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A number sign (#) is used with this entry because of evidence that Jervell and Lange-Nielsen syndrome-2 (JLNS2) is caused by homozygous or compound heterozygous mutation in the KCNE1 gene (176261) on chromosome 21q22. Long QT syndrome-5 (LQT5; 613695) is caused by heterozygous mutation in the KCNE1 gene. Description The Jervell and Lange-Nielsen syndrome is an autosomal recessive syndrome of abnormal cardiac ventricular repolarization with prolonged QT interval and bilateral congenital deafness. For a general description and a discussion of genetic heterogeneity of Jervell and Lange-Nielsen syndrome, see 220400. Mapping In a small consanguineous British family with JLNS, Tyson et al. (1997) excluded linkage to KCNQ1 (607542), and found that the affected children were homozygous by descent for markers on chromosome 21, in a region containing the KCNE1 gene (176261). Tyson et al. (1997) found that most of the families they studied showed linkage consistent with mutation at the KCNQ1 gene. Molecular Genetics In a small consanguineous British family in which the JLNS phenotype had been mapped to chromosome 21, Tyson et al. (1997) detected a homozygous mutation in the KCNE1 gene (176261.0001). The KCNE1 gene encodes a transmembrane protein that associates with KCNQ1 to form the delayed rectifier potassium channel. Schulze-Bahr et al. (1997) found compound heterozygosity for mutations in the KCNE1 gene (176261.0002, 176261.0003) in affected members of a Lebanese family with JLNS. Duggal et al. (1998) reported a family in which a young girl with JLNS was homozygous for a mutation in the KCNE1 gene (176261.0003), whereas her heterozygous first-degree relatives showed a milder phenotype with partial hearing loss and QT prolongation more in keeping with LQT1. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Congenital sensorineural hearing loss CARDIOVASCULAR Heart \- Prolonged QT interval on EKG \- Syncope \- Torsades de pointes \- Sudden cardiac death MISCELLANEOUS \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the potassium voltage-gated channel, Isk-related subfamily, member 1 gene (KCNE1, 176261.0001 ) ▲ Close

JERVELL AND LANGE-NIELSEN SYNDROME 2

c0022387

omim

https://www.omim.org/entry/612347

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Ethanol is the type of alcohol found in alcoholic beverages. It is a volatile, flammable, colorless liquid that acts as a central nervous system depressant.[1] Ethanol can impair different types of memory. Ethanol Alcoholic beverages ## Contents * 1 Mode of actions * 1.1 Effects on the hippocampus * 1.2 Molecular effects on GABA and NMDA receptors * 1.3 Effects on other brain regions * 2 Long-term memory * 2.1 Explicit memory * 2.2 Implicit memory * 3 Short-term memory * 3.1 Brain areas affected by alcohol * 3.2 Tasks and intoxication findings * 4 Effects on working memory * 4.1 In the short term * 4.2 In the long term * 5 Prospective memory * 6 In popular culture * 7 See also * 8 References ## Mode of actions[edit] ### Effects on the hippocampus[edit] Alcohol acts as a general central nervous system depressant, but it also affects some specific areas of the brain to a greater extent than others. Memory impairment caused by alcohol has been linked to the disruption of hippocampal function — particularly affecting gamma-Aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) neurotransmission which negatively impacts long-term potentiation (LTP).[2] The molecular basis of LTP is associated with learning and memory.[3] Particularly, damage to hippocampal CA1 cells adversely affects memory formation,[4] and this disruption has been linked to dose-dependent levels of alcohol consumption.[5] At higher doses, alcohol significantly inhibits neuronal activity in both the CA1 and CA3 pyramidal cell layers of the hippocampus.[6][7][8] This impairs memory encoding,[9] since the hippocampus plays an important role in the formations of new memories. A Hippocampal Pyramidal Cell ### Molecular effects on GABA and NMDA receptors[edit] A GABAA Receptor Alcohol also acts as a positive allosteric modulator of GABA receptors, specifically type GABAA.[10] Upon activation, these GABA receptors conduct Cl-, resulting in neuronal hyperpolarization. This hyperpolarization decreases the chance of an action potential occurring and thus, it has an inhibitory effect on neurotransmission in the central nervous system. GABAA receptor subtypes vary in their sensitivities to dosage of alcohol consumed. Furthermore, acute alcohol intake promotes GABAergic neurotransmission via the presynaptic release of GABA, the dephosphorylation of GABAA receptors (increasing GABA sensitivity), and the elevation of endogenous GABAergic neuroactive steroids.[11] Protein kinase C (PKC) has been implicated in differentially modulating the response of the GABAA receptor to alcohol, with effects depending on the PKC isozyme.[12] Alcohol effects have also implicated protein kinase A in affecting GABAA receptor function, such as promoting sensitivity.[13] Enhancement of GABAergic transmission due to alcohol consumption can also be brought about by neuroactive steroids, such as allopregnanolone, which act as GABAA receptor agonists.[11][14] Both chronic alcohol consumption and alcohol dependence are correlated with the altered expression, properties, and functions of the GABAA receptor that may contribute to alcohol tolerance.[11] There is still much yet to be discovered about alcohol's specific and varying effects on both the GABAA receptor and its subtypes. At higher doses, ethanol also affects NMDA receptors (NMDARs) by inhibiting the ion current induced by NMDA, a glutamate receptor agonist.[15] This inhibition of synaptic excitation by alcohol has been shown to be dose-dependent (up to a certain point, after which it did not differ by much).[16] Alcohol appears to produce this inhibition by using a site of the NMDAR that is accessible from the extracellular environment.[17] Therefore, this inhibition of an ion current usually produced by NMDAR activation leads to decreased LTP in hippocampal areas.[18] Alcohol negatively affects LTP to a greater degree in immature versus mature animals.[19] In adolescents, alcohol decreases the expression of both the NMDAR NR2A subunit in the hippocampus and the NR1 subunit in the prefrontal cortex.[20] Studies have also found that a decrease in phosphorylation of 2B subunit in the prefrontal cortex, the hippocampus, the nucleus accumbens, and the striatum.[21] NMDARS may be affected by PKA regulation due to the actions of alcohol.[22] Alcohol's effects on GABAA neurotransmission may indirectly inhibit the activity of the NMDAR, and they may contribute to its blockade of LTP induction; however, alcohol's direct effects on NMDAR alone are sufficient for the inhibition of LTP.[23] The varying dose-dependent response to alcohol relies on the combined interactions and responses of the GABAA receptors, NMDARs, and metabotropic glutamate receptors subtype 5 (mGluR5).[24][25][26] These changes prevent excitatory synaptic transmissions from occurring, affecting synaptic plasticity and, in turn, memory and learning. However, there is still much yet to be elucidated concerning specific molecular mechanisms of how alcohol affects memory formation. ### Effects on other brain regions[edit] Alcohol also impairs and alters the functioning in the cerebellum, which affects both motor function and coordination.[27] It has a notable inhibitory effect on the neurons of the cerebral cortex, affecting and altering thought processes, decreasing inhibition, and increasing the pain threshold. It also decreases sexual performance by depressing nerve centers in the hypothalamus.[28][29] Alcohol also has an effect on urine excretion via inhibition of anti-diuretic hormone (ADH) secretion of the pituitary gland. Lastly, it depresses breathing and heart rate by inhibiting neuronal functioning of the medulla.[30] ## Long-term memory[edit] Long-term memory (LTM) has both a long duration and a large capacity.[31] Memories that are stored in LTM can last from a few days to a lifetime.[31] LTM consists of both explicit memory (requiring conscious awareness) and implicit memory (unconscious awareness).[31] Information selected for LTM goes through three processes. First of all, in the encoding stage, information from the senses is incorporated into mental activity in the form of a memory.[31] Secondly, storage involves taking this information and holding it indefinitely in memory.[31] Lastly, retrieval is the ability to recall information from the long-term memory storage. Each of these processes can be affected by alcohol.[31] Animation: Hippocampus (red) ### Explicit memory[edit] Explicit memory requires conscious and intentional effort for recall.[31] It includes both episodic memory (for specific events, such as a party) and semantic memory (for general information, such as one's name).[31] Alcohol impairs episodic encoding, specifically for cued recall, recognition of completed word fragments, and free recall.[32] A blackout is an example of a difficulty in encoding episodic memories due to alcohol. Blackouts are caused by a rapid increase in blood alcohol concentration (BAC) which in turn distorts the neurons in the hippocampus.[33] This distortion impairs a person's ability to form new episodic memories.[33] High doses of alcohol severely disrupt the storage process of semantic memories.[34] Alcohol was found to impair the storage of novel stimuli but not that of previously learned information.[34] Since alcohol affects the central nervous system, it hinders semantic storage functioning by restricting the consolidation of the information from encoding.[34] Retrieval of explicit memory is significantly impaired by alcohol. When compared to sober participants, intoxicated participants performed quite poorly on a recall task for everyday events (i.e., episodic memory).[35] Intoxicated participants are also slower to respond in reaction time tasks.[36] Alcohol also impairs retrieval in word recognition tasks.[32] When both encoding and retrieval take place during intoxication, there are surprisingly more impairments for cued recall than for free recall.[32] In terms of gender differences in retrieval processes, females tend to score lower than males on recall tasks when intoxicated.[36] ### Implicit memory[edit] Implicit memory does not require conscious effort or intention for recall.[31] It occurs when previous experience influences performance on a certain task.[31] This is evident in priming experiments. Implicit memory includes procedural memory, which influences our everyday behaviours, such as riding a bike or tying shoes.[31] People can perform these abilities without even thinking about them, which means procedural memory functions automatically. While retrieval of explicit memory is severely impaired by alcohol, retrieval of implicit memory is not.[35] Intoxicated subjects score higher on recognition tasks (involving implicit memory) than they can on recall tasks (involving explicit memory).[35] ## Short-term memory[edit] Short-term memory refers to the temporary storage of small amounts of information over short delays.[31] Digit span refers to the proposed number of pieces of information (5-9) that can be held in short-term memory. This is also referred to as the magic number seven – plus or minus two. Any more pieces of information than this, and newer items replace previous items.[37] Alcohol intoxication has been found to have dissociative effects on both short-term memory and cognitive functioning.[38][39] Anterior Cingulate Cortex (yellow) Animation: Parietal Lobe (red) ### Brain areas affected by alcohol[edit] Alcohol affects the functioning of the brain. Neurochemical changes occurring in the anterior cingulate are correlated with altered short-term memory functions in the brains of young alcoholic men.[40] fMRIs of alcohol-dependent women displayed significantly less blood oxygen in the frontal and parietal regions, especially in the right hemisphere.[41] This is supported by findings of short-term memory impairment by lesions of both the parietal lobe[42] and the prefrontal cortex.[43] Associations between Third ventricle volume and cognitive performance on memory tests have been found in alcoholics.[44] Specifically, increases in third ventricular volume correlate with a decline in memory performance.[44] ### Tasks and intoxication findings[edit] Short-term memory is commonly tested with visual tasks. Short-term memory, especially for non-verbal and spatial material, are impaired by intoxication.[44] Alcohol decreases iconic memory (a type of visual short-term memory).[45] With BACs between 80–84 mg/dl, more intrusion errors occur in a delayed recall task compared to a control group.[46] Intrusion errors, which represent reflective cognitive functioning, occur when irrelevant information is produced. Alcoholics have less control of inhibiting intrusions.[46] Acute alcohol intoxication in social drinkers caused more intrusion errors in delayed recall tasks than in immediate free recall tasks.[46] Acute alcohol intoxication increases the susceptibility to interference, which allows for more intrusion errors when there is a short delay.[46] Free recall (given list of words then asked to recall list) is significantly lower and therefore impaired by alcohol intoxication.[47][48] Encoding deficits were found in verbal free recall and recognition tasks under the influence of alcohol.[49] A discrimination task found significant alcohol-related impairments both in depth perception and in visual short-term memory.[50] State-dependent learning and relearning studies in male heavy drinkers demonstrate that the condition of intoxication while learning and sobriety when tested caused a performance deficit in free recall tasks.[51] These findings are supportive of alcohol-induced storage deficits (not retrieval deficits).[51] The effects of acute alcohol consumption on visual short-term memory, stereoscopic depth perception, and attention were all studied. A 33% alcohol condition showed significant impairments both in depth perception and in visual short-term memory (assessed by the vernier discrimination task).[52] Working Memory Model. Alcohol intoxication can disrupt rehearsal strategies which may involve the phonological loop and/or the visuospatial sketchpad. ## Effects on working memory[edit] Working memory allows one to keep things in mind while simultaneously performing complex tasks.[31] It involves a system for both the temporary storage and the manipulation of information, subsequently forming a crucial link between perception and controlled action.[53] Evidence suggests that working memory involves three components: the central executive which controls attention, the visuo-spatial sketchpad which holds and manipulates spatial information, and the phonological loop which performs a similar function for auditory and speech-based information.[53] ### In the short term[edit] Alcohol consumption has substantial, measurable effects on working memory, although these effects vary greatly between individual responses. Not much is really known about the neural mechanisms that underlie these individual differences.[54] It is also found that alcohol impairs working memory by affecting mnemonic strategies and executive processes rather than by shrinking the basic holding capacity of working memory. Isolated acute-moderate levels of alcohol intoxication do not physically alter the structures that are critical for working memory function, such as the frontal cortex, the parietal cortex, the anterior cingulate, and parts of the basal ganglia.[38] One finding regarding the effects of alcohol on working memory points out that alcohol reduces working memory only in individuals with a high baseline working memory capacity,[55] which suggests that alcohol might not uniformly affect working memory in many different individuals. Alcohol appears to impair the capacity of working memory to modulate response inhibition.[55] Alcohol disinhibits behaviour, but it only does so in individuals with a low baseline working memory capacity.[55] An interesting finding is that the incentive to perform well with working memory measurement tasks while under the influence of alcohol 'does, in fact, have some effect on working memory, as it boosts scores in the rate of mental scanning and reaction time to stimulus; however, it did not reduce the number of errors as opposed to subjects with no incentive to perform well.[56] Even acute alcohol intoxication (a blood alcohol concentration of 0.08-0.09%) produces a substantial impairment of working memory processes that require mnemonic rehearsal strategies.[38] It is less likely for alcohol to impair a working memory task that does not rely on memory rehearsal or associated mnemonic strategies.[38] Because of this, working memory is very susceptible to falter when an individual participates in tasks involving retention concerning both auditory and visual sequences.[38] An interesting example of this is the failure of guitarists or other musicians performing concerts to cue in on auditory patterns and make it known that their performance is hindered by intoxication, whereas professional basketball (a less sequence-heavy activity for working memory) standout Ron Artest recently admitted in an interview with Sporting News to drinking heavily during half-time early in his career and the fact that it had little — if not any recognizable — effect on his working memory. His former coach Fran Fraschilla has gone on record saying:[citation needed] > "It's a surprise because every day at practice, he came out in a mood to play. He came out in a basketball rage. He was fully committed; he wanted to let our upperclassmen know that he was the alpha male. It never came up that he had any sort of a problem with alcohol. This is the first I've heard of it." ### In the long term[edit] This article needs more medical references for verification or relies too heavily on primary sources, specifically: primary sources should be replaced; consider using PMID 23905882 and PMID 28470828. 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: "Effects of alcohol on memory" – news · newspapers · books · scholar · JSTOR (July 2017) Alcohol has been shown to have just some long-term effects on working memory. Findings have shown that in order for working memory to be substantially affected, long-term heavy drinking must be sustained over a long period of time, as up to one drink per day does not impair any cognitive function and may actually decrease the risk of a cognitive decline.[57] Furthermore, chronic alcoholism is associated with the impairment in both sustained attention and visual working memory. As a result, alcoholics have reduced ability, but not necessarily inability, to perform these executive tasks. This is assumed to be subserved by regions of the prefrontal cortex.[58] While it may not serve as a surprise that chronic alcoholism is linked to any decreased cognitive function such as working memory, one surprising finding is not only that even moderate levels of alcohol consumption during pregnancy were shown to have an adverse effect on the child's working memory when tested at 7.5 years of age, but also that working memory may be the most important aspect of attention that is adversely affected by prenatal alcohol exposure.[59] ## Prospective memory[edit] Prospective memory involves remembering to carry out an intended action in the future without an explicit reminder.[31] Alcohol has been found to impair this ability. Chronic heavy alcohol users report significantly more prospective forgetting compared to low-dose and alcohol-free controls.[60] The Prospective Memory Questionnaire assesses short-term habitual prospective memory, long-term episodic prospective memory, and internally cued prospective memory.[60] Chronic heavy alcohol users reported significantly greater deficits for all three aspects of prospective memory.[60] Individuals that report heavy alcohol use report 24% more difficulties with prospective memory than those who report that they are light drinkers and 30% more difficulties than those who report that they never drink.[61] The effects of alcohol on prospective memory can also be assessed in the laboratory by simulating prospective memory tasks that individuals face in everyday life. Individuals who are given 0.6 g/kg alcohol prior to performing prospective memory tasks do significantly poorer than a placebo group.[62] Alcohol can damage the prefrontal and frontal areas of the brain, and this may be responsible for prospective memory impairments since prospective memory performance is highly correlated with frontal executive functions.[60] ## In popular culture[edit] The memory inhibiting effects of alcohol are often a prominent topic in popular culture. It appears in movies, books, and television shows. Several movies show characters drinking alcohol to the point of memory loss and awakening the next morning with a host of problems due to actions they performed while intoxicated. One example is The Hangover, where three groomsmen lose the groom during a bachelor party in Las Vegas, so they retrace their steps to find him.[63] The characters still had functioning implicit/procedural memory, which allowed them to carry out the many acts they performed that night, but their episodic memory was impaired and thus they had no recollection of the events occurring. In addition to alcohol the characters were also under the influence of flunitrazepam. Another movie is What Happens in Vegas. After an intoxicated night in "Sin City," two people wake-up to find they got married.[64] Songs such as Waking Up in Vegas by Katy Perry[65] and Last Name by Carrie Underwood[66] also depict characters waking up and not remembering the night before due to alcohol consumption. By some accounts, popular culture makes light of the memory problems that can result from alcohol consumption. The court case R. v. Daviault [1994] concerned the viability of a legal defense based on intoxication. Law and Order: Special Victims Unit; in season 11 episode 4, Hammered, a recovering alcoholic was coerced to drink by a business partner and later wakes up to a dead woman in his bed. ## See also[edit] * Confabulation * Wernicke–Korsakoff syndrome ## References[edit] 1. ^ Merriam-Webster's Online Dictionary 2. ^ Rose, M. E.; Grant, J. E. (2010). "Alcohol-Induced Blackout". Journal of Addiction Medicine. 4 (2): 61–73. doi:10.1097/ADM.0b013e3181e1299d. PMID 21769024. S2CID 23068837. 3. ^ Bliss, T. V. P.; Collingridge, G. L. (1993). "A synaptic model of memory: Long-term potentiation in the hippocampus". Nature. 361 (6407): 31–39. Bibcode:1993Natur.361...31B. doi:10.1038/361031a0. PMID 8421494. S2CID 4326182. 4. ^ Zola-Morgan, S.; Squire, L. R.; Amaral, D. G. (1986). "Human amnesia and the medial temporal region: Enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus". The Journal of Neuroscience. 6 (10): 2950–2967. doi:10.1523/JNEUROSCI.06-10-02950.1986. PMC 6568782. PMID 3760943. 5. ^ White, A. M.; Best, P. J. (2000). "Effects of ethanol on hippocampal place-cell and interneuron activity". Brain Research. 876 (1–2): 154–165. doi:10.1016/S0006-8993(00)02629-9. PMID 10973604. S2CID 37879454. 6. ^ Ryabinin AE, Criado JR, Henriksen SJ, Bloom FE, Wilson MC (1997). Differential sensitivity of c-Fos expression in hippocampus and other brain regions to moderate and low doses of alcohol. Mol Psychiatry, (1),32-43. 7. ^ Ryabinin, AE (1998). "Role of hippocampus in alcohol-induced memory impairment: implications from behavioral and immediate early gene studies". Psychopharmacology. 139 (1–2): 1–2. doi:10.1007/s002130050687. PMID 9768540. S2CID 22730822. 8. ^ Weiner, JL; Gu, C; Dunwiddie, TV (1997). "Differential Ethanol Sensitivity of Subpopulations of GABAA Synapses Onto Rat Hippocampal CA1 Pyramidal Neurons". The Journal of Neurophysiology. 77 (3): 1306–1312. doi:10.1152/jn.1997.77.3.1306. PMID 9084598. 9. ^ White, A (2003). "What Happened? Alcohol, Memory Blackouts and the Brain". Alcohol Research & Health. 27 (2): 186–196. 10. ^ Paul, S. M. (2006). "Alcohol-sensitive GABA receptors and alcohol antagonists". Proceedings of the National Academy of Sciences. 103 (22): 8307–8308. doi:10.1073/pnas.0602862103. PMC 1482489. PMID 16717187.. 11. ^ a b c Kumar, S.; Porcu, P.; Werner, D. F.; Matthews, D. B.; Diaz-Granados, J. L.; Helfand, R. S.; Morrow, A. L. (2009). "The role of GABAA receptors in the acute and chronic effects of ethanol: A decade of progress". Psychopharmacology. 205 (4): 529–564. doi:10.1007/s00213-009-1562-z. PMC 2814770. PMID 19455309. 12. ^ Proctor, W. R.; Poelchen, W.; Bowers, B. J.; Wehner, J. M.; Messing, R. O.; Dunwiddie, T. V. (2003). "Ethanol Differentially Enhances Hippocampal GABAA Receptor-Mediated Responses in Protein Kinase Cgamma (PKCgamma ) and PKCepsilon Null Mice". Journal of Pharmacology and Experimental Therapeutics. 305 (1): 264–270. doi:10.1124/jpet.102.045450. PMID 12649378. S2CID 6395717. 13. ^ Park, S. K.; Sedore, S. A.; Cronmiller, C.; Hirsh, J. (2000). "Type II cAMP-dependent Protein Kinase-deficient Drosophila Are Viable but Show Developmental, Circadian, and Drug Response Phenotypes". Journal of Biological Chemistry. 275 (27): 20588–20596. doi:10.1074/jbc.M002460200. PMID 10781603. 14. ^ Silvers, J. M.; Tokunaga, S.; Berry, R. B.; White, A. M.; Matthews, D. B. (2003). "Impairments in spatial learning and memory: Ethanol, allopregnanolone, and the hippocampus". Brain Research. Brain Research Reviews. 43 (3): 275–284. doi:10.1016/j.brainresrev.2003.09.002. PMID 14629930. S2CID 43784032. 15. ^ Lovinger, DM; White, G; Weight, FF (1989). "Ethanol inhibits NMDA-activated ion current in hippocampal neurons". Science. 243 (4899): 1721–1724. Bibcode:1989Sci...243.1721L. doi:10.1126/science.2467382. PMID 2467382. 16. ^ Lovinger, D. M.; White, G.; Weight, F. F. (1990). "NMDA receptor-mediated synaptic excitation selectively inhibited by ethanol in hippocampal slice from adult rat". The Journal of Neuroscience. 10 (4): 1372–1379. doi:10.1523/jneurosci.10-04-01372.1990. PMC 6570208. PMID 2158533. 17. ^ Peoples, R. W.; Stewart, R. R. (2000). "Alcohols inhibit N-methyl-D-aspartate receptors via a site exposed to the extracellular environment". Neuropharmacology (Submitted manuscript). 39 (10): 1681–1691. doi:10.1016/S0028-3908(00)00067-8. PMID 10884550. S2CID 26168622. 18. ^ Morrisett, R. A.; Swartzwelder, H. S. (1993). "Attenuation of hippocampal long-term potentiation by ethanol: A patch-clamp analysis of glutamatergic and GABAergic mechanisms". The Journal of Neuroscience. 13 (5): 2264–2272. doi:10.1523/jneurosci.13-05-02264.1993. PMC 6576561. PMID 8478698. 19. ^ Swartzwelder, H. S.; Wilson, W. A.; Tayyeb, M. I. (1995). "Age-dependent inhibition of long-term potentiation by ethanol in immature versus mature hippocampus". Alcoholism: Clinical and Experimental Research. 19 (6): 1480–1485. doi:10.1111/j.1530-0277.1995.tb01011.x. PMID 8749814. 20. ^ Pian, J. P.; Criado, J. R.; Milner, R.; Ehlers, C. L. (2010). "NMDAR subunit expression in adult and adolescent brain following chronic ethanol exposure". Neuroscience. 170 (2): 645–654. doi:10.1016/j.neuroscience.2010.06.065. PMC 2945397. PMID 20603193. 21. ^ Pascual, M.; Boix, J.; Felipo, V.; Guerri, C. (2009). "Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat". Journal of Neurochemistry. 108 (4): 920–931. doi:10.1111/j.1471-4159.2008.05835.x. PMID 19077056. 22. ^ Lai, C. C.; Kuo, T. I.; Lin, H. H. (2007). "The Role of Protein Kinase a in Acute Ethanol-Induced Neurobehavioral Actions in Rats". Anesthesia & Analgesia. 105 (1): 89–96. CiteSeerX 10.1.1.333.5710. doi:10.1213/01.ane.0000263030.13249.36. PMID 17578962. S2CID 15529888. 23. ^ Schummers, J.; Browning, M. D. (2001). "Evidence for a role for GABA(A) and NMDA receptors in ethanol inhibition of long-term potentiation". Brain Research. Molecular Brain Research. 94 (1–2): 9–14. doi:10.1016/s0169-328x(01)00161-9. PMID 11597760. 24. ^ Besheer, J.; Cox, A. A.; Hodge, C. W. (2003). "Coregulation of Ethanol Discrimination by the Nucleus Accumbens and Amygdala". Alcoholism: Clinical and Experimental Research. 27 (3): 450–456. doi:10.1097/01.ALC.0000057036.64169.C1. PMID 12658110. 25. ^ Besheer, J.; Hodge, C. W. (2004). "Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol". Neuropsychopharmacology. 30 (4): 747–757. doi:10.1038/sj.npp.1300616. PMC 2892057. PMID 15549054. 26. ^ Hodge, C. W.; Cox, A. A. (1998). "The discriminative stimulus effects of ethanol are mediated by NMDA and GABA(A) receptors in specific limbic brain regions". Psychopharmacology. 139 (1–2): 95–107. doi:10.1007/s002130050694. PMID 9768547. S2CID 38391993. 27. ^ Ming, Z; Criswell, HE; Yu, G; Breese, GR (2006). "Competing presynaptic and postsynaptic effects of ethanol on cerebellar purkinje neurons". Alcoholism: Clinical and Experimental Research. 30 (8): 1400–1407. doi:10.1111/j.1530-0277.2006.00167.x. PMC 2949273. PMID 16899043. 28. ^ Waltman, C; Blevins Jr, LS; Boyd, G; Wand, GS (1993). "The effects of mild ethanol intoxication on the hypothalamic-pituitary-adrenal axis in nonalcoholic men". Journal of Clinical Endocrinology & Metabolism. 77 (2): 518–522. doi:10.1210/jc.77.2.518. PMID 8393888. 29. ^ Halpern-Felsher, BL; Millstein, SG; Ellen, JM (1996). "Relationship of alcohol use and risky sexual behavior: a review and analysis of findings". Journal of Adolescent Health. 19 (5): 331–336. doi:10.1016/s1054-139x(96)00024-9. PMID 8934293. 30. ^ Sun, MK; Reis, DJ (1992). "Effects of systemic ethanol on medullary vasomotor neurons and baroreflexes". Neuroscience Letters. 137 (2): 232–236. doi:10.1016/0304-3940(92)90411-y. PMID 1584465. S2CID 45576960. 31. ^ a b c d e f g h i j k l m n Baddeley, A., Eysenck, M.W. and Anderson, M.C. (2009). Memory. New York, NY: Psychology Press. 32. ^ a b c Soderlund, H.; Parker, E.S.; Schwartz, B.L.; Tulving, E. (2005). "Memory encoding and retrieval on the ascending and descending limbs of the blood alcohol concentration curve". Psychopharmacology. 182 (2): 305–317. doi:10.1007/s00213-005-0096-2. PMID 16160875. S2CID 2084273. 33. ^ a b Lee, H.; Roh, S.; Kim, D. (2009). "Alcohol-Induced Blackout". International Journal of Environmental Research and Public Health. 6 (11): 2783–2792. doi:10.3390/ijerph6112783. PMC 2800062. PMID 20049223. 34. ^ a b c Parker, Birnbaum; Noble (1976). "Alcohol and Memory: Storage and State Dependency". Journal of Verbal Learning and Verbal Behavior. 15 (6): 691–702. doi:10.1016/0022-5371(76)90061-x. 35. ^ a b c Nelson, T.; McSpadden, M.; Fromme, K.; Marlatt, G. (1986). "Effects of Alcohol Intoxication on Metamemory and on Retrieval from Long-Term Memory". Journal of Experimental Psychology. 115 (3): 247–254. doi:10.1037/0096-3445.115.3.247. PMID 2944987. 36. ^ a b Haut, J.; Beckwith, B.; Petros, T.; Russell, S. (1989). "Gender Differences in Retrieval From Long-Term Memory Following Acute Intoxication With Ethanol". Physiology & Behavior. 45 (6): 1161–1165. doi:10.1016/0031-9384(89)90103-0. PMID 2813540. S2CID 40873039. 37. ^ Miller, G.A. (1994). "The magical number seven, plus or minus two: some limits on our capacity for processing information". Psychological Review. 101 (2): 343–352. doi:10.1037/0033-295x.101.2.343. PMID 8022966. 38. ^ a b c d e Saults, J.S.; Cowan, N.; Sher, K.J.; Moreno, M.V. (2007). "Differential short Term effects of Alcohol on Working Memory: Distinguishing Multiple Processes". Experimental and Clinical Psychopharmacology. 15 (6): 576–587. doi:10.1037/1064-1297.15.6.576. PMC 2658822. PMID 18179311. 39. ^ Bates, M. E. (2006). "Acute alcohol effects on repetition priming and word recognition memory with equivalent memory cues". Brain Cogn. 60 (2): 118–127. doi:10.1016/j.bandc.2005.07.009. PMID 16377048. S2CID 41154421. 40. ^ Eun, L.; Dong-Pyo, J.; Jae-Jin, K.; Suk Kyoon, A.; Sangjin, P.; In-Young, K.; Sun, I.K.; Kang-Jun, Y.; Kee, N. (2007). "Alteration of brain metabolites in young alcoholics without structural changes". NeuroReport. 18 (14): 1511–1514. doi:10.1097/WNR.0b013e3282ef7625. PMID 17712285. S2CID 20409183. 41. ^ Tapert, S.F.; Brown, G.G.; Kindermann, S.S.; Cheung, E.H.; Frank, L.R.; Brown, S.A. (2006). "fMRI measurement of brain dysfunctions in alcohol-dependent young women". Alcoholism: Clinical and Experimental Research. 25 (2): 26–245. 42. ^ Warrington, E. K.; James, M.; Maciejewski, C. (1986). "The WAIS as a lateralizing and localizing diagnostic instrument: A study of 656 patients with unilateral cerebral lesions". Neuropsychologia. 24 (2): 223–239. doi:10.1016/0028-3932(86)90055-2. PMID 3714027. S2CID 33190123. 43. ^ Goldman-Rakic, P. S. (1992). "Working memory and the mind". Scientific American. 267 (3): 110–117. Bibcode:1992SciAm.267c.110G. doi:10.1038/scientificamerican0992-110. PMID 1502513. 44. ^ a b c Sullivan, E.V.; Rosenbloom, M.J.; Lim, K.O.; Pfefferbam, A. (2000). "Longitudinal changes in cognition, gait, and balance in abstinent and relapsed alcoholic men: relationships to changes in brain structure". Neuropsychology. 14 (2): 178–188. doi:10.1037/0894-4105.14.2.178. PMID 10791858. 45. ^ Subhan (1983). "The effects of midazolam in conjunction with alcohol in iconic memory and free recall". Neuropsychobiology. 9 (4): 230–234. doi:10.1159/000117970. PMID 6646395. 46. ^ a b c d Ray, S.; Bates, M.E. (2007). "Acute effects of alcohol on intrusion errors in free recall tasks". International Journal on Disability and Human Development. 6 (2): 201–205. doi:10.1515/ijdhd.2007.6.2.201. S2CID 147314783. 47. ^ Hashtroudi, S.; Parker, DeLisi; Wyatt, R.J.; Mutter, S.A. (1984). "Intact retention in acute alcohol amnesia". Journal of Experimental Psychology: Learning, Memory, and Cognition. 10 (1): 156–163. doi:10.1037/0278-7393.10.1.156. PMID 6242732. 48. ^ Tracy, J.I.; Bates, M.E. (1999). "The selective effects of alcohol on automatic and effortful memory processes". Neuropsychology. 13 (2): 282–290. doi:10.1037/0894-4105.13.2.282. PMID 10353377. 49. ^ Williams, H.L.; Rundell, U.H. (1984). "Effect of alcohol on recall and recognition as functions of processing levels". Journal of Studies on Alcohol. 45 (1): 10–15. doi:10.15288/jsa.1984.45.10. PMID 6700218. 50. ^ Wegner, A.J.; Fahle, M. (1999). "Alcohol and visual performance". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 23 (3): 465–482. doi:10.1016/S0278-5846(99)00009-3. PMID 10378230. S2CID 24469283. 51. ^ a b Miller, M.E.; Adesso, V.J.; Fleming, J.P.; Gino, A.; Lauerman, R. (1978). "Effects of alcohol on the storage and retrieval processes of heavy social drinkers". Journal of Experimental Psychology: Human Learning and Memory. 4 (3): 246–255. doi:10.1037/0278-7393.4.3.246. PMID 660094. 52. ^ Wegner, A.J.; Fahle, M. (1999). "Alcohol and visual performance". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 23 (3): 465–482. doi:10.1016/S0278-5846(99)00009-3. PMID 10378230. S2CID 24469283. 53. ^ a b Baddeley, A. (1998) Comptes Rendus de l'Académie des Sciences – Série III, 321(2-3), 167-173. 54. ^ Paulus, Martin P, Tapert, Susan F, Pulido, Carmen, & Schuckit, Marc A. (2006). Alcohol attenuates load-related activation during a working memory task: Relation to level of response to alcohol. Dept of Psychiatry, University of California. PP 2 55. ^ a b c Finn, P.R.; Justus, A.; Mazas, C.; Steinmetz, J.E. (1999). "Working memory, executive processes and the effects of alcohol on Go/No-Go learning: testing a model of behavioral regulation and impulsivity". Psychopharmacology. 146 (4): 465–472. doi:10.1007/pl00005492. PMID 10550497. S2CID 23894568. 56. ^ Grattan-Miscio, K.E. and Vogel-Sprott, M. (2005) Effects of alcohol and performance incentives on immediate working memory. Springer Berlin / Heidelberg, 188-196 57. ^ Stampfer MJ, Kang JH, Chen J, Cherry R, Grodstein F (2005). "Effects of moderate alcohol consumption on cognitive function in women". N Engl J Med. 352 (3): 245–253. doi:10.1056/NEJMoa041152. PMID 15659724. 58. ^ Pfefferbaum A, Desmond JE, Galloway C, Menon V, Glover GH, Sullivan EV (July 2001). "Reorganization of frontal systems used by alcoholics for spatial working memory: an fMRI study". NeuroImage. 14 (1 pt 1): 7–20. doi:10.1006/nimg.2001.0785. PMID 11525339. S2CID 508770. 59. ^ Burden MJ, Jacobson SW, Sokol RJ, Jacobson JL (March 2005). "Effects of prenatal alcohol exposure on attention and working memory at 7.5 years of age". Alcohol Clin Exp Res. 29 (3): 443–52. doi:10.1097/01.ALC.0000156125.50577.EC. PMID 15770121. 60. ^ a b c d Heffernan, T.M.; Moss, M; Ling, J. (2002). "Subjective Ratings of Prospective Memory Deficits in Chronic Heavy Alcohol Users". Alcohol and Alcoholism. 37 (3): 269–271. doi:10.1093/alcalc/37.3.269. PMID 12003916. 61. ^ Ling, J.; Heffernan, T.M.; Buchanan, T.; Rodgers, J.; Scholey, A.B.; Parrot, A.C. (2003). "Effects of Alcohol on Subjective Ratings of Prospective and Everyday Memory Deficits" (PDF). Alcoholism: Clinical and Experimental Research. 27 (6): 970–974. doi:10.1097/01.alc.0000071741.63467.cb. PMID 12824818. 62. ^ Leitz, J.R.; Morgan, C. A. J.; Bisby, J.A.; Rendell, P.G.; Curran, V.H. (2009). "Global impairment of prospective memory following acute alcohol". Psychopharmacology. 205 (3): 379–387. doi:10.1007/s00213-009-1546-z. PMID 19440700. S2CID 21923512. 63. ^ "The Hangover" (2009). Retrieved from https://www.imdb.com/title/tt1119646/. 64. ^ "What Happens in Vegas" (2008). Retrieved from https://www.imdb.com/title/tt1033643/plotsummary. 65. ^ "YouTube – Waking Up in Vegas Lyrics – Katy Perry" (2009). Retrieved from https://www.youtube.com/watch?v=06Qf7GdAF70 66. ^ "YouTube – Carrie Underwood – Last Name" (2009). 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Effects of alcohol on memory

