in North America, South America, Europe, Asia and Australasia).[7][8][9][10] While more than 400 cases have been described, the prevalence and incidence of the disease still remains unknown.[11][12] ## Contents * 1 Presentation * 1.1 Additional Characteristics * 2 Genetics * 2.1 The NDP gene * 3 Diagnosis * 4 Management * 5 Research * 6 History * 7 Culture * 8 References * 9 External links ## Presentation[edit] The most prominent symptoms initially observed in Norrie disease are ocular (affect the eye). Initial characteristics are usually identified at birth or in early infancy, with parents often noticing abnormal eye features or that their child fails to show a response to light.[13][14][15] The first visible finding is leukocoria, a grayish-yellow pupillary reflection that originates from a mass of disorganized tissue behind the lens. This material, which possibly includes an already detached retina, may be confused with a tumor and thus is termed pseudoglioma.[2][11] However, an affected baby may have a normally sized eye globe and unremarkable iris, anterior chamber, cornea and intraocular pressure. Over the first few months of life, complete or partial retinal detachment evolves. From infancy through childhood, the patient may undergo progressive changes in the disease.[2] Disease progression often includes vitreoretinal hemorrhages, the formation of cataracts, deterioration of the iris with adhesions forming between the iris and the lens or the cornea, and shallowing of the anterior chamber which may increase intraocular pressure, causing eye pain.[2] As the situation worsens, there is corneal opacification, where the cornea becomes opaque, and band keratopathy. Intraocular pressure is lost and the globe shrinks. In the last stage of Norrie disease, the globes appear small and sunken in (phthisis bulbi) and the cornea appears to be milky.[2] Auditory symptoms (affect the ear) are common with Norrie disease. Progressive hearing loss has been reported to occur in 85–90% of patients and onset is generally in childhood and before the patient reaches their mid-20s.[7][16] Early hearing loss is sensorineural (caused by damage to the inner ear or auditory nerve), mild and asymmetric.[2] By adolescence, high-frequency hearing loss begins to appear. Hearing loss is severe, symmetric, and broad-spectrum by the age of 35 years. However, studies show that while hearing deteriorates, the ability to speak well is highly preserved.[3] The slowly progressing hearing loss is more problematic to adjust to than the congenital blindness for most people with Norrie disease.[2] ### Additional Characteristics[edit] Individuals with Norrie disease can also have cognitive and behavioral symptoms. Developmental delay or learning difficulties are present in about 30 to 50% of males who have Norrie disease.[2] Psycho-social disturbances and poorly characterized behavior abnormalities may also be present. In a study reporting extraocular manifestations in 56 patients with Norrie disease, conditions reported included cognitive impairment (28% of patients), behavioral issues, for example autism spectrum disorder (27% of patients presented with autism or autism-like disorders), neurological features, including seizure disorders and epilepsy (16% of patients reported seizures or seizure history), and peripheral vascular disease (38% of patients).[7] Additionally, children with visual impairment have been shown to struggle establishing regular sleep/wake cycles due to reduced light perception impacting on their understanding of night and day; this can impact on the individual’s behavior, mood and cognitive ability.[17] Consistent with this, some case reports of Norrie disease patients have reported the presence of sleep disorders.[18] Peripheral vascular disease (PVD) has also been associated with Norrie disease. In a study of 56 patients with Norrie disease, 21 patients (38%) reported PVD (including varicose veins, peripheral venous stasis ulcers and erectile dysfunction).[7] Due to the known role of the protein norrin in the vascular development of the eye and inner ear, as well as the association with PVD, norrin is thought to have an important angiogenic role in the body.[19] ## Genetics[edit] X-linked recessive inheritance. Norrie disease is a rare genetic disorder caused by mutations in the NDP gene, located on Xp11.4 (GeneID: 4693).[20] It is inherited in an X-linked recessive manner. This means that almost only males are affected. Sons of affected men will not have the mutation, while all of their daughters will be genetic carriers of the mutation. Female carriers usually show no clinical symptoms, but will pass the mutation to 50% of their offspring. Daughters with the mutated gene will also be, like their mother, asymptomatic carriers, but 50% of their sons will express clinical symptoms.[citation needed] Females are very unlikely to express clinical signs. However, there have been a few rare cases where females have shown symptoms associated with Norrie disease such as retinal abnormalities and mild hearing loss.[11] Additionally, cases of symptomatic female carriers have been reported.[5][6] One possible scenario that could lead to a female case of Norrie disease is if both of their copies of the NDP gene bear mutations, which could be the case in consanguineous families or due to a spontaneous somatic mutation. Another explanation for affected females could be skewed X-chromosome inactivation. In this latter case, carrier females with one mutated NDP allele could have a higher proportion of defective norrin being expressed, leading to the presentation of symptoms of Norrie disease.[5][6] ### The NDP gene[edit] Norrie disease is caused by a mutation in the Norrin cystine knot growth factor gene, also known as the Norrie disease (pseudoglioma) gene or NDP gene. Mutations could include splicing or mis-sense mutations, as well as partial or full gene deletion.[2] The normal function of the NDP gene is to produce the instructions for creating a protein called norrin. For the normal development of the eye and other body systems, norrin is believed to be crucial.[21] Norrin also appears to be crucial in the specialization of the cells of the retina and the establishment of a blood supply to the inner ear and the tissues of the retina. The role of norrin in the specialization of retinal cells for their unique sensory function is interfered by the mutation of NDP.[21] This results in an accumulation of immature retinal cells in the back of the eye. When norrin's role in the establishment of blood vessels supplying the eye is disrupted, the tissues cannot develop properly.[21] Norrin is not only important in the development of the eye. The mutation of the NDP gene can affect other systems of the body as well. The most severe problems are caused by chromosomal deletions in the region of the NDP gene, causing the prevention of the gene product, or even that of the neighboring MAO genes. When the mutations simply change a single amino acid in norrin, the effects are less widespread and severe. However, the location and type of the NDP mutation does not necessarily determine the degree of severity of the disease, since highly varying clinical signs have been diagnosed in patients carrying exactly the same mutation. Therefore, the involvement of other modifying genes is very likely. On the other hand, if certain structurally important amino acids are changed (e.g. the cysteines forming the putative cystine knot), the clinical outcome has been shown to be more serious.[22] ## Diagnosis[edit] Norrie disease and other NDP related diseases are diagnosed with the combination of clinical findings and molecular genetic testing. Molecular genetic testing identifies the mutations that cause the disease in about 95% of affected males.[2] Clinical diagnoses rely on ocular findings. Norrie disease is diagnosed when grayish-yellow fibrovascular masses are found behind the eye from birth through three months. Doctors also look for progression of the disease from three months through 8–10 years of age. Some of these progressions include cataracts, iris atrophy, shallowing of anterior chamber, and shrinking of the globe.[2] Children with the condition either have only light perception or no vision at all.[citation needed] In addition to its use for initial diagnosis, molecular genetic testing is used to confirm diagnostic testing (such as diagnosis by ocular examination), for carrier testing females, prenatal diagnosis, and preimplantation genetic diagnosis. There are three types of clinical molecular genetic testing. In approximately 95% of males, mis-sense and splice mutations of the NDP gene and partial or whole gene deletions are detected using sequence analysis.[2] Deletion/duplication analysis can be used to detect the 15% of mutations that are submicroscopic deletions. This is also used when testing for carrier females. The last testing used is linkage analysis, which is used when the first two types are unavailable. Linkage analysis is also recommended for those families who have more than one member affected by the disease.[2] MRI is often used to diagnose the retinal dysplasia that occurs with the Norrie disease. However, the retinal dysplasia can be indistinguishable on MRI from persistent hyperplastic primary vitreous, or the dysplasia of trisomy 13 and Walker–Warburg syndrome.[23] For families with an existing history of Norrie disease, genetic counselling and in utero diagnosis of Norrie disease may be considered.[24] In utero diagnosis has been reported to include genetic testing by amniocentesis and ultrasonography to examine fetal eyes. Confirmation of diagnosis on the first day of life by ophthalmological examination under anesthesia has also been reported in some cases.[24][25] ## Management[edit] Ocular, auditory and behavioral management are the most common areas of intervention and treatment for patients with Norrie disease. For ocular (eye) management, often patients already suffer from complete retinal detachment at birth, or by the time of diagnosis, so surgical intervention is often not offered. However, there is some evidence for the benefit of early surgery or laser therapy for cases where retinal detachment is incomplete.[2][25][26] Surgery may also be used to treat increased intraocular pressure and in rare cases enucleation (removal) of the eye is considered to control pain.[2] A high proportion (85–90%) of individuals with Norrie disease experience progressive hearing loss in their second decade of life. In most cases, use of hearing aids has been shown to be effective into middle or late adulthood. For more significantly impaired hearing, cochlear implants may also be considered.[2][7][16] 30-50% of individuals with Norrie disease have been reported to present with developmental delay or cognitive impairment. Additionally, behavioral issues have also been reported. Supportive intervention and therapy, for example working with speech and language therapists and occupational therapists, can be used to maximize educational opportunities for these individuals.[2] Furthermore, training of teachers and school counselors on how to best support children with vision and hearing impairment can be extremely beneficial.[citation needed] Routine monitoring of individuals with Norrie disease is recommended to best manage the disease. This includes regular follow-up with an ophthalmologist, even when vision is severely compromised. Additionally, due to the high proportion of individuals with Norrie disease who develop hearing loss, regular monitoring of hearing loss is beneficial to allow any hearing loss to be detected early and then correctly managed.[2] More recently, the use of dual sensory clinics has been proposed to provide improved care to patients living with conditions such as Norrie disease. For example, Great Ormond Street Hospital (GOSH), London are building a new Sight and Sound center, with the aim of improving the patient experience for individuals with conditions such as Norrie disease.[27] The benefits of dual sensory clinics include improved communication between the different health care professionals (HCPs) involved in management of Norrie disease (e.g. ophthalmologists and audiologists) as well as allowing more consistent training of staff on best practices for managing and interacting with individuals suffering from sensory impairment.[citation needed] Individuals with Norrie disease can often feel isolated from society due to difficulties in communication. In cases where hearing loss is also experienced, this psychological burden has been shown to increase. For example, a number of Norrie disease patients have been reported to experience transient depression correlating with the onset of hearing loss.