c0001940

wikipedia

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

{"mesh": ["D000425"], "umls": ["C0001940"], "wikidata": ["Q5347361"]}

Argentine hemorrhagic fever SpecialtyInfectious disease Argentine hemorrhagic fever (AHF) or O'Higgins disease, also known in Argentina as mal de los rastrojos (stubble disease) is a hemorrhagic fever and zoonotic infectious disease occurring in Argentina. It is caused by the Junín virus[1] (an arenavirus, closely related to the Machupo virus, causative agent of Bolivian hemorrhagic fever). Its vector is the drylands vesper mouse, a rodent found in Argentina and Paraguay. ## Contents * 1 Epidemiology * 2 Clinical aspects * 2.1 Vaccine * 3 Weaponization * 4 References * 4.1 Notes * 4.2 Bibliography * 5 External links ## Epidemiology[edit] The disease was first reported in the town of O'Higgins [es] in Buenos Aires province, Argentina in 1958, giving it one of the names by which it is known.[2] Various theories about its nature were proposed: it was Weil's disease, leptospirosis, caused by chemical pollution.[2] It was associated with fields containing stubble after the harvest, giving it another of its names. The endemic area of AHF covers approximately 150,000 km², compromising the provinces of Buenos Aires, Córdoba, Santa Fe and La Pampa, with an estimated risk population of 5 million. The vector, a small rodent known locally as ratón maicero ("maize mouse"; Calomys musculinus), suffers from chronic asymptomatic infection, and spreads the virus through its saliva and urine. Infection is produced through contact of skin or mucous membranes, or through inhalation of infected particles. It is found mostly in people who reside or work in rural areas; 80% of those infected are males between 15 and 60 years of age. ## Clinical aspects[edit] AHF is a grave acute disease which may progress to recovery or death in 1 to 2 weeks. The incubation time of the disease is between 10 and 12 days, after which the first symptoms appear: fever, headaches, weakness, loss of appetite and will. These intensify less than a week later, forcing the infected to lie down, and producing stronger symptoms such as vascular, renal, hematological and neurological alterations. This stage lasts about 3 weeks. If untreated, the mortality of AHF reaches 15–30%. The specific treatment includes plasma of recovered patients, which, if started early, is extremely effective and reduces mortality to 1%.[3] Ribavirin also has shown some promise in treating arenaviral diseases. The disease was first detected in the 1950s in the Junín Partido in Buenos Aires, after which its agent, the Junín virus, was named upon its identification in 1958. In the early years, about 1,000 cases per year were recorded, with a high mortality rate (more than 30%). The initial introduction of treatment serums in the 1970s reduced this lethality. ### Vaccine[edit] This section needs to be updated. Please update this article to reflect recent events or newly available information. (August 2011) The Candid #1 vaccine for AHF was created in 1985 by Argentine virologist Dr. Julio Barrera Oro. The vaccine was manufactured by the Salk Institute in the United States, and became available in Argentina in 1990. The Junín vaccine has also shown cross-reactivity with Machupo virus and, as such, has been considered as a potential treatment for Bolivian hemorrhagic fever. Candid #1 has been applied to adult high-risk population and is 95.5% effective.[4] Between 1991 and 2005 more than 240,000 people were vaccinated, achieving a great decrease in the numbers of reported cases (94 suspect and 19 confirmed in 2005). On 29 August 2006 the Maiztegui Institute obtained certification for the production of the vaccine in Argentina. The vaccine produced in Argentina was found to be of similar effectiveness to the US vaccine.[5] Details of the vaccine were published in 2011,[4] and a protocol for production of the vaccine was published in 2018.[6] Demand for the vaccine is insufficient to be commercially appealing due to the small target population, and it is considered an orphan drug; the Argentine government committed itself to manufacture and sponsor C#1 vaccine.[4] ## Weaponization[edit] Argentine hemorrhagic fever was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program.[7] The Soviet Union also conducted research and developing programs on the potential of the hemorragic fever as a biological weapon.[8] ## References[edit] ### Notes[edit] 1. ^ Grant, A.; Seregin, A.; Huang, C.; Kolokoltsova, O.; Brasier, A.; Peters, C.; Paessler, S. (2012). "Junín Virus Pathogenesis and Virus Replication". Viruses. National Institutes of Health. 4 (10): 2317–2339. doi:10.3390/v4102317. PMC 3497054. PMID 23202466. "Junín virus, the etiological agent of Argentine hemorrhagic fever, causes significant morbidity and mortality." 2. ^ a b Graciela Agnese: “Una rara enfermedad alarma a la modesta población de O’Higgins” Análisis del discurso de la prensa escrita sobre la epidemia de Fiebre Hemorrágica Argentina de 1958, Revista de Historia & Humanidades Médicas Vol. 3 Nº 1, Julio 2007, www.fmv-uba.org.ar/histomedicina(in Spanish) 3. ^ van Griensven, Johan; De Weiggheleire, Anja; Delamou, Alexandre; Smith, Peter G.; Edwards, Tansy; Vandekerckhove, Philippe; Bah, Elhadj Ibrahima; Colebunders, Robert; Herve, Isola; Lazaygues, Catherine; Haba, Nyankoye; Lynen, Lutgarde (2015). "The Use of Ebola Convalescent Plasma to Treat Ebola Virus Disease in Resource-Constrained Settings: A Perspective From the Field". Clinical Infectious Diseases. 62 (1): 69–74. doi:10.1093/cid/civ680. ISSN 1058-4838. PMC 4678103. PMID 26261205. 4. ^ a b c Ambrosio A, Saavedra M, Mariani M, Gamboa G, Maiza A (2011). "Argentine hemorrhagic fever vaccines". Hum Vaccin. 7 (6): 694–700. doi:10.4161/hv.7.6.15198. PMID 21451263.CS1 maint: multiple names: authors list (link) 5. ^ Enria DA1, Ambrosio AM, Briggiler AM, Feuillade MR, Crivelli E (2010). "Vacuna contra la fiebre hemorrágica argentina Candid#1 producida en la Argentina. Inmunogenicidad y seguridad" [Candid#1 vaccine against Argentine hemorrhagic fever produced in Argentina. Immunogenicity and safety]. MEDICINA (Buenos Aires). 70: 215–222.CS1 maint: uses authors parameter (link) Article in Spanish with abstract in English. 6. ^ Ambrosio, Ana María; Mariani, Mauricio Andrés; Maiza, Andrea Soledad; Gamboa, Graciela Susana; Fossa, Sebastián Edgardo; Bottale, Alejando Javier (2018). "Protocol for the Production of a Vaccine Against Argentinian Hemorrhagic Fever". Hemorrhagic Fever Viruses. Methods in Molecular Biology. 1604. pp. 305–329. doi:10.1007/978-1-4939-6981-4_24. ISBN 978-1-4939-6980-7. ISSN 1064-3745. PMID 28986845. 7. ^ "Chemical and Biological Weapons: Possession and Programs Past and Present", James Martin Center for Nonproliferation Studies, Middlebury College, April 9, 2002, accessed November 14, 2008. 8. ^ Wheelis, Mark; Rózsa, Lajos & Dando, Malcolm: Deadly cultures: biological weapons since 1945. Harvard University Press, 2006. Page 141. ISBN 0-674-01699-8 ### Bibliography[edit] * Argentine Ministry of Health and Environment, 8 October 2006. Argentina fabricará vacuna contra la fiebre hemorrágica. * Clarín, 29 September 2006. La vacuna contra el mal de los rastrojos ya se puede elaborar en el país. * TodoAmbiente \- Infectious diseases. * ANLIS. Fiebre hemorrágica argentina. ## External links[edit] Classification D * ICD-10: A96.0 * ICD-9-CM: 078.7 * MeSH: D018051 * DiseasesDB: 31900 * v * t * e Zoonotic viral diseases (A80–B34, 042–079) Arthropod -borne Mosquito -borne Bunyavirales * Arbovirus encephalitides: La Crosse encephalitis * LACV * Batai virus * BATV * Bwamba Fever * BWAV * California encephalitis * CEV * Jamestown Canyon encephalitis * Tete virus * Tahyna virus * TAHV * Viral hemorrhagic fevers: Rift Valley fever * RVFV * Bunyamwera fever * BUNV * Ngari virus * NRIV Flaviviridae * Arbovirus encephalitides: Japanese encephalitis * JEV * Australian encephalitis * MVEV * KUNV * Saint Louis encephalitis * SLEV * Usutu virus * West Nile fever * WNV * Viral hemorrhagic fevers: Dengue fever * DENV-1-4 * Yellow fever * YFV * Zika fever * Zika virus Togaviridae * Arbovirus encephalitides: Eastern equine encephalomyelitis * EEEV * Western equine encephalomyelitis * WEEV * Venezuelan equine encephalomyelitis * VEEV * Chikungunya * CHIKV * O'nyong'nyong fever * ONNV * Pogosta disease * Sindbis virus * Ross River fever * RRV * Semliki Forest virus Reoviridae * Banna virus encephalitis Tick -borne Bunyavirales * Viral hemorrhagic fevers: Bhanja virus * Crimean–Congo hemorrhagic fever (CCHFV) * Heartland virus * Severe fever with thrombocytopenia syndrome (Huaiyangshan banyangvirus) * Tete virus Flaviviridae * Arbovirus encephalitides: Tick-borne encephalitis * TBEV * Powassan encephalitis * POWV * Viral hemorrhagic fevers: Omsk hemorrhagic fever * OHFV * Kyasanur Forest disease * KFDV * AHFV * Langat virus * LGTV Orthomyxoviridae * Bourbon virus Reoviridae * Colorado tick fever * CTFV * Kemerovo tickborne viral fever Sandfly -borne Bunyavirales * Adria virus (ADRV) * Oropouche fever * Oropouche virus * Pappataci fever * Toscana virus * Sandfly fever Naples virus Rhabdoviridae * Chandipura virus Mammal -borne Rodent -borne Arenaviridae * Viral hemorrhagic fevers: Lassa fever * LASV * Venezuelan hemorrhagic fever * GTOV * Argentine hemorrhagic fever * JUNV * Brazilian hemorrhagic fever * SABV * Bolivian hemorrhagic fever * MACV * LUJV * CHPV Bunyavirales * Hemorrhagic fever with renal syndrome * DOBV * HTNV * PUUV * SEOV * AMRV * THAIV * Hantavirus pulmonary syndrome * ANDV * SNV Herpesviridae * Murid gammaherpesvirus 4 Bat -borne Filoviridae * BDBV * SUDV * TAFV * Marburg virus disease * MARV * RAVV Rhabdoviridae * Rabies * ABLV * MOKV * DUVV * LBV * CHPV Paramyxoviridae * Henipavirus encephalitis * HeV * NiV Coronaviridae * SARS-related coronavirus * SARS-CoV * MERS-CoV * SARS-CoV-2 Primate -borne Herpesviridae * Macacine alphaherpesvirus 1 Retroviridae * Simian foamy virus * HTLV-1 * HTLV-2 Poxviridae * Tanapox * Yaba monkey tumor virus Multiple vectors Rhabdoviridae * Rabies * RABV * Mokola virus Poxviridae * Monkeypox *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Argentine hemorrhagic fever

c0019097

wikipedia

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

{"mesh": ["D006478"], "umls": ["C0019097"], "icd-9": ["078.7"], "icd-10": ["A96.0"], "orphanet": ["319223"], "wikidata": ["Q2583514"]}

Bilateral frontalparietal polymicrogyria Other namesBFPP Bilateral frontoparietal polymicrogyria is a genetic disorder with autosomal recessive inheritance that causes a cortical malformation. Our brain has folds in the cortex to increase surface area called gyri and patients with polymicrogyri have an increase number of folds and smaller folds than usual.[1] Polymicrogyria is defined as a cerebral malformation of cortical development in which the normal gyral pattern of the surface of the brain is replaced by an excessive number of small, fused gyri separated by shallow sulci and abnormal cortical lamination. From ongoing research, mutation in GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, results in BFPP. These mutations are located in different regions of the protein without any evidence of a relationship between the position of the mutation and phenotypic severity.[2] It is also found that GPR56 plays a role in cortical pattering.[3] ## Contents * 1 Presentation * 1.1 Associated conditions * 2 Genetics * 2.1 Mode of inheritance * 3 Diagnosis * 3.1 Methods/tests * 4 Treatment * 5 Prognosis * 6 See also * 7 References * 8 External links ## Presentation[edit] Left:Normal Middle:polymicrgyria Right:Lissencephaly * Symptoms: Developmental delay, Psychomotor delay, Mental retardation - moderate to severe, Exaggerated reflexes and Seizures (epilepsy) ### Associated conditions[edit] BFPP is a cobblestone-like cortical malformation of the brain. Disruptions of cerebral cortical development due to abnormal neuronal migration and positioning usually lead to cortical disorders, which includes cobblestone lissencephaly. Cobblestone lissencephaly is typically seen in three different human congenital muscular dystrophy syndromes: Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, and muscle-eye-brain disease.[4] In cobblestone lissencephaly, the brain surface actually has a bumpy contour caused by the presence of collections of misplaced neurons and glial cells that have migrated beyond the normal surface boundaries of the brain. Sometimes regions populated by these misplaced cells have caused a radiologic misdiagnosis of polymicrogyria. However, the presence of other abnormalities in these cobblestone lissencephaly syndromes, including ocular anomalies, congenital muscular dystrophy, ventriculomegaly, and cerebellar dysplasia, usually distinguishes these disorders from polymicrogyria.[5] There are no anatomopathologic studies that have characterized the pattern of cortical laminar alterations in patients with GPR56 gene mutations, but it has been suggested that the imaging characteristics of BFPP, including myelination defects and cerebellar cortical dysplasia, are reminiscent of those of the so-called cobblestone malformations (muscle-eye-brain disease and Fukuyama congenital muscular dystrophy) that are also associated with N-glycosylation defects in the developing brain.[6] Lissencephaly ("smooth brain") is the extreme form of pachygyria. In lissencephaly, few or no sulci are seen on the cortical surface, resulting in a broad, smooth appearance to the entire brain. Lissencephaly can be radiologically confused with polymicrogyria, particularly with low-resolution imaging, but the smoothness and lack of irregularity in the gray-white junction, along with markedly increased cortical thickness, distinguishes lissencephaly. GPR56 mutation also can cause a severe encelphalopathy which is associated with electro clinical features of the Lennox-Gastaut syndrome. Lennox-Gastaut syndrome can be cryptogenic or symptomatic, but the symptomatic forms have been associated with multiple etiologies and abnormal cortical development. BFPP caused by GPR56 mutations is a manifestation of a malformation of cortical development that causes Lennox-Gastaut Syndrome.[7] Polymicrogyria is often confused with pachygyria; therefore, it needs to be distinguished from pachygyria, a distinct brain malformation in which the surface folds are excessively broad and sparse. Pachygyria and polymicrogyria may look similar on low-resolution neuroimaging such as CT because the cortical thickness can appear to be increased and the gyri can appear to be broad and smooth in both conditions. This is why higher resolution neuroimaging, such as an MRI, is necessary for proper diagnosis.[5] Lissencephaly:Brain MRI, T1 weighted, transverse plane, that shows lyssencephaly, manifested as scarce and wide circumvolutions, mostly in the occipital, parietal and temporal lobes. As aggregated findings, there is ventriculomegaly, no true Sylvian fissure, too thick gray matter and ectopic gray matter in the white matter. ## Genetics[edit] The GPR56 is grouped in the B family of GPCRs. This GPCR group have long N termini characterized by an extracellular “cysteine box” and hydrophilic, potentially mucin-rich. The cysteine box contains four conserved cysteines and two tryptophans arranged in a specific fashion (C-x2-W-x6-16-W-x4-C-x10-22-C-x-C) just before the first transmembrane domain and serves as a cleavage site in some members of this group of G protein–coupled receptors.[8] Although, the molecular and cellular mechanisms of how GPR56 regulates brain development remain largely unknown.[9] These types of receptors play an essential role in biological processes including embryonic development, central nervous system (CNS), immune system, and tumorigenesis.[10] GPCR classification ### Mode of inheritance[edit] Parents of a proband * The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele. * Heterozygotes (carriers) are asymptomatic. Sibs of a proband * At conception, each sibling 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 an at-risk sibling is known to be unaffected, the risk of his/her being a carrier is 2/3. * Heterozygotes (carriers) are asymptomatic. Offspring of a proband * Offspring of a proband are obligate heterozygotes and will therefore carry one mutant allele. * In populations with a high rate of consanguinity, the offspring of a person with GPR56-related BFPP and a reproductive partner who is a carrier of GPR56-related BFPP have a 50% chance of inheriting two GPR56 disease-causing alleles and having BFPP and a 50% chance of being carriers. Other family members of a proband. * Each sibling of the proband's parents is at a 50% risk of being a carrier[5] ## Diagnosis[edit] Diagnostic criteria for a BFPP patient entails a heterozygous genotype for a deletion of chromosome 16q12.1-q21 region, including GPR56 gene.[11] To date the only gene known to be associated with polymicrogyria is GPR56. Testing for GPR56-related bilateral frontoparietal polymicrogyria is available clinically. Mutations in GPR56 hinders Collagen III, its specific ligand, to bind in a developing brain. To date, a total of fourteen BFPP-associated mutations have been identified, including one deletion, two splicing, and eleven missense mutations. Two mutations in the GPCR proteolytic site (GPS) domain, C346S and W349S, cause a brain malformation through trapping the mutated proteins in the endoplasmic reticulum.[12] GPR56 are a part of the B class of the GPCR family, the largest cell surface gene family in the human genome. Within this family there are different types of bio-active molecules that transduce their signal to the intracellular compartment via interaction with this type of receptor. Children often present with developmental delay, spasticity, or seizures; they are also often microcephalic. Some patients with polymicrogyria go undiagnosed until they produce children with the disorder who have more severe manifestations. Retrospectively, these patients will often report some difficulty in their medical or educational history.[13] BFPP patients demonstrate mental retardation, language impairment, motor developmental delay, and seizure disorders such as epilepsy.[14] The association of epilepsy is in approximately 50% to 85% of affected BFPP patients. The clinical manifestations of polymicrogyria are stable neurologic deficits: In the mildest form, polymicrogyria is unilateral with only one small region of the brain involved; neurologic problems may not be evident. In more severe forms, focal motor, sensory, visual, or cognitive problems may be present, depending on the location of the brain region affected. In the most severe forms, polymicrogyria is bilateral and generalized, resulting in severe intellectual disability, cerebral palsy, and refractory epilepsy. Individuals with the milder forms of polymicrogyria survive into adulthood, while those with the most severe forms, such as BFPP, may die at a young age as a result of such complications as seizures or pneumonia.[5] The prevalence of isolated polymicrogyria is unknown. Researchers believe that it may be relatively common overall, although BFPP is probably rare.[15] * Radiological findings (MRI) demonstrated symmetric generalized polymicrogyria with decreasing anterior-posterior gradient, most prominent in frontoparietal cortex.[5] * Numerous gyrus on the cortex * Small gyri and sulci * Thin cortex ### Methods/tests[edit] This child presented with seizures. The coronal true inversion recovery sequence shows thickened and disordered cortex in superior frontal and cingulate gyri bilaterally (arrow). There are small convolutions visible at the corticomedullary junction. The appearance is that of cortical dysplasia, with polymicrogyria more likely than pachygyria due to the small convolutions visible. There are also small foci of grey matter signal in the corpus callosum, deep to the dysplastic cortex (double arrows). These probably represent areas of grey matter heterotopia. There are different tests or methods used to determine GPR56 expression or visuals of the brain to analyze the specific sections that are affected. These tests for example, using animals such as mice, RNAi, Behavioral assay, Electron microscopy, CT scan, or MRI demonstrate different results that concludes an affected BFPP patient.[16] MRI's reveal either irregularity to the cortical surface suggestive of multiple small folds or an irregular, scalloped appearance of the gray matter-white matter junction. Neuroimaging The diagnosis of polymicrogyria is typically made by magnetic resonance imaging (MRI) since computed tomography (CT) and other imaging methods generally do not have high enough resolution or adequate contrast to identify the small folds that define the condition. The cerebral cortex often appears abnormally thick as well because the multiple small gyri are fused, infolded, and superimposed in appearance.[5] Neuropathology Gross neuropathologic examination reveals a pattern of complex convolutions to the cerebral cortex, with miniature gyri fused and superimposed together, often resulting in an irregular brain surface. The cortical ribbon can appear excessively thick as a result of the infolding and fusion of multiple small gyri.[5] Microscopic examination demonstrates that the cerebral cortex is in fact abnormally thin and has abnormal lamination; typically the cortex is unlayered or has four layers, in contrast to the normal six layers. The most superficial layers between adjacent small gyri appear fused, with the pia (layer of the meninges) bridging across multiple gyri. Prenatal diagnosis for BFPP is also available for pregnancies at risk if the GPR56 mutations have been identified in an affected family member.[5] ## Treatment[edit] Treatment plans will vary depending on the severity of the condition and its evidences in each patient. Areas that will probably need to be evaluated and assessed include speech, vision, hearing and EEG. Treatment measures may include physical therapy, occupational therapy, Speech therapy, anti-seizure drugs and orthotic devices. Surgery may be needed to assuage spastic motor problems. Various supportive measures such as joint contractures that could prevent complications. Genetic counseling may also be recommended[17] ## Prognosis[edit] Once the diagnosis of polymicrogyria has been established in an individual, the following approach can be used for discussion of prognosis: A pregnancy history should be sought, with particular regard to infections, trauma, multiple gestations, and other documented problems. Screening for the common congenital infections associated with polymicrogyria with standard TORCH testing may be appropriate. Other specific tests targeting individual neurometabolic disorders can be obtained if clinically suggested. The following may help in determining a genetic etiology: Family history It is important to ask for the presence of neurologic problems in family members, including seizures, cognitive delay, motor impairment, pseudobulbar signs, and focal weakness because many affected family members, particularly those who are older, may not have had MRI performed, even if these problems came to medical attention. In addition, although most individuals with polymicrogyria do present with neurologic difficulties in infancy, childhood, or adulthood, those with mild forms may have no obvious deficit or only minor manifestations, such as a simple lisp or isolated learning disability. Therefore, if a familial polymicrogyria syndrome is suspected, it may be reasonable to perform MRI on relatives who are asymptomatic or have what appear to be minor findings. The presence of consanguinity in a child's parents may suggest an autosomal recessive familial polymicrogyria syndrome. Physical examination A general physical examination of the proband may identify associated craniofacial, musculoskeletal, or visceral malformations that could indicate a particular syndrome. Neurologic examination should assess cognitive and mental abilities, cranial nerve function, motor function, deep tendon reflexes, sensory function, coordination, and gait (if appropriate).[5] Genetic testing ## See also[edit] * Epilepsy Phenome/Genome Project ## References[edit] 1. ^ "Bilateral Frontoparietal Polymicrogyria (BFPP)." Welcome to the Research View. N.p., n.d. Web. 05 Nov. 2012. <http://www.neuroscienceandgenetics.it/syndrome/bilateral-frontoparietal-polymicrogyria-bfpp>. 2. ^ Bahi-Buisson, N., K. Poirier, N. Boddaert, C. Fallet-Bianco, N. Specchio, E. Bertini, O. Caglayan, K. Lascelles, C. Elie, J. Rambaud, M. Baulac, I. An, P. Dias, V. Des Portes, M. L. Moutard, C. Soufflet, M. El Maleh, C. Beldjord, L. Villard, and J. Chelly. "GPR56-related Bilateral Frontoparietal Polymicrogyria: Further Evidence for an Overlap with the Cobblestone Complex." Brain 133.11 (2010): 3194-209. Print 3. ^ Piao, Xianhua, and Christopher A. Walsh. "A Novel Signaling Mechanism in Brain Development." Pediatric Research 56.3 (2004): 309-10. Print. 4. ^ Lin, Dr. Hsi-Hsien. Personal Interview. 29 October 2012. 5. ^ a b c d e f g h i Chang B, Walsh CA, Apse K, et al. Polymicrogyria Overview. 2005 Apr 18 [Updated 2007 Aug 6]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1329/ 6. ^ Parrini, Elena, Anna Rita Ferrari, Thomas Dorn, Christopher A. Walsh, and Renzo Guerrini. "Bilateral Frontoparietal Polymicrogyria, Lennox-Gastaut Syndrome, Andgene Mutations." Epilepsia 50.6 (2009): 1344-353. Print. 7. ^ Parriniy, E., Ferrariz A.R., Dorn T., Walsh C.A., Guerrini, R., Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations, Epilepsia, Volume 50 Issue 6, Pages 1344–1353, 2009. 8. ^ Piao, X., Chang, B. S., Bodell, A., Woods, K., BenZeev, B., Topcu, M., Guerrini, R., Goldberg-Stern, H., Sztriha, L., Dobyns, W. B., Barkovich, A. J. and Walsh, C. A. (2005), Genotype–phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol., 58: 680–687. doi: 10.1002/ana.20616 9. ^ Luo, R., S.-J. Jeong, Z. Jin, N. Strokes, S. Li, and X. Piao. "G Protein-coupled Receptor 56 and Collagen III, a Receptor-ligand Pair, Regulates Cortical Development and Lamination." Proceedings of the National Academy of Sciences 108.31 (2011): 12925-2930. Print. 10. ^ Chiang NY, Hsiao CC, Huang YS, Chen HY, Hsieh IJ, et al. Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. J Biol Chem. 2011;286:14215–14225 11. ^ Borgatti, Renato, Susan Marelli, Laura Bernardini, Antonio Novelli, Anna Cavallini, Alessandra Tonelli, Maria Teresa Bassi, and Bruno Dallapiccola. "Bilateral Frontoparietal Polymicrogyria (BFPP) Syndrome Secondary to a 16q12.1-q21 Chromosome Deletion Involving GPR56 Gene." Clinical Genetics 79 (2009): 573-76. Print. 12. ^ Singer K, Luo R, Jeong S, Piao X. "GPR56 and the Developing Cerebral Cortex: Cells, Matrix, and Neuronal Migration." Molecular Neurobiology 2012. doi:10.1007/s12035-012-8343-0 13. ^ "Polymicrogyria." MedLink. N.p., 1 May 2011. Web. 28 Nov. 2012. <http://www.medlink.com/medlinkcontent.asp> 14. ^ Jeong, S.-J., Luo, R., Li, S., Strokes, N. and Piao, X. (2012), Characterization of G protein-coupled receptor 56 protein expression in the mouse developing neocortex. J. Comp. Neurol., 520: 2930–2940. doi: 10.1002/cne.23076 15. ^ "Polymicrogyria." Genetics Home Reference. N.p., 12 Nov. 2012. Web. 18 Nov. 2012. <http://ghr.nlm.nih.gov/condition/polymicrogyria>. 16. ^ Koirala, S., Z. Jin, X. Piao, and G. Corfas. "GPR56-Regulated Granule Cell Adhesion Is Essential for Rostral Cerebellar Development." Journal of Neuroscience 29.23 (2009): 7439-449 17. ^ Guerrini, R., W. Dobyns, and A. Barkovich. "Abnormal Development of the Human Cerebral Cortex: Genetics, Functional Consequences and Treatment Options." Trends in Neurosciences 31.3 (2008): 154-62. Print. ## External links[edit] Classification D * OMIM: 606854 * MeSH: C564652 * DiseasesDB: 33974 External resources * Orphanet: 101070 * Bilateral Frontalparietal Polymicrogyria at NIH's Office of Rare Diseases *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Bilateral frontoparietal polymicrogyria

c1847352

wikipedia

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

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Amaurosis fugax The arteries of the choroid and iris. The greater part of the sclera has been removed. SpecialtyNeurology, ophthalmology SymptomsTemporary fleeting of vision in one or both eyes ComplicationsStroke[1][2] DurationSeconds to hours Amaurosis fugax (Greek amaurosis meaning darkening, dark, or obscure, Latin fugax meaning fleeting) is a painless temporary loss of vision in one or both eyes.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Embolic and hemodynamic origin * 2.2 Ocular origin * 2.3 Neurologic origin * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] The experience of amaurosis fugax is classically described as a temporary loss of vision in one or both eyes that appears as a "black curtain coming down vertically into the field of vision in one eye;" however, this altitudinal visual loss is relatively uncommon. In one study, only 23.8 percent of patients with transient monocular vision loss experienced the classic "curtain" or "shade" descending over their vision.[4] Other descriptions of this experience include a monocular blindness, dimming, fogging, or blurring.[5] Total or sectorial vision loss typically lasts only a few seconds, but may last minutes or even hours. Duration depends on the cause of the vision loss. Obscured vision due to papilledema may last only seconds, while a severely atherosclerotic carotid artery may be associated with a duration of one to ten minutes.[6] Certainly, additional symptoms may be present with the amaurosis fugax, and those findings will depend on the cause of the transient monocular vision loss.[citation needed] ## Cause[edit] Prior to 1990, amaurosis fugax could, "clinically, be divided into four identifiable symptom complexes, each with its underlying pathoetiology: embolic, hypoperfusion, angiospasm, and unknown".[7] In 1990, the causes of amaurosis fugax were better refined by the Amaurosis Fugax Study Group, which has defined five distinct classes of transient monocular blindness based on their supposed cause: embolic, hemodynamic, ocular, neurologic, and idiopathic (or "no cause identified").[8] Concerning the pathology underlying these causes (except idiopathic), "some of the more frequent causes include atheromatous disease of the internal carotid or ophthalmic artery, vasospasm, optic neuropathies, giant cell arteritis, angle-closure glaucoma, increased intracranial pressure, orbital compressive disease, a steal phenomenon, and blood hyperviscosity or hypercoagulability."[9] ### Embolic and hemodynamic origin[edit] With respect to embolic and hemodynamic causes, this transient monocular visual loss ultimately occurs due to a temporary reduction in retinal artery, ophthalmic artery, or ciliary artery blood flow, leading to a decrease in retinal circulation which, in turn, causes retinal hypoxia.[10] While, most commonly, emboli causing amaurosis fugax are described as coming from an atherosclerotic carotid artery, any emboli arising from vasculature preceding the retinal artery, ophthalmic artery, or ciliary arteries may cause this transient monocular blindness. * Atherosclerotic carotid artery: Amaurosis fugax may present as a type of transient ischemic attack (TIA), during which an embolus unilaterally obstructs the lumen of the retinal artery or ophthalmic artery, causing a decrease in blood flow to the ipsilateral retina. The most common source of these athero-emboli is an atherosclerotic carotid artery.[11] However, a severely atherosclerotic carotid artery may also cause amaurosis fugax due to its stenosis of blood flow, leading to ischemia when the retina is exposed to bright light.[12] "Unilateral visual loss in bright light may indicate ipsilateral carotid artery occlusive disease and may reflect the inability of borderline circulation to sustain the increased retinal metabolic activity associated with exposure to bright light."[13] * Atherosclerotic ophthalmic artery: Will present similarly to an atherosclerotic internal carotid artery. * Cardiac emboli: Thrombotic emboli arising from the heart may also cause luminal obstruction of the retinal, ophthalmic, and/or ciliary arteries, causing decreased blood flow to the ipsilateral retina; examples being those arising due to (1) atrial fibrillation, (2) valvular abnormalities including post-rheumatic valvular disease, mitral valve prolapse, and a bicuspid aortic valve, and (3) atrial myxomas. * Temporary vasospasm leading to decreased blood flow can be a cause of amaurosis fugax.[14][15] Generally, these episodes are brief, lasting no longer than five minutes,[16] and have been associated with exercise.[10][17] These vasospastic episodes are not restricted to young and healthy individuals. "Observations suggest that a systemic hemodynamic challenge provoke[s] the release of vasospastic substance in the retinal vasculature of one eye."[16] * Giant cell arteritis: Giant cell arteritis can result in granulomatous inflammation within the central retinal artery and posterior ciliary arteries of eye, resulting in partial or complete occlusion, leading to decreased blood flow manifesting as amaurosis fugax. Commonly, amaurosis fugax caused by giant cell arteritis may be associated with jaw claudication and headache. However, it is also not uncommon for these patients to have no other symptoms.[18] One comprehensive review found a two to nineteen percent incidence of amaurosis fugax among these patients.[19] * Systemic lupus erythematosus[20][21] * Periarteritis nodosa[22] * Eosinophilic vasculitis[23] * Hyperviscosity syndrome[24] * Polycythemia[25] * Hypercoagulability[26] * Protein C deficiency[27] * Antiphospholipid antibodies[28] * Anticardiolipin antibodies[29] * Lupus anticoagulant[30][31] * Thrombocytosis[29] * Subclavian steal syndrome * Malignant hypertension can cause ischemia of the optic nerve head leading to transient monocular visual loss.[32] * Drug abuse-related intravascular emboli[8] * Iatrogenic: Amaurosis fugax can present as a complication following carotid endarterectomy, carotid angiography, cardiac catheterization, and cardiac bypass.[29] ### Ocular origin[edit] Ocular causes include: * Iritis[33] * Keratitis[24] * Blepharitis[24] * Optic disc drusen[29] * Posterior vitreous detachment[24] * Closed-angle glaucoma[34] * Transient elevation of intraocular pressure[8][33] * Intraocular hemorrhage[8] * Coloboma[29] * Myopia[29] * Orbital hemangioma[35] * Orbital osteoma[36] * Keratoconjunctivitis sicca[29] testing ### Neurologic origin[edit] Neurological causes include: * Optic neuritis[8] * Compressive optic neuropathies[8][29] * Papilledema: "The underlying mechanism for visual obscurations in all of these patients appear to be transient ischemia of the optic nerve head consequent to increased tissue pressure. Axonal swelling, intraneural masses, and increased influx of interstitial fluid may all contribute to increases in tissue pressure in the optic nerve head. The consequent reduction in perfusion pressure renders the small, low-pressure vessels that supply the optic nerve head vulnerable to compromise. Brief fluctuations in intracranial or systemic blood pressure may then result in transient loss of function in the eyes."[37] Generally, this transient visual loss is also associated with a headache and optic disk swelling. * Multiple sclerosis can cause amaurosis fugax due to a unilateral conduction block, which is a result of demyelination and inflammation of the optic nerve, and "...possibly by defects in synaptic transmission and putative circulating blocking factors."[38] * Migraine[39][40][41][42][43][44][45][46] (auras often involve temporary scotomas, and a spectrum up to transient full vision loss exists) * Idiopathic Intracranial Hypertension[47] * Intracranial tumor[47] * Psychogenic[24] ## Diagnosis[edit] Despite the temporary nature of the vision loss, those experiencing amaurosis fugax are usually advised to consult a physician immediately as it is a symptom that may herald serious vascular events, including stroke.[1][2] Restated, “because of the brief interval between the transient event and a stroke or blindness from temporal arteritis, the workup for transient monocular blindness should be undertaken without delay.” If the patient has no history of giant cell arteritis, the probability of vision preservation is high; however, the chance of a stroke reaches that for a hemispheric TIA. Therefore, investigation of cardiac disease is justified.[8] A diagnostic evaluation should begin with the patient's history, followed by a physical exam, with particular importance being paid to the ophthalmic examination with regards to signs of ocular ischemia. When investigating amaurosis fugax, an ophthalmologic consult is absolutely warranted if available. Several concomitant laboratory tests should also be ordered to investigate some of the more common, systemic causes listed above, including a complete blood count, erythrocyte sedimentation rate, lipid panel, and blood glucose level. If a particular cause is suspected based on the history and physical, additional relevant labs should be ordered.[8] If laboratory tests are abnormal, a systemic disease process is likely, and, if the ophthalmologic examination is abnormal, ocular disease is likely. However, in the event that both of these routes of investigation yield normal findings or an inadequate explanation, noninvasive duplex ultrasound studies are recommended to identify carotid artery disease. Most episodes of amaurosis fugax are the result of stenosis of the ipsilateral carotid artery.[48] With that being the case, researchers investigated how best to evaluate these episodes of vision loss, and concluded that for patients ranging from 36–74 years old, "...carotid artery duplex scanning should be performed...as this investigation is more likely to provide useful information than an extensive cardiac screening (ECG, Holter 24-hour monitoring, and precordial echocardiography)."[48] Additionally, concomitant head CT or MRI imaging is also recommended to investigate the presence of a “clinically silent cerebral embolism.”[8] If the results of the ultrasound and intracranial imaging are normal, “renewed diagnostic efforts may be made,” during which fluorescein angiography is an appropriate consideration. However, carotid angiography is not advisable in the presence of a normal ultrasound and CT.[49] ## Treatment[edit] If the diagnostic workup reveals a systemic disease process, directed therapies to treat that underlying cause should be initiated. If the amaurosis fugax is caused by an atherosclerotic lesion, aspirin is indicated, and a carotid endarterectomy considered based on the location and grade of the stenosis. Generally, if the carotid artery is still patent, the greater the stenosis, the greater the indication for endarterectomy. "Amaurosis fugax appears to be a particularly favorable indication for carotid endarterectomy. Left untreated, this event carries a high risk of stroke; after carotid endarterectomy, which has a low operative risk, there is a very low postoperative stroke rate."[50] However, the rate of subsequent stroke after amaurosis is significantly less than after a hemispheric TIA, therefore there remains debate as to the precise indications for which a carotid endarterectomy should be performed. If the full diagnostic workup is completely normal, patient observation is recommended.[8] ## See also[edit] * Ocular ischemic syndrome * Amaurosis * Hemianopsia ## References[edit] 1. ^ a b Benavente O, Eliasziw M, Streifler JY, Fox AJ, Barnett HJ, Meldrum H (October 2001). "Prognosis after transient monocular blindness associated with carotid-artery stenosis". N. Engl. J. Med. 345 (15): 1084–90. doi:10.1056/NEJMoa002994. PMID 11596587. 2. ^ a b Rothwell PM, Warlow CP (March 2005). "Timing of TIAs preceding stroke: time window for prevention is very short". Neurology. 64 (5): 817–20. doi:10.1212/01.WNL.0000152985.32732.EE. PMID 15753415. S2CID 19550244. 3. ^ Fisher CM (December 1989). "'Transient monocular blindness' versus 'amaurosis fugax'". Neurology. 39 (12): 1622–4. doi:10.1212/wnl.39.12.1622. PMID 2685658. S2CID 13315378. 4. ^ North American Symptomatic Carotid Endarterectomy Trial Collaborators; Barnett HJM; Taylor, D. W.; Haynes, R. B.; Sackett, D. L.; Peerless, S. J.; Ferguson, G. G.; Fox, A. J.; Rankin, R. N.; Hachinski, V. C.; Wiebers, D. O.; Eliasziw, M. (August 1991). "Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators". N. Engl. J. Med. 325 (7): 445–53. doi:10.1056/NEJM199108153250701. PMID 1852179. 5. ^ Lord RS (August 1990). "Transient monocular blindness". Aust N Z J Ophthalmol. 18 (3): 299–305. doi:10.1111/j.1442-9071.1990.tb00624.x. PMID 2261177. 6. ^ Donders RC; Dutch Tmb Study Group (August 2001). "Clinical features of transient monocular blindness and the likelihood of atherosclerotic lesions of the internal carotid artery". J. Neurol. Neurosurg. Psychiatry. 71 (2): 247–9. doi:10.1136/jnnp.71.2.247. PMC 1737502. PMID 11459904. 7. ^ Burde RM (September 1989). "Amaurosis fugax. An overview". J Clin Neuroophthalmol. 9 (3): 185–9. PMID 2529279. 8. ^ a b c d e f g h i j "Current management of amaurosis fugax. The Amaurosis Fugax Study Group". Stroke. 21 (2): 201–8. February 1990. doi:10.1161/01.STR.21.2.201. PMID 2406992.[permanent dead link] 9. ^ Newman NJ. (1998). "Cerebrovascular disease". In Hoyt, William Graves; Miller, Neil; Newman, Nancy J.; Walsh, Frank (eds.). Walsh and Hoyt's Clinical Neuro-Ophthalmology. 3 (5th ed.). Baltimore: Williams & Wilkins. pp. 3420–6. ISBN 0-683-30232-9. 10. ^ a b Jehn A, Frank Dettwiler B, Fleischhauer J, Sturzenegger M, Mojon DS (February 2002). "Exercise-induced vasospastic amaurosis fugax". Arch. Ophthalmol. 120 (2): 220–2. doi:10.1001/archopht.120.2.220 (inactive 2021-01-17). PMID 11831932. Archived from the original on 2007-09-29. Retrieved 2007-03-26.CS1 maint: DOI inactive as of January 2021 (link) 11. ^ Braat A, Hoogland PH, DeVries AC, de Mol VanOtterloo JC (2001). "Amaurosis Fugax and Stenosis of the Ophthalmic Artery". Vasc Endovascular Surg. 35 (2): 141–2. doi:10.1177/153857440103500210. PMID 11668383. S2CID 38943888. 12. ^ Kaiboriboon K, Piriyawat P, Selhorst JB (May 2001). "Light-induced amaurosis fugax". Am. J. Ophthalmol. 131 (5): 674–6. doi:10.1016/S0002-9394(00)00874-6. PMID 11336956. 13. ^ Furlan AJ, Whisnant JP, Kearns TP (November 1979). "Unilateral visual loss in bright light. An unusual symptom of carotid artery occlusive disease". Arch. Neurol. 36 (11): 675–6. doi:10.1001/archneur.1979.00500470045007. PMID 508123. 14. ^ Fisher M (1952). "Transient monocular blindness associated with hemiplegia". Arch. Ophthalmol. 47 (2): 167–203. doi:10.1001/archopht.1952.01700030174005. PMID 14894017. 15. ^ Ellenberger C, Epstein AD (June 1986). "Ocular complications of atherosclerosis: what do they mean?". Semin Neurol. 6 (2): 185–93. doi:10.1055/s-2008-1041462. PMID 3332423. 16. ^ a b Burger SK, Saul RF, Selhorst JB, Thurston SE (September 1991). "Transient monocular blindness caused by vasospasm". N. Engl. J. Med. 325 (12): 870–3. doi:10.1056/NEJM199109193251207. PMID 1875972. 17. ^ Imes RK, Hoyt WF (1989). "Exercise-induced transient visual events in young healthy adults". J Clin Neuroophthalmol. 9 (3): 178–80. PMID 2529277. 18. ^ Hayreh SS, Podhajsky PA, Zimmerman B (April 1998). "Occult giant cell arteritis: ocular manifestations". Am. J. Ophthalmol. 125 (4): 521–6. doi:10.1016/S0002-9394(99)80193-7. PMID 9559738. 19. ^ Goodman BW (November 1979). "Temporal arteritis". Am. J. Med. 67 (5): 839–52. doi:10.1016/0002-9343(79)90744-7. PMID 389046. 20. ^ Giorgi D, David V, Afeltra A, Gabrieli CB (March 2001). "Transient visual symptoms in systemic lupus erythematosus and antiphospholipid syndrome". Ocul. Immunol. Inflamm. 9 (1): 49–57. doi:10.1076/ocii.9.1.49.3980. PMID 11262668. S2CID 35161683. 21. ^ Gold D, Feiner L, Henkind P (September 1977). "Retinal arterial occlusive disease in systemic lupus erythematosus". Arch. Ophthalmol. 95 (9): 1580–5. doi:10.1001/archopht.1977.04450090102008. PMID 901267. 22. ^ Newman NM, Hoyt WF, Spencer WH (May 1974). "Macula-sparing monocular blackouts. Clinical and pathologic investigations of intermittent choroidal vascular insufficiency in a case of periarteritis nodosa". Arch. Ophthalmol. 91 (5): 367–70. doi:10.1001/archopht.1974.03900060379006. PMID 4150748.[permanent dead link] 23. ^ Schwartz ND, So YT, Hollander H, Allen S, Fye KH (1986). "Eosinophilic vasculitis leading to amaurosis fugax in a patient with acquired immunodeficiency syndrome". Arch. Intern. Med. 146 (10): 2059–60. doi:10.1001/archinte.146.10.2059. PMID 3767551. 24. ^ a b c d e Bacigalupi M (April 2006). "Amaurosis Fugax-A Clinical Review" (PDF). The Internet Journal of Allied Health Sciences and Practice. 4 (2): 1–6. 25. ^ Berdel WE, Theiss W, Fink U, Rastetter J (March 1984). "Peripheral arterial occlusion and amaurosis fugax as the first manifestation of polycythemia vera. A case report". Blut. 48 (3): 177–80. doi:10.1007/BF00320341. PMID 6697006. S2CID 13588599. 26. ^ Mundall J, Quintero P, Von Kaulla KN, Harmon R, Austin J (March 1972). "Transient monocular blindness and increased platelet aggregability treated with aspirin. A case report". Neurology. 22 (3): 280–5. doi:10.1212/wnl.22.3.280. PMID 5062262. S2CID 552116. 27. ^ Smith DB, Ens GE (March 1987). "Protein C deficiency: a cause of amaurosis fugax?". J. Neurol. Neurosurg. Psychiatry. 50 (3): 361–2. doi:10.1136/jnnp.50.3.361. PMC 1031809. PMID 3559620. 28. ^ Digre KB, Durcan FJ, Branch DW, Jacobson DM, Varner MW, Baringer JR (March 1989). "Amaurosis fugax associated with antiphospholipid antibodies". Annals of Neurology. 25 (3): 228–32. doi:10.1002/ana.410250304. PMID 2729913. S2CID 28110036. 29. ^ a b c d e f g h Corbett, James W.; Digre, Kathleen B. (2003). "Amaurosis Fugax and Not So Fugax—Vascular Disorders of the Eye" (PDF). Practical viewing of the optic disc. Oxford: Butterworth-Heinemann. pp. 269–344. ISBN 0-7506-7289-7. 30. ^ Landi G, Calloni MV, Grazia Sabbadini M, Mannuccio Mannucci P, Candelise L (1983). "Recurrent ischemic attacks in two young adults with lupus anticoagulant". Stroke. 14 (3): 377–9. doi:10.1161/01.STR.14.3.377. PMID 6419415.[permanent dead link] 31. ^ Elias M, Eldor A (March 1984). "Thromboembolism in patients with the 'lupus'-type circulating anticoagulant". Arch. Intern. Med. 144 (3): 510–5. doi:10.1001/archinte.144.3.510. PMID 6367679.[permanent dead link] 32. ^ Hayreh SS, Servais GE, Virdi PS (January 1986). "Fundus lesions in malignant hypertension. V. Hypertensive optic neuropathy". Ophthalmology. 93 (1): 74–87. doi:10.1016/s0161-6420(86)33773-4. PMID 3951818. 33. ^ a b Sørensen PN (August 1983). "Amaurosis fugax. A unselected material". Acta Ophthalmol (Copenh). 61 (4): 583–8. doi:10.1111/j.1755-3768.1983.tb04348.x. PMID 6637419. S2CID 221395995. 34. ^ Ravits J, Seybold ME (September 1984). "Transient monocular visual loss from narrow-angle glaucoma". Arch. Neurol. 41 (9): 991–3. doi:10.1001/archneur.1984.04050200097026. PMID 6477235.[permanent dead link] 35. ^ Brown GC, Shields JA (October 1981). "Amaurosis fugax secondary to presumed cavernous hemangioma of the orbit". Ann Ophthalmol. 13 (10): 1205–9. PMID 7316347. 36. ^ Wilkes SR, Trautmann JC, DeSanto LW, Campbell RJ (April 1979). "Osteoma: an unusual cause of amaurosis fugax". Mayo Clin. Proc. 54 (4): 258–60. PMID 423606. 37. ^ Sadun AA, Currie JN, Lessell S (October 1984). "Transient visual obscurations with elevated optic discs". Annals of Neurology. 16 (4): 489–94. doi:10.1002/ana.410160410. PMID 6497356. S2CID 2245543. 38. ^ Smith KJ, McDonald WI (October 1999). "The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease". Philosophical Transactions of the Royal Society B. 354 (1390): 1649–73. doi:10.1098/rstb.1999.0510. PMC 1692682. PMID 10603618. 39. ^ Mattsson, Lundberg; Lundberg, PO (June 1999). "Characteristics and prevalence of transient visual disturbances indicative of migraine visual aura". Cephalalgia. 19 (5): 479–84. doi:10.1046/j.1468-2982.1999.019005479.x. PMID 10403062. S2CID 5961275. 40. ^ Cologno D, Torelli P, Manzoni GC (October 2002). "Transient visual disturbances during migraine without aura attacks". Headache. 42 (9): 930–3. doi:10.1046/j.1526-4610.2002.02216.x. PMID 12390623. S2CID 32304894. 41. ^ Connor RC (November 1962). "Complicated migraine. A study of permanent neurological and visual defects caused by migraine". Lancet. 2 (7265): 1072–5. doi:10.1016/s0140-6736(62)90782-1. PMID 14022628. 42. ^ Carroll D (April 1970). "Retinal migraine". Headache. 10 (1): 9–13. doi:10.1111/j.1526-4610.1970.hed1001009.x. PMID 5444866. S2CID 46246035. 43. ^ McDonald WI, Sanders MD (September 1971). "Migraine complicated by ischaemic papillopathy". Lancet. 2 (7723): 521–3. doi:10.1016/s0140-6736(71)90440-5. PMID 4105666. 44. ^ Wolter JR, Burchfield WJ (1971). "Ocular migraine in a young man resulting in unilateral transient blindness and retinal edema". Pediatr Ophthalmol. 8: 173–6. 45. ^ Kline LB, Kelly CL (September 1980). "Ocular migraine in a patient with cluster headaches". Headache. 20 (5): 253–7. doi:10.1111/j.1526-4610.1980.hed2005253.x. PMID 7451120. S2CID 29684052. 46. ^ Corbett JJ. (1983). "Neuro-ophthalmologic complications of migraine and cluster headaches". Neurol. Clin. 1 (4): 973–95. doi:10.1016/S0733-8619(18)31134-4. PMID 6390159. 47. ^ a b Hedges TR (1984). "The terminology of transient visual loss due to vascular insufficiency". Stroke. 15 (5): 907–8. doi:10.1161/01.STR.15.5.907. PMID 6474546. S2CID 8664120.[permanent dead link] 48. ^ a b Smit RL, Baarsma GS, Koudstaal PJ (1994). "The source of embolism in amaurosis fugax and retinal artery occlusion" (PDF). Int Ophthalmol. 18 (2): 83–6. doi:10.1007/BF00919244. PMID 7814205. S2CID 394747. 49. ^ Walsh J, Markowitz I, Kerstein MD (August 1986). "Carotid endarterectomy for amaurosis fugax without angiography". Am. J. Surg. 152 (2): 172–4. doi:10.1016/0002-9610(86)90236-9. PMID 3526933. 50. ^ Bernstein EF, Dilley RB (October 1987). "Late results after carotid endarterectomy for amaurosis fugax". J. Vasc. Surg. 6 (4): 333–40. doi:10.1067/mva.1987.avs0060333. PMID 3656582. ## External links[edit] Classification D * ICD-10: G45.3 * ICD-9-CM: 362.34 * MeSH: D020757 * DiseasesDB: 501 External resources * MedlinePlus: 000784 * eMedicine: neuro/480 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis * v * t * e Cerebrovascular diseases including stroke Ischaemic stroke Brain * Anterior cerebral artery syndrome * Middle cerebral artery syndrome * Posterior cerebral artery syndrome * Amaurosis fugax * Moyamoya disease * Dejerine–Roussy syndrome * Watershed stroke * Lacunar stroke Brain stem * Brainstem stroke syndrome * Medulla * Medial medullary syndrome * Lateral medullary syndrome * Pons * Medial pontine syndrome / Foville's * Lateral pontine syndrome / Millard-Gubler * Midbrain * Weber's syndrome * Benedikt syndrome * Claude's syndrome Cerebellum * Cerebellar stroke syndrome Extracranial arteries * Carotid artery stenosis * precerebral * Anterior spinal artery syndrome * Vertebrobasilar insufficiency * Subclavian steal syndrome Classification * Brain ischemia * Cerebral infarction * Classification * Transient ischemic attack * Total anterior circulation infarct * Partial anterior circulation infarct Other * CADASIL * Binswanger's disease * Transient global amnesia Haemorrhagic stroke Extra-axial * Epidural * Subdural * Subarachnoid Cerebral/Intra-axial * Intraventricular Brainstem * Duret haemorrhages General * Intracranial hemorrhage Aneurysm * Intracranial aneurysm * Charcot–Bouchard aneurysm Other * Cerebral vasculitis * Cerebral venous sinus thrombosis *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Amaurosis fugax

c0149793

wikipedia

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

{"gard": ["9660"], "mesh": ["D020757"], "umls": ["C0149793"], "icd-9": ["362.34"], "icd-10": ["G45.3"], "wikidata": ["Q2146228"]}