[7] Because of this, the provision of emotional support to individuals with Norrie disease can be as important as clinical treatment strategies in terms of improving their quality of life and reducing disease burden.[citation needed] ## Research[edit] Research into understanding Norrie disease and how to improve the lives of those with Norrie disease is ongoing. For example, research is taking place at Great Ormond Street Institute of Child Health, University College London (UCL GOSICH) to study the developmental changes in the ear and eye in Norrie disease, with the hope to understand how to improve current treatment strategies.[28] The group at UCL GOSICH is focusing particularly on the hearing loss aspect of the disease, and whether it might be possible to treat by gene therapy.[citation needed] ## History[edit] In 1961, a Danish ophthalmologist named Mette Warburg reported on a Danish family that showed seven cases of a hereditary degenerative disease throughout seven generations. The first member of the family to be thoroughly studied was a 12-month-old boy. At the child's examination at three months, it was noticed that he was normal except that his lens appeared to be opaque and his irises were deteriorating.[29] The area behind his lens was filled with a growing yellowish mass. Five months later, his left eye was removed due to suspicion of retinoblastoma, a cancerous tumor on the retina. A histologic examination showed a hemorrhagic necrotic mass in the posterior chamber, surrounded by undifferentiated (immature, undeveloped) glial tissue. The diagnosis included a pseudotumor of the retina, hyperplasia of retinal, ciliary, and iris pigment epithelium, hypoplasia and necrosis of the inner layer of the retina, cataract, and phthisis bulbi. The physician had suspected a tumor, although it emerged that it was a developmental defect that led to the malformation of inner parts of the eye. Because the eye was not functional, cells had already begun to die (necrosis) and the eye globe began to shrink due to its dysfunction (phthisi bulbi). In this Danish family, five of the seven people in these cases developed deafness later in life. Also, in four of the seven, mental capacity was determined to be low. After Warburg researched literature under various medical categories, she discovered 48 similar cases which she believed were caused by this disease as well.[29] She then suggested this disease be named after another famous Danish ophthalmologist, Gordon Norrie (1855–1941). Norrie was greatly recognized for his work with the blind and for being a surgeon at the Danish Institute for the Blind for 35 years.[30] The NDP gene was previously named the “Norrie disease (pseudoglioma)” gene, which is still used widely when referring to NDP. However, the current approved name for NDP is “Norrin cystine knot growth factor”.[1] ## Culture[edit] There are two patient organizations for people affected by Norrie disease. The Norrie Disease Association (NDA) was founded in 1994 and is a US-based non-profit organization aiming to provide information and support to people living with Norrie disease and their families. The NDA holds a conference on Norrie disease every three years in Boston, US. The Norrie Disease Foundation (NDF) is a UK-based charity established in 2016. The main aims of NDF are to provide support for families and promote pioneering research into Norrie disease. They organize two family days a year where families with Norrie disease can come together to share experiences, meet each other and build relationships and supportive networks. The websites for both patient organizations contain useful information for patients and their families about the disease. ## References[edit] 1. ^ a b "Symbol Report for NDP". Retrieved 23 January 2020. 2. ^ a b c d e f g h i j k l m n o p q r s t Sims K (1993). "NDP-Related Retinopathies". GeneReviews. University of Washington, Seattle. PMID 20301506. Retrieved 28 January 2007. 3. ^ a b Halpin C, Owen G, Gutiérrez-Espeleta GA, Sims K, Rehm HL (July 2005). "Audiologic features of Norrie disease". The Annals of Otology, Rhinology, and Laryngology. 114 (7): 533–8. doi:10.1177/000348940511400707. hdl:10669/15119. PMID 16134349. S2CID 29284047. 4. ^ Dickinson JL, Sale MM, Passmore A, FitzGerald LM, Wheatley CM, Burdon KP, et al. (2006). "Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity". Clinical & Experimental Ophthalmology. 34 (7): 682–8. doi:10.1111/j.1442-9071.2006.01314.x. PMID 16970763. 5. ^ a b c Seller MJ, Pal K, Horsley S, Davies AF, Berry AC, Meredith R, McCartney AC (July 1995). "A fetus with an X;1 balanced reciprocal translocation and eye disease". Journal of Medical Genetics. 32 (7): 557–60. doi:10.1136/jmg.32.7.557. PMC 1050552. PMID 7562972. 6. ^ a b c Shastry BS, Hiraoka M, Trese DC, Trese MT (1999). "Norrie disease and exudative vitreoretinopathy in families with affected female carriers". European Journal of Ophthalmology. 9 (3): 238–42. doi:10.1177/112067219900900312. PMID 10544980. S2CID 37371789. 7. ^ a b c d e f Smith SE, Mullen TE, Graham D, Sims KB, Rehm HL (August 2012). "Norrie disease: extraocular clinical manifestations in 56 patients". American Journal of Medical Genetics. Part A. 158A (8): 1909–17. doi:10.1002/ajmg.a.35469. PMID 22786811. S2CID 9397893. 8. ^ Chini V, Stambouli D, Nedelea FM, Filipescu GA, Mina D, Kambouris M, El-Shantil H (June 2014). "Utilization of gene mapping and candidate gene mutation screening for diagnosing clinically equivocal conditions: a Norrie disease case study". Eye Science. 29 (2): 104–7. PMID 26011961. 9. ^ Donnai D, Mountford RC, Read AP (February 1988). "Norrie disease resulting from a gene deletion: clinical features and DNA studies". Journal of Medical Genetics. 25 (2): 73–8. doi:10.1136/jmg.25.2.73. PMC 1015446. PMID 3162283. 10. ^ Halpin C, Sims K (November 2008). "Twenty years of audiology in a patient with Norrie disease". International Journal of Pediatric Otorhinolaryngology. 72 (11): 1705–10. doi:10.1016/j.ijporl.2008.08.007. PMID 18817988. 11. ^ a b c "Norrie Disease". Genetics Home Reference. Retrieved 28 January 2007. 12. ^ Sims K. "Norrie Disease". Retrieved 6 December 2019. 13. ^ Saini JS, Sharma A, Pillai P, Mohan K (1992). "Norries disease". Indian Journal of Ophthalmology. 40 (1): 24–6. PMID 1464451. 14. ^ Sukumaran K (March 1991). "Bilateral Norrie's disease in identical twins". The British Journal of Ophthalmology. 75 (3): 179–80. doi:10.1136/bjo.75.3.179. PMC 1042303. PMID 2012789. 15. ^ Zhang XY, Jiang WY, Chen LM, Chen SQ (2013). "A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family". International Journal of Ophthalmology. 6 (6): 739–43. doi:10.3980/j.issn.2222-3959.2013.06.01. PMC 3874509. PMID 24392318. 16. ^ a b "Al-Yassin A, Norrie Disease Foundation, Unique. Unique and NDF Norrie Disease Information Leaflet" (PDF). 2018. 17. ^ Stores G, Ramchandani P (May 1999). "Sleep disorders in visually impaired children". Developmental Medicine and Child Neurology. 41 (5): 348–52. doi:10.1017/S0012162299000766. PMID 10378763. 18. ^ Vossler DG, Wyler AR, Wilkus RJ, Gardner-Walker G, Vlcek BW (May 1996). "Cataplexy and monoamine oxidase deficiency in Norrie disease". Neurology. 46 (5): 1258–61. doi:10.1212/WNL.46.5.1258. PMID 8628463. S2CID 45839803. 19. ^ Michaelides M, Luthert PJ, Cooling R, Firth H, Moore AT (November 2004). "Norrie disease and peripheral venous insufficiency". The British Journal of Ophthalmology. 88 (11): 1475. doi:10.1136/bjo.2004.042556. PMC 1772398. PMID 15489496. 20. ^ "NDP Norrie disease (pseudoglioma) [ Homo sapiens (human) ]". Gene. National Center for Biotechnology Information. Retrieved 26 October 2013. 21. ^ a b c "Norrie disease (pseudoglioma)". Genetics Home Reference. U.S. National Library of Medicine. March 2008. Retrieved 18 March 2008. 22. ^ Meitinger T, Meindl A, Bork P, Rost B, Sander C, Haasemann M, Murken J (December 1993). "Molecular modelling of the Norrie disease protein predicts a cystine knot growth factor tertiary structure". Nature Genetics. 5 (4): 376–80. doi:10.1038/ng1293-376. PMID 8298646. S2CID 29858707. 23. ^ Castillo M (2011). Neuroradiology companion : methods, guidelines, and imaging fundamentals (4th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 9781451111750. 24. ^ a b Liu J, Zhu J, Yang J, Zhang X, Zhang Q, Zhao P (January 2019). "Prenatal diagnosis of familial exudative vitreoretinopathy and Norrie disease". Molecular Genetics & Genomic Medicine. 7 (1): e00503. doi:10.1002/mgg3.503. PMC 6382493. PMID 30474316. 25. ^ a b Chow CC, Kiernan DF, Chau FY, Blair MP, Ticho BH, Galasso JM, Shapiro MJ (December 2010). "Laser photocoagulation at birth prevents blindness in Norrie's disease diagnosed using amniocentesis". Ophthalmology. 117 (12): 2402–6. doi:10.1016/j.ophtha.2010.03.057. PMID 20619898. 26. ^ Walsh MK, Drenser KA, Capone A, Trese MT (April 2010). "Early vitrectomy effective for Norrie disease". Archives of Ophthalmology. 128 (4): 456–60. doi:10.1001/archophthalmol.2009.403. PMID 20385941. 27. ^ "National Sensory Impairment Partnership. Calling UK Norrie families - Dual Sensory Clinics for children and young people up to 18 yrs". 2019. Retrieved 21 January 2020. 28. ^ "Norrie Disease Foundation. Research". 2017-10-31. Retrieved 23 January 2020. 29. ^ a b Warburg M (1961). "Norrie's disease: a new hereditary bilateral pseudotumour of the retina". Acta Ophthalmol. 39 (5): 757–772. doi:10.1111/j.1755-3768.1961.tb07740.x. S2CID 2525905. 30. ^ Gordon Norrie at Who Named It?. Retrieved 13 February 2007. ## External links[edit] * NCBI Genetic Testing Registry Classification D * ICD-10: Q15.8 * ICD-9-CM: 743.8 * OMIM: 310600 * MeSH: C537849 C537849, C537849 * DiseasesDB: 31165 External resources * Orphanet: 649 * v * t * e Congenital malformations and deformations of eyes Adnexa Eyelid * Ptosis * Ectropion * Entropion * Distichia * Blepharophimosis * Ablepharon * Marcus Gunn phenomenon Lacrimal apparatus * Congenital lacrimal duct obstruction Globe Entire eye * Anophthalmia (Cystic eyeball, Cryptophthalmos) * Microphthalmia Lens * Ectopia lentis * Aphakia Iris * Aniridia Anterior segment * Axenfeld–Rieger syndrome Cornea * Keratoglobus * Megalocornea Other * Buphthalmos * Coloboma (Coloboma of optic nerve) * Hydrophthalmos * Norrie disease * v * t * e X-linked disorders X-linked recessive Immune * Chronic granulomatous disease (CYBB) * Wiskott–Aldrich syndrome * X-linked severe combined immunodeficiency * X-linked agammaglobulinemia * Hyper-IgM syndrome type 1 * IPEX * X-linked lymphoproliferative disease * Properdin deficiency Hematologic * Haemophilia A * Haemophilia B * X-linked sideroblastic anemia Endocrine * Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy * KAL1 Kallmann syndrome * X-linked adrenal hypoplasia congenita Metabolic * Amino acid: Ornithine transcarbamylase deficiency * Oculocerebrorenal syndrome * Dyslipidemia: Adrenoleukodystrophy * Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency * Pyruvate dehydrogenase deficiency * Danon disease/glycogen storage disease Type IIb * Lipid storage disorder: Fabry's disease * Mucopolysaccharidosis: Hunter syndrome * Purine–pyrimidine metabolism: Lesch–Nyhan syndrome * Mineral: Menkes disease/Occipital horn syndrome Nervous system * X-linked intellectual disability: Coffin–Lowry syndrome * MASA syndrome * Alpha-thalassemia mental retardation syndrome * Siderius X-linked mental retardation syndrome * Eye disorders: Color blindness (red and green, but not blue) * Ocular albinism (1) * Norrie disease * Choroideremia * Other: Charcot–Marie–Tooth disease (CMTX2-3) * Pelizaeus–Merzbacher disease * SMAX2 Skin and related tissue * Dyskeratosis congenita * Hypohidrotic ectodermal dysplasia (EDA) * X-linked ichthyosis * X-linked endothelial corneal dystrophy Neuromuscular * Becker's muscular dystrophy/Duchenne * Centronuclear myopathy (MTM1) * Conradi–Hünermann syndrome * Emery–Dreifuss muscular dystrophy 1 Urologic * Alport syndrome * Dent's disease * X-linked nephrogenic diabetes insipidus Bone/tooth * AMELX Amelogenesis imperfecta No primary system * Barth syndrome * McLeod syndrome * Smith–Fineman–Myers syndrome * Simpson–Golabi–Behmel syndrome * Mohr–Tranebjærg syndrome * Nasodigitoacoustic syndrome X-linked dominant * X-linked hypophosphatemia * Focal dermal hypoplasia * Fragile X syndrome * Aicardi syndrome * Incontinentia pigmenti * Rett syndrome * CHILD syndrome * Lujan–Fryns syndrome * Orofaciodigital syndrome 1 * Craniofrontonasal dysplasia *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Norrie disease

c0266526

wikipedia

https://en.wikipedia.org/wiki/Norrie_disease

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Caudal regression-sirenomelia spectrum is a group of rare genetic developmental defect during embryogenesis disorders characterized by varying degrees of caudal abdomen, pelvic, renal, anorectal, urogenital and/or lumbosacral spine malformations, with or without lower limb fusion. Phenotype is highly variable ranging from minor forms with isolated coccygeal agenesis to severe forms presenting with a single rudimentary limb. Central nervous system anomalies have also been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Caudal regression-sirenomelia spectrum

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=444941

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A number sign (#) is used with this entry because of evidence that multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3) is caused by homozygous or compound heterozygous mutation in the PIGT gene (610272) on chromosome 20q13. Description Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). Clinical Features Kvarnung et al. (2013) reported a consanguineous family of Turkish origin in which 4 patients had severe intellectual and motor disability and multiple congenital anomalies. The patients were born with mild macrosomia and macrocephaly and showed hypotonia and delayed psychomotor development from an early age. Dysmorphic features included brachycephaly, high forehead with bitemporal narrowing, depressed nasal bridge, long philtrum with a deep groove, and open mouth due to hypotonia. Brain imaging showed variable abnormalities, including frontotemporal atrophy, cerebellar hypoplasia, and primitive Sylvian fissures, suggesting a possible neuronal migration defect. All patients developed seizures of various type before age 2 years. Ophthalmologic findings included poor vision, strabismus, nystagmus, and hyperopia. Tooth abnormalities included premature loss of incisors, and renal abnormalities included nephrocalcinosis and ureteral dilation; 1 patient had renal cysts. All patients also had some type of skeletal findings, including scoliosis, pectus excavatum, short upper extremities, slender and osteopenic long bones with large secondary ossification centers, wide and long femoral necks, and delayed bone age. Other features included inverted nipples and restrictive cardiomyopathy. Laboratory studies showed decreased alkaline phosphatase, increased serum calcium, and hypercalciuria. Nakashima et al. (2014) reported a Japanese girl with MCAHS3. She showed poor feeding soon after birth and presented at age 4 months with tonic seizures with apnea and myoclonic seizures. The seizures were refractory to most medications, and she had repeated episodes of convulsive status epilepticus induced by infection. Other features included hypotonia, unstable head control, strabismus, nystagmus, cerebral visual impairment, patent ductus arteriosus, and left hydronephroureter with ureteral stenosis. She also had dysmorphic features, including low-set ears, micrognathia, malar flattening, upslanting palpebral fissures, depressed nasal bridge with anteverted nares, downturned corners of the mouth, tented lip, and high-arched palate. Brain imaging showed progressive cerebral, cerebellar, and brainstem atrophy, and EEG showed low-amplitude irregular background activity and spike-and-slow wave epileptic discharges. Radiographs showed neurogenic arthrogryposis and osteoporosis. Laboratory studies showed decreased serum alkaline phosphatase with normal calcium. At age 12 years, she had profound psychomotor retardation and was bedridden with absent speech. Lam et al. (2015) described 2 children with MCAHS3, born of nonconsanguineous parents of mixed African American and Caucasian background. The sister and brother, aged 7 and 6, had hypotonia and severe global developmental delay and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Both were born at 31 weeks' gestation and were cared for in the neonatal intensive care unit for approximately 6 weeks with cardiorespiratory and feeding support. Both experienced onset of seizures at 5 weeks of age; seizures progressed to poorly controlled myoclonic, tonic, and tonic-clonic that occasionally generalized. Strabismus and nystagmus were present in both. Echocardiogram in the girl showed patent foramen ovale and small muscular ventricular septal defect, and in the boy showed dilated right atrium and atrial septal defect with left to right shunt, which was treated with an Amplatzer device at 25 months of age. MRI showed progressive cerebellar and cerebral atrophy. Lam et al. (2015) noted that their patients differed from patients in previous reports in bone and endocrine features; their patients had normal to advanced bone age and normal alkaline phosphatase, plasma calcium, plasma phosphate, urine calcium, and parathyroid hormone values. Skauli et al. (2016) described 2 brothers, born to first-cousin parents of Somali origin, with features of MCAHS3. In addition to findings typically seen in patients with MCAHS3, the brothers had pyramidal tract neurologic signs including spasticity of the lower limbs, increased lower limb reflexes, bilateral ankle clonus, and Babinski sign. In contrast to previously reported patients, they did not have skeletal, cardiac, or genitourinary anomalies. Kohashi et al. (2018) reported an 11-month-old boy who was born to healthy, nonconsanguineous Japanese parents. He presented with distinctive external features, including micrognathia, high-arched eyebrows, epicanthus, telecanthus, depressed nasal bridge, short anteverted nose, long philtrum, tented lip, and high-arched palate. He had skeletal abnormalities including pectus excavatum, clinodactyly, middle phalanx defect, and delayed bone age. Urogenital abnormalities included nephrocalcinosis, cryptorchidism, and perineal groove. He also had duplication of the esophagus. There were no cardiovascular abnormalities. He developed epileptic apnea at 2 months of age that was successfully controlled with valproic acid; however, epileptic apnea recurred with additional tonic and myoclonic seizures at 8 months of age. The patient exhibited psychomotor regression and increased frequency of epileptic apnea during sleep. Seizures were refractory to 3 antiepileptics. At 11 months he was bedridden, in a frog-like position, and could move only his arms and feet in response to noxious stimuli. Height and weight were normal. Alkaline phosphatase was extremely low. Seizures were intractable and required hospitalization for 6 months. Acetazolamide was effective for the treatment of the epileptic apnea. Kohashi et al. (2018) reviewed previously reported patients with MCAHS3, all of whom shared profound intellectual disability, hypotonia, skeletal anomalies, ophthalmologic problems, global cerebral and cerebellar atrophy, and seizures. Cardiologic, gastrointestinal, and urologic manifestations were variable. Inheritance The transmission pattern of MCAHS3 in the family reported by Kvarnung et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics In 4 affected members of a consanguineous Turkish family with multiple congenital anomalies-hypotonia-seizures syndrome-3, Kvarnung et al. (2013) identified a homozygous mutation in the PIGT gene (T183P; 610272.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases, including 6,500 Exome Sequencing Project exomes and the 1000 Genomes Project, or in 200 Danish exomes. Flow cytometric analysis of patient granulocytes and monocytes showed decreased amounts of GPI-anchored proteins CD16B (610665) and CD59 (107271) compared to controls, indicating that the mutation results in impaired membrane anchoring of GPI-linked proteins. The T183P variant was unable to rescue gastrulation defects of morpholino-knockout zebrafish, consistent with a defect in enzyme function. In a Japanese girl with MCAHS3, Nakashima et al. (2014) identified compound heterozygous mutations in the PIGT gene (E84X, 610272.0003 and R488W, 610272.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient granulocytes showed decreased surface expression of certain GPI-anchored proteins. Transfection of the mutations into PIGT-deficient CHO cells showed that the R488W mutation could partially restore surface expression of GPI-anchored proteins, whereas the E84X mutation resulted in a complete loss of function. In 2 brothers with features of MCAHS3, who were born to first-cousin parents of Somali origin, Skauli et al. (2016) identified a homozygous mutation in the PIGT gene (G360V; 610272.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not seen in the 1000 Genomes or ExAC databases or in an in-house database of 443 exomes of mixed ethnicity. The mutation alters a highly conserved amino acid located in the GPI-transamidase domain, which transfers mature GPI anchors to target proteins. In vitro studies in cells from the 2 brothers showed reduced levels of GPI anchors and GPI-anchored proteins on the cell surface. In 2 sibs with MCAHS3, Lam et al. (2015) reported compound heterozygosity for a missense mutation (R488W; 610272.0004) and a frameshift mutation (610272.0006). Kohashi et al. (2018) reported an 11-month-old boy with acetazolamide-responsive epileptic apnea who presented with decreased serum alkaline phosphatase associated with compound heterozygous PIGT mutations, glu84 to ter (E84X; 610272.0003) and a novel missense variant, gly366 to trp (G366W; 610272.0007). INHERITANCE \- Autosomal recessive GROWTH Other \- Macrosomia, mild HEAD & NECK Head \- Macrocephaly, mild \- Brachycephaly Face \- High forehead \- Bitemporal narrowing \- Long philtrum \- Deep philtrum Ears \- Low-set ears Eyes \- Impaired vision \- Abnormal eye movements \- Strabismus \- Esotropia \- Nystagmus \- Hyperopia Nose \- Depressed nasal bridge \- Short nose \- Anteverted nares Mouth \- Open mouth \- Tented lips \- Downturned corners of the mouth \- High-arched palate Teeth \- Tooth abnormalities \- Premature loss of incisors CARDIOVASCULAR Heart \- Restrictive cardiomyopathy Vascular \- Patent ductus arteriosus CHEST External Features \- Pectus excavatum Breasts \- Inverted nipples GENITOURINARY Kidneys \- Nephrocalcinosis \- Renal cysts Ureters \- Ureteral dilation \- Ureteral stenosis SKELETAL \- Osteopenia \- Osteoporosis \- Delayed bone age Skull \- Abnormal skull shape \- Premature close of sutures Spine \- Scoliosis Limbs \- Secondary ossification centers \- Wide and long femoral necks \- Short ulnae MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Motor and intellectual disability, severe \- Psychomotor regression \- Seizures \- EEG abnormalities \- Variable intracranial abnormalities \- Frontotemporal atrophy \- Cerebral atrophy \- Cerebellar hypoplasia \- Cerebellar atrophy \- Primitive Sylvian fissures \- Increased patellar and Achilles reflexes \- Ankle clonus \- Babinski sign \- Spasticity of lower limbs \- Ataxia LABORATORY ABNORMALITIES \- Decreased alkaline phosphatase \- Increased serum calcium \- Hypercalciuria MISCELLANEOUS \- Onset in infancy \- Some features are variably expressed MOLECULAR BASIS \- Caused by mutation in the phosphatidylinositol glycan, class T gene (PIGT, 610272.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 3