Drug-induced purpura SpecialtyDermatology Drug-induced purpura is a skin condition that may be related to platelet destruction, vessel fragility, interference with platelet function, or vasculitis.[1]:824 ## See also[edit] * Food-induced purpura * Rumpel-Leede sign * Skin lesion ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: Clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 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

Drug-induced purpura

c1264038

wikipedia

https://en.wikipedia.org/wiki/Drug-induced_purpura

{"umls": ["C1264038"], "wikidata": ["Q5308822"]}

The prevalence of HIV/AIDS in Cambodia is among the highest in Asia. Although Cambodia is one of the poorest countries in the world, extensive HIV prevention and control efforts by the Royal Government of Cambodia and its partners have helped to reduce the spread of HIV. Between 2003 and 2005, the estimated HIV prevalence among Cambodian adults aged 15 to 49 declined from 2.0 percent to 1.6 percent.[1] ## Contents * 1 Dynamics * 2 History * 3 See also * 4 References ## Dynamics[edit] Cambodia’s HIV/AIDS epidemic is spread primarily through heterosexual transmission and revolves largely around the sex trade. HIV transmission occurs mainly in sexual partnerships where one partner has engaged in high-risk behaviors. Women constitute a growing share of people living with HIV/AIDS, comprising an estimated 47 percent of people living with HIV/AIDS in 2003, compared with 37 percent in 1998.[1] This increased proportion of infections among women may reflect declining prevalence rates among males, as well as deaths among males infected in the early years of Cambodia’s epidemic. Significantly, a low prevalence rate in the general population masks far higher prevalence rates in certain sub-populations, such as injecting drug users, people in prostitution, men who have sex with men, karaoke hostesses and beer girls, and mobile and migrant populations.[1] By 2014, HIV prevalence was reduced to 0.4 percent through a successful prevention program. However, in 2015 a massive outbreak of HIV stemming mostly from Roka occurred. The cause is thought to be the reuse of syringes by an unlicensed doctor operating in the region who has since been jailed.[2] ## History[edit] After the first case of HIV was detected in Cambodia in 1991, the prevalence of infection increased steadily to a high of 2 percent in 1998. In the general population, the prevalence declined to 0.5 percent in 2009, down from 1.2 percent in 2001. The prevalence of HIV infection among women visiting antenatal care (ANC) clinics also declined, from a high of 2.1 percent in 1999 to 1.1 percent in 2006.[1] Among HIV-infected pregnant women, there was also a gradual increase in the percentage who received antiretroviral therapy (ART) to reduce the risk of mother-to-child transmission, from 1.2 percent in 2003 to 11.2 percent in 2007 to 32.3 percent in 2009.[1] ## See also[edit] * National Centre for HIV/AIDS Dermatology and STDs, Cambodia * Health in Cambodia * HACC Cambodia ## References[edit] 1. ^ a b c d e "2008 Country Profile: Cambodia" Archived 2008-09-13 at the Wayback Machine. U.S. Department of State (2008). Accessed September 7, 2008. This article incorporates text from this source, which is in the public domain. 2. ^ https://news.vice.com/article/were-testing-about-20-people-a-day-inside-the-cambodian-village-devastated-by-an-hiv-outbreak * v * t * e HIV/AIDS in Asia Sovereign states * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor (Timor-Leste) * Egypt * Georgia * India * Indonesia * Iran * Iraq * Israel * Japan * Jordan * Kazakhstan * North Korea * South Korea * Kuwait * Kyrgyzstan * Laos * Lebanon * Malaysia * Maldives * Mongolia * Myanmar * Nepal * Oman * Pakistan * Philippines * Qatar * Russia * Saudi Arabia * Singapore * Sri Lanka * Syria * Tajikistan * Thailand * Turkey * Turkmenistan * United Arab Emirates * Uzbekistan * Vietnam * Yemen States with limited recognition * Abkhazia * Artsakh * Northern Cyprus * Palestine * South Ossetia * Taiwan Dependencies and other territories * British Indian Ocean Territory * Christmas Island * Cocos (Keeling) Islands * Hong Kong * Macau * Book * Category * Asia portal * v * t * e HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance Database * Innate resistance to HIV * Serostatus * HIV-positive people * Nutrition * Pregnancy History * History * Epidemiology * Multiple sex partners * Timeline * AIDS Museum * Timothy Ray Brown * Women and HIV/AIDS Social * AIDS orphan * Catholic Church and HIV/AIDS * Circumcision and HIV * Criminal transmission * Discrimination against people * Economic impact * Cost of treatment * HIV-affected community * HIV/AIDS activism * HIV/AIDS denialism * Red ribbon * Safe sex * Sex education * List of HIV-positive people * People With AIDS Self-Empowerment Movement * HIV/AIDS in the porn industry Culture * Discredited HIV/AIDS origins theories * International AIDS Conference * International AIDS Society * Joint United Nations Programme on HIV/AIDS (UNAIDS) * Media portrayal of HIV/AIDS * Misconceptions about HIV/AIDS * President's Emergency Plan for AIDS Relief (PEPFAR) * The SING Campaign * Solidays * Treatment Action Campaign * World AIDS Day * YAA/Youthforce * "Free Me" * Larry Kramer * Gay Men's Health Crisis * ACT UP * Silence=Death Project HIV/AIDS pandemic by region / country Africa * Angola * Benin * Botswana * Democratic Republic of the Congo * Egypt * Eswatini * Ethiopia * Ghana * Guinea * Côte d'Ivoire (Ivory Coast) * Kenya * Lesotho * Madagascar * Malawi * Mali * Mozambique * Namibia * Niger * Nigeria * Rwanda * Senegal * Tanzania * South Africa * Uganda * Zambia * Zimbabwe North America * Canada * Mexico * El Salvador * Guatemala * Honduras * Nicaragua United States * New York City Caribbean * Haiti * Jamaica * Dominican Republic South America * Bolivia * Brazil * Colombia * Guyana * Peru Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Cambodia * China (PRC) (Yunnan) * East Timor * India * Indonesia * Iran * Iraq * Japan * Jordan * North Korea * Laos * Malaysia * Myanmar (Burma) * Nepal * Pakistan * Philippines * Saudi Arabia * Sri Lanka * Taiwan (ROC) * Thailand * United Arab Emirates * Turkey * Vietnam Europe * United Kingdom * Russia * Ukraine Oceania * Australia * New Zealand * Papua New Guinea * List of countries by HIV/AIDS adult prevalence rate * List of HIV/AIDS cases and deaths registered by region HIV/AIDS - adult prevalence rate: 2.6% (2003 est.) HIV/AIDS - people living with HIV/AIDS: 170,000 (2003 est.) HIV/AIDS - deaths: 15,000 (2003 est.) Major infectious diseases: degree of risk: very high food or waterborne diseases: bacterial and protozoal diarrhea, hepatitis A, and typhoid fever vectorborne diseases: dengue fever, Japanese encephalitis, and malaria note: highly pathogenic H5N1 avian influenza has been identified in this country; it poses a negligible risk with extremely rare cases possible among US citizens who have close contact with birds (2008) *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

HIV/AIDS in Cambodia

None

wikipedia

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

{"wikidata": ["Q5629824"]}

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-55 (EIEE55) is caused by compound heterozygous or homozygous mutation in the PIGP gene (605938) on chromosome 21q22. For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). Clinical Features Johnstone et al. (2017) reported 2 sibs, born of unrelated parents of European ancestry, with early infantile epileptic encephalopathy. The patients presented in the first weeks of life with refractory seizures. EEG showed various abnormalities, including focal-spreading sharp waves, multifocal epileptiform discharges, slow background activity, and modified hypsarrhythmia. The older patient showed progressive growth impairment and small head circumference (less than 2nd percentile). Brain imaging showed thin corpus callosum and abnormal T2-weighted signals in the periventricular and subcortical white matter. At age 10 years, he had profound intellectual disability with little purposeful movements, no head control, no speech, central hypotonia, peripheral hypertonia, and feeding difficulties necessitating a G-tube. His younger sister had a similar disorder with refractory seizures, no eye contact or tracking, and hypotonia with fisted hands, clonus, and hyperreflexia. She died at age 26 months. Both patients had cortical visual impairment. Krenn et al. (2019) reported a girl, born of unrelated Polish parents, with EIEE55. The neonatal period was complicated by lethargy and poor feeding. Her first seizure occurred at 7 months of age and was associated with status epilepticus and EEG sharp waves. She continued to have refractory seizures and showed global developmental delay and hypotonia. At age 2 years, she was unable to speak and had not achieved sitting or crawling. Brain imaging showed transient diffusion-weighted abnormalities and hippocampal asymmetry. Inheritance The transmission pattern of EIEE55 in the family reported by Johnstone et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 sibs with early infantile epileptic encephalopathy-55, Johnstone et al. (2017) identified compound heterozygous mutations in the PIGP gene isoform 1 (M25T, 605938.0001 and c.456delA, 605938.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased PIGP mRNA and presumably decreased protein levels, as well as decreased cell surface expression of GPI-anchored proteins; this defect could be rescued by overexpression of PIGP isoform 2. The findings implicated a role for PIGP and GPI-anchored proteins in neurodevelopment. In a Polish girl with EIEE55, Krenn et al. (2019) identified a homozygous frameshift mutation in the PIGP gene (c.456delA; 605938.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Flow cytometric analysis of patient lymphocytes showed decreased expression of GPI-anchored proteins, suggesting a loss-of-function effect. The findings confirmed PIGP as a monogenic disease causing developmental and epileptic encephalopathy. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor growth HEAD & NECK Head \- Small head circumference Eyes \- Cortical visual impairment \- No eye contact ABDOMEN Gastrointestinal \- Feeding difficulties \- Tube feeding SKELETAL \- Contractures \- Hyperlaxity MUSCLE, SOFT TISSUES \- Axial hypotonia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Seizures, refractory \- Delayed psychomotor development \- Intellectual disability, profound \- Absent speech \- Poor head control \- Inability to walk \- Multifocal epileptiform discharges seen on EEG \- Background slowing \- Hypsarrhythmia \- Limb hypertonia \- Hyperreflexia \- Clonus \- Thin corpus callosum \- Subcortical white matter abnormalities LABORATORY ABNORMALITIES \- Patient lymphocytes show decreased expression of GPI-anchored proteins MISCELLANEOUS \- Onset in infancy \- Three patients from 2 unrelated families have been reported (last curated June 2019) MOLECULAR BASIS \- Caused by mutation in the phosphatidylinositol glycan anchor biosynthesis class P protein (PIGP, 605938.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 55

c0393706

omim

https://www.omim.org/entry/617599

{"doid": ["0080283"], "omim": ["617599"], "orphanet": ["1934"], "synonyms": ["Alternative titles", "GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 14"]}

## Summary ### Clinical characteristics. Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and hepatomegaly with elevated liver enzymes and splenomegaly. Anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are common. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described. ### Diagnosis/testing. The diagnosis of prolidase deficiency is established by detection of either biallelic PEPD pathogenic variants or reduced prolidase enzyme activity in a proband who has characteristic clinical findings and imidodipeptiduria. ### Management. Treatment of manifestations: No curative treatment is available. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal. Developmental and educational interventions as needed to address motor and cognitive delays. Prevention of secondary complications: Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection. Antibiotic prophylaxis should also be considered in the appropriate setting. Surveillance: In the absence of formal surveillance guidelines, the authors recommend annual: skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcers, complete blood count, liver function tests, and abdominal ultrasound examination to assess the size of the liver and spleen. Follow up as recommended by a pulmonologist and immunologist. Follow-up assessments of motor and cognitive development as recommended for educational planning. Agents/circumstances to avoid: In those with splenomegaly: avoid contact sports given the increased risk for splenic rupture. ### Genetic counseling. Prolidase deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PEPD pathogenic variants in the family have been identified. ## Diagnosis No formal diagnostic criteria or testing algorithms for prolidase deficiency have been published. ### Suggestive Findings Prolidase deficiency should be suspected in individuals with the following clinical, laboratory, and biochemical findings. Clinical * Skin lesions, typically lower extremity ulcers. Other lesions such as telangiectasias of the face and hands are also common [Royce & Steinmann 2002, Dunn et al 2011]. * Recurrent infections, particularly of the skin and respiratory tract [Cleary et al 1994] * Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype [Luder et al 2007] * Dysmorphic facial features, including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline [Goodman et al 1968, Falik-Zaccai et al 2010, Dunn et al 2011] * Developmental delay of variable degree [Hechtman 2001, Lupi et al 2008, Falik-Zaccai et al 2010, Besio et al 2015] * Splenomegaly [Nasser et al 2015] * Systemic lupus erythematosus-like phenotype [Falik-Zaccai et al 2010, Klar et al 2010, Butbul Aviel et al 2012] Laboratory. Frequent, although not universal, laboratory findings include the following: * Anemia, usually mild (hemoglobin >10 g/dL), but occasionally below that value [Powell et al 1974, Moulonguet et al 1989, Cleary et al 1994] * Thrombocytopenia, usually mild (>100,000 platelets per μL), although rarely it can be lower [Ogata et al 1981] * Elevated liver enzymes, with elevation of aspartate aminotransferase in the 100s [Sekiya et al 1985] * Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM. Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG ~1600 mg/dL, IgA 350 mg/dL, and IgM 280 mg/dL. * IgG levels >2,000 mg/dL have been reported numerous times [Ogata et al 1981, Gray et al 1983, Freij et al 1984, Cantatore et al 1993, Shrinath et al 1997, Lopes et al 2002, Kelly et al 2010] and as high as 3,680 mg/dL [Klar et al 2010]. * IgA levels >500 mg/dL have been reported on several occasions [Gray et al 1983, Freij et al 1984, Lopes et al 2002, Butbul Aviel et al 2012] and as high as 850 mg/dL [Ogata et al 1981]. * IgM concentrations as high as 568 mg/dL have been described [Shrinath et al 1997]. * Hypocomplementemia. Levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) have been published [Klar et al 2010], with C4 as low as 9 mg/dL (normal: 20-40 mg/dL) [Cleary et al 1994, Shrinath et al 1997]. Biochemical. Prolidase deficiency is characterized by massive imidodipeptiduria* (10-30 mmol/day) on urine amino acid analysis [Hechtman 2001]. * In individuals with prolidase deficiency imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease. (This finding has been used as the basis for urinary newborn screening in Quebec [Lemieux et al 1984].) * Under normal circumstances the urinary excretion of glycylproline is negligible [Royce & Steinmann 2002]; thus, the absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency [Freij & Der Kaloustian 1986]. Click here (pdf) for information on laboratory methods used to detect imidodipeptiduria. Other biochemical findings: * The concentration of imidodipeptides is much lower in serum than urine [Royce & Steinmann 2002]. * Gly-Pro has been reported in the plasma by some investigators [Freij et al 1984], but not others [Hechtman 2001]. * CSF amino acid analysis was normal in the first report of probable prolidase deficiency [Goodman et al 1968]. *Note: A number of published reports mistakenly refer to imidodipeptiduria as "iminodipeptiduria." Iminodipeptides are dipeptides in which proline or hydroxyproline is the N-terminal amino acid (i.e., Pro/Hyp-X, for example prolylglycine), whereas imidodipeptides are dipeptides in which proline or hydroxyproline is the C-terminal amino acid (i.e., X-Pro/Hyp, for example glycylproline). ### Establishing the Diagnosis The diagnosis of prolidase deficiency is established in a proband (who has the characteristic clinical findings and imidodipeptiduria) by detection of either biallelic PEPD pathogenic variants (see Table 2) or reduced prolidase enzyme activity. Molecular genetic testing approaches include single gene testing and targeted analysis for pathogenic variants. * Single-gene testing. For most individuals, sequence analysis of PEPD is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. * Targeted analysis for pathogenic variants. For Amish from Geauga County, Ohio and Druze and Arab Muslims from northern Israel, testing for the founder variants p.Arg265Ter and p.Ser202Phe, respectively, may be performed first followed by sequence analysis and gene-targeted deletion/duplication analysis if one or no pathogenic variant is identified. ### Table 2. Summary of Molecular Genetic Testing Used in Prolidase Deficiency View in own window Gene 1Test MethodPathogenic Variants DetectedProportion of Probands with Pathogenic Variants 2 Detectable by This Method PEPDSequence analysis 3Sequence variants28/30 4 Gene-targeted deletion/duplication analysis 5Exon or whole-gene deletions2/30 4 Targeted analysis for pathogenic variantsp.Arg265Ter4/4 6 p.Ser202Phe17/20 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\. Lupi et al [2008] 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 gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Amish from Geauga County, Ohio [Wang et al 2006] 7\. Druze and Arab Muslims from northern Israel [Falik-Zaccai et al 2010] Measurement of prolidase enzyme activity. In affected individuals, prolidase enzyme activity in erythrocytes, leukocytes, or cultured fibroblasts ranges from none to <10% [Lupi et al 2008]. Click here (pdf) for a short review of laboratory techniques used in the diagnosis of prolidase deficiency; see also Kurien et al [2006] and Viglio et al [2006]. ## Clinical Characteristics ### Clinical Description Skin. The hallmark of prolidase deficiency is severe, chronic, recalcitrant, and painful skin ulcers. The ulcers are located mainly on the lower extremities, particularly the feet. However, individuals are reported with upper extremity involvement, including one with recurrent upper extremity ulceration beginning at age nine years [Sheffield et al 1977], one with active ulcers on the hands [Cantatore et al 1993], and one with a healed scar from prior ulcers in the dorsum of the hand [El-Darouti 2013]. One had scarring from healed ulcers over most of her body; however, at the time of publication active ulcers were mainly on the legs [Wysocki et al 1988]. Skin ulcers can begin as early as age six months [Mandel et al 2000] or as late as age 30 years [Dyne et al 2001]. Ulceration is recurrent, and individual ulcers can take months to heal. Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor in at least two individuals [Gray et al 1983, Royce & Steinmann 2002]. See Figure 1. #### Figure 1. Typical skin ulcerations in individuals with prolidase deficiency. A variety of skin findings can precede the appearance of ulcers by many years [Hechtman 2001]. In the first 20 patients reported [Freij et al 1984], eight had telangiectasias of the face, shoulders, and hands; five had scaly, erythematous, maculopapular lesions; and two had purpuric lesions in the absence of hematologic abnormalities. In addition, five had premature graying of the hair. Occasional findings: * Lymphedema [Sheffield et al 1977, Dunn et al 2011] * Hyperkeratosis of the elbows and knees [Ogata et al 1981] * Hirsutism [Ogata et al 1981] * Perioral pitted scars [Dunn et al 2011] or radial scars [Tiller 1977] As prolidase deficiency is associated with chronic recalcitrant lower extremity ulcers, an increased risk of squamous cell carcinoma of the skin could be expected, and indeed has been reported in one individual [Fimiani et al 1999]. Dysmorphic facial features. Although not a universal finding, facial features typically described include prominent forehead, widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairlines [Royce & Steinmann 2002, Falik-Zaccai et al 2010, Besio et al 2015]. See Figure 2. #### Figure 2. Prominent forehead, proptosis, depressed nasal bridge, and thin vermilion of the upper lip can be appreciated. Neurologic manifestations. Intellectual disability of variable degree has been described in approximately 75% of individuals with prolidase deficiency [Hechtman 2001]. Table 3 summarizes IQ scores reported in the medical literature to date. * In a review 12 of 30 individuals with molecularly confirmed prolidase deficiency had intellectual disability [Lupi et al 2008]. * In a case series of 12 individuals with prolidase deficiency, one had speech delay, two had mild developmental delay, and six had intellectual disability; three had no delays [Besio et al 2015]. * In a case series of 20 Druze and Arab Muslims with prolidase deficiency living in northern Israel all had some degree of developmental delay, mainly moderate cognitive or speech delay [Falik-Zaccai et al 2010]. More specifically, two had speech delay, eight had mild developmental delay, five had moderate delay, and three had severe delay. ### Table 3. IQ Scores Reported in Individuals with Prolidase Deficiency View in own window IQ ScoreTest UsedReference 30NRArata et al [1979] 48NROgata et al [1981] 52WISC-RFreij et al [1984] 52NRSekiya et al [1985] 55WISC-RMonafo et al [2000] 61WISC-RTiller [1977] 66NRCleary et al [1994] 74WISC-RDunn et al [2011] 85WISC-RPowell et al [1974] 87Peabody Picture Vocabulary Test, Form BPowell et al [1977] 80-90NRGoodman et al [1968] NR = not reported; WISC-R = Wechsler Intelligence Scale for Children – Revised Microcephaly was described in five of 11 individuals [Besio et al 2015]. Seizures have been described in rare cases [De Rijcke et al 1989, Wang et al 2006, Butbul Aviel et al 2012]. Brain MRI findings include: * Multiple microthromboses bilaterally in the cerebral white matter [Arata et al 1991] * Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [Butbul Aviel et al 2012] * Findings compatible with vasculitis [Falik-Zaccai et al 2010] * Normal (one affected individual) [Cantatore et al 1993] On nerve conduction studies one affected individual had decreased amplitude of motor action potentials and sensory action potentials [Cantatore et al 1993]. Organomegaly. Hepatomegaly and splenomegaly are common [Royce & Steinmann 2002] and variable in severity; in one instance massive splenomegaly (spleen measuring 35 cm) has been reported [Nasser et al 2015]. Liver enzymes may be mildly elevated [Wang et al 2006, Butbul Aviel et al 2012]. Hematologic manifestations. Anemia can be either mild microcytic hypochromic anemia [Powell et al 1974, Powell et al 1977, Pedersen et al 1983, Milligan et al 1989] or normocytic normochromic anemia [Dunn et al 2011]. Hemolysis has been described [Lapiere & Nusgens 1969], with reticulocytosis varying from 5.9% [Powell et al 1977] to 8.6% [Powell et al 1974]. Thrombocytopenia is fairly common [Powell et al 1974, Ogata et al 1981, Kavala et al 2006, Wang et al 2006, Butbul Aviel et al 2012]. Immunologic manifestations. Recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis are common [Royce & Steinmann 2002]. Elevated levels of IgG, IgA and IgM, and hypocomplementemia have been reported [Cleary et al 1994], as has decreased neutrophil chemotaxis [Cleary et al 1994, Shrinath et al 1997, Lopes et al 2002]. Serum levels of C1q have been normal [Gray et al 1983, Kurien et al 2013]. Increased serum IgE levels have been reported [Di Rocco et al 2007, Kelly et al 2010, Klar et al 2010]: * Martins et al [2000] reported a patient with an IgE level of 20,000 IU/mL, which was as high as 77,600 IU/mL on follow up, with a Grimbacher score of 34 [Lopes et al 2002]. * Fukumura et al [2009] reported an individual with a level of 23,000 IU/mL. * Hershkovitz et al [2006] reported a patient with levels of 1,000-2,000 IU/mL with a Grimbacher score of 41, suggestive of autosomal dominant hyper IgE syndrome. Pulmonary manifestations. Asthma-like chronic reactive airway disease was described in three of four Amish individuals with prolidase deficiency [Wang et al 2006]. Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis phenotype including elevated sweat chloride and transepithelial potential difference has been described [Luder et al 2007]. One male developed severe progressive restrictive lung disease at age 45 years [Luder et al 2007]. A Druze woman age 24 years had progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity [Butbul Aviel et al 2012]. She experienced further deterioration in her pulmonary function and secondary pulmonary hypertension, and became oxygen dependent. An Amish boy age six years with pulmonary hypertension required supplemental oxygen [Kelly et al 2010]. Systemic lupus erythematosus-like findings. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described in at least ten individuals, including three of 23 individuals from northern Israel [Butbul Aviel et al 2012]. This association, first described by Bissonnette et al [1993] in a female age 16 years, included Raynaud's phenomenon, photosensitivity, arthritis, nephritis (with segmental mesangial deposits of IgA, IgM, and C3), antinuclear antibodies 1:650, and a positive rheumatoid factor. Shrinath et al [1997] reported two cousins with prolidase deficiency and SLE: * One had a malar facial rash, joint swellings, thrombocytopenia, neutropenia, proteinuria, pericarditis, hypocomplementemia, positive antinuclear antibody test (ANA), and strongly positive anti-dsDNA; * The other had recurrent mouth ulcers, a malar rash, thrombocytopenia, neutropenia, positive ANA, positive anti-dsDNA, and positive pANCA. A boy age 11 years had photosensitivity, malar erythema, and a positive ANA of 1:40 [Cabrera et al 2004]. A boy age six years diagnosed with SLE was treated for two years with steroids and azathioprine, with amelioration of the immunologic abnormalities but worsening of the skin lesions [Lupi et al 2004]. A male age 25 years had bilateral and symmetric synovitis affecting hands, elbows, and knees, a positive rheumatoid factor (516 IU/mL) and homogeneous ANA (1:640), and low C4 and CH50 (0.07 g/L and 61%) [Marotte et al 2010]. He fulfilled the American College of Rheumatology (ACR) criteria for rheumatoid arthritis and SLE (rhupus). Although he was diagnosed with prolidase deficiency based on increased imidodipeptiduria, prolidase enzymatic activity was not measured and PEPD sequencing was not performed. This patient did have increased bone turnover, a known cause of imidodipeptiduria in the absence of prolidase deficiency. An Amish boy age 2.5 years with fever of unknown etiology had urinalysis with 2+ proteinuria and hypoalbuminemia, ANA of 1:1080 with speckled pattern, and a positive anti-dsDNA [D'Souza et al 2006]. Of two sibs reported by Klar et al [2010]: * A girl age eight years had Raynaud's phenomenon, a positive ANA (1:1280; homogenous pattern), a positive anti ds-DNA >1:160, positive anti-ENA, anti-RNP and anti-Smith; * Her brother, age 12 years, had Raynaud's phenomenon, a positive ANA (1:40; homogeneous) and anti ds-DNA (1.6 μg/mL), and low C3 (30-74 mg/dL). An individual with positive ANA and anti-dsDNA titers, as well as low complement levels had no hematologic, renal, or articular problems; although he was given a diagnosis of SLE, he did not fulfill ACR diagnostic criteria [Di Rocco et al 2007]. Falik-Zaccai et al [2010] reported two individuals: * One with Coombs-positive hemolytic anemia, severe medication-resistant thrombocytopenia which required splenectomy, high levels of ANA and anti-cardiolipin antibodies, and a strongly positive anti-dsDNA; * One with aphthous stomatitis, macroscopic hematuria and proteinuria eventually leading to renal failure (with a renal biopsy compatible with lupus nephritis), seizures, pancytopenia, Coombs-positive hemolytic anemia, hypocomplementemia, and elevated ANA and anti-dsDNA antibodies). Butbul Aviel et al [2012] reported three individuals with the SLE/prolidase deficiency association: * A boy age 4.5 years with a rash consistent with hypertrophic discoid lupus on biopsy, proteinuria and mild hematuria with a renal biopsy consistent with WHO Class IV lupus nephritis, low C3 and C4 levels, positive ANA (1:640; homogeneous pattern), anti ds-DNA, anti-RNP, anti-SM, anti Ro (SS-A) and anti La (SS-B) * A girl age 16 years with macroscopic hematuria and proteinuria, with a renal biopsy demonstrating WHO Class IV lupus nephritis; she had low C3 and C4, as well as a highly positive ANA and positive anti ds-DNA titer * A woman age 24 years with thrombocytopenia, a positive Coombs test, low C3 and C3 levels, and positive ANA and anti ds-DNA titers Positive ANA, anti-dsDNA, anti-ENA (anti-Ro), anti-Sm and anti-chromatin have been found in individuals with prolidase deficiency even in the absence of clinical findings of SLE [Kurien et al 2013]. Bone manifestations. Among 12 affected individuals reported by Besio et al [2015], short stature was described in seven, osteopenia in six, and genu valgum in four. Other bone findings include spina bifida of C3 and 13 thoracic vertebrae [Freij et al 1984]; fusion of C2 and C3 [Lacarbonara et al 2014]; and delayed bone age [Pedersen at al 1983, Lacarbonara et al 2014]. Digital clubbing, in the presence and in the absence of pulmonary abnormalities, has also been reported [Luder et al 2007, Kelly et al 2010]. Other manifestations * Joint laxity [Pasquali Ronchetti et al 1991, Lombeck et al 1986, Kavala et al 2006], including hip dislocation [Arata et al 1979, Ogata et al 1981] * Protuberant abdomen in five of the first 17 cases reported [Freij et al 1984] * Obesity [Andry et al 1992] * Optic and chorioretinal atrophy [Ogata et al 1981], keratitis [Ogata et al 1981, Freij et al 1984] and pathologic myopia [Kiratli & Satilmiş 1998] * Erosive cystitis (one individual) [Milligan et al 1989] * Dental dysplasia [Moulonguet et al 1989] * Autoimmune adrenal failure (one individual) [Luder et al 2007] Prognosis. The severity of prolidase deficiency is quite variable: in some individuals skin ulcerations lead to amputation of one [Lupi et al 2006] or all toes [Sekiya et al 1985], whereas others remain entirely asymptomatic. Two individuals diagnosed through systematic urinary newborn screening in Quebec [Lemieux et al 1984] remained asymptomatic 14 years later [Hechtman 2001]. A man age 26 years, whose younger sister was affected, had imidodipeptiduria and prolidase deficiency in erythrocytes but no clinical manifestations [Isemura et al 1979]. A woman age 29 years, the sister of an affected individual, had absence of prolidase activity in serum or erythrocytes, but no skin ulcers or other clinical manifestations of prolidase deficiency [Lupi et al 2006]. In most instances, individuals with prolidase deficiency experience severe morbidity and early death, usually due to infection. The individual with probable prolidase deficiency reported by Goodman et al [1968] had died of influenza by the time of a follow-up biochemical report four years later [Buist et al 1972]. He was about age 50 years at the time of death [Royce & Steinmann 2002]. The female reported by Lapiere & Nusgens [1969] died at age 36 years [Endo et al 1990]; she had superinfection of skin ulcers with Pseudomonas aeruginosa, which lead to septic shock and disseminated intravascular coagulation [Royce & Steinmann 2002]. A female died of a fungal infection and disseminated intravascular coagulation [Sekiya et al 1985]. A girl age 16 years with prolidase deficiency and SLE developed cellulitis of the leg, followed by adult respiratory distress syndrome and death [Bissonnette et al 1993]. A male died at 15 years of age of unknown reasons [Endo et al 1990]. A patient age 15 years died of terminal liver failure and cardiac failure [Royce & Steinmann 2002]. A patent age 11 years died of unknown causes [Besio et al [2015]. A boy age eight years with prolidase deficiency and SLE died after developing a facial abscess and septicemia [Shrinath et al 1997]. The youngest reported death was at age four years [Mandel et al 2000]. ### Genotype-Phenotype Correlations There are no known genotype-phenotype correlations. Marked phenotypic variability has been found among affected individuals from the same family (who have the same pathogenic variants) [Falik-Zaccai et al 2010]. ### Nomenclature Prolidase deficiency was also known as hyperimidodipeptiduria, although increased excretion of imidodipeptides is not exclusive to prolidase deficiency. Other names used in the past include imidodipeptidase deficiency and peptidase D deficiency. ### Prevalence Approximately 90 affected individuals have been reported in the literature; however, prolidase deficiency likely remains underdiagnosed as a result of under-recognition by physicians. The Québec Newborn Urine Screening Program (Programme québécois de dépistage neonatal Urinaire, PQDNU) identified two affected infants out of 2,469,929 screened between 1973 and 2006, for an incidence of 1:1,235,000 [Renaud & Dagenais 2009]. Thus, a few thousand cases would be predicted to exist worldwide, as opposed to only 90 cases reported to date. Prolidase deficiency has been diagnosed throughout the world [Lupi et al 2008]. A founder variant has been described in the Geauga County settlement in Ohio [Wang et al 2006], as well as in the Druze population in northern Israel, the latter with a carrier frequency of 1:21 [Falik-Zaccai et al 2008]. ## Differential Diagnosis ### Disorders with Imidodipeptiduria Imidodipeptiduria has been described in bone disorders, presumably originating from collagen under conditions of high bone turnover. Glycylproline has been found in the urine of: * A child with severe bone disease and hyperphosphatasia [Seakins 1963]; * Two sisters with multiple fractures and striking bone deformities of unknown etiology [Alderman et al 1969]; * A woman age 28 years with osteomalacia and severe hyperparathyroidism who excreted large amounts of glycylproline, equivalent to ~1 g/day [Cahill et al 1970]; * Three individuals with rickets [Scriver 1964] who excreted decreasing amounts of glycylproline concomitant with clinical improvement, until the imidodipeptiduria disappeared with recovery from the disease. ### Disorders with Skin Ulcers Werner syndrome is characterized by cancer predisposition and the premature appearance of features associated with normal aging. Findings shared by prolidase deficiency and Werner syndrome are chronic lower extremity ulcers [Sternberg et al 1982, Yeong & Yang 2004, Noda et al 2011], premature graying of the hair, and a "bird-like" facial appearance [Milligan et al 1989, Pasquali Ronchetti et al 1991, Zanaboni et al 1994]. Imidodipeptiduria has not been reported in Werner syndrome. Werner syndrome is caused by biallelic pathogenic variants in WRN and inherited in an autosomal recessive manner. Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Leg ulcers which are relatively common in SCD were found in 2.5% of patients from the Cooperative Study of Sickle Cell Disease in the US [Koshy et al 1989], in 43% in the Jamaican Cohort Study [Clare et al 2002], and in 1.7% [Akinyanju & Akinsete 1979] to 13.2% [Knox-Macaulay 1983] of Africans. Although urinary excretion of hydroxyproline has been shown to be significantly increased in persons with sickle cell disease compared to controls [Mohammed et al 1991] (presumably due to bone involvement), glycylprolinuria has not been reported in SCD. More importantly, although individuals with prolidase deficiency can have mild findings of hemolysis, they do not have veno-occlusive episodes. SCD is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner. Beta-thalassemia is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in reduced amounts of hemoglobin A, microcytic hypochromic anemia, and an abnormal peripheral blood smear with nucleated red blood cells. Affected individuals with other hemoglobinopathies such as β-thalassemia can also have chronic leg ulcers [Stevens et al 1977, Gimmon et al 1982, Levin & Koren 2011, Taher et al 2013], but again no imidopeptiduria is known to occur. Persons with prolidase deficiency should have a normal hemoglobin electrophoretic pattern. β-thalassemia is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner. Acquired causes of lower-extremity ulcers include arterial insufficiency, venous insufficiency, pressure ulcers, vasculitis, systemic lupus erythematosus, and infectious etiologies, among others. Although glycineprolinuria could be anticipated in cases of secondary skin ulcers given the high content of collagen in the dermis, a number of patients with extensive skin ulceration have been tested, and imidodipeptiduria was only found when accompanied by severe concurrent bone disease (e.g., multiple fractures) [Sheffield et al 1977]. ### Disorders with Hyper IgE Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency syndrome characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE. It is now recognized that other common manifestations include eczema, mucocutaneous candidiasis, and several connective tissue and skeletal abnormalities like osteopenia, minimal trauma fractures, and scoliosis. AD-HIES is caused by mutation of STAT3. A Grimbacher score of >40 is suggestive of AD-HIES. Autosomal recessive hyper IgE syndrome (AR-HIES) (OMIM 243700) is a distinct clinical disorder, characterized by elevated serum concentration of IgE, severe eczema, and recurrent skin and lung infections [Renner et al 2004], all of which can also be seen in prolidase deficiency. Prolidase deficiency differs from AD-HIES by an increased incidence of neurologic abnormalities, an increased occurrence of viral infections of the skin (e.g., Molluscum contagiosum, warts) and virus-driven malignancies, as well as absence of the non-immunologic findings of AD-HIES (e.g., connective tissue, skeletal and dental involvement) [Renner et al 2004]. AR-HIES is caused by biallelic pathogenic variants in DOCK8. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with prolidase deficiency, the following evaluations are recommended: * Review of systems to assess for the possibility of pulmonary complications. In those with a history of pulmonary complications, consider chest imaging, pulmonary function tests, an echocardiogram to assess for pulmonary hypertension, and consultation with a pulmonologist. * Physical examination to evaluate for splenomegaly. If present, perform an abdominal ultrasound examination to evaluate the extent of splenomegaly. * Complete blood count to evaluate for anemia and thrombocytopenia * Liver function tests to assess for the possibility of elevated liver enzymes * Developmental assessment * Consultation with a wound care specialist * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations No curative treatment is available. Care is preferably provided by a multidisciplinary team. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal. Click here (pdf) for further details, including treatments in which only partial or short-term benefit was reported. ### Prevention of Secondary Complications Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection. Antibiotic prophylaxis should also be considered in the appropriate setting. ### Surveillance In the absence of formal surveillance guidelines, the authors recommend: * Annual: * Skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcers * Complete blood count * Liver function tests * Abdominal ultrasound examination to assess liver and spleen size * Follow up as recommended by a pulmonologist and immunologist; * Follow-up assessments of motor and cognitive development as recommended for educational planning. ### Agents/Circumstances to Avoid Individuals with prolidase deficiency who have splenomegaly should avoid contact sports given the increased risk for splenic rupture. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Adenovirus-mediated gene transfer. Ikeda et al [1997] performed transfer of the human prolidase cDNA into fibroblasts from patients with prolidase deficiency. This increased the fibroblast prolidase activity up to 75 times normal. Intracellular delivery of liposome-encapsulated prolidase. Perugini et al [2005] showed that active prolidase encapsulated in liposomes was completely transported via endocytosis into fibroblasts six days after incubation. 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. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Prolidase Deficiency