c3809356

omim

https://www.omim.org/entry/615398

{"doid": ["0080140"], "omim": ["615398"], "orphanet": ["369837"], "synonyms": ["Congenital disorder of glycosylation due to PIGT deficiency", "Multiple congenital anomalies-hypotonia-seizures syndrome type 3", "PIGT-CDG", "MCAHS type 3", "Alternative titles", "GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 7"]}

## Summary ### Clinical characteristics. Autosomal dominant tubulointerstitial kidney disease, MUC1-related (ADTKD-MUC1) was previously known as medullary cystic kidney disease type 1. It is characterized by slowly progressive tubulointerstitial disease that leads to end-stage renal disease (ESRD) and the need for dialysis or kidney transplantation. ESRD typically occurs in adulthood but is extremely variable, occurring at any age between 20 and 70 years. There are no other systemic manifestations. ### Diagnosis/testing. Diagnosis of ADTKD-MUC1 is suspected in individuals with an elevated serum creatinine, bland urinary sediment (i.e., little blood or protein), and a family history of kidney disease inherited in an autosomal dominant manner. Renal ultrasound examination may reveal normal or small kidneys. Renal biopsy findings are nonspecific (and, hence, not diagnostic). Identification of a heterozygous MUC1 pathogenic variant on molecular genetic testing confirms the diagnosis. ### Management. Treatment of manifestations: Treatment follows standard guidelines for chronic kidney disease (CKD) and its sequelae, which can include hypertension, anemia, and gout. Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD-MUC1, by staying in optimal health (e.g., by exercising, avoiding obesity and tobacco usage, and maintaining strict control of hypertension, dyslipidemia, and other cardiovascular risk factors). Transplantation is curative, and the outcome from kidney transplantation in this group of patients is excellent. Surveillance: Measurement of hemoglobin, serum concentrations of uric acid and creatinine and blood pressure annually prior to entering CKD Stage 3. Thereafter, follow up is determined by the treating nephrologist. Agents/circumstances to avoid: Drugs or agents known to be nephrotoxic such as nonsteroidal anti-inflammatory drugs, especially when dehydrated. Evaluation of relatives at risk: If the MUC1 pathogenic variant has been identified in an affected family member, predictive molecular genetic testing of at-risk relatives allows early diagnosis and treatment of renal disease and its sequelae. Additionally, all related potential kidney donors should be tested for the family-specific MUC1 pathogenic variant, as only those without the pathogenic variant should be assessed as eligible kidney donors. ### Genetic counseling. ADTKD-MUC1 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, molecular genetic testing can clarify the genetic status of at-risk family members. While prenatal testing is theoretically possible, the complexities of molecular genetic testing make it difficult. ## Diagnosis ### Suggestive Findings Autosomal dominant tubulointerstitial kidney disease, MUC1-related (ADTKD-MUC1) should be suspected in individuals with the following findings. #### Clinical Signs Tubulointerstitial kidney disease. Urinalysis of affected individuals reveals few or no red cells or white cells and less than 500 mg of urinary protein. Slowly progressive chronic kidney disease. Affected individuals usually develop asymptomatic elevations in their serum creatinine concentration or reduced estimated glomerular filtration rate (eGFR), which may initially appear in the late teens or early twenties. ESRD typically occurs in adulthood but is extremely variable, occurring at any age between 20 and 70 years. Autosomal dominant inheritance. The presence of chronic kidney disease (elevated serum creatinine) or end-stage renal disease inherited in an autosomal dominant manner is another important clue to this disorder. No other systemic findings are present. #### Testing The majority of patients with ADTKD-MUC1 have the following lab test abnormalities. Serum creatinine (eGFR). As individuals with ADTKD-MUC1 age, kidney function worsens, and the serum creatinine rises. * The serum creatinine is an indirect measure of glomerular filtration rate, and there are formulas that calculate the eGFR from the serum creatinine. * On most laboratory reports, the eGFR is included. However, calculators are available online for this purpose (e.g., MDRD GFR Equation). * A reduced eGFR (<90 mL/min/1.73 m2) is a sensitive indicator of ADTKD-MUC1 in adults, but it is not specific, as many individuals in the general population have mildly decreased eGFR measurements. * The age at ESRD requiring dialysis or transplant may vary from the early 20s [Kimmel et al 2005] to the 70s [Stavrou et al 2002, Kirby et al 2013]. Urinalysis. Hematuria is not present, and excretion of protein is <500 mg/24 hours until kidney failure is advanced. Kidney imaging and histology * Renal ultrasound examination is usually normal or shows small kidneys. As with other patients with chronic kidney disease, occasional cysts may be seen. * Kidney biopsy reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis. Biopsy findings are nonspecific and usually do NOT lead to the diagnosis of ADTKD-MUC1. ### Establishing the Diagnosis The diagnosis of ADTKD-MUC1 is established in a proband with the above suggestive findings and identification of a heterozygous MUC1 pathogenic variant on molecular genetic testing (see Table 1). The only molecular genetic testing approach used to date is targeted analysis for the duplicated C or inserted A nucleotide within the coding variable-number tandem repeat (VNTR) in MUC1 [Kirby et al 2013] Note: The pathogenic variant cannot be detected with routine single-gene sequencing or deletion/duplication testing techniques. Likewise, existing multigene panels and genomic testing (i.e., exome and genome sequencing) will not identify the causative pathogenic variants in MUC1. Currently, genetic testing for ADTKD-MUC1 is available on a limited basis; see Author Notes. To date, no individual with a de novo MUC1 pathogenic variant has been identified [Author, personal observation]: individuals with no family history of the disorder are unlikely to have ADTKD-MUC1. ### Table 1. Molecular Genetic Testing Used in Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1-Related View in own window Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method MUC1Targeted analysis for pathogenic variants 321/24 families tested 4 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\. Specific genotyping assays are needed to detect the C (cytosine) duplication in the VNTR region; the pathogenic variant is not identifiable by routine sequence analysis (Sanger or massively parallel sequence analysis) due to the repetitive nature of the surrounding sequence [Kirby et al 2013]. 4\. 21 of 24 families with autosomal dominant interstitial kidney disease (without a pathogenic variant in either UMOD or REN) [A Bleyer, personal communication] ## Clinical Characteristics ### Clinical Description Autosomal dominant tubulointerstitial kidney disease, MUC1-related (ADTKD-MUC1) is characterized by slowly progressive tubulointerstitial disease that leads to end-stage renal disease (ESRD). Onset. ADTKD-MUC1 rarely manifests in childhood. Abnormal serum creatinine concentration or reduced eGFR may initially appear in the late teens or early twenties. As the overlap between a normal serum creatinine value and a mildly abnormal value is considerable, ADTKD-MUC1 may be difficult to diagnose in the early stages. Progression. With time, kidney function slowly worsens and serum creatinine concentration slowly rises from the normal range to the high normal range, and then to above normal. In adults the eGFR (calculated using the serum creatinine concentration, age, gender, and race) will show a progressive reduction over time. * With age, the serum creatinine concentration rises at a rate unique in each affected individual. Two groups of families have been identified; in one family the age of onset of ESRD is before 40 years in all affected family members [Kimmel et al 2005], and in the other group of families the age of onset of ESRD varies between the late 20s to older than 70 years [Stavrou et al 2002, Kiser et al 2004, Kirby et al 2013, Bleyer et al 2014]. * As kidney function worsens, manifestations of chronic kidney disease (CKD) develop, including high blood pressure, gout, and anemia. Kidney function progressively worsens until dialysis or kidney transplantation is required. Post-transplantation. ADTKD-MUC1 does not recur in the transplanted kidney. ### Genotype-Phenotype Correlations There are no known genotype-phenotype correlations. ### Penetrance CKD occurs in all affected individuals; however, the age of onset of ESRD ranges from age 20 years to older than 70 years. ### Nomenclature Medullary cystic kidney disease type 1 is the name that has historically been given to this disorder. The name is a misnomer in that cysts in the renal medulla are not a common clinical characteristic, and the presence of medullary cysts is not a good predictor of the presence of ADTKD-MUC1. According to the nomenclature from 2015 [Eckardt et al 2015], the term "autosomal dominant tubulointerstitial kidney disease" (ADTKD) refers to the following disorders characterized by: (1) autosomal dominant inheritance; (2) slowly progressive chronic tubulointerstitial kidney disease resulting in ESRD in the third through seventh decade of life; (3) urinalysis revealing a bland urinary sediment (i.e., little blood or protein); and (4) renal ultrasound examination that is normal early in the disease course [Bleyer et al 2010]. Subtypes include the following: * Autosomal dominant tubulointerstitial kidney disease, MUC1-related (ADTKD-MUC1; previously medullary cystic kidney disease type 1 [MCKD1]) * Autosomal dominant tubulointerstitial kidney disease, UMOD-related (ADTKD-UMOD; previously UMOD-associated kidney disease, familial juvenile hyperuricemic nephropathy type 1, medullary cystic kidney disease type 2 [MCKD2], and uromodulin storage disease) * Autosomal dominant tubulointerstitial kidney disease, REN-related (ADTKD-REN; previously familial juvenile hyperuricemic nephropathy type 2, also known as REN-associated kidney disease [Zivná et al 2009] Note: (1) The term "nephronophthisis/medullary cystic kidney disease (NPH/MCKD) complex" was used in the past to refer to both autosomal recessive and autosomal dominant forms of hereditary chronic tubulointerstitial disease [Hildebrandt et al 1992]. Nephronophthisis is now used to refer to a group of conditions with autosomal recessive inheritance that present in childhood with chronic kidney failure. These conditions are caused by pathogenic variants in at least 12 different genes, denoted as nephrocystins (NPHP1-NPHP11, NPHP1L) [Wolf & Hildebrandt 2011]. Clinical characteristics include polyuria, anemia, and slowly progressive kidney failure. (2) Medullary sponge kidney (MSK), associated with calcifications of the medulla of the kidney, hypercalciuria, hematuria, and tubular acidification defects [Gambaro et al 2006], is not in any way related to medullary cystic kidney disease. See Nephronopthisis. ### Prevalence ADTKD-MUC1 is estimated to affect about 100 families in the United States and about 1000 families worldwide. This is likely to be an underestimate and will increase with accurate molecular diagnostics. ## Differential Diagnosis Figure 1, a diagnostic algorithm for inherited kidney disease, recommends the following. #### Figure 1. Testing strategy for inherited kidney disease – 2015 update Urinalysis. If blood and protein are present, consider evaluation for inherited glomerulonephritis. If the urine sediment is bland (trace or no blood and protein <1 gm/24 h), obtain a family history to determine the likely inheritance pattern. If autosomal recessive (i.e., only sibs are affected), consider autosomal recessive polycystic kidney disease or the group of disorders termed "nephronophthisis." Renal imaging. Renal imaging should always be performed. Ultrasound examination is typically performed first. If numerous cortical and medullary cysts and enlarged kidneys are present, consider autosomal dominant polycystic kidney disease (ADPKD). If the number of cysts is fewer than required for a diagnosis of ADPKD, the family history suggests autosomal dominant inheritance, the urine is bland, the kidneys are normal or reduced in size with or without medullary cysts, and renal histology (if performed) has shown interstitial fibrosis, consider screening for pathogenic variants in UMOD, REN, or MUC1. * If there is a strong family history of gout [Bleyer et al 2010], consider autosomal dominant tubulointerstitial kidney disease, UMOD-related, and perform UMOD molecular genetic testing. UMOD pathogenic variants are the most common cause of autosomal dominant interstitial kidney disease. * If family members have a history of anemia in childhood and mildly elevated serum potassium concentrations, consider autosomal dominant tubulointerstitial kidney disease, REN-related and perform REN molecular genetic testing [Zivná et al 2009]. * If none of the above clinical characteristics are present or if molecular genetic testing has not revealed a pathogenic variant, consider MUC1 molecular genetic testing. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ADTKD-MUC1, the following evaluations are recommended: * Measurement of hemoglobin concentration and serum concentration of uric acid and creatinine * Measurement of blood pressure * Referral to a nephrologist for further evaluation * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Care by a nephrologist is recommended. Treatment follows standard guidelines for chronic kidney disease – based on the level of the serum creatinine and estimated glomerular filtration rate (eGFR) – and its sequelae, which can include hypertension, anemia, and gout. Affected individuals are encouraged to prepare for kidney transplantation, the definitive treatment of ADTKD-MUC1, by staying in optimal health (e.g., by exercising, avoiding obesity and tobacco usage, and maintaining strict control of hypertension, dyslipidemia, and other cardiovascular risk factors). Transplantation is curative, and the outcome from kidney transplantation in this group of patients is excellent. ### Surveillance Annually, starting at the time of diagnosis and continuing until chronic kidney disease (CKD) Stage 3: * Hemoglobin concentration * Serum concentrations of uric acid and creatinine * Blood pressure After CKD Stage 3, follow up as determined by the treating nephrologist is appropriate. ### Agents/Circumstances to Avoid Avoid use of nonsteroidal anti-inflammatory drugs (NSAIDs), especially when dehydrated, as NSAIDs can further impair kidney function in individuals with CKD. Avoid all nephrotoxic drugs or use with caution depending on the clinical indication. ### Evaluation of Relatives at Risk For the purpose of early diagnosis and treatment. If the pathogenic variant has been identified in an affected family member, molecular genetic testing can be used to clarify the genetic status of at-risk relatives (parents, sibs, and offspring). Relatives found to have a pathogenic variant can be monitored with serum creatinine measurements to allow early diagnosis and treatment (see Related Genetic Counseling Issues for discussion of testing of children.) For the purpose of kidney donation. If an MUC1 pathogenic variant is known to be present in an affected family member, any relative who is a potential kidney donor should undergo molecular genetic testing to clarify his/her genetic status so that only those without the pathogenic variant are evaluated further. Several individuals with what appeared to be clinically normal kidney function have donated kidneys and later been found to have ADTKD, MUC1.Thus, it is important to test even those family members with normal kidney function to be certain that they do not have a pathogenic variant. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1-Related

c1868139

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK153723/

{"mesh": ["C536137"], "synonyms": ["ADTKD-MUC1", "MCKD1", "Medullary Cystic Kidney Disease Type 1"]}

Beare–Stevenson cutis gyrata syndrome Other namesCutis gyrata-acanthosis nigricans-craniosynostosis syndrome[1] Diagnostic methodidentification of the p.Pro250Arg pathogenic variant in FGFR3; the diagnosis of FGFR2-related isolated coronal synostosis is based on identification of a FGFR2 pathogenic variant. The diagnosis of the other six FGFR-related craniosynostosis syndromes is based on clinical findings; molecular genetic testing of FGFR1, FGFR2, and FGFR3 may be helpful in establishing the specific diagnosis in questionable cases. differential = Deaths0 Beare–Stevenson cutis gyrata syndrome is a rare genetic disorder characterized by craniosynostosis (premature fusion of certain bones of the skull, sometimes resulting in a characteristic 'cloverleaf skull'; further growth of the skull is prevented, and therefore the shape of the head and face is abnormal) and a specific skin abnormality, called cutis gyrata, characterized by a furrowed and wrinkled appearance (particularly in the face and on the palms and soles of the feet); thick, dark, velvety areas of skin (acanthosis nigricans) are sometimes found on the hands and feet and in the groin.[2][3] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 Incidence * 6 See also * 7 References * 8 External links ## Presentation[edit] Signs and symptoms of Beare–Stevenson cutis gyrata syndrome can include a blockage of the nasal passages (choanal atresia), overgrowth of the umbilical stump, and abnormalities of the genitalia and anus. The medical complications associated with this condition are often severe and may well be life-threatening in infancy or early childhood. ## Genetics[edit] Several mutations in the FGFR2 gene (a gene coding for a protein called fibroblast growth factor receptor 2, which is involved in important signaling pathways) are known to cause Beare–Stevenson cutis gyrata syndrome;[3] however, not all patients with the condition have a mutation in their FGFR2 gene. Any alternative underlying causes are currently unidentified. The syndrome follows an autosomal dominant pattern, meaning that if one of the two available genes carries a mutation the syndrome will result. Currently, no familial histories are known (in other words, there are no reports of cases in which a parent carrying a mutation in their FGFR2 gene then propagated said mutation to his or her child). ## Diagnosis[edit] This section is empty. You can help by adding to it. (April 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (April 2017) ## Incidence[edit] Beare–Stevenson cutis gyrata syndrome is so rare that a reliable incidence cannot be established as of yet; fewer than 25 patients with the condition have been reported. ## See also[edit] * Cutis verticis gyrata * List of cutaneous conditions ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Cutis gyrata acanthosis nigricans craniosynostosis syndrome". www.orpha.net. Retrieved 14 March 2019. 2. ^ http://ghr.nlm.nih.gov/condition/beare-stevenson-cutis-gyrata-syndrome The Genetic Home Reference entry on Beare-Stevenson cutis gyrata syndrome 3. ^ a b Hall BD, Cadle RG, Golabi M, Morris CA, Cohen MM (September 1992). "Beare-Stevenson cutis gyrata syndrome". Am J Med Genet. 44 (1): 82–89. doi:10.1002/ajmg.1320440120. PMID 1519658. ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 123790 * MeSH: C565129 * SNOMED CT: 703528008 External resources * Orphanet: 1555 This Genodermatoses article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Beare–Stevenson cutis gyrata syndrome

c1852406

wikipedia

https://en.wikipedia.org/wiki/Beare%E2%80%93Stevenson_cutis_gyrata_syndrome

{"gard": ["332"], "mesh": ["C565129"], "umls": ["C1852406"], "orphanet": ["1555"], "wikidata": ["Q4876717"]}