c0268532

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK299584/

{"mesh": ["D056732"], "synonyms": []}

Polyneuropathy associated with IgM monoclonal gammapathy (MG) with anti-MAG (myelin-associated-glycoprotein) activity is a demyelinating polyneuropathy characterized clinically by sensory ataxia, tremor, paresthesia, and impaired gait. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Polyneuropathy associated with IgM monoclonal gammapathy with anti-MAG

c1736154

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=639

{"umls": ["C1736154"], "icd-10": ["G61.8"], "synonyms": ["Anti-MAG neuropathy", "Neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein"]}

A number sign (#) is used with this entry because of evidence that presynaptic congenital myasthenic syndrome-20 (CMS20) is caused by homozygous or compound heterozygous mutation in the SLC5A7 gene (608761) on chromosome 2q12. Description Congenital myasthenic syndrome-20 is an autosomal recessive neuromuscular disorder characterized by severe hypotonia associated with episodic apnea soon after birth. Patients have muscle weakness resulting in delayed walking, ptosis, poor sucking and swallowing, and generalized limb fatigability and weakness. EMG studies usually show a decremental response to repetitive nerve stimulation, and some patients may show a good response to AChE inhibitors (summary by Bauche et al., 2016). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). Clinical Features Bauche et al. (2016) reported 7 patients, including 2 brothers, with CMS20. The patients presented at birth with hypotonia and frequent episodic apneas often requiring ventilatory assistance. The 2 brothers had a more severe phenotype with antenatal hydramnios and arthrogryposis; these infants died at day 10 and day 15 of life. The 5 remaining patients, who ranged in age from 3 years and 9 months to 16 years, had delayed walking, proximal weakness of the lower limbs, axial weakness, fatigability, ptosis, ophthalmoparesis, chronic hypoventilation, and bulbar signs, such as poor sucking and swallowing, dysphonia, dysphagia, and stridor. There was daily or several-day fluctuations of the disease course. Four patients showed a decremental response on repetitive nerve stimulation, all of whom had a favorable response to treatment with AChE inhibitors. Three patients were noted to have cognitive deficits, whereas the other 2 had normal cognition. Muscle biopsies from the 16-year-old male and 1 of the deceased brothers with the antenatal form of the disorder showed abnormalities at the neuromuscular junction (NMJ). The older surviving boy had evidence of a denervation-renervation process with small nerve terminals and empty synaptic gutters, although the postsynaptic element looked normal. The deceased infant had immature NMJs with thin and unbranched terminal axons. Both biopsies showed abnormally strong immunostaining for butyrylcholinesterase (BChE), possibly suggesting synaptic remodeling or impaired maintenance. Inheritance The transmission pattern of CMS20 in the families reported by Bauche et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 7 patients, including 2 sibs, with CMS20, Bauche et al. (2016) identified biallelic mutations in the SLC5A7 gene (see, e.g., 608761.0002-608761.0006). The mutations in the first 2 families were found by whole-exome sequencing; mutations in the 4 subsequent families were found by Sanger sequencing of exons in the SLC5A7 gene in 95 individuals with a similar disorder. In vitro functional expression studies in HEK293 cells of 5 missense mutations showed that all were expressed at normal levels, but had significantly decreased choline uptake compared to controls, consistent with a recessive loss of function. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial weakness Eyes \- Ptosis \- Ophthalmoparesis Neck \- Neck muscle weakness RESPIRATORY \- Episodic apnea due to muscle weakness \- Chronic hypoventilation \- Stridor ABDOMEN Gastrointestinal \- Poor feeding \- Poor sucking \- Poor swallowing \- Dysphagia SKELETAL \- Arthrogryposis (in some patients) Spine \- Kyphosis \- Scoliosis MUSCLE, SOFT TISSUES \- Hypotonia \- Muscle weakness \- Muscle fatigability \- Proximal muscle weakness of the lower limbs \- Delayed walking \- Axial weakness \- Bulbar muscle weakness \- Decremental muscle response to repetitive nerve stimulation NEUROLOGIC Central Nervous System \- Cognitive impairment (in some patients) VOICE \- Dysphonia PRENATAL MANIFESTATIONS Amniotic Fluid \- Hydramnios (in some patients) MISCELLANEOUS \- Onset at birth or in utero \- Variable severity \- Death in infancy may occur \- Fluctuating disease course \- Favorable response to AChE inhibitors MOLECULAR BASIS \- Caused by mutation in the solute carrier family 5 (choline transporter), member 7 gene (SLC5A7, 608761.0002 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

MYASTHENIC SYNDROME, CONGENITAL, 20, PRESYNAPTIC

c0751884

omim

https://www.omim.org/entry/617143

{"doid": ["0110661"], "mesh": ["D020294"], "omim": ["617143"], "orphanet": ["98914", "590"]}

For a phenotypic description and a discussion of genetic heterogeneity of progressive supranuclear palsy (PSP), see PSNP1 (601104). Clinical Features De Yebenes et al. (1995) studied a 5-generation Spanish family in which progressive supranuclear palsy was transmitted as an autosomal dominant trait. The proband had the classic presentation of this disorder beginning with axial rigidity, slowness of movement, and gait difficulty. Over the course of 2 years he progressed to complete vertical gaze palsy, axial dystonia, and retrocollis, as well as generalized severe akinesia. Postmortem examination demonstrated neuronal loss and atrophy of the brainstem, cerebellum, and diencephalon. There were also neurofibrillary tangles and gliosis without prominent senile plaques, the same pathology that was observed in the sporadic cases of progressive supranuclear palsy originally reported by Steele et al. (1964). Rojo et al. (1999) reported clinical findings on an additional 25 family members. Ros et al. (2005) reported follow-up on the family originally reported by de Yebenes et al. (1995). Four members had typical PSP, characterized by supranuclear gaze palsy, dysarthria, dysphagia, akinesia, rigidity, postural tremor, and frontal lobe dysfunction. At least 5 ancestors were reportedly affected. Several asymptomatic or mildly symptomatic individuals showed abnormal neuroimaging results on PET scan, including decreased dopa uptake and/or reduced frontal lobe glucose metabolism; these individuals were considered to be presymptomatic and thus affected (Piccini et al., 2001). Mapping By genomewide linkage analysis of the large family with PSP, Ros et al. (2005) achieved a maximum multipoint lod score of 3.53 between markers D1S428 and D1S461 assuming autosomal dominant inheritance and 90% penetrance. Haplotype analysis identified a 3.4-cM candidate disease locus between markers D1S238 and D1S2823 on chromosome 1q31.1. Ros et al. (2005) noted that the power of the linkage analysis was increased by detecting presymptomatic individuals with PET scans and assuming that they were affected. No linkage was found to the MAPT gene (157140) on chromosome 17q21. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Blurred vision \- Diplopia \- Photophobia \- Eyelid apraxia \- Supranuclear gaze palsy ABDOMEN Gastrointestinal \- Dysphagia NEUROLOGIC Central Nervous System \- Parkinsonism \- Bradykinesia \- Akinesia \- Rigidity \- Axial dystonia \- Poor mobility \- Gait imbalance \- Falls \- Supranuclear gaze palsy \- Dysarthria \- Retrocollis \- Postural tremor \- Frontolimbic dementia \- Neuropathology shows neuronal loss in basal ganglia, brainstem, and cerebellum \- Granulovacuolar degeneration \- Gliosis \- Neurofibrillary tangles Behavioral Psychiatric Manifestations \- Forgetfulness \- Irritability \- Apathy \- Frontal release signs MISCELLANEOUS \- Genetic heterogeneity (see PSNP1 601104 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

SUPRANUCLEAR PALSY, PROGRESSIVE, 2

c0038868

omim

https://www.omim.org/entry/609454

{"doid": ["678"], "mesh": ["D013494"], "omim": ["609454"], "orphanet": ["240071", "683"]}

A rare, genetic, inborn error of metabolism disorder characterized by psychomotor delay and severe myopathy (hypotonia, absent tendon reflexes and delayed myelination) from birth, associated with hypermethioninemia and elevated serum creatine kinase levels. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

S-adenosylhomocysteine hydrolase deficiency

c3151058

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=88618

{"mesh": ["C564683"], "omim": ["613752"], "umls": ["C3151058"], "icd-10": ["E72.1"]}

Keratoendotheliitis fugax hereditaria Other namesKeratitis fugax hereditaria SpecialtyOphthalmology Keratoendotheliitis fugax hereditaria is an autosomal dominantly inherited disease of the cornea, caused by a point mutation in cryopyrin[1] (also known as NALP3) that in humans is encoded by the NLRP3 gene [2] located on the long arm of chromosome 1.[3] In keratoendotheliitis fugax hereditaria, patients suffer from periodical transient inflammation of the corneal endothelium and stroma, leading to short term obscuration of vision and, in some patients after repeated attacks, to central corneal stromal opacities.[4][5][6] Approximately 50 known cases have been reported in the literature. The disease so far has only been described from Finland, but exome databases suggest it may be more widely distributed in people of European ancestry.[1] Keratoendotheliitis fugax hereditaria is thought to belong to cryopyrin-associated periodic syndromes. ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 History * 7 References * 8 External links ## Presentation[edit] Patients experience repeated unilateral attacks of keratitis 1 to 6 times per year, beginning at the age of 5 to 28 years. Men and women are equally affected. Attacks get less severe and less frequent in middle age. No seasonal variation has been reported. The symptoms are redness of the eye, pain, and photophobia. The attack may be associated with anterior chamber flare. These symptoms disappear in 1 to 2 days, but blurred vision may last for a few weeks. During the acute symptoms, a slit lamp shows pseudoguttae, dark patches in the corneal endothelium, thought to represent patchy corneal endothelial swelling. The endothelium appears normal between attacks. The attack can be misdiagnosed and treated as an acute iridocyclitis. Visual acuity transiently deteriorates during the attack. A typical corneal opacity of the patient with keratoendotheliitis fugax hereditaria. Older patients may show faint to definite central, horizontally oval, bilateral stromal opacities. The opacities may be associated with decreased visual acuity, but they have not been severe enough to need corneal transplantation. ## Genetics[edit] Keratoendotheliitis fugax hereditaria is inherited in an autosomal dominant manner, meaning an affected individual must inherit only one mutated allele from one parent. The protein, cryopyrin is coded for by the gene NLRP3, located at 1q44. The disease is frequent in Finland,[1] and this population has a common mutation D21H accounting for all reported cases in this population. It has not been described in any other populations. However, the mutation was found in exome databases at a minor allele frequency (MAF) of 0.023% and in the Finnish and at an MAF of 0.0090% in aggregated non-Finnish European populations.[1] ## Diagnosis[edit] Upon clinical suspicion, diagnostic testing will consist of identifying cornea pseudoguttata by using a specular microscope or confocal microscope. Molecular genetic testing is also an option.[1] ## Treatment[edit] Patients have reported benefit from immediate treatment of their attacks with a topical corticosteroid or non-steroidal anti-inflammatory drug (NSAID) applied a few times a day for up to one week. Some patients have found more benefit from an oral NSAID. ## Prognosis[edit] The repeated corneal inflammation over time can lead to reduced visual acuity. ## History[edit] Keratoendotheliitis fugax hereditaria was first described in 1964 by Olavi Valle (1934-2013),[4] a Finnish ophthalmologist with an interest in hereditary eye diseases. He reported this disease as keratitis fugax hereditaria in a family with 10 affected members over 4 generations.[5] Two decades later, a second Finnish family with 21 affected members in 5 generations was reported by other Finnish ophthalmologists who highlighted transient corneal endothelial changes, and proposed the term keratoendotheliitis fugax hereditaria.[6] ## References[edit] 1. ^ a b c d e Turunen JA, Wedenoja J, Repo P, Järvinen RS, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivelä TT (Jan 2018). "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology. 184: 41–50. doi:10.1016/j.ajo.2018.01.017. PMID 29366613. 2. ^ Anon. (2015). "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3 [Homo sapiens (human)], Gene ID: 114548 (updated on 13-Nov-2015)". Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. Retrieved 13 November 2015. 3. ^ Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD (May 2000). "Identification of a locus on chromosome 1q44 for familial cold urticaria". American Journal of Human Genetics. 66 (5): 1693–8. doi:10.1086/302874. PMC 1378006. PMID 10741953. 4. ^ a b Valle O (1964). "Keratitis fugax hereditaria". Duodecim. 80: 659–664. PMID 14213210. 5. ^ a b Valle O (1964). "Keratitis fugax hereditaria - a new eye syndrome". Ophthalmologica. 151 (5): 537–547. doi:10.1159/000304912. PMID 4380911. 6. ^ a b Ruusuvaara P, Setälä K (1987). "Keratoendotheliitis fugax hereditaria. A clinical and specular microscopic study of a family with dominant inflammatory corneal disease". Acta Ophthalmol (Copenh). 65 (2): 159–169. doi:10.1111/j.1755-3768.1987.tb06995.x. PMID 3604606. ## External links[edit] Classification D * ICD-10: H16.39 * OMIM: 148200 * MeSH: C11.204.564 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Keratoendotheliitis fugax hereditaria

c1835697

wikipedia

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

{"mesh": ["C563650"], "umls": ["C1835697"], "wikidata": ["Q55615849"]}

For a general phenotypic description and a discussion of genetic heterogeneity of familial temporal lobe epilepsy, see 600512. Clinical Features Deprez et al. (2007) reported a 5-generation Belgian family with dominantly inherited occipitotemporal lobe epilepsy and migraine with visual aura. Age at onset ranged from childhood to adulthood. A total of 14 individuals were affected. Ten individuals had occipitotemporal lobe epilepsy, 5 of whom also had migraine with aura. Nine of the 10 patients had simple partial seizures with visual symptoms being most common (60%), followed by cognitive (50%), autonomic (50%), motor (50%), and somatosensory (20%) symptoms and olfactory (40%) and auditory (20%) hallucinations. None had deja vu. Three of the 10 patients had complex partial seizures, and 3 had secondary generalization. Four family members had a single isolated seizure; only 1 of the 4 also had migraine with aura. Median age at the onset of aura was 42 years (range 30 to 65). Seizures and migraine attacks were temporally independent in all patients except one. There was no history of febrile seizures. EEG and brain MRI were normal except in 2 patients with age-related white matter changes. Disease penetrance was about 75%. Teive et al. (2008) commented that the possible relationship between epilepsy and migraine in the family reported by Deprez et al. (2007) was consistent with the hypothesis of cortical spreading depression in epilepsy and migraine put forth by Leao (1944). Mapping By genomewide linkage and haplotype analysis of an affected Belgian family, Deprez et al. (2007) identified a 9.95-cM candidate region on chromosome 9q21-q22 between markers GATA152H04 and D9S253 (maximum 2-point lod score of 3.3 at D9S257). The disease haplotype was present in all those with epilepsy and in all those with migraine with aura. The findings suggested a causal monogenic link between epilepsy and migraine with aura in this family. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Seizures, simple partial \- Seizures, complex partial \- Visual symptoms (in 60% of patients) \- Autonomic symptoms \- Olfactory or auditory hallucinations \- Secondary generalization (rare) \- Migraine with aura, usually visual (in 50% of patients) MISCELLANEOUS \- Variable age at onset of seizures \- Mean age at onset of migraines is 42 years \- Reduced penetrance (75%) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

EPILEPSY, FAMILIAL TEMPORAL LOBE, 4

c1842564

omim

https://www.omim.org/entry/611631

{"doid": ["0060753"], "mesh": ["C536956"], "omim": ["611631"], "orphanet": ["98819"], "synonyms": ["Alternative titles", "EPILEPSY, OCCIPITOTEMPORAL LOBE, AND MIGRAINE WITH AURA"]}

Disease of children; pediatric comorbidity from COVID-19 Paediatric multisystem inflammatory syndrome (PMIS/PIMS/PIMS-TS) Other names * Multisystem inflammatory syndrome in children (MIS-C)[1] * Multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19[2] * Paediatric inflammatory multisystem syndrome (PIMS), temporally associated with SARS-CoV-2 infection (PIMS-TS)[3] * Kawa-COVID-19[4] TEM image of SARS-CoV-2, the coronavirus responsible for COVID-19: PMIS / MIS-C is thought to be caused by an unusual biological response to infection in certain children SpecialtyPaediatrics SymptomsFever, abdominal pain, diarrhoea/vomiting, low blood pressure, insufficient blood supply (shock), pink eye, "strawberry tongue", rashes, large lymph nodes, swollen hands/feet, neurological disturbances, among others ComplicationsCardiac dysfunction; coronary artery abnormalities, including aneurysms; acute kidney injury; coagulopathy Usual onsettypically 2–6 weeks[5] after COVID-19 exposure CausesSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Diagnostic methodClinical evaluation by specialists Differential diagnosisAlternative infectious/non-infectious causes, Kawasaki disease TreatmentIntravenous immunoglobulin (IVIG); corticosteroids; oxygen, supportive care PrognosisResponse to treatment, generally good; long-term prognosis, unclear[6] FrequencyRare Deaths<2% of reported cases Multisystem inflammatory syndrome in children (MIS-C), or paediatric inflammatory multisystem syndrome (PIMS / PIMS-TS), is a rare systemic illness involving persistent fever and extreme inflammation following exposure to SARS-CoV-2, the virus responsible for COVID-19.[6] It can rapidly lead to medical emergencies such as insufficient blood flow around the body (a condition known as shock).[6] Failure of one or more organs can occur.[7] A warning sign is unexplained persistent fever with severe symptoms following exposure to COVID-19.[8] Prompt referral to paediatric specialists is essential, and families need to seek urgent medical assistance.[6] Most affected children will need intensive care.[6] All affected children have persistent fever.[6] Other clinical features vary.[8] The first symptoms often include acute abdominal pain with diarrhoea or vomiting.[6] Muscle pain and general tiredness are frequent,[6] and low blood pressure is also common.[9] Symptoms can also include pink eye, rashes, enlarged lymph nodes, swollen hands and feet, and "strawberry tongue".[5] Various mental disturbances are possible.[5] A cytokine storm may take place,[10] in which the child's innate immune system stages an excessive and uncontrolled inflammatory response.[11] Heart failure is common.[9] Clinical complications can include damage to the heart muscle, respiratory distress, acute kidney injury, and increased blood coagulation.[12] Coronary artery abnormalities can develop (ranging from dilatation to aneurysms).[5] This life-threatening disease has proved fatal in under 2% of reported cases.[6] Early recognition and prompt specialist attention are essential.[13] Anti-inflammatory treatments have been used, with good responses being recorded for intravenous immunoglobulin (IVIG), with or without corticosteroids.[14] Oxygen is often needed.[6] Supportive care is key for treating clinical complications.[12] Most children who receive expert hospital care survive.[6] Knowledge of this newly described syndrome is evolving rapidly.[15] Its clinical features may appear somewhat similar to Kawasaki disease, a rare disease of unknown origin that typically affects young children, in which blood vessels become inflamed throughout the body.[9] It can also show features of other serious inflammatory conditions of childhood, including toxic shock and macrophage activation syndromes.[9] Nevertheless, it appears to be a separate syndrome.[16] Older children tend to be affected.[17] This emerging condition has been defined slightly differently (using different names), by the World Health Organization (WHO),[18] the Royal College of Paediatrics and Child Health (RCPCH),[7] and the Centers for Disease Control and Prevention (CDC).[1] Although the condition is thought to follow SARS-CoV-2 viral infection, antigen or antibody tests are not always positive.[3] Exclusion of alternative causes, including bacterial and other infections, is essential for differential diagnosis.[3] Some general clinical guidance has been provided by the RCPCH,[7] the National Institutes of Health,[17] the American College of Rheumatology,[19] and the American Academy of Pediatrics.[20] Clusters of new cases have been reported 2–6 weeks after local peaks in viral transmission.[5] The disease is thought to be driven by a delayed biological mechanism in certain predisposed children.[14] The European Centre for Disease Prevention and Control (ECDC) has rated risk to children in Europe as being 'low' overall, based on a 'very low' likelihood of a child developing this 'high impact' disease.[3] Regarding ethnicity, the condition seems to affect more children of African, Afro-Caribbean, and Hispanic descent, whereas Kawasaki disease affects more of East Asian ancestry.[13] Initial reports regarded children in various parts of Europe and the United States, and it was unclear to what extent the condition had gone unrecognized elsewhere.[18] Reports have since emerged of cases in various other countries around the world.[21][22] In adults, a similar condition has occasionally been reported, which has been called multisystem inflammatory syndrome in adults (MIS-A).[23] ## Contents * 1 Name * 2 Background * 3 Characteristics * 3.1 Clinical course * 4 Diagnosis * 4.1 Case definitions and guidance * 4.2 Differential diagnosis * 5 Treatment * 6 Causes * 7 Mechanism * 8 Epidemiology * 8.1 In adults * 9 History * 10 Notes * 11 References * 12 External links ## Name[edit] The disorder has been called by various names, including: * Multisystem inflammatory syndrome in children (MIS-C)[1] * Multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19[2] * Paediatric inflammatory multisystem syndrome (PIMS)[7] * Paediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2 infection (PIMS-TS)[3][6] * Paediatric multisystem inflammatory syndrome (PMIS)[9] * Kawa-COVID-19[4] ## Background[edit] Symptomatic cases of COVID-19 in children have been relatively uncommon,[24] possibly because they generally experience milder disease.[25] Early infection tends to be associated with mild or no symptoms, while the later pulmonary phase, which can be life-threatening in adults, is usually mild or absent.[26][27] While cases of children with severe symptoms are exceptional, they can occasionally require intensive care.[28][29][30] Fatalities have been rare.[27][31] In April 2020, a small group of children with evidence of SARS-CoV-2 infection or exposure to COVID-19 were found to display clinical features corresponding to the diagnostic criteria of Kawasaki disease, sometimes accompanied by shock.[28][32] Kawasaki disease is a rare syndrome which mainly affects young children (adult onset has occasionally been reported[33]).[3][34][35] It is a form of vasculitis, where blood vessels become inflamed throughout the body, and it results in a persistent fever.[3] Recovery typically occurs spontaneously, though some children later develop mid-sized or giant coronary artery aneurysms in the heart – a potentially fatal complication.[3][36] Symptoms of toxic shock (a syndrome caused by bacterial toxins) occasionally occur – an association sometimes referred to as 'Kawasaki shock syndrome',[37] which is characterized by systolic hypotension or signs of poor perfusion.[3][38] While the exact cause of Kawasaki disease is unknown, one plausible explanation is that it may stem from an infection triggering an autoimmune and/or autoinflammatory response in children who are genetically predisposed.[39][40] No specific diagnostic test exists for Kawasaki disease, and its recognition is based on various combinations of clinical and laboratory findings (including persistent fever, widespread rashes, enlarged lymph nodes, conjunctivitis, changes to the mucous membranes, and swollen hands and feet).[3][34][41] ## Characteristics[edit] MIS-C / PIMS-TS is a systemic disorder involving persistent fever, extreme[6] inflammation (hyperinflammation), and organ dysfunction, which is temporally associated with exposure to COVID-19.[1][7] Onset may be delayed or contemporary with ongoing SARS-CoV-2 infection,[42] which may pass without symptoms.[6] The time the syndrome takes to appear following the initial viral infection is debated, though it may develop between the first and second week.[43] Epidemiological data suggest that recognition of the disease may typically be delayed by 2–6 weeks,[5] and usually by 3–4 weeks.[6] By the time of presention, children have often developed antibodies to SARS-CoV-2, but test negative for the virus at RT-PCR.[6] The condition may match some or all of the diagnostic criteria for Kawasaki disease (i.e. the 'complete' or 'incomplete'/'atypical' subtypes[6][41]),[7] or for Kawasaki disease shock syndrome.[37] It tends to affect all paediatric age groups, ranging from infancy to adolescence.[5][14] It can also share clinical features with other paediatric inflammatory conditions, including toxic shock syndrome, and secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome.[7][26] Coinfections with other pathogens have been recorded.[3] Affected children always present with persistent fever.[6] Other clinical features at presentation vary.[8] In contrast to acute COVID-19, most children have gastrointestinal symptoms, such as diarrhoea, vomiting, and intense abdominal pain (sometimes severe enough to suggest appendicitis).[6] Muscle pain and feelings of tiredness and general physical weakness are also very common.[6][9] Some Kawasaki-like symptoms that may be present (especially in children under the age of 5)[43] include mucosal changes around the mouth ("strawberry tongue", cracked lips, etc.), red eyes (conjunctivitis without pus), widespread rash (consistent with leukocytoclastic vasculitis[44]), red or swollen hands and feet, and enlarged lymph nodes.[5][8][9] Chest or neck pain may also be present.[45] Severe headache and altered mental state have been reported, along with various neurological disturbances.[5][16][46] Features of meningitis have been reported.[8][14] Some patients present with very low blood pressure and shock, and they may require urgent admission to a paediatric intensive care unit.[9] Cardiovascular involvement is very frequent.[6][16][43] Acute heart failure is common in the form of left ventricular dysfunction,[9][47] and a left ventricular ejection fraction under 60% is frequent.[12] Shock is often of myocardial – mainly left ventricular – origin.[14] Respiratory symptoms are less common,[16] and are not usually a prominent feature.[14][8][47] When present, breathing difficulties are often linked to shock,[3] and are suggestive of heart failure.[8] Some children display features of a cytokine storm,[8] including extremely high serum interleukin-6 (IL-6) levels,[16] and need inotropic support to maintain cardiac output.[10] Coronary artery abnormalities, such as dilatation, are frequent.[9] Some children have developed coronary artery aneurysms.[8] Electrocardiographic (ECG) abnormalities are common.[9] Other cardiological features sometimes include inflammation of the heart valves (valvulitis) and of the fibrous sac surrounding the heart (pericarditis).[5][47] Echocardiographic features of myocarditis (inflammation of the heart muscle) have been recorded.[5][6] Affected children consistently show laboratory evidence of hyperinflammation.[9] Pronounced biological markers of inflammation generally include strongly raised erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin, ferritin, and IL6.[9] Low platelet counts and impaired blood clotting (coagulopathy) are also common,[14] with increased levels of D-dimer and fibrinogen.[9] Other haematological features include raised numbers of white blood cells (leukocytosis), characterized by high numbers of neutrophils, with many immature forms, and low numbers of lymphocytes (lymphopaenia).[9] Numbers of red blood cells and platelets may be either normal or decreased.[9] Acute kidney injury and low albumin levels in the blood (hypoalbuminaemia) are common.[26] Low blood sodium levels and raised liver enzymes have been reported.[14] Accumulations of fluid in the lungs (pleural effusion), around the heart (pericardial effusion), and in the abdomen (ascites) have also been reported, consistent with generalized inflammation.[26] Differences with respect to Kawasaki disease include frequent presentation with gastrointestinal symptoms such as vomiting, diarrhoea, and abdominal pain.[5][6] Neurological involvement also appears to be relatively frequent.[8] It often affects older children, whereas Kawasaki disease usually occurs before the age of five.[6][14] Multiorgan disease appears to be more frequent.[16] Myocarditis and cardiogenic shock shock seem to be relatively common.[16] Myocarditis may be more evident in older children and adolescents.[43] Preschool children tend to display more Kawasaki-like characteristics.[43] Features of macrophage activation syndrome appear to be more frequent than in Kawasaki disease.[17][48] Characteristic laboratory findings that are not usually encountered in Kawasaki disease include very high levels of ventricular natriuretic peptide (a marker of heart failure),[10] as well as somewhat lower platelet counts, lower absolute lymphocyte counts, and higher CRP levels.[13] Very high troponin levels (suggestive of myocardial damage) are also common.[14][26][16] ### Clinical course[edit] Clinical course tends to be more severe than with Kawasaki disease.[42] A child's condition can deteriorate rapidly, even in the presence of reassuring laboratory findings.[15] Many children develop shock and heart failure.[6] Most require paediatric intensive care.[6] Supplemental oxygen is often needed, and mechanical ventilation is sometimes used.[6] Most children who receive expert multidisciplinary care survive.[6] In addition to respiratory distress, major complications that may need aggressive supportive care can include myocardial damage, acute kidney injury, and coagulopathy (thrombophilia).[12] In some cases, sustained cardiac arrhythmias have led to haemodynamic collapse and need for extracorporeal membrane oxygenation (ECMO).[9] Deaths have been recorded in a small minority (under 2%) of the cases reported.[6][49] Occasionally, fatalities have followed complications of ECMO.[10] Some children exposed to COVID-19 also appear to have a less severe Kawasaki-like disease.[32] Ventricular function often recovers before discharge from hospital (often after 6–10 days).[6] Coronary artery aneurysms can develop even in the absence of Kawasaki-like features.[5] Their frequency and severity is uncertain.[13] So far, they have been recorded in 7% of reported cases.[6] Long-term prognosis is unclear.[9] ## Diagnosis[edit] Preliminary WHO case definition[18] Children and adolescents * 0–19 years of age with fever >3 days AND * Two of the following: 1. Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet) 2. Hypotension or shock 3. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP) 4. Evidence of coagulopathy (by PT, PTT, elevated d-Dimers) 5. Acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain) AND * Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin AND * No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes AND * Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19 (Note: Consider this syndrome in children with features of typical or atypical Kawasaki disease or toxic shock syndrome.) Diagnosis is by specialist clinical evaluation.[50] Diagnostic suspicion may be raised by unexplained persistent fever and clinically concerning symptoms following exposure to COVID-19.[8] Families need to seek immediate medical care, as the child's condition can deteriorate rapidly.[6] Paediatricians' first involvement is often in the emergency department.[43] Early recognition and multidisciplinary referral to paediatric specialists (in intensive care, infectious diseases, cardiology, haematology, rheumatology, etc.) is essential.[7][17][8][13] Examinations may include blood tests, chest x-ray, heart ultrasound (echocardiography), and abdominal ultrasound.[51] Clinicians worldwide have been urged to consider this condition in children who display some or all the features of Kawasaki disease or toxic shock syndrome.[18] ### Case definitions and guidance[edit] A universally accepted case definition for this newly described syndrome has still not been agreed.[21][52] In the meantime, different names and provisional case definitions are being used around the world.[21][52] The initial case definitions released by the World Health Organization (WHO), the Royal College of Paediatrics and Child Health (RCPCH) and Centers for Disease Control and Prevention (CDC) all include involvement of more than one organ system, along with fever and elevated inflammatory markers.[37] Criteria that vary among these three definitions include the ways in which involvement of different organs is defined, the duration of fever, and how exposure to COVID-19 is assessed.[9] * The preliminary WHO case definition is for "multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19"[2] (box).[18] The WHO has established a platform for standardized, anonymized clinical data, along with a dedicated case report form, and underlines the "urgent need for collection of standardized data describing clinical presentations, severity, outcomes, and epidemiology."[18] * Diagnostic guidance by the RCPCH proposes a broader case definition (for PIMS-TS),[21] which was also endorsed by an expert panel convened by the American College of Cardiology.[53] Key clinical criteria set out in the RCPHC case definition are: persistent fever, inflammation (indicated by neutrophilia, high CRP levels and low lymphocyte count), and evidence of organ dysfunction (shock; cardiac, respiratory, renal, gastrointestinal, or neurological disorder), coupled with additional clinical features, including laboratory, imaging and ECG findings.[3][7] Coronary artery abnormalities, such as dilatation, may be apparent at echocardiography and ECG (or contrast CT of the chest).[7] Biomarkers supporting the diagnosis include abnormal fibrinogen levels, high D-dimers (possible coagulopathy), high troponin, low albumin, and high ferritin.[7] According to the RCPCH definition, the child may test positive or negative for SARS-CoV-2, but other possible microbial causes need to be excluded.[3][7] * The CDC case definition for MIS-C comprises individuals "aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological)."[1] It also requires that there should either be a positive antigen/antibody SARS-CoV-2 test or COVID-19 exposure in the 4 weeks before onset of symptoms, along with exclusion of other plausible diagnoses.[1] This case definition is quite broad (it overlaps not only with Kawasaki disease, but also with juvenile rheumatoid arthritis, and various infectious/inflammatory conditions of childhood, including other viral diseases),[10] but not as broad as the RCPCH definition.[21] The CDC advises health providers in the United States to inform their public health authorities of suspected cases, even if they also meet full or partial criteria for Kawasaki disease, and to consider MIS-C after any childhood fatality in which there is evidence of SARS-CoV-2 infection.[1] Further case definitions have been formulated by the British Paediatric Surveillance Unit (BPSU) and the Canadian Paediatric Surveillance Program (CPSP).[52] Some provisional diagnostic guidance has been provided by both the American College of Rheumatology[13] and the American Academy of Pediatrics.[8] In the UK, consensus has been reached for diagnostic investigation of children with suspected PIMS-TS.[54] A clinical pathway for diagnostic evaluation of suspected MIS-C has also been proposed by the Children's Hospital of Philadelphia.[50] A set of guidelines proposed by Western New York recommends also evaluating children with clinical features that overlap with the MIS-C case definition, but who have been screened with mild illness and laboratory abnormalities, and who do not have an alternative diagnosis.[15] ### Differential diagnosis[edit] It is essential to exclude alternative non-infectious[8] and infectious causes of the inflammatory condition, including bacterial sepsis, staphylococcal and streptococcal shock, and infections associated with myocarditis, such as enterovirus.[7][3] (Coinfection with additional pathogens, including human metapneumovirus and various other microbes, may sometimes occur.)[3] Other potentially unrelated sources of abdominal pain include appendicitis and mesenteric adenitis.[55] Differential diagnosis with Kawasaki disease can be challenging, given the lack of a diagnostic test for either condition.[10] It is not currently known whether the newly described condition is superimposable with Kawasaki disease shock syndrome.[37] Since prompt diagnosis and timely treatment of actual Kawasaki disease is important to prevent complications, a call has been made to "Keep a high suspicion for Kawasaki disease in all children with prolonged fever, but especially in those younger than 1 year of age."[56] ## Treatment[edit] Due to the limited information available on this rare new diagnosis, clinical management has been largely based on expert opinion, including knowledge acquired from treating Kawasaki disease and other systemic inflammatory disorders of childhood, in addition to experience with COVID-19 in adults.[9] Treatment is tailored for each individual child, with input from the various consulting specialists.[15] Approaches vary.[57] The RCPCH initially outlined a provisional approach to clinical management, including guidance on early medical management, monitoring and some general principles of treatment;[7] for the UK, consensus has since been reached regarding a recommended pathway for clinical management (including access to registered clinical trials).[54] The National Institutes of Health provides some general considerations.[17] The American College of Rheumatology provides guidance for clinical management of MIS-C.[13][5] The American Academy of Pediatrics has also provided some interim guidance.[8] Other proposals have also been made.[9][15][45][57][58] RCPCH guidance recommends that all affected children should be treated as having suspected COVID-19.[7] Little specific information is available regarding therapeutic effectiveness.[17] Most children who have been treated as for Kawasaki disease have recovered.[6] Supportive care is a mainstay of therapy,[17] and for mild or moderate disease it may be sufficient.[7][14] Major complications may respond well to more aggressive supportive care.[12] Cardiac and respiratory support may benefit children who present predominantly with shock.[15] Strategies for clinical management tend to be broadly based on anti-inflammatory medications, treatment of shock, and prevention of thrombosis.[57] Most children have received immunomodulatory treatment with intravenous immunoglobulin (IVIG).[9] Other anti-inflammatory treatments have been used, including corticosteroids at various doses.[9] Good responses have been recorded for IVIG, with or without corticosteroids.[6][14][26] Cases requiring steroids due to resistance to IVIG may be more common than in Kawasaki disease.[42] In a minority of cases,[6] cytokine blockers have been used as a supplemental therapy to inhibit production of IL-6 (tocilizumab) or IL-1 (anakinra); TNF-α-inhibitors (infliximab) have also been used.[9] Inotropic or vasoactive agents are often used for children with cardiac dysfunction and hypotension.[21] Anticoagulants have been used.[21] Low-dose aspirin has been used as an antiplatelet drug.[9][8][14] Treatment strategies are being considered to prevent serious long-term complications such as coronary artery aneurysms (the main complication of Kawasaki disease).[32] Close outpatient follow-up by a paediatric cardiology team has been recommended.[9][8] ## Causes[edit] While it has been hypothesized that the condition is related to COVID-19,[18] it has also been emphasized that the potential link "is neither established nor well understood."[3] A temporal association between SARS-CoV-2 infection and clinical presentation of the syndrome is plausible.[3] A causality assessment found that 'temporality' was among the five (out of nine) Bradford Hill criteria that supported a causal relationship between SARS-CoV-2 infection and the development of the syndrome.[3] Further characterization of the syndrome is essential to identify risk factors and help understand causality.[18] It is unclear to what extent this emerging syndrome has a similar aetiology to Kawasaki disease (a condition predating the emergence of SARS-CoV-2, which is currently thought to be triggered by a distinct viral agent).[10] Although some cases resemble toxic shock syndrome, there is no evidence that staphylococcal or streptococcal toxins are involved.[21] The role of comorbidities is unclear.[9] Improved understanding will have potential implications for clinical management.[59] Genome-wide association studies are expected to provide insights on susceptibility and potential biological mechanisms.[42] ## Mechanism[edit] The pathogenesis is unknown.[1][3] SARS-CoV-2 could have one of several roles; it could act as an environmental trigger for the condition either directly or indirectly (by somehow paving the way for a different trigger).[39] As with Kawasaki disease, antibody-dependent enhancement, whereby development of antibodies could facilitate viral entry into host cells, has been proposed as a potential mechanism.[3][60] Epidemiological considerations make a post-infectious mechanism seem likely,[14][16][10][61] possibly coinciding with the development of acquired immune responses to the virus.[21] It has been suggested that the condition may be caused by the cytokine storms induced by COVID-19.[11][61] The characteristic ability of coronaviruses to block type I and type III interferon responses could help explain a delayed cytokine storm in children whose immune systems struggle to control SARS-CoV-2 viral replication, or are overwhelmed by a high initial viral load.[10] One plausible chain of events leading up to a hyperimmune response could involve early viral triggering of macrophage activation, followed by T helper cell stimulation, in turn leading to cytokine release, stimulation of macrophages, neutrophils, and monocytes, in conjunction with B cell and plasma cell activation, and antibody production.[26] It is unknown to what extent the pathophysiology resembles that of other paediatric inflammatory syndromes that share similar clinical features.[60] Clinical overlaps with syndromes that have different causes (Kawasaki disease, toxic shock, macrophage activation syndrome, and secondary haemophagocytic lymphohistiocytosis) may be explained by immunological activation and dysregulation of similar inflammatory pathways.[62] In each of these syndromes, a cytokine storm leads to failure of multiple organs.[43] They also share with MIS-C and severe cases of COVID-19 high levels both of ferritin (released by neutrophils) and of haemophagocytosis.[43] The frequent gastrointestinal presentation and mesenteric lymph node inflammation are in keeping with the known liking of SARS-CoV-2 to replicate in enterocytes.[10] Association of Kawasaki-like disease with COVID-19 could support the view that SARS-CoV-2 can cause systemic vasculitis by targeting endothelial tissue via angiotensin-converting enzyme 2 (ACE2), the protein which the virus uses to gain access to cells.[63] While the initial infection is known to be capable of causing acute myocardial damage, occurrence of myocarditis could also plausibly be linked to systemic hyperinflammation triggered by a disorderly post-infectious immune response.[9] It has been suggested that SARS-CoV-2 might lead to immune-mediated damage to the heart and coronary arteries via immune complexes or increased T-cell responses.[21] Understanding the pathophysiology is a key research priority.[64] Questions regarding the underlying molecular mechanisms that lead to the disorder following exposure to SARS-CoV-2 include identification of: any genetic predisposition factors; any associations with particular viral variant/s; any molecular patterns capable of triggering the autoimmune/autoinflammatory responses.[42] Another key question is whether the molecular mechanisms that trigger autoimmune/autoinflammatory responses in children with PMIS and adults with severe COVID-19 (including the induction of high concentrations of IL-6) are similar or distinct.[42] A potential link with Kawasaki disease is under discussion.[65] It has been noted that a leading hypothesis for the pathogenesis of Kawasaki disease also involves a hyperinflammatory response to viral infection (such as by a novel RNA virus[41][66]) in some genetically predisposed children, and that SARS-CoV-2 is now "added to the list" of implicated viral triggers.[42] Hopes have been expressed that study of the new condition may help understand the hidden mechanisms behind Kawasaki disease.[32] ## Epidemiology[edit] Epidemiological information is limited, and clinical statistics currently derive from review of case series.[5][16][a] This emerging condition is considered rare.[3] Its incidence is not known.[5][47][b] Based on available reports, the fatality rate among diagnosed cases appears to have been about 1.7% (notably higher than the rate of 0.07% recorded among children with Kawasaki disease in Japan).[6] A rapid risk assessment conducted by the European Centre for Disease Prevention and Control (ECDC) concluded that the overall risk to children in the European Union (EU), European Economic Area (EEA) and the UK "is considered 'low', based on a 'very low' probability of [the disease] in children and a 'high' impact of such disease."[3] Clusters of cases of the newly described condition have been recorded 3–4 weeks after peaks in SARS-CoV-2 viral transmission through various local communities.[14][c] Such observations have been seen to support the concept that SARS-CoV-2 infection may be capable of triggering a severe form of a Kawasaki-like disease.[66] Frequent presentation without prominent respiratory symptoms in children who do not appear to have ongoing SARS-CoV-2 infection but who have already developed antibodies suggests that the disease may be driven by a delayed, post-infectious mechanism.[14] The median age of onset appears to be at least 7 years (compared with 2 years for Kawasaki disease, which primarily affects children under the age of 5).[16] Male children seem to be more frequently affected (broadly in line with Kawasaki disease, where the male to female ratio is about 1.5 to 1).[16] Many affected children appear not to have underlying health conditions, such as asthma or autoimmune disorders, and there have been relatively few reports of known congenital heart disease or preexisting cardiovascular disease.[6][9] Over half (52%) the children with available information had no recorded underlying health condition, including being overweight or obese (among those who did have some comorbidity, 51% were either overweight or obese).[6] Regarding ethnicity, reports from France and the UK raised the possibility that children of Afro-Caribbean descent may be at greater risk, plausibly due to a genetic predisposition.[42] In the US (as of mid-July), the majority of cases were classified as Hispanic/Latino (38%) or non-Hispanic Black (33%) people.[72] Based on reports confined to Europe and the US, the condition seems to affect more children of African, Afro-Caribbean, and Hispanic descent, whereas Kawasaki disease affects more of East Asian and Pacific Islander ancestry.[13][65] The role of socioeconomic and other environmental factors in such discrepancies is unclear.[39] As regards geographical distribution, there has been uncertainty as to whether the initial reports of cases in Europe and North America reflected a true pattern, or whether the condition had gone unrecognized elsewhere.[3][18] In Japan and other Southeast and East Asian countries where Kawasaki disease is usually much more prevalent than in Europe, no case of Kawasaki-like disease linked to COVID-19 had been reported during the first wave of transmission.[3][10][66][73][d] Reports of confirmed or suspected cases have since emerged in many different countries around the world.[21][e] None of the three main provisional case-definitions of the emerging entity is diagnostically specific.[65] Concerns have been raised regarding the potential for missed or delayed diagnosis of Kawasaki disease due to heightened diagnostic suspicion for the new entity.[56] Misclassification of cases of Kawasaki disease and of other inflammatory and infectious diseases of childhood whose case definitions overlap with MIS-C could skew understanding of the new entity, such as the frequency of coronary artery aneurysms.[93][94] Another concern is that clinically less severe cases of the new entity may be missed, and that the actual spectrum of disease severity could be broader,[21][95] especially given the reliance on early observations of severe disease for provisional case definition.[96] Some statistical modeling has been used to explore possible subdivision of cases satisfying the CDC's case definition into three distinct subgroups based on underlying clinical similarities: Class 1, characterized by pronounced multiorgan involvement, with little overlap with Kawasaki disease or acute COVID-19; Class 2, more predominantly characterized by respiratory symptoms typical of acute COVID-19; Class 3, a clinically less severe grouping, where rashes and mucosal symptoms are prevalent, with less multiorgan involvement, and generally greater overlap with Kawasaki disease.[97][49] A suggestion[96] that research into the biology of the disease might benefit from considering cases of Kawasaki disease and of the provisionally defined entity in conjunction is debated.[97] ### In adults[edit] There has been uncertaintly as to whether the condition is confined to children,[15] and the appropriateness of excluding adults from case definitions has been questioned.[98] Sporadic reports exist of a similar life-threatening condition, denominated 'multisystem inflammatory syndrome in adults' (MIS-A), which also usually requires intensive care.[23] ## History[edit] Cases of Kawasaki disease with concurrent SARS-CoV-2 infection have been recorded among children in Europe and in the United States since 7 April 2020, when a report was published by the American Academy of Pediatrics regarding a case of 'classic' Kawasaki disease in a six-month old girl who tested positive for COVID-19 in California.[3][99] In this case, COVID-19 did not appear to have significant clinical implications.[59][99] On 25 April, concerns were initially raised in the United Kingdom regarding a cluster of children of various ages presenting with a multisystem inflammatory state who required intensive care, and who all displayed "overlapping features of toxic shock syndrome and atypical Kawasaki disease with blood parameters consistent with severe COVID-19 in children."[32][100] Details of the eight cases which helped trigger this alert (not all with confirmed exposure to COVID-19) were later reported in The Lancet, where the authors summarized the clinical picture as "a hyperinflammatory syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome."[59][101] Accounts of analogous cases – including some that appeared less clinically severe – were also being informally shared among clinicians around Europe.[32] The EU's Early Warning and Response System flagged suspected cases in Austria, Germany and Portugal that had tested positive for SARS-CoV-2.[3] In Bergamo, at the heart of the COVID-19 epidemic in Lombardy, a cluster of 20 cases of Kawasaki disease appeared to be roughly equivalent to the number commonly recorded there over the course of three years.[59] In France, the government reported on 29 April that around 15 children were in hospital in Paris with symptoms of Kawasaki disease,[59][102] an observation which prompted the organization of national surveillance programme for recent cases of Kawasaki-like disease.[68] On 1 May, the RCPCH published a preliminary case definition based on review of the characteristics of the cases identified in the UK, accompanied by some clinical guidance.[7][32] Two weeks later, on 15 May, two further preliminary case definitions were published separately by the WHO[18] and by the CDC,[1] while the ECDC released a 'rapid risk assessment' of the condition on behalf of the European Union.[3] In the following weeks, further clinical guidance was released by other medical organizations, including the NIH,[17] the American College of Rheumatology,[19] and the American Academy of Pediatrics.[20] On 4 May, the New York City Department of Health and Mental Hygiene issued an alert to identify children with the condition in New York City hospitals,[3] where 15 such cases were already being treated.[103] On 9 May, the governor of New York, Andrew Cuomo announced a collaboration with the CDC to help develop national criteria for identifying and responding to the newly identified childhood disease.[104] By 12 May, some 230 suspected cases had been reported across the EU and EEA, and in the UK[3] (in the following days, sources were reporting up to 100 in the UK,[105] over 135 in France,[106] 20 in the Netherlands,[107] 10 in Switzerland[108] and 10 in Germany[109]). In the United States, more than 200 cases were suspected by mid-May,[110] including some 145 in New York;[111][112] 186 confirmed cases were eventually diagnosed between 15 March and 20 May in 26 US states.[113][114] As of 11 May 2020, five fatalities were reported (1 in France, 1 in the UK, 3 in the US).[3] In peer-reviewed medical journals, case series and related studies of the new condition were rapidly reported from countries including the UK;[115][116] Italy;[69] Spain;[117][118][119] France and Switzerland;[120] France;[4][121][122] and across the US,[113][123] including New York.[67][124][125] The emerging observations suggested somewhat greater variety in the severity of symptoms than was originally thought.[17] The proposal of a new clinical entity during a pandemic also prompted scientific discussion about its possible distinction from Kawasaki disease, and the potential role of COVID-19.[32][52][59][65][66][73][94][96] By 15 July, 342 confirmed MIS-C cases (including 6 deaths) had been recorded in the US across 36 states plus Washington DC.[72][126] Most (71%) of the children were Hispanic/Latino or non-Hispanic Black people, and the CDC underlined the need to learn the reasons for such a preponderance.[72][127] By 29 July, a total of 570 cases and 10 deaths had been reported across 40 states, Washington DC, and New York City.[49] Until late May, no confirmed case had been documented outside the EU/EEA/UK and USA.[3] No suspicious case had been observed in East Asia or Southeast Asia (or in Australia or New Zealand).[73][128][129] The absence of documented cases in China and other Asian countries that had already experienced a COVID-19 epidemic led to conjectures regarding the possibility of a significant evolution of the virus, or variations in susceptibility in different populations.[26] On 2 June, news emerged of a first case of MIS-C diagnosed in Peru.[130][131] In Brazil, cases of MIS-C have been reported in São Paulo,[132] and in the context of a prospective study in Pará;[133] more children with severe late manifestations of COVID-19 were being admitted to paediatric intensive care units in the region.[133] In Chile, 42 confirmed cases of MIS-C had been recorded nationally by June 28, including 27 in the capital, Santiago.[134] In Russia, 13 children had been treated (5 with intensive care) by mid-June for a multisystem inflammatory syndrome at the Morozov Children's Hospital in Moscow, including a 2-year-old girl with the COVID-19 infection who died on 23 May following an initial diagnosis of suspected Kawasaki disease.[78] In Iran, a case report (first submitted in May) described severe MIS-C in a 5-year-old girl who had presented with shock and was initially diagnosed with Kawasaki disease,[85] and further cases of the new syndrome have been recorded.[86] In India, a case of suspected MIS-C was reported in late May regarding a child who had presented in a COVID-19 hotspot in Kerala.[80] An editorial commentary urged clinicians to have a high level of diagnostic suspicion and follow WHO and CDC definitions to facilitate timely identification and treatment of cases.[135] During July, suspected cases were being flagged and reported in Mumbai,[136] in Delhi,[137] Chennai,[79] and elsewhere.[138] In Pakistan,[139] at least 24 children were said to have Kawasaki-like symptoms in Lahore,[140] where 8 cases fulfilling WHO criteria were prospectively identified by 30 June.[81] In Kazakhstan, 14 cases were confirmed by 20 August (among 2,357 children known to have been infected).[82] Cases have been recorded in Israel,[88] including one of a child who presented with severe central nervous system involvement and complement deficiency.[89] In Turkey, four children with a Kawasaki-like disease probably associated with COVID-19 are reported to have been admitted to the children's hospital of Hacettepe University in Ankara between 13 April and 11 July.[84] In Algeria, a first case was recorded in June.[90] In Egypt, on 10 July the authorities denied rumours of the existence of cases of Kawasaki-like disease in the country.