Tracheobronchomalacia Other namesExcessive Dynamic Airway Collapse Trachea anatomy SpecialtyPulmonology SymptomsChronic cough, stridor, inability to raise secretions, breathlessness Usual onsetFrom birth (Congenital ), Adulthood (Acquired) DurationCongenital: Significant improvement after 18-24 months although some symptoms may be present for life. Acquired: Long-term. Risk factorsRelapsing polychondritis, Chronic obstructive pulmonary disease, Asthma, Gastroesophageal reflux disease (GERD), Heritable connective tissue disorders (Particularly Ehlers-Danlos Syndrome), Prolonged tracheal intubation, Long-term use of inhaled corticosteroids Diagnostic methodBronchoscopy, Dynamic Expiratory Computed Tomography Differential diagnosisAsthma, Chronic Obstructive Pulmonary Disease (COPD), Bronchiectasis, Tracheal stenosis, Tracheal tumors, Laryngomalacia PreventionTreatment of inflammatory disorders of the airway, avoiding hard impacts TreatmentContinuous Positive Airway Pressure (CPAP) , Airway Stenting, Aortopexy, Tracheopexy, Tracheobronchoplasty PrognosisVariable: Disease can range from asymptomatic to life-threatening Tracheobronchomalacia or TBM is a condition characterized by flaccidity of the tracheal support cartilage which leads to tracheal collapse.[1] This condition can also affect the bronchi. There are two forms of this condition: primary TBM and secondary TBM. Primary TBM is congenital and starts as early as birth. It is mainly linked to genetic causes. Secondary TBM is acquired and starts in adulthood. It is mainly developed after an accident or chronic inflammation.[2] Tracheobronchomalacia may also occur in people who have normal cartliginous structure of the trachea, but significant atrophy of the posterior wall, causing significant invagination of the trachea on expiration. In these cases it is more commonly known as Excessive Dynamic Airway Collapse (EDAC). ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Initially TBM may be asymptomatic or some patients do not experience symptoms at all. In a progressive TBM case symptoms include: * shortness of breath * a cough * mucus build up * stridor (a wheeze-like sound on breathing out) * difficulty in breathing * bluish coloration to skin around the nose and mouth[3] * Chronic cough[4] Symptoms may become worse if the patient is stressed, sick, lying down, or forcing a cough. ## Cause[edit] Congenital TBM is present from birth. Acquired TBM often has no clear cause but is frequently found together with other pulmonary diseases like Asthma and Chronic obstructive pulmonary disease, as well as Gastroesophageal reflux disease. TBM can be caused by damage to the support cartilage or membranous wall of the trachea, this can be the result of physical trauma (such as from prolonged Tracheal intubation) or pathological changes caused by inflammatory diseases like Relapsing polychondritis.[citation needed] In patients with TBM in one study, the number of longitudinal elastic fibers in the pars of membranacea was reduced throughout the whole trachea.[5] People with heritable connective tissue disorders like Ehlers–Danlos syndrome seem to have at an increased risk of both congenital and acquired TBM.[citation needed] There have been studies linking long-term use of inhaled Corticosteroids to Tracheobronchomalacia. ## Diagnosis[edit] Diagnosis is conducted according to the severity of the symptoms. Initially pulmonary function tests[6] are administered. These tests include the lungs' capability of air intake and outtake, and gas flow of oxygen and carbon dioxide between the body and environment. Following these function tests a special type of Chest CT scan or a bronchoscopy will be ordered. The results of the scan and bronchoscopy[7] will display the status of the condition. A mild case of tracheobronchomalacia would be if the patient's trachea condenses 50% of its normal space when exhaling. Moderate tracheobronchomalacia would be 25% of the normal trachea space constricting and a severe case would be if the walls touch each other.[citation needed] Tracheobronchomalacia is thought to be underdiagnosed as mild cases may be asymptomatic and symptoms are ofen mistaken for more common respiratory conditions like Athsma and Chronic obstructive pulmonary disease[citation needed] ## Treatment[edit] To properly treat a patient with tracheobronchomalacia, the subtype must be determined (primary or secondary). After the type is named, the cause must be identified, whether it is from genetics, a trauma accident, or chronic tracheal illness. If a trauma case or chronic tracheal illnesses were the cause, the first steps of treatment would be to fix or help these underlying issues. If the cause is genetic or the previous underlying issues could not be fixed, other treatments would be assessed. More severe treatments include silicone stenting to prevent tracheal constriction, surgery to strengthen or attempt to rebuild the walls, continuous positive airway pressure[8] that has a machine blow small amounts of air into the trachea to keep it open (mainly at night), or a tracheostomy,[9] which is surgically put into your neck that leads to your trachea to help with breathing. Another form of treatment may include a tracheobronchoplasty which is a specific surgical procedure that helps control the airway by splinting the trachea. The splint helps strengthen the trachea with the hopes that the symptoms improve.[2] People with tracheobronchomalacia who do not experience symptoms do not need treatment and are often undiagnosed.[2] On 28 May 2013, it was reported that a cure had been developed via a 3D printed windpipe.[10] This cure has currently saved the lives of at least 3 infants. ## See also[edit] * Bronchomalacia * Tracheomalacia ## References[edit] 1. ^ Lee, EY; Boiselle, PM (July 2009). "Tracheobronchomalacia in infants and children: multidetector CT evaluation". Radiology. 252 (1): 7–22. doi:10.1148/radiol.2513081280. PMID 19561247. 2. ^ a b c "Tracheobronchomalacia". Genetic and Rare Diseases Information Center. 3. ^ "Tracheaobronchomalacia - Cedars-Sinai". www.cedars-sinai.edu. Retrieved 2015-12-03. 4. ^ Baroni, RH; Feller-Kopman, D; Nishino, M; Hatabu, H; Loring, SH; Ernst, A; Boiselle, PM (May 2005). "Tracheobronchomalacia: comparison between end-expiratory and dynamic expiratory CT for evaluation of central airway collapse". Radiology. 235 (2): 635–41. doi:10.1148/radiol.2352040309. PMID 15798155. 5. ^ Jokinen, K; Palva, T; Sutinen, S; Nuutinen, J (April 1977). "Acquired tracheobronchomalacia". Annals of Clinical Research. 9 (2): 52–7. PMID 883758. 6. ^ MedlinePlus Encyclopedia: Pulmonary function tests 7. ^ MedlinePlus Encyclopedia: Bronchoscopy 8. ^ "What Is CPAP? - NHLBI, NIH". www.nhlbi.nih.gov. Archived from the original on 2015-12-08. Retrieved 2015-12-03. 9. ^ "What Is a Tracheostomy? - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 2015-12-03. 10. ^ "3-D printed windpipe gives infant breath of life". Retrieved 2015-09-09. ## External links[edit] * Tracheobronchomalacia in Children on Medscape * Tracheobronchomalacia on Genetic and Rare Diseases Information Center (GARD) Classification D * ICD-10: J39.8 * MeSH: D055089 * v * t * e Congenital malformations and deformations of respiratory system Upper RT Nose * Choanal atresia * Arrhinia Larynx * Laryngeal cyst * Laryngocele * Laryngomalacia Lower RT Trachea and bronchus * Tracheomalacia * Tracheal stenosis * Bronchomalacia * Tracheobronchomegaly Lung * Bronchiectasis * Pulmonary hypoplasia * Pulmonary sequestration * Congenital cystic adenomatoid malformation *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Tracheobronchomalacia

c0340231

wikipedia

https://en.wikipedia.org/wiki/Tracheobronchomalacia

{"gard": ["7791"], "mesh": ["D055089"], "umls": ["C0340231"], "wikidata": ["Q7831316"]}

A form of congenital disorders of N-linked glycosylation characterized by facial dysmorphism (prominent forehead, large ears, thin upper lip), generalized hypotonia, feeding difficulties, moderate to severe developmental delay, progressive microcephaly, frequent upper respiratory tract infections due to impaired immunity with decreased immunoglobulin levels, and decreased coagulation factors. Additional features include hypogonadism with or without hypospadias in males, skeletal anomalies, seizures and cardiac anomalies in some cases. The disease is caused by loss of function mutations of the gene ALG12 (22q13.33). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ALG12-CDG

c2931001

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79324

{"gard": ["9833"], "mesh": ["C535745"], "omim": ["607143"], "umls": ["C2931001"], "icd-10": ["E77.8"], "synonyms": ["CDG syndrome type Ig", "CDG-Ig", "CDG1G", "Carbohydrate deficient glycoprotein syndrome type Ig", "Congenital disorder of glycosylation type 1g", "Congenital disorder of glycosylation type Ig", "Mannosyltransferase 8 deficiency"]}

Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome is a rare, genetic, neuro-ophthalmological syndrome characterized by post-natal, progressive microcephaly and early-onset seizures, associated with delayed global development, bilateral cortical visual impairment and moderate to severe intellectual disability. Additional manifestations include short stature, generalized hypotonia and pulmonary complications, such as recurrent respiratory infections and bronchiectasis. Auditory and metabolic screenings are normal. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

c4225261

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=477814

{"omim": ["616632"]}

Epithelioid cell histiocytoma SpecialtyDermatology Epithelioid cell histiocytoma is a rare skin condition that is considered to be a variant of a dermatofibroma.[1] ## See also[edit] * Pleomorphic lipoma * 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. * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor 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

Epithelioid cell histiocytoma

c1275242

wikipedia

https://en.wikipedia.org/wiki/Epithelioid_cell_histiocytoma

{"umls": ["C1275242"], "wikidata": ["Q5383706"]}

Oculotrichoanal syndrome is a form of rare, multiple congenital anomalies/dysmorphic syndrome characterized by a combination of various nose, eye, gastrointestinal and genitourinary abnormalities. Clinical presentation is variable and often includes bifid and broad nasal tip, aberrant anterior hairline, coloboma, cryptophthalmos or unilateral anophthalmia, anal anomalies, and omphalocele. Intelligence and global development is normal. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Oculotrichoanal syndrome

c1855425

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2717

{"gard": ["3395"], "mesh": ["C536022"], "omim": ["248450"], "umls": ["C1855425"], "icd-10": ["Q87.8"], "synonyms": ["MOTA syndrome", "Manitoba oculotrichoanal syndrome", "Marles syndrome", "Marles-Greenberg-Persaud syndrome"]}