[141] In South Africa, the first 23 affected children were treated in Cape Town – the initial epicentre of the national COVID-19 epidemic – between 4 June and 24 July.[91] In Ecuador, the Ministry of Health announced on 19 July the presence of 46 probable cases.[142] In Costa Rica, a national public health organization announced towards the end of August that three children had been diagnosed with MIS-C.[143] Cases of MIS-C had also been recorded in many other Latin American countries, including Argentina, Bolivia, Colombia, Cuba, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Uruguay, and Venezuela, as well as in Puerto Rico.[22] News of a first confirmed case of PIMS-TS in Australia emerged (from Victoria) on 4 September, along with news of other suspected cases under review.[144] In South Korea, news of two confirmed cases broke on 5 October[83] (and the existence of a case dating back to the end of April was reported in November[75]). A similar condition began to be recognized in some adults.[98][23][145] In June, an adult case of a Kawasaki-like multisystem inflammatory syndrome following SARS-CoV-2 infection was described in a 54-year-old woman from Israel with no history of autoimmune disease, who experienced uveitis in both eyes.[146] (A further suspected adult case was covered in the Israeli national press.)[147] A case involving a 36-year-old Hispanic American woman with clinical features otherwise consistent with MIS-C was reported from New York.[148] A diagnosis consistent with PMIS was also reported in a UK-born, 21-year-old man of Somali origin.[149] A case report published in The Lancet regarding a 45-year-old Hispanic man who presented in New York with features strongly resembling MIS-C called for awareness of "a potential MIS-C-like condition in adults."[150] Further reports of multisystem inflammatory syndrome linked to COVID-19 exposure emerged in adults.[145][151][152][153][154] In October, the CDC reported on the condition and named it 'multisystem inflammatory syndrome in adults' (MIS-A).[23] Questions have been raised regarding possible relationships between MIS-C and certain severe manifestations of COVID-19 in adults.[98] ## Notes[edit] 1. ^ Given that hospital case series can be selected on the basis of clinical factors such as presence of heart failure or admission to intensive care units, available statistical information regarding the frequencies of different clinical features may be skewed by selection bias.[47] 2. ^ In the state of New York, about 2 out of 100,000 individuals under 21 years of age are thought to have been affected in conjunction with the COVID-19 epidemic there (with the numbers of new cases peaking 31 days after the local peak in viral infection).[5][67] 3. ^ A nationwide surveillance programme in France, set up to investigate the temporal relationship between SARS-CoV-2 infection and PMIS, revealed that 95 of the 156 cases of Kawasaki-like disease notified between 1 March and 17 May 2020 were "confirmed or probable post-COVID-19 cases", with a peak in incidence 4–5 weeks after the peak of the COVID-19 epidemic in the country.[68] Clinicians in Bergamo, Italy, reported an apparent (not seasonally adjusted[9]) 30-fold increase in the incidence of Kawasaki-like disease during the first six weeks after the arrival there of SARS-CoV-2 virus infection, at a time when Bergamo was experiencing the highest rates of infections and deaths in Italy.[32][69] In the UK, the number of intensive care admissions for children fulfilling the RCPCH case definition of PMIS during 40 days through April and early May, following the first national surge in COVID-19 cases, was at least 11-fold higher than historical trends for paediatric inflammatory conditions.[70] Time series analysis of cases of Kawasaki disease admitted to a paediatric centre in Paris, France, revealed a spike that started 2 weeks after the first peak of the COVID-19 epidemic there, corresponding to a roughly 5-fold increase in incidence.[71] These cases from Paris had a similarly severe clinical profile to those reported in Bergamo (and differed from the more typical Kawasaki disease profile observed in a newly uncovered spike following the peak of the 2009 H1N1 swine flu epidemic in Paris).[71] 4. ^ No apparent rise in new cases of Kawasaki disease was noted in these countries,[42] including in South Korea[74] (where one diagnosis was subsequently reclassified as MIS-C[75]), and in Singapore.[76] There had been no report of Kawasaki disease or Kawasaki-like symptoms in mainland China.[77] 5. ^ An extensive Latin-American Kawasaki disease surveillance network (REKAM-LATINA) has recorded cases of MIS-C across all its participating countries.[22] Some other countries where cases have been reported include Russia,[78] India,[79][80] Pakistan,[81] Kazakhstan,[82] South Korea,[75][83] Turkey,[84] Iran,[85][86] Saudi Arabia,[87] Israel,[88][89] Algeria,[90] South Africa,[91] and Australia.[92] ## References[edit] * Medicine portal * Coronavirus disease 2019 portal 1. ^ a b c d e f g h i "Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19)". emergency.cdc.gov. Centers for Disease Control and Prevention. 14 May 2020. Archived from the original on 15 May 2020. 2. ^ a b c "Case Report Form for suspected cases of multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19". www.who.int. World Health Organization. Archived from the original on 24 June 2020. 3. ^ 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 "Rapid risk assessment: Paediatric inflammatory multisystem syndrome and SARS-CoV-2 infection in children" (PDF). European Centre for Disease Prevention and Control. 15 May 2020. Archived from the original on 15 May 2020. 4. ^ a b c Pouletty M, Borocco C, Ouldali N, et al. (June 2020). "Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort". Annals of the Rheumatic Diseases. 79 (8): 999–1006. doi:10.1136/annrheumdis-2020-217960. PMC 7299653. PMID 32527868. S2CID 219607184. 5. ^ a b c d e f g h i j k l m n o p q Henderson LA, Canna SW, Friedman KG, et al. (July 2020). "American College of Rheumatology clinical guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19. Version 1". Arthritis & Rheumatology. 72 (11): 1791–1805. doi:10.1002/art.41454. PMC 7405113. PMID 32705809. 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 ai aj ak al Ahmed M, Advani S, Moreira A, et al. (September 2020). "Multisystem inflammatory syndrome in children: a systematic review". EClinicalMedicine. 26: 100527. doi:10.1016/j.eclinm.2020.100527. ISSN 2589-5370. PMC 7473262. PMID 32923992. S2CID 221494176. 7. ^ a b c d e f g h i j k l m n o p q "Guidance - Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS)". RCPCH. Royal College of Paediatrics and Child Health. May 2020. Archived from the original on 16 June 2020. 8. ^ a b c d e f g h i j k l m n o p q "Multisystem inflammatory syndrome in children (MIS-C) interim guidance". services.aap.org. American Academy of Pediatrics. July 2020. Archived from the original on 17 July 2020. 9. ^ 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 Sperotto F, Friedman KG, Son MB, et al. (2020). "Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: a comprehensive review and proposed clinical approach". European Journal of Pediatrics. doi:10.1007/s00431-020-03766-6. PMC 7429125. PMID 32803422. 10. ^ a b c d e f g h i j k Rowley AH (June 2020). "Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children". Nature Reviews. Immunology. 20 (8): 453–454. doi:10.1038/s41577-020-0367-5. PMC 7296515. PMID 32546853. 11. ^ a b Alunno A, Carubbi F, Rodríguez-Carrio J (2020). "Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm that has a different origin". RMD Open. 6 (1): e001295. doi:10.1136/rmdopen-2020-001295. PMC 7299508. PMID 32423970. 12. ^ a b c d e Aronoff SC, Hall A, Del Vecchio MT (September 2020). "The natural history of SARS-Cov-2 related multisystem inflammatory syndrome in children (MIS-C): a systematic review". Journal of the Pediatric Infectious Diseases Society. doi:10.1093/jpids/piaa112. PMID 32924059. 13. ^ a b c d e f g h ACR MIS-C and COVID-19 Related Hyperinflammation Task Force (17 June 2020). "Clinical guidance for pediatric patients with multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19" (PDF). rheumatology.org. American College of Rheumatology. Archived (PDF) from the original on 25 June 2020. 14. ^ a b c d e f g h i j k l m n o p Rajapakse N, Dixit D (June 2020). "Human and novel coronavirus infections in children: a review". Paediatrics and International Child Health: 1–20. doi:10.1080/20469047.2020.1781356. PMID 32584199. 15. ^ a b c d e f g Hennon TR, Penque MD, Abdul-Aziz R, et al. (May 2020). "COVID-19 associated multisystem inflammatory syndrome in children (MIS-C) guidelines; a Western New York approach". Progress in Pediatric Cardiology. 57: 101232. doi:10.1016/j.ppedcard.2020.101232. PMC 7244417. PMID 32837142. 16. ^ a b c d e f g h i j k l Abrams JY, Godfred-Cato SE, Oster ME, et al. (August 2020). "Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: a systematic review". The Journal of Pediatrics. doi:10.1016/j.jpeds.2020.08.003. PMC 7403869. PMID 32768466. 17. ^ a b c d e f g h i "Special Considerations in Children". NIH - COVID-19 Treatment Guidelines. National Institutes of Health. 11 June 2020. Archived from the original on 19 July 2020. 18. ^ a b c d e f g h i j "Multisystem inflammatory syndrome in children and adolescents with COVID-19: scientific brief". www.who.int. World Health Organization. Archived from the original on 15 May 2020. 19. ^ a b Pond, E (20 July 2020). "ACR guidelines for the management of pediatric multisystem inflammatory syndrome associated with SARS-CoV-2". Rheumatology Advisor. Archived from the original on 21 July 2020. 20. ^ a b Hester, M (21 July 2020). "AAP issues interim guidance for MIS-C". Contemporary Pediatrics. Archived from the original on 21 July 2020. 21. ^ a b c d e f g h i j k l Jiang L, Tang K, Levin M, et al. (August 2020). "COVID-19 and multisystem inflammatory syndrome in children and adolescents". Lancet Infectious Diseases. 20 (11): e276–e288. doi:10.1016/S1473-3099(20)30651-4. PMC 7431129. PMID 32818434. 22. ^ a b c Ulloa-Gutierrez R, Ivankovich-Escoto G, Yock-Corrales A, Tremoulet AH (September 2020). "Multisystem inflammatory syndrome (MIS-C) surveillance and COVID-19 in Latin America". The Pediatric Infectious Disease Journal. 39 (12): e473–e474. doi:10.1097/INF.0000000000002901. PMID 32947601. 23. ^ a b c d Morris SB, Schwartz NG, Patel P, et al. (October 2020). "Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection - United Kingdom and United States, March-August 2020". MMWR. Morbidity and Mortality Weekly Report. 69 (40): 1450–1456. doi:10.15585/mmwr.mm6940e1. PMC 7561225. PMID 33031361. 24. ^ Lu X, Zhang L, Du H, et al. (April 2020). "SARS-CoV-2 infection in children". The New England Journal of Medicine. 382 (17): 1663–1665. doi:10.1056/NEJMc2005073. PMC 7121177. PMID 32187458. 25. ^ Zimmermann P, Curtis N (May 2020). "Coronavirus infections in children including COVID-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children". The Pediatric Infectious Disease Journal. 39 (5): 355–368. doi:10.1097/INF.0000000000002660. PMC 7158880. PMID 32310621. 26. ^ a b c d e f g h Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S (July 2020). "Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: review of clinical presentation, hypothetical pathogenesis, and proposed management". Children. 7 (7): 69. doi:10.3390/children7070069. PMC 7401880. PMID 32630212. 27. ^ a b Hoang A, Chorath K, Moreira A, et al. (July 2020). "COVID-19 in 7780 pediatric patients: a systematic review". EClinicalMedicine. 24: 100433. doi:10.1016/j.eclinm.2020.100433. PMC 7318942. PMID 32766542. 28. ^ a b Yasuhara J, Kuno T, Takagi H, Sumitomo N (July 2020). "Clinical characteristics of COVID-19 in children: a systematic review". Pediatric Pulmonology. 55 (10): 2565–2575. doi:10.1002/ppul.24991. PMID 32725955. 29. ^ Jeng MJ (June 2020). "Coronavirus disease 2019 in children: current status". Journal of the Chinese Medical Association. 83 (6): 527–533. doi:10.1097/JCMA.0000000000000323. PMC 7199766. PMID 32502117. 30. ^ Choi SH, Kim HW, Kang JM, et al. (April 2020). "Epidemiology and clinical features of coronavirus disease 2019 in children". Clinical and Experimental Pediatrics. 63 (4): 125–132. doi:10.3345/cep.2020.00535. PMC 7170785. PMID 32252139. 31. ^ Castagnoli R, Votto M, Licari A, et al. (April 2020). "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review". JAMA Pediatrics. 174 (9): 882–889. doi:10.1001/jamapediatrics.2020.1467. PMID 32320004. 32. ^ a b c d e f g h i Viner RM, Whittaker E (2020). "Kawasaki-like disease: emerging complication during the COVID-19 pandemic". The Lancet. 395 (10239): 1741–1743. doi:10.1016/S0140-6736(20)31129-6. PMC 7220168. PMID 32410759. 33. ^ Wolff AE, Hansen KE, Zakowski L (May 2007). "Acute Kawasaki disease: not just for kids". Journal of General Internal Medicine. 22 (5): 681–4. doi:10.1007/s11606-006-0100-5. PMC 1852903. PMID 17443379. 34. ^ a b Dietz SM, van Stijn D, Burgner D, et al. (2017). "Dissecting Kawasaki disease: a state-of-the-art review". European Journal of Pediatrics. 176 (8): 995–1009. doi:10.1007/s00431-017-2937-5. PMC 5511310. PMID 28656474. 35. ^ "Kawasaki Disease". PubMed Health. NHLBI Health Topics. 11 June 2014. Archived from the original on 11 September 2017. Retrieved 26 August 2016. 36. ^ Brogan P, Burns JC, Cornish J, et al. (2020). "Lifetime cardiovascular management of patients with previous Kawasaki disease". Heart. 106 (6): 411–420. doi:10.1136/heartjnl-2019-315925. PMC 7057818. PMID 31843876. 37. ^ a b c d Walker DM, Tolentino VR (June 2020). "COVID-19: The impact on pediatric emergency care". Pediatric Emergency Medicine Practice. 17 (Suppl 6-1): 1–27. PMID 32496723. 38. ^ Taddio A, Rossi ED, Monasta L, et al. (2017). "Describing Kawasaki shock syndrome: results from a retrospective study and literature review". Clinical Rheumatology. 36 (1): 223–228. doi:10.1007/s10067-016-3316-8. PMID 27230223. S2CID 1104479. 39. ^ a b c McCrindle BW, Manlhiot C (2020). "SARS-CoV-2-related inflammatory multisystem syndrome in children: different or shared etiology and pathophysiology as Kawasaki disease?". JAMA. 324 (3): 246–248. doi:10.1001/jama.2020.10370. PMID 32511667. 40. ^ Marrani E, Burns JC, Cimaz R (2018). "How should we classify Kawasaki disease?". Frontiers in Immunology. 9: 2974. doi:10.3389/fimmu.2018.02974. PMC 6302019. PMID 30619331. 41. ^ a b c McCrindle BW, Rowley AH, Newburger JW, et al. (2017). "Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association". Circulation. 135 (17): e927–e999. doi:10.1161/CIR.0000000000000484. PMID 28356445. 42. ^ a b c d e f g h i Galeotti C, Bayry J (2020). "Autoimmune and inflammatory diseases following COVID-19". Nature Reviews. Rheumatology. 16 (8): 413–414. doi:10.1038/s41584-020-0448-7. PMC 7271827. PMID 32499548. 43. ^ a b c d e f g h Junior HS, Sakano TM, Rodrigues RM, et al. (September 2020). "Multisystem inflammatory syndrome associated with COVID-19 from the pediatric emergency physician's point of view". Jornal de Pediatria. doi:10.1016/j.jped.2020.08.004. PMC 7486073. PMID 32946801. 44. ^ Kaya G, Kaya A, Saurat JH (June 2020). "Clinical and histopathological features and potential pathological mechanisms of skin lesions in COVID-19: review of the literature". Dermatopathology. 7 (1): 3–16. doi:10.3390/dermatopathology7010002. PMC 7583593. PMID 32608380. 45. ^ a b Kache S, Chisti MJ, Gumbo F, et al. (July 2020). "COVID-19 PICU guidelines: for high- and limited-resource settings". Pediatric Research. 88 (5): 705–716. doi:10.1038/s41390-020-1053-9. PMC 7577838. PMID 32634818. 46. ^ Chen TH (August 2020). "Neurological involvement associated with COVID-19 infection in children". Journal of the Neurological Sciences. 418: 117096. doi:10.1016/j.jns.2020.117096. PMC 7423535. PMID 32823135. 47. ^ a b c d e Alsaied T, Tremoulet AH, Burns JC, et al. (November 2020). "Review of cardiac involvement in multisystem inflammatory syndrome in children". Circulation. doi:10.1161/CIRCULATIONAHA.120.049836. PMID 33166178. 48. ^ Rodríguez Y, Novelli L, Rojas M, et al. (June 2020). "Autoinflammatory and autoimmune conditions at the crossroad of COVID-19". Journal of Autoimmunity. 114: 102506. doi:10.1016/j.jaut.2020.102506. PMC 7296326. PMID 32563547. 49. ^ a b c Godfred-Cato S, Bryant B, Leung J, et al. (August 2020). "COVID-19-associated multisystem inflammatory syndrome in children - United States, March-July 2020". MMWR. Morbidity and Mortality Weekly Report. 69 (32): 1074–1080. doi:10.15585/mmwr.mm6932e2. PMC 7440126. PMID 32790663. 50. ^ a b "Multisystem inflammatory syndrome (MIS-C) clinical pathway – emergency, ICU and inpatient". www.chop.edu. The Children's Hospital of Philadelphia. 20 May 2020. Archived from the original on 26 June 2020. 51. ^ "For parents: multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19". cdc.com. Centers for Disease Control and Prevention. 20 May 2020. Archived from the original on 1 September 2020. 52. ^ a b c d Kanthimathinathan HK, Scholefield BR (September 2020). "Pediatric inflammatory multisystem syndrome: time to collaborate". Journal of the Pediatric Infectious Diseases Society. doi:10.1093/jpids/piaa105. PMC 7543404. PMID 32945863. 53. ^ Newburger, JW (15 May 2020). "Pediatric hyperinflammatory syndrome and COVID-19: statement and recommendations from a pediatric intensive care international collaborative conference call". www.acc.org. American College of Cardiology. Archived from the original on 19 May 2020. 54. ^ a b Harwood R, Allin B, Jones CE, et al. (September 2020). "A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process". The Lancet Child & Adolescent Health. doi:10.1016/S2352-4642(20)30304-7. ISSN 2352-4642. PMC 7500943. PMID 32956615. 55. ^ Harwood R, Partridge R, Minford J, Almond S (September 2020). "Paediatric abdominal pain in the time of COVID-19: a new diagnostic dilemma". Journal of Surgical Case Reports. 2020 (9): rjaa337. doi:10.1093/jscr/rjaa337. PMC 7505408. PMID 32994918. 56. ^ a b Harahsheh AS, Dahdah N, Newburger JW, et al. (May 2020). "Missed or delayed diagnosis of Kawasaki disease during the 2019 novel coronavirus disease (COVID-19) pandemic". The Journal of Pediatrics. 222: 261–262. doi:10.1016/j.jpeds.2020.04.052. PMC 7196408. PMID 32370951. 57. ^ a b c Elias MD, McCrindle BW, Larios G, et al. (September 2020). "Management of multisystem inflammatory syndrome in children associated with COVID-19: a survey from the International Kawasaki Disease Registry". CJC Open. 2 (6): 632–640. doi:10.1016/j.cjco.2020.09.004. PMC 7484693. PMID 32935083. 58. ^ García-Salido A, Antón J, Martínez-Pajares JD, et al. (October 2020). "[Spanish consensus document on diagnosis, stabilisation and treatment of pediatric multisystem inflammatory syndrome related to SARS-CoV-2 (SIM-PedS)]". Anales de Pediatria (in Spanish). doi:10.1016/j.anpedi.2020.09.005. PMC 7604157. PMID 33132066. 59. ^ a b c d e f Schroeder AR, Wilson KM, Ralston SL (2020). "COVID-19 and Kawasaki disease: finding the signal in the noise" (PDF). Hospital Pediatrics. 10 (10): e1–e3. doi:10.1542/hpeds.2020-000356 (inactive 26 December 2020). PMID 32404331.CS1 maint: DOI inactive as of December 2020 (link) 60. ^ a b Tanner T, Wahezi DM (July 2020). "Hyperinflammation and the utility of immunomodulatory medications in children with COVID-19". Paediatric Respiratory Reviews. 35: 81–87. doi:10.1016/j.prrv.2020.07.003. PMC 7387280. PMID 32792288. 61. ^ a b Fialkowski A, Gernez Y, Arya P, et al. (July 2020). "Insight into the pediatric and adult dichotomy of COVID-19: age-related differences in the immune response to SARS-CoV-2 infection". Pediatric Pulmonology. 55 (10): 2556–2564. doi:10.1002/ppul.24981. PMID 32710693. 62. ^ Radia T, Williams N, Agrawal P, et al. (August 2020). "Multi-system inflammatory syndrome in children & adolescents (MIS-C): a systematic review of clinical features and presentation". Paediatric Respiratory Reviews. doi:10.1016/j.prrv.2020.08.001. PMC 7417920. PMID 32891582. 63. ^ Sardu C, Gambardella J, Morelli MB, et al. (2020). "Hypertension, thrombosis, kidney failure, and diabetes: is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence". Journal of Clinical Medicine. 9 (5): 1417. doi:10.3390/jcm9051417. PMC 7290769. PMID 32403217. 64. ^ Irfan O, Tang K, Arii M, Bhutta ZA (June 2020). "Epidemiology, spectrum, and impact of COVID-19 on children, adolescents, and pregnant women" (PDF). ipa-world.org (Joint IPA-UNICEF COVID-19 information brief). International Pediatric Association, UNICEF. Retrieved 25 November 2020. 65. ^ a b c d Loke YH, Berul CI, Harahsheh AS (July 2020). "Multisystem inflammatory syndrome in children: is there a linkage to Kawasaki Disease?". Trends in Cardiovascular Medicine. 30 (7): 389–396. doi:10.1016/j.tcm.2020.07.004. PMC 7370900. PMID 32702413. 66. ^ a b c d Kam KQ, Ong JS, Lee JH (July 2020). "Kawasaki disease in the COVID-19 era: a distinct clinical phenotype?". The Lancet. Child & Adolescent Health. 4 (9): 642–643. doi:10.1016/S2352-4642(20)30207-8. PMID 32622377. 67. ^ a b Dufort EM, Koumans EH, Chow EJ, et al. (June 2020). "Multisystem inflammatory syndrome in children in New York State". The New England Journal of Medicine. 383 (4): 347–358. doi:10.1056/NEJMoa2021756. PMC 7346766. PMID 32598830. 68. ^ a b Belot A, Antona D, Renolleau S, et al. (2020). "SARS-CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020". Eurosurveillance. European Communicable Disease Bulletin. 25 (22). doi:10.2807/1560-7917.ES.2020.25.22.2001010. PMC 7336112. PMID 32524957. 69. ^ a b Verdoni L, Mazza A, Gervasoni A, et al. (2020). "An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study". The Lancet. 395 (10239): 1771–1778. doi:10.1016/S0140-6736(20)31103-X. PMC 7220177. PMID 32410760. 70. ^ Davies P, Evans C, Kanthimathinathan HK, et al. (July 2020). "Intensive care admissions of children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the UK: a multicentre observational study". The Lancet. Child & Adolescent Health. 4 (9): 669–677. doi:10.1016/S2352-4642(20)30215-7. PMC 7347350. PMID 32653054. 71. ^ a b Ouldali N, Pouletty M, Mariani P, et al. (July 2020). "Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a time-series analysis". The Lancet. Child & Adolescent Health. 4 (9): 662–668. doi:10.1016/S2352-4642(20)30175-9. PMC 7332278. PMID 32622376. 72. ^ a b c "Multisystem Inflammatory Syndrome in Children (MIS-C)". cdc.com. Centers for Disease Control and Prevention. 15 July 2020. Archived from the original on 17 July 2020. "As of 7/15/2020, CDC has received reports of 342 cases and 6 deaths in 37 jurisdictions... the majority of MIS-C patients have been Hispanic/Latino or Non-Hispanic Black....Additional studies into MIS-C are needed to learn why certain racial or ethnic groups may be affected in greater numbers..." 73. ^ a b c Wiwanitkit V (June 2020). "COVID-19 and Kawasaki syndrome". Cardiology in the Young. 30 (9): 1372. doi:10.1017/S1047951120001894. PMC 7322145. PMID 32618551. 74. ^ Kim YJ, Park H, Choi YY, et al. (June 2020). "Defining association between COVID-19 and the multisystem inflammatory syndrome in children through the pandemic". Journal of Korean Medical Science. 35 (22): e204. doi:10.3346/jkms.2020.35.e204. PMC 7279946. PMID 32508068. 75. ^ a b c Kim H, Shim JY, Ko JH, et al. (November 2020). "Multisystem inflammatory syndrome in children related to COVID-19: the first case in Korea". Journal of Korean Medical Science. 35 (43): e391. doi:10.3346/jkms.2020.35.e391. PMC 7653165. PMID 33169560. 76. ^ Yung CF, Nadua KD, Oh BK, Thoon KC (July 2020). "Epidemiological trends in Kawasaki disease during COVID-19 in Singapore". The Journal of Pediatrics. doi:10.1016/j.jpeds.2020.07.063. PMC 7380241. PMID 32717229. 77. ^ Xu S, Chen M, Weng J (May 2020). "COVID-19 and Kawasaki disease in children". Pharmacological Research. 159: 104951. doi:10.1016/j.phrs.2020.104951. PMC 7247462. PMID 32464327. 78. ^ a b Семенова, Мария (17 June 2020). "В Москве умер первый ребенок из-за новой болезни, вызванной COVID-19" (in Russian). RIA Novosti. Retrieved 18 June 2020. 79. ^ a b Dhanalakshmi K, Venkataraman A, Balasubramanian S, et al. (August 2020). "Epidemiological and clinical profile of pediatric inflammatory multisystem syndrome - temporally associated with SARS-CoV-2 (PIMS-TS) in Indian children". Indian Pediatrics. 57 (11): 1010–1014. doi:10.1007/s13312-020-2025-1. PMC 7678572. PMID 32769230. 80. ^ a b Rauf A, Vijayan A, John ST, Krishnan R, Latheef A (May 2020). "Multisystem inflammatory syndrome with features of atypical Kawasaki disease during COVID-19 pandemic". Indian Journal of Pediatrics. 87 (9): 745–747. doi:10.1007/s12098-020-03357-1. PMID 32462354. 81. ^ a b Sadiq M, Aziz OA, Kazmi U (August 2020). "Multisystem inflammatory syndrome associated with COVID-19 in children in Pakistan". The Lancet Child & Adolescent Health. 4 (10): e36–e37. doi:10.1016/S2352-4642(20)30256-X. PMC 7417160. PMID 32791052. 82. ^ a b Ali M (20 August 2020). "Kazakh ministry refutes claims about Kawasaki syndrome outbreak in children amid COVID-19". www.urdupoint.com. UrduPoint. Archived from the original on 21 August 2020. 83. ^ a b "S. Korea confirms 2 MIS-C cases". Yonhap News Agency. 5 October 2020. Archived from the original on 31 October 2020. 84. ^ a b Akca UK, Kesici S, Ozsurekci Y, et al. (September 2020). "Kawasaki-like disease in children with COVID-19". Rheumatology International. 40 (12): 2105–2115. doi:10.1007/s00296-020-04701-6. PMC 7492688. PMID 32936318. 85. ^ a b Bahrami A, Vafapour M, Moazzami B, Rezaei N (July 2020). "Hyperinflammatory shock related to COVID-19 in a patient presenting with multisystem inflammatory syndrome in children: first case from Iran". Journal of Paediatrics and Child Health. doi:10.1111/jpc.15048. PMC 7361532. PMID 32640066. 86. ^ a b Mamishi S, Heydari H, Aziz-Ahari A, et al. (August 2020). "Novel coronavirus disease 2019 (COVID-19) outbreak in children in Iran: atypical CT manifestations and mortality risk of severe COVID-19 infection". Journal of Microbiology, Immunology, and Infection. doi:10.1016/j.jmii.2020.07.019. PMC 7406416. PMID 32814650. 87. ^ Al Ameer HH, AlKadhem SM, Busaleh F, et al. (September 2020). "Multisystem inflammatory syndrome in children temporally related to COVID-19: a case report from Saudi Arabia". Cureus. 12 (9): e10589. doi:10.7759/cureus.10589. PMC 7580961. PMID 33110725. 88. ^ a b "New inflammatory syndrome". Sheba Medical Center. 25 May 2020. Archived from the original on 11 July 2020. 89. ^ a b Regev T, Antebi M, Eytan D, et al. (June 2020). "Pediatric inflammatory multisystem syndrome with central nervous system involvement and hypocomplementemia following SARS-CoV-2 infection". The Pediatric Infectious Disease Journal. 39 (8): e206–e207. doi:10.1097/INF.0000000000002804. PMID 32639461. 90. ^ a b Saada H. "Algeria registers first case of Kawasaki disease". DZ Breaking. Archived from the original on 11 July 2020. 91. ^ a b Webb K, Abraham DR, Faleye A, et al. (August 2020). "Multisystem inflammatory syndrome in children in South Africa". The Lancet Child & Adolescent Health. 4 (10): S2352464220302728. doi:10.1016/S2352-4642(20)30272-8. PMC 7442431. PMID 32835654. S2CID 221217603. 92. ^ COVID-19 National Incident Room Surveillance Team (September 2020). "COVID-19, Australia: Epidemiology Report 25 (Fortnightly reporting period ending 13 September 2020)". Communicable Diseases Intelligence. 44. doi:10.33321/cdi.2020.44.77. PMID 32981492.CS1 maint: uses authors parameter (link) 93. ^ Rowley AH (July 2020). "Diagnosing SARS-CoV-2 related multisystem inflammatory syndrome in children (MIS-C): focus on the gastrointestinal tract and the myocardium". Clinical Infectious Diseases. doi:10.1093/cid/ciaa1080. PMC 7454389. PMID 32717055. 94. ^ a b Rowley AH (June 2020). "Multisystem inflammatory syndrome in children and Kawasaki disease: two different illnesses with overlapping clinical features". The Journal of Pediatrics. 224: 129–132. doi:10.1016/j.jpeds.2020.06.057. PMC 7308002. PMID 32585239. 95. ^ Levin M (June 2020). "Childhood multisystem inflammatory syndrome - a new challenge in the pandemic". The New England Journal of Medicine. 383 (4): 393–395. doi:10.1056/NEJMe2023158. PMC 7346677. PMID 32598829. 96. ^ a b c Yeung RS, Ferguson PJ (July 2020). "Is multisystem inflammatory syndrome in children on the Kawasaki syndrome spectrum?". The Journal of Clinical Investigation. 130 (11): 5681–5684. doi:10.1172/JCI141718. PMC 7598074. PMID 32730226. 97. ^ a b Rowley AH, Shulman ST, Arditi M (September 2020). "Immune pathogenesis of COVID-19-related multisystem inflammatory syndrome in children (MIS-C)". The Journal of Clinical Investigation. 130 (11): 5619–5621. doi:10.1172/JCI143840. PMC 7598032. PMID 32870815. 98. ^ a b c Most ZM, Hendren N, Drazner MH, Perl TM (August 2020). "The striking similarities of multisystem inflammatory syndrome in children and a myocarditis-like syndrome in adults: overlapping manifestations of COVID-19". Circulation. doi:10.1161/CIRCULATIONAHA.120.050166. PMID 32787714. 99. ^ a b Jones VG, Mills M, Suarez D, et al. (2020). "COVID-19 and Kawasaki disease: novel virus and novel case" (PDF). Hospital Pediatrics. 10 (6): 537–540. doi:10.1542/hpeds.2020-0123. PMID 32265235. S2CID 215406465. 100. ^ Mahase E (2020). "COVID-19: concerns grow over inflammatory syndrome emerging in children". BMJ. 369: m1710. doi:10.1136/bmj.m1710. PMID 32345602. "The alert, which relayed information from NHS England, said, 'It has been reported that over the past three weeks there has been an apparent rise in the number of children of all ages presenting with a multisystem inflammatory state requiring intensive care across London and other regions of the UK.'" 101. ^ Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P (7 May 2020). "Hyperinflammatory shock in children during COVID-19 pandemic". The Lancet. 395 (10237): 1607–1608. doi:10.1016/S0140-6736(20)31094-1. PMC 7204765. PMID 32386565. "During a period of 10 days in mid-April, 2020, we noted an unprecedented cluster of eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, or toxic shock syndrome (typical number is one or two children per week). This case cluster formed the basis of a national alert." 102. ^ "Rising cases of kids with Kawasaki disease possibly linked to coronavirus". Kyodo News. 30 April 2020. Archived from the original on 13 May 2020. Retrieved 22 May 2020. 103. ^ Daskalakis, DC (4 May 2020). "2020 Health alert #13: pediatric multi-system inflammatory syndrome potentially associated with COVID-19" (PDF). NYC Health. Archived (PDF) from the original on 6 May 2020. 104. ^ "Governor Cuomo announces State is helping to develop the national criteria for identifying and responding to COVID-related illness in children". Governor Andrew M. Cuomo. 9 May 2020. Archived from the original on 10 May 2020. 105. ^ "Coronavirus: Children affected by rare Kawasaki-like disease". BBC News. 14 May 2020. Retrieved 24 May 2020. 106. ^ d'Adhémar, Margaux (15 May 2020). "Coronavirus : 135 enfants français atteints d'une forme proche de la maladie de Kawasaki, un mort". Le Figaro.fr (in French). Retrieved 16 May 2020. 107. ^ Deloughry, Rachel (26 May 2020). "20 children in the Netherlands contract illness thought to be linked to COVID-19". www.iamexpat.nl. Retrieved 27 May 2020. 108. ^ "COVID-19 Fragen und Antworten Teil 11". Paediatrica (in German). 12 May 2020. Retrieved 16 May 2020. 109. ^ Irmer, Juliette (15 May 2020). ""Kawasaki" durch Covid-19?: Auch deutsche Kinder mit schweren Entzündungsreaktionen". Faz.net (in German). Retrieved 16 May 2020. 110. ^ "With over 200 possible cases, doctors warn reports of rare, coronavirus-linked child inflammatory illness likely to rise". ABC News. 15 May 2020. Retrieved 16 May 2020. 111. ^ McNamara, Audrey (13 May 2020). "15 states now investigating child illness possibly linked to coronavirus, Cuomo says". www.cbsnews.com. Retrieved 14 May 2020. 112. ^ Marsh, Julia; Musumeci, Natalie (18 May 2020). "145 NYC kids have rare Kawasaki-like disease linked to coronavirus". New York Post. Retrieved 19 May 2020. 113. ^ a b Feldstein LR, Rose EB, Horwitz SM, et al. (June 2020). "Multisystem inflammatory syndrome in U.S. children and adolescents". The New England Journal of Medicine. 383 (4): 334–346. doi:10.1056/NEJMoa2021680. PMC 7346765. PMID 32598831. 114. ^ "Infographic: Early Cases of MIS-C: Multi-System Inflammatory Syndrome in U.S. Children". cdc.gov. Centers for Disease Control and Prevention. 9 July 2020. Archived from the original on 10 July 2020. 115. ^ Whittaker E, Bamford A, Kenny J, et al. (June 2020). "Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2". JAMA. 324 (3): 259–269. doi:10.1001/jama.2020.10369. PMC 7281356. PMID 32511692. 116. ^ Ramcharan T, Nolan O, Lai CY, et al. (June 2020). "Paediatric inflammatory multisystem syndrome: temporally associated with SARS-CoV-2 (PIMS-TS): cardiac features, management and short-term outcomes at a UK tertiary paediatric hospital". Pediatric Cardiology. 41 (7): 1391–1401. doi:10.1007/s00246-020-02391-2. PMC 7289638. PMID 32529358. 117. ^ Cabrero-Hernández M, García-Salido A, Leoz-Gordillo I, et al. (May 2020). "Severe SARS-CoV-2 infection in children with suspected acute abdomen: a case series from a tertiary hospital in Spain". The Pediatric Infectious Disease Journal. 39 (8): e195–e198. doi:10.1097/INF.0000000000002777. PMID 32467457. S2CID 218984945. 118. ^ Moraleda C, Serna-Pascual M, et al. (July 2020). "Multi-inflammatory syndrome in children related to SARS-CoV-2 in Spain". Clinical Infectious Diseases. doi:10.1093/cid/ciaa1042. PMC 7454331. PMID 32710613. 119. ^ Pino R, Izurieta AC, Ríos-Barnés M, et al. (August 2020). "Correspondence on: 'Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort' by Pouletty et al". Annals of the Rheumatic Diseases: annrheumdis-2020-218538. doi:10.1136/annrheumdis-2020-218538. PMID 32759264. 120. ^ Belhadjer Z, Méot M, Bajolle F, et al. (2020). "Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic". Circulation. 142 (5): 429–436. doi:10.1161/CIRCULATIONAHA.120.048360. PMID 32418446. 121. ^ Grimaud M, Starck J, Levy M, et al. (June 2020). "Acute myocarditis and multisystem inflammatory emerging disease following SARS-CoV-2 infection in critically ill children". Annals of Intensive Care. 10 (1): 69. doi:10.1186/s13613-020-00690-8. PMC 7266128. PMID 32488505. 122. ^ Toubiana J, Poirault C, Corsia A, et al. (June 2020). "Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study". BMJ. 369: m2094. doi:10.1136/bmj.m2094. PMC 7500538. PMID 32493739. 123. ^ Chiotos K, Bassiri H, Behrens EM, et al. (May 2020). "Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series". Journal of the Pediatric Infectious Diseases Society. 9 (3): 393–398. doi:10.1093/jpids/piaa069. PMC 7313950. PMID 32463092. 124. ^ Kaushik S, Aydin SI, Derespina KR, et al. (June 2020). "Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 infection: a multi-institutional study from New York City". The Journal of Pediatrics. 224: 24–29. doi:10.1016/j.jpeds.2020.06.045. PMC 7293760. PMID 32553861. 125. ^ Cheung EW, Zachariah P, Gorelik M, et al. (June 2020). "Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City". JAMA. 324 (3): 294–296. doi:10.1001/jama.2020.10374. PMC 7281352. PMID 32511676. 126. ^ "U.S. counts 342 child inflammatory syndrome cases". TribLIVE.com. Associated Press. 16 July 2020. Archived from the original on 17 July 2020. 127. ^ Jenco M (16 July 2020). "CDC: 71% of MIS-C patients Hispanic or Black". AAP News. American Academy of Pediatrics. Archived from the original on 17 July 2020. 128. ^ "Australian Health Protection Principal Committee (AHPPC) coronavirus (COVID-19) statements on 14 May 2020". Australian Government Department of Health. 15 May 2020. Archived from the original on 24 May 2020. 129. ^ Barraclough B (18 May 2020). "Chances of Kiwi kids contracting mysterious syndrome linked to Covid-19 'very low', but authorities on the lookout". TVNZ. Archived from the original on 2 June 2020. 130. ^ Yáñez JA, Alvarez-Risco A, Delgado-Zegarra J (June 2020). "COVID-19 in Peru: from supervised walks for children to the first case of Kawasaki-like syndrome". BMJ. 369: m2418. doi:10.1136/bmj.m2418. PMID 32571770. S2CID 219970740. 131. ^ "COVID-19: aparece primer caso de Kawasaki en Perú". Panamericana Televisión (in Spanish). 2 June 2020. Archived from the original on 10 June 2020. 132. ^ Pereira MF, Litvinov N, Farhat SC, et al. (2020). "Severe clinical spectrum with high mortality in pediatric patients with COVID-19 and multisystem inflammatory syndrome". Clinics (Sao Paulo). 75: e2209. doi:10.6061/clinics/2020/e2209 (inactive 26 December 2020). PMC 7426591. PMID 32844958.CS1 maint: DOI inactive as of December 2020 (link) 133. ^ a b de Farias EC, Pedro Piva J, de Mello ML, et al. (August 2020). "Multisystem inflammatory syndrome associated with coronavirus disease in children: a multi-centered study in Belém, Pará, Brazil". The Pediatric Infectious Disease Journal. 39 (11): e374–e376. doi:10.1097/INF.0000000000002865. PMID 32826724. 134. ^ Torres JP, Izquierdo G, Acuña M, et al. (August 2020). "Multisystem inflammatory syndrome in children (MIS-C): report of the clinical and epidemiological characteristics of cases in Santiago de Chile during the SARS-CoV-2 pandemic". International Journal of Infectious Diseases. 0: 75–81. doi:10.1016/j.ijid.2020.08.062. PMC 7452906. PMID 32861823. 135. ^ Shah SK, Munoz AC (July 2020). "Multisystem inflammatory syndrome in children in COVID-19 pandemic". Indian Journal of Pediatrics. 87 (9): 671–673. doi:10.1007/s12098-020-03440-7. PMC 7332842. PMID 32621172. 136. ^ Jain S, Sen S, Lakshmivenkateshiah S, et al. (August 2020). "Multisystem inflammatory syndrome in children with COVID-19 in Mumbai, India". Indian Pediatrics. 57 (11): 1015–1019. doi:10.1007/s12098-020-03497-4. PMC 7678602. PMID 32788432. S2CID 221674522. 137. ^ Saxena A (18 July 2020). "Delhi hospitals see Kawasaki-like symptoms in children with Covid". The Indian Express. Archived from the original on 18 July 2020. 138. ^ "Kawasaki syndrome or MIS-C: Children recovering from COVID-19 also face the brunt of the disease". Firstpost. 20 July 2020. Archived from the original on 20 July 2020. Retrieved 20 July 2020. 139. ^ Khan KS, Ullah I (July 2020). "SARS-CoV-2 causes Kawasaki like disease in children; cases reported in Pakistan". Journal of Medical Virology. doi:10.1002/jmv.26340. PMC 7405107. PMID 32706410. 140. ^ Umer D, Ahmed T (8 July 2020). "Post-coronavirus Kawasaki-like inflammatory syndrome reported in eight children in Lahore". Samaa TV. Archived from the original on 9 July 2020. 141. ^ "Egypt free from Kawasaki disease: Cabinet". EgyptToday. 10 July 2020. Archived from the original on 11 July 2020. 142. ^ "45 casos probables de menores con síndrome inflamatorio multisistémico". Teleamazonas (in Spanish). 19 July 2020. Archived from the original on 20 July 2020. 143. ^ "Costa Rica registra récord de casos diarios y niños con peligroso síndrome". www.diariolibre.com (in Spanish). Diario Libre. 29 August 2020. Archived from the original on 31 August 2020. 144. ^ Scott S, McElroy N (4 September 2020). "A children's inflammatory illness associated with COVID-19 has emerged in Australia. Here's what we know". ABC news. Retrieved 4 September 2020. 145. ^ a b Wood, S (22 July 2020). "COVID-19's Kawasaki-like MIS-C diagnosis is cropping up in adults". TCTMD.com. Archived from the original on 23 July 2020. 146. ^ Bettach E, Zadok D, Weill Y, Brosh K, Hanhart J (June 2020). "Bilateral anterior uveitis as a part of a multisystem inflammatory syndrome secondary to COVID-19 infection". Journal of Medical Virology. doi:10.1002/jmv.26229. PMC 7361787. PMID 32592496. 147. ^ "Youngest Israeli victim: 26-year-old man dies from rare complication of COVID-19". Times of Israel. 14 June 2020. Archived from the original on 6 July 2020. 148. ^ Sokolovsky S, Soni P, Hoffman T, Kahn P, Scheers-Masters J (June 2020). "COVID-19 associated Kawasaki-like multisystem inflammatory disease in an adult". The American Journal of Emergency Medicine. 39: 253.e1–253.e2. doi:10.1016/j.ajem.2020.06.053. PMC 7315983. PMID 32631771. 149. ^ Jones I, Bell L, Manson J, Last A (July 2020). "An adult presentation consistent with PIMS-TS". The Lancet Rheumatology. 2 (9): e520–e521. doi:10.1016/S2665-9913(20)30234-4. PMC 7351404. PMID 32838310. S2CID 220460929. 150. ^ Shaigany S, Gnirke M, Guttmann A, et al. (July 2020). "An adult with Kawasaki-like multisystem inflammatory syndrome associated with COVID-19". The Lancet. 396 (10246): e8–e10. doi:10.1016/S0140-6736(20)31526-9. PMC 7351414. PMID 32659211. 151. ^ Fox SE, Lameira FS, Rinker EB, Vander Heide RS (July 2020). "Cardiac endotheliitis and multisystem inflammatory syndrome after COVID-19". Annals of Internal Medicine. 173 (12): 1025–1027. doi:10.7326/L20-0882. PMC 7506743. PMID 32726150. 152. ^ Chérif MY, de Filette JM, André S, et al. (August 2020). "Coronavirus disease 2019-related Kawasaki-like disease in an adult: a case report". JAAD Case Reports. 6 (8): 780–782. doi:10.1016/j.jdcr.2020.06.023. PMC 7311326. PMID 32754629. 153. ^ Lidder AK, Pandit SA, Lazzaro DR (December 2020). "An adult with COVID-19 kawasaki-like syndrome and ocular manifestations". American Journal of Ophthalmology Case Reports. 20: 100875. doi:10.1016/j.ajoc.2020.100875. PMC 7437437. PMID 32839740. 154. ^ Chowdhary A, Joy E, Plein S, Abdel-Rahman SE (September 2020). "Multisystem inflammatory syndrome in an adult with SARS-CoV-2 infection". European Heart Journal Cardiovascular Imaging. doi:10.1093/ehjci/jeaa232. PMC 7499519. PMID 32887992. ## External links[edit] * Fact sheet for parents released by New York City's Health Department * Information for parents provided by the Children's Hospital Los Angeles * Information for paediatric health care providers in the U.S.A. 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Multisystem inflammatory syndrome in children

None

wikipedia

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

{"wikidata": ["Q93629491"]}

Pseudoachondroplasia is an inherited disorder of bone growth which is characterized by short stature. Other features include short arms and legs, a waddling walk, early-onset joint pain (osteoarthritis), and a limited range of motion at the elbows and hips. Intelligence, facial features and head size are normal. Pseudoachondroplasia is caused by mutations in the COMP gene. This condition is inherited in an autosomal dominant pattern. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Pseudoachondroplasia

c0410538

gard

https://rarediseases.info.nih.gov/diseases/4540/pseudoachondroplasia

{"mesh": ["C535819"], "omim": ["177170"], "orphanet": ["750"], "synonyms": ["Pseudoachondroplastic dysplasia", "PSACH", "Pseudoachondroplastic spondyloepiphyseal dysplasia", "Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome", "Spondyloepiphyseal dysplasia, pseudoachondroplastic"]}

Childhood onset nemaline myopathy, or mild nemaline myopathy is a type of nemaline myopathy (NM; see this terms) characterized by distal muscle weakness, and sometimes slowness of muscle contraction. ## Epidemiology The annual incidence of NM has been estimated at 1/50,000 live births. ## Clinical description Childhood onset NM might represent 10-15% of total cases. Onset is around 10 years of age, with initial presentation of symmetric weakness of ankle dorsiflexion and foot drop, or a general slowness of muscle contraction. All movements at the ankle and more proximal limb muscles may be disturbed. Weakness is slowly progressive. Facial, respiratory and cardiac muscles are generally normal, but patients are unable to jump or run because of muscle weakness or slowness. ## Etiology This form of NM is caused by mutations in the ACTA1 (1q42.13), NEB (2q22), TPM2 (9p13.3) or TPM3 (1q21.2) genes, and its transmission follows an autosomal dominant pattern. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Childhood-onset nemaline myopathy

c0546125

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=171439

{"gard": ["7171"], "mesh": ["D017696"], "omim": ["161800", "256030", "609273", "609284", "609285", "615731", "617336"], "umls": ["C0546125"], "icd-10": ["G71.2"], "synonyms": ["Mild nemaline myopathy"]}

This article is written like a personal reflection, personal essay, or argumentative essay that states a Wikipedia editor's personal feelings or presents an original argument about a topic. Please help improve it by rewriting it in an encyclopedic style. (September 2009) (Learn how and when to remove this template message) Cartilage structures and functions can be damaged. Such damage can result from a variety of causes, such as a bad fall or traumatic sport-accident, previous knee injuries or wear and tear over time. Immobilization for long periods can also result in cartilage damage.[citation needed] Articular cartilage damage in the knee may be found on its own but it will more often be found in conjunction with injuries to ligaments and menisci. People with previous surgical interventions face more chances of articular cartilage damage due to altered mechanics of the joint. Articular cartilage damage may also be found in the shoulder causing pain, discomfort and limited movement. Articular cartilage does not usually regenerate (the process of repair by formation of the same type of tissue) after injury or disease leading to loss of tissue and formation of a defect. This fact was first described by William Hunter in 1743.[1] Several surgical techniques have been developed in the effort to repair articular cartilage defects. ## Contents * 1 Diagnoses * 1.1 Measuring cartilage damage * 2 Consequences * 3 Treatment * 4 References ## Diagnoses[edit] No non-invasive tests are currently able to diagnose articular cartilage damage. Additionally, symptoms vary considerably from person to person. Or as Dr. Karen Hambly stated: > You may or may not have pain and you could have no, or limited, swelling. Yes you may experience locking if a piece of articular cartilage has broken off and is a loose body in the joint or you may experience catching or giving way. You are likely to have some muscle wasting and difficulty in activities such as going up and down stairs, walking or running but then people with any moderate knee injury are likely to as well. This is why articular cartilage damage is the 'Cinderella' of knee problems. It tends to be diagnosed only after other structures have been ruled out – well if it isn't your meniscus or ligaments, what else could it be, perhaps we should look at the articular cartilage? > > — Dr. Karen Hambly, Articular Cartilage Repair of the Knee[2] MRI-scans are becoming more valuable in the analysis of articular cartilage but their use is still expensive and time consuming. X-rays show only bone injuries and are therefore not very helpful in diagnosing cartilage damage, especially not in early stages. The best tool for diagnosing articular damage is the use of arthroscopy. ### Measuring cartilage damage[edit] The International Cartilage Repair Society has set up an arthroscopic grading system by which cartilage defects can be ranked: * grade 0: (normal) healthy cartilage * grade 1: the cartilage has a soft spot, blisters, or superficial wear * grade 2: minor tears of less than one-half the thickness of the cartilage layer * grade 3: lesions have deep crevices of more than one-half the thickness of the cartilage layer * grade 4: the cartilage tear is full thickness and exposes the underlying (subchondral) bone Doctors will often also measure the size of each defect. Defects smaller than 2 cm2, for example, are considered to be small. It is also important to remember that although the amount of damage is an important factor, the location of the defect(s) can also influence the symptoms you are getting in terms of pain and function and their repair options available.[2] In contrast to popular perception, pain is not a good indicator for determining the extent of articular cartilage damage. One person can have severe pain with a single small defect while another person can have very little pain with several large full thickness defects.[2] Since articular cartilage does not have a blood supply and chondrocytes (cells in articular cartilage) have limited mobility, the articular cartilage has very limited ability to heal itself. If left untreated, the cartilage lesions will gradually worsen and the grade of the lesion or defect will increase.[3] ## Consequences[edit] Articular cartilage has a very limited capacity for self repair. Small damage does not repair itself and can often get worse over time. As cartilage is aneural and avascular (lack of nerve and blood supply, respectively), shallow damage often does not trigger pain. When the damage increases and the chondral defect reaches the subchondral bone, the blood supply in the bone starts a healing process in the defect. Scar tissue made up of a type of cartilage called fibrocartilage is then formed. Although fibrocartilage is able to fill in articular cartilage defects, its structure is significantly different from that of hyaline cartilage; it is much denser and it doesn't withstand the demands of everyday activities as much as hyaline cartilage. It is therefore at a higher risk of breaking down.[2] Wang et al.(2006) found that small articular cartilage defects can progress to osteoarthritis over time if left untreated.[4] An articular cartilage defect that initially may be small still has the potential to have a physical and chemical "domino effect" on the surrounding "normal" articular cartilage.[2] ## Treatment[edit] Though articular cartilage damage is not life-threatening, it does strongly affect one's quality of life. Articular cartilage damage is often the cause of severe pain, knee swelling, substantial reduction in mobility and severe restrictions to one's activities. Over the last decades, however, research has focused on regenerating damaged joints. These regenerative procedures are believed to delay osteoarthritis of injuries on the articular cartilage of the knee, by slowing down the degeneration of the joint compared to untreated damage.[2] According to Mithoefer et al. (2006), these articular cartilage repair procedures offer the best results when the intervention takes place in the early stages of the cartilage damage.[5] ## References[edit] 1. ^ Hunter W. On the structure and diseases of articulating cartilages. Trans R Soc Lond 1743;42B:514-21[full citation needed] 2. ^ a b c d e f "Articular Cartilage Repair of the Knee" Karen Hambly, www.cartilagehealth.com/acr.html 3. ^ http://www.neocartimplant.com 4. ^ Wang, Y.; Ding, C.; Wluka, A. E.; Davis, S.; Ebeling, P. R.; Jones, G.; Cicuttini, F. M. (2006). "Factors affecting progression of knee cartilage defects in normal subjects over 2 years". Rheumatology. 45 (1): 79–84. doi:10.1093/rheumatology/kei108. PMID 16188947. 5. ^ Mithoefer, K.; Williams, R. J.; Warren, R. F.; Wickiewicz, T. L.; Marx, R. G. (2006). "High-Impact Athletics After Knee Articular Cartilage Repair: A Prospective Evaluation of the Microfracture Technique". American Journal of Sports Medicine. 34 (9): 1413–8. doi:10.1177/0363546506288240. PMID 16735588. * 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 * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Articular cartilage damage

c0158073

wikipedia

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

{"umls": ["C0158073"], "icd-10": ["M24.1"], "wikidata": ["Q938793"]}

Mucinous adenocarcinoma of ovary is a rare, malignant epithelial tumor of the ovary characterized, macroscopically, by a large, usually unilateral tumor with smooth surface and evenly distributed cystic and solid areas and, histologically, by a complex papillary growth pattern with microscopic cystic glands and necrotic debris. Patients often present with pelvic pain and pressure, abdominal mass or gastrointestinal problems such as early satiety or bloating. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Mucinous adenocarcinoma of ovary

c1335167

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=398961

{"icd-10": ["C56"], "synonyms": ["Ovarian mucinous adenocarcinoma"]}

Intracranial dolichoectasias SpecialtyVascular surgery The term dolichoectasia means elongation and distension. It is used to characterize arteries throughout the human body which have shown significant deterioration of their tunica intima (and occasionally the tunica media), weakening the vessel walls and causing the artery to elongate and distend. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 References * 7 External links ## Signs and symptoms[edit] VBD * Hemifacial spasm * Paresis * Trigeminal neuralgia ICD * Progressive visual field defect ## Cause[edit] Most commonly caused by hypertension, continued stress on the walls of the artery will degrade the vessel wall by damaging and loosening the collagen and elastin meshwork which comprises the intima. Similarly, hypercholesterolemia or hyperlipidemia can also provide sufficient trauma to the vessel wall resulting in dolichoectasia. As the arrangement of connective tissue is disturbed, the vessel wall is no longer able to hold its original conformation and begins to unravel due to the continued hypertension. High blood pressure mold and force the artery to now take on an elongated, tortuous course to better withstand the higher pressures. ## Pathophysiology[edit] Fig. 1: Dolichoectasia of the suprasellar segment of the left internal carotid artery with compression of the optic chiasm Most commonly affected are the vertebral and basilar arteries (Vertebral Basilar Dolichoectasia or Vertebrobasillar Dolichoectasia). The internal carotid artery may also be affected. Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) are more likely to be subject to dolichoectasias. Dolichoectasias are most common in elderly males.[1] In cases involving the basilar artery (VBD), pathology can occur due to direct compression of cranial nerves, by ischemia related to the dolichoectatic vessel, or by the development of hydrocephalus. Rupture of the dolichoectatic vessel can lead to catastrophic intracerebral hemorrhage. Internal carotid artery dolichoectasia is particularly interesting because the artery normally already contains one hairpin turn. Seen in an MRI as two individual arteries at this hairpin, a carotid artery dolichoectasia can progress so far as to produce a second hairpin turn and appear as three individual arteries on an MRI. In the case of a dolichoectasia of the Internal Carotid Artery (ICD), the pathogenesis is primarily related to compression of the optic nerves at the optic chiasma (see Fig. 1 and 2).[citation needed] ## Diagnosis[edit] This section is empty. You can help by adding to it. (October 2017) ## Treatment[edit] There are no standard treatments for existing dolichoectasias. Prevention is most important, usually related to control of high blood pressure. Interventions can include medications or lifestyle changes. ## References[edit] 1. ^ Yu, YL; Moseley, IF; Pullicino, P; McDonald, WI (1982). "The clinical picture of ectasia of the intracerebral arteries". J Neurol Neurosurg Psychiatry. 45 (1): 29–36. doi:10.1136/jnnp.45.1.29. ISSN 0022-3050. PMC 491261. PMID 7062068. ## External links[edit] Classification D * Relation between ADPKD and Dolichoectasia Wikimedia Commons has media related to Intracranial dolichoectasias. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Intracranial dolichoectasias

None

wikipedia

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

{"wikidata": ["Q6058362"]}

Renal tubulopathy - encephalopathy - liver failure describes a spectrum of phenotypes with manifestations similar but milder than those seen in GRACILE syndrome (see this term) and that can be associated with encephalopathy and psychiatric disorders. ## Epidemiology The prevalence is unknown. Several cases have been described in Turkey, Spain, New Zealand and Australia. ## Clinical description Disease presentation is variable. Most of the characteristics of GRACILE syndrome are present (fetal growth restriction, proximal tubulopathy and hepatopathy, as well as lactic acidosis) but they are often less severe. Signs of disturbances in iron metabolism have been described, such as increased serum ferritin levels, but it is unclear whether severe liver iron overload is present. Most infants die during the neonatal period. In those who survive, encephalopathy and psychiatric disorders have been described. ## Etiology This disease is due to different mutations in the BCS1L gene (2q35) encoding a protein essential in the assembly of complex III in the mitochondrial respiratory chain. ## Genetic counseling Renal tubulopathy - encephalopathy - liver failure is inherited autosomal recessively and genetic counseling is possible. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Renal tubulopathy-encephalopathy-liver failure syndrome

c3541471

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=254902

{"omim": ["124000"], "icd-10": ["E88.8"]}

Spinocerebellar ataxia type 17 (SCA17) is a rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by a variable clinical picture which can include dementia, psychiatric disorders, parkinsonism, dystonia, chorea, spasticity, and epilepsy. ## Epidemiology Worldwide prevalence is unknown. Local prevalence is