A rare, genetic, constitutional thrombocytopenia disease characterized by mild to moderate thrombocytopenia, abnormal platelet function and a propensity to develop hematological malignancies, mainly of myeloid origin. ## Epidemiology The estimated prevalence at birth is less than 1/ 1 000 000. There are no available data on the incidence of the disease. ## Clinical description Patients present mild to moderate thrombocytopenia (with normal platelet size) and/or abnormalities of platelet function, in particular defective release of delta granules and/or aggregation defects. However, a clear bleeding history (i.e., severe epistaxis, easy bruising, petechial or prolonged bleeding) is absent in many affected individuals. In the event of severe thrombocytopenia or profound platelet dysfunction, thrombocytopenia is usually recognized during the perinatal or infancy period. ## Etiology Heterozygous germline nonsense or missense variants as well as deletions in or of RUNX1 gene (21q22.12) have been identified as the causative alteration of the disease. ## Diagnostic methods Diagnosis is suspected in patients who present with mild to moderate thrombocytopenia, thrombocyte aggregation defect and/or a hematological malignancy (mainly MDS/AML, but also T-ALL) and may have a history of the same in various other family members. Genetic testing including sequencing and copy number analyses that identifies a pathogenic variant in RUNX1 confirms diagnosis. ## Differential diagnosis Differential diagnoses for hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome include several inherited disorders such as Congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia with absent radii (TAR), and Wiskott-Aldrich syndrome (WAS). ## Antenatal diagnosis Prenatal diagnosis is possible in families in which a causative gene mutation has been previously identified in an affected family member. ## Genetic counseling The disease is inherited as an autosomal dominant trait exhibiting incomplete penetrance and variable expressivity. Genetic counseling informing patients with a causative mutation of the 50% risk of transmission to future offspring and their risk to leukemia should be offered in expert centers. ## Management and treatment Currently, hematopoietic stem cell transplantation (HSCT) in preleukaemic patients with the disease remains debatable due to transplantation-associated risks and incomplete penetrance of the disease. In patients with a hematologic malignancy, HSCT may be indicated. However, HSCT using cells of HLA-matched relatives carrying the familial gene variant have to be avoided. ## Prognosis Prognosis depends on the development of a hematological malignancy and its disease course. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Familial platelet disorder with associated myeloid malignancy

c1832388

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=71290

{"gard": ["10352"], "mesh": ["C563324"], "omim": ["601399", "616216"], "umls": ["C1832388"], "icd-10": ["D69.4"], "synonyms": ["FPD/AML", "FPDMM", "FPS/AML", "Familial platelet disorder with predisposition to acute myelogenous leukemia", "Familial platelet disorder with predisposition to myeloid malignancy", "Familial platelet disorder with propensity to acute myeloid leukemia", "Familial thrombocytopenia with propensity to acute myelogenous leukemia"]}

Amyoplasia is a condition characterized by a generalized lack in the newborn of muscular development and growth, with contracture and deformity at most joints. It is the most common form of arthrogryposis.[1] It is characterized by the four limbs being involved, and by the replacement of skeletal muscle by dense fibrous and adipose tissue.[2] Studies involving amyoplasia have revealed similar findings of the muscle tissue due to various causes including that seen in sacral agenesis and amyotrophic lateral sclerosis. So amyoplasia may also include an intermediate common pathway, rather than the primary cause of the contractors. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Characteristic appearance * 4 Treatment * 5 Prognosis * 6 References ## Signs and symptoms[edit] Amyoplasia results when a fetus is unable to move sufficiently in the womb. Mothers of children with the disorder often report that their baby was abnormally still during the pregnancy. The lack of movement in utero (also known as fetal akinesia) allows extra connective tissue to form around the joints and, therefore, the joints become fixed. This extra connective tissue replaces muscle tissue, leading to weakness and giving a wasting appearance to the muscles. Additionally, due to the lack of fetal movement, the tendons that connect the muscles to bone are not able to stretch to their normal length and this contributes to the lack of joint mobility as well.[3] ## Causes[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2015) (Learn how and when to remove this template message) There is no single factor that is consistently found in the prenatal history of individuals affected with amyoplasia and, in some cases, there is no known cause of the disorder. Amyoplasia is a sporadic condition that occurs due to lack of fetal movement in the womb. There is no specific gene that is known to cause the disorder. It is thought to be multifactorial, meaning that numerous genes and environmental factors play a role in its development. The recurrence risk is minimal for siblings or children of affected individuals. There have been no reports of recurrent cases of amyoplasia in a family.[3] The fetal akinesia in amyoplasia is thought to be caused by various maternal and fetal abnormalities. In some cases, the mother's uterus does not allow for adequate fetal movement because of a lack of amniotic fluid, known as oligohydramnios, or an abnormal shape to the uterus, called a bicornuate uterus. There may also be a myogenic cause to the fetal akinesia, meaning that fetal muscles do not develop properly due to a muscle disease (for example, a congenital muscular dystrophy). Similarly, connective tissue tendon and skeletal defects may contribute to the fetal akinesia and be the primary cause of amyoplasia. Additionally, malformations may occur in the central nervous system and/or spinal cord that can lead to a lack of fetal movement in utero. This neurogenic cause is often accompanied by a wide range of other conditions. Other causes of fetal akinesia may include a maternal fever during pregnancy or a virus. ## Diagnosis[edit] It is the most common form of arthrogryposis multiplex congenita (AMC), where multiple joint contractures are present at birth. Arthrogryposis is derived from the Greek word meaning "with crooking of joints." It occurs in about one out of every 3,000 live births. There are more than 150 types of AMC. Amyoplasia accounts for 40% of AMC cases.[3] ### Characteristic appearance[edit] Children with amyoplasia often suffer from internally rotated shoulders, extended elbows, ulnar flexed wrists. The type of displacement of the hips and knees is more variable, and they often have club feet.[citation needed] About 10% of children with amyoplasia have evidence of vascular compromise including Intestinal atresia, abdominal wall defects, and gastroschisis.[citation needed] ## Treatment[edit] Surgery may be necessary to address the congenital deformities frequently occurring in conjunction with arthrogryposis. Surgery on feet, knees, hips, elbows and wrists may also be useful if more range of motion is needed after therapy has achieved maximum results. In some cases, tendon transfers can improve function. Congenital deformities of the feet, hips and spine may require surgical correction at or about one year of age.[4] ## Prognosis[edit] Overall prognosis for children with amyoplasia is good. Intensive therapies throughout developing years include physical therapy, occupational therapy and multiple orthopedic procedures. Most children require therapy for years, but almost 2/3 are eventually able to walk, with or without braces, and attend school.[citation needed] ## References[edit] 1. ^ Jill M. Sells; Kenneth M. Jaffe; Judith G. Hall (1 February 1996). "Amyoplasia, the Most Common Type of Arthrogryposis: The Potential for Good Outcome". Pediatrics. 97 (2): 225–231. PMID 8584382. 2. ^ Bernstein, RM (2002). "Arthrogryposis and amyoplasia". The Journal of the American Academy of Orthopaedic Surgeons. 10 (6): 417–24. doi:10.5435/00124635-200211000-00006. PMID 12470044. S2CID 36302153. 3. ^ a b c "Amyoplasia Information on Healthline". Archived from the original on 11 December 2008. Retrieved 30 October 2008. 4. ^ "Shriners Hospitals for Children - Chicago: Arthrogryposis". Retrieved 30 October 2008. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Amyoplasia

c0432185

wikipedia

https://en.wikipedia.org/wiki/Amyoplasia

{"orphanet": ["488586"], "synonyms": ["Amyoplasia congenita"], "wikidata": ["Q4749575"]}

A rare congenital malformation where a second structure with individual lumen and stratified squamous mucosa and muscularis mucosa lies within or adjacent to the true esophagus causing dysphagia, nausea, vomiting, retrosternal pain and respiratory problems (stridor and recurrent pneumonia) and usually presenting in children. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Tubular duplication of the esophagus

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100048

{"icd-10": ["Q39.8"]}

Dermatofibroma Other namesDermal dendrocytoma,[1] Dermatofibroma,[2] Fibrous dermatofibroma,[2] Fibrous histiocytoma,[2] Fibroma simplex,[1] Nodular subepidermal fibrosis,[1] and Sclerosing hemangioma[1]) SpecialtyOncology A dermatofibroma, or benign fibrous histiocytomas, is a benign skin growth.[3] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 Immunohistochemical staining * 3 See also * 4 References * 5 External links ## Signs and symptoms[edit] Dermatofibromas[4] are hard solitary slow-growing papules (rounded bumps) that may appear in a variety of colours, usually brownish to tan; they are often elevated or pedunculated. A dermatofibroma is associated with the dimple sign; by applying lateral pressure, there is a central depression of the dermatofibroma. Although typical dermatofibromas cause little or no discomfort, itching and tenderness can occur. Dermatofibromas can be found anywhere on the body, but most often they are found on the legs and arms.[5] They occur most often in women; the male to female ratio is about 1:4.[6] The age group in which they most commonly occur is 20 to 45 years. Some physicians and researchers believe dermatofibromas form as a reaction to previous injuries such as insect bites or thorn pricks.[6] They are composed of disordered collagen laid down by fibroblasts. Dermatofibromas are classed as benign skin lesions, meaning they are completely harmless, though they may be confused with a variety of subcutaneous tumours.[7] Deep penetrating dermatofibromas may be difficult to distinguish, even histologically, from rare malignant fibrohistocytic tumours like dermatofibrosarcoma protuberans.[8] Dermatofibromas typically have a positive buttonhole sign, or central dimpling in the center.[9] ## Diagnosis[edit] ### Immunohistochemical staining[edit] Neoplasm CD34[1] Stromelysin-3[10] Factor XIIIa[6] Dermatofibroma \- \+ \+ Dermatofibrosarcoma protuberans \+ \- \- ## See also[edit] * Acrochordon, also called skin tags * Dermatology * List of cutaneous conditions * Seborrheic keratosis ## References[edit] 1. ^ a b c d e Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.[page needed] 2. ^ a b c Freedberg; et al. (2003). Fitzpatrick's Dermatology in General Medicine (6th ed.). McGraw-Hill. p. 668. ISBN 978-0-07-138076-8. 3. ^ "benign fibrous histiocytoma" at Dorland's Medical Dictionary 4. ^ "Dermatofibroma | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-17. 5. ^ "dermatofibroma" at Dorland's Medical Dictionary 6. ^ a b c Dermatofibroma at eMedicine 7. ^ Jung, Kyu Dong; Lee, Dong-Youn; Lee, Joo-Heung; Yang, Jun-Mo; Lee, Eil-Soo (2011). "Subcutaneous Dermatofibroma". Annals of Dermatology. 23 (2): 254–7. doi:10.5021/ad.2011.23.2.254. PMC 3130878. PMID 21747634. 8. ^ Hanly, A. J.; Jordà, M; Elgart, G. W.; Badiavas, E; Nassiri, M; Nadji, M (2006). "High proliferative activity excludes dermatofibroma: Report of the utility of MIB-1 in the differential diagnosis of selected fibrohistiocytic tumors". Archives of Pathology & Laboratory Medicine. 130 (6): 831–4. doi:10.1043/1543-2165(2006)130[831:HPAEDR]2.0.CO;2 (inactive 2021-01-10). PMID 16740036.CS1 maint: DOI inactive as of January 2021 (link) 9. ^ Boursicot, Katharine (24 January 2013). Oxford Assess and Progress: Clinical Specialties. Oxford University Press. p. 249. ISBN 9780199657582. 10. ^ Kim, H.J.; Lee, J.Y.; Kim, S.H.; Seo, Y.J.; Lee, J.H.; Park, J.K.; Kim, M.H.; Cinn, Y.W.; Cho, K.H.; Yoon, T.Y. (2007). "Stromelysin-3 expression in the differential diagnosis of dermatofibroma and dermatofibrosarcoma protuberans: Comparison with factor XIIIa and CD34". British Journal of Dermatology. 157 (2): 319–24. doi:10.1111/j.1365-2133.2007.08033.x. PMID 17596171. S2CID 7049937. ## External links[edit] Classification D * ICD-10: D23 (ILDS D23.L62) * ICD-9-CM: 216.9 * ICD-O: M8830/0 * MeSH: D018219 * DiseasesDB: 29384 External resources * eMedicine: derm/96 * Patient UK: Dermatofibroma * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Connective/soft tissue tumors and sarcomas Not otherwise specified * Soft-tissue sarcoma * Desmoplastic small-round-cell tumor Connective tissue neoplasm Fibromatous Fibroma/fibrosarcoma: * Dermatofibrosarcoma protuberans * Desmoplastic fibroma Fibroma/fibromatosis: * Aggressive infantile fibromatosis * Aponeurotic fibroma * Collagenous fibroma * Diffuse infantile fibromatosis * Familial myxovascular fibromas * Fibroma of tendon sheath * Fibromatosis colli * Infantile digital fibromatosis * Juvenile hyaline fibromatosis * Plantar fibromatosis * Pleomorphic fibroma * Oral submucous fibrosis Histiocytoma/histiocytic sarcoma: * Benign fibrous histiocytoma * Malignant fibrous histiocytoma * Atypical fibroxanthoma * Solitary fibrous tumor Myxomatous * Myxoma/myxosarcoma * Cutaneous myxoma * Superficial acral fibromyxoma * Angiomyxoma * Ossifying fibromyxoid tumour Fibroepithelial * Brenner tumour * Fibroadenoma * Phyllodes tumor Synovial-like * Synovial sarcoma * Clear-cell sarcoma Lipomatous * Lipoma/liposarcoma * Myelolipoma * Myxoid liposarcoma * PEComa * Angiomyolipoma * Chondroid lipoma * Intradermal spindle cell lipoma * Pleomorphic lipoma * Lipoblastomatosis * Spindle cell lipoma * Hibernoma Myomatous general: * Myoma/myosarcoma smooth muscle: * Leiomyoma/leiomyosarcoma skeletal muscle: * Rhabdomyoma/rhabdomyosarcoma: Embryonal rhabdomyosarcoma * Sarcoma botryoides * Alveolar rhabdomyosarcoma * Leiomyoma * Angioleiomyoma * Angiolipoleiomyoma * Genital leiomyoma * Leiomyosarcoma * Multiple cutaneous and uterine leiomyomatosis syndrome * Multiple cutaneous leiomyoma * Neural fibrolipoma * Solitary cutaneous leiomyoma * STUMP Complex mixed and stromal * Adenomyoma * Pleomorphic adenoma * Mixed Müllerian tumor * Mesoblastic nephroma * Wilms' tumor * Malignant rhabdoid tumour * Clear-cell sarcoma of the kidney * Hepatoblastoma * Pancreatoblastoma * Carcinosarcoma Mesothelial * Mesothelioma * Adenomatoid tumor * v * t * e Skin cancer of the dermis Dermis * Benign fibrous histiocytoma/dermatofibrosarcoma protuberans * Dermatofibrosarcoma protuberans Subcutaneous tumors Connective and vascular * see Template:Soft tissue tumors and sarcomas, Template:Vascular tumors, Template:Myeloid malignancy (for mastocytosis) Other urogenital: * Hirsuties coronae glandis neuro: * Solitary neurofibroma * Cutaneous meningioma * Ganglioneuroma * Schwannoma * Palisaded encapsulated neuroma * Infantile neuroblastoma * Neuroma cutis bone/cartilage: * Chordoma * Extraskeletal chondroma nevus: * Nevus anemicus * Nevus flammeus * Nevus flammeus nuchae * Nevus lipomatosus superficialis * Nevus oligemicus * Connective tissue nevus * Midline nevus flammeus * Porokeratotic eccrine ostial and dermal duct nevus histiocytoma: * Pleomorphic undifferentiated sarcoma * Plexiform fibrohistiocytic tumor * Progressive nodular histiocytoma * Teratoma * Adenoma sebaceum * Metastatic carcinoma * Giant-cell tumor of the tendon sheath * Glomus tumor * Granular cell tumor * Carcinoid * Desmoid tumor * Neurothekeoma * Angiokeratoma * Zosteriform metastasis * Keratinizing metaplasia * Epithelioid sarcoma *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Dermatofibroma

c1509148

wikipedia

https://en.wikipedia.org/wiki/Dermatofibroma

{"umls": ["C1509148"], "icd-9": ["216.9"], "icd-10": ["D23"], "wikidata": ["Q1200237"]}

In the legal profession and courts, a querulant (from the Latin querulus \- "complaining") is a person who obsessively feels wronged, particularly about minor causes of action. In particular the term is used for those who repeatedly petition authorities or pursue legal actions based on manifestly unfounded grounds. These applications include in particular complaints about petty offenses. Querulant behavior is to be distinguished from either the obsessive pursuit of justice regarding major injustices, or the proportionate, reasonable, pursuit of justice regarding minor grievances. According to Mullen and Lester, the life of the querulant individual becomes consumed by their personal pursuit of justice in relation to minor grievances.[1] ## Contents * 1 Use in psychiatry * 2 Frequency * 3 See also * 4 References * 5 External links ## Use in psychiatry[edit] In psychiatry, the terms querulous paranoia (Kraepelin, 1904)[1][2] and litigious paranoia[3] have been used to describe a paranoid condition which manifested itself in querulant behavior. The concept had, until 2004, disappeared from the psychiatric literature; largely because it had been misused to stigmatise the behavior of people seeking the resolution of valid grievances.[4] It also appears in ICD-10, under its Latin name Paranoia querulans, in section F22.8, "Other persistent delusional disorders".[5] ## Frequency[edit] According to Lester et al. querulous behavior remains common, as shown in petitions to the courts and complaints organizations.[6] They state that "persistent complainants’ pursuit of vindication and retribution fits badly with complaints systems established to deliver reparation and compensation [and that these] complainants damaged the financial and social fabric of their own lives and frightened those dealing with their claims."[6] ## See also[edit] * Idée fixe * Monomania * Persecutory delusion * Vexatious litigation ## References[edit] 1. ^ a b Mullen, P. E.; Lester, G. (2006). "Vexatious litigants and unusually persistent complainants and petitioners: from querulous paranoia to querulous behaviour" (PDF). Behavioral Sciences & the Law. 24 (3): 333–49. doi:10.1002/bsl.671. PMID 16705656. 2. ^ Kraepelin, E. (1904). Lectures in clinical psychiatry (trans. ed. T. Johnstone). London: Bailliere, Tindall and Cox. 3. ^ Glueck, B. (1914). "The Forensic Phase of Litigious Paranoia". Journal of the American Institute of Criminal Law and Criminology. 5 (3): 371–386. doi:10.2307/1133011. JSTOR 1133011. 4. ^ Stålström, O. W. (1980). "Querulous paranoia: diagnosis and dissent". The Australian and New Zealand Journal of Psychiatry. 14 (2): 145–150. doi:10.3109/00048678009159370. PMID 6932870. S2CID 13557826. 5. ^ ICD-10 F22.8 6. ^ a b Lester, Grant; Franzcp, Beth Wilson; Griffin, Lynn; Mullen, Paul E. (2004). "Unusually persistent complainants" (PDF). The British Journal of Psychiatry. 184 (4): 352–356. doi:10.1192/bjp.184.4.352. PMID 15056581. ## External links[edit] Look up querulant, querulous, or querulousness in Wiktionary, the free dictionary. * Blaney, Paul H.; Millon, Theodore (20 November 2008). Oxford Textbook of Psychopathology. Oxford University Press. ISBN 978-0-19-988836-8. * Lee, Kyoungmi; Kim, Hakkyun; Vohs, Kathleen D. (1 January 2011). "Stereotype Threat in the Marketplace: Consumer Anxiety and Purchase Intentions". Journal of Consumer Research. 38 (2): 343–357. CiteSeerX 10.1.1.640.678. doi:10.1086/659315. JSTOR 659315. * Vohs, Kathleen D.; Baumeister, Roy F.; Chin, Jason. "Feeling Duped: Emotional, Motivational, and Cognitive Aspects of Being Exploited by Others". CiteSeerX 10.1.1.186.4833. Cite journal requires `|journal=` (help) *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Querulant

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wikipedia

https://en.wikipedia.org/wiki/Querulant

{"wikidata": ["Q252110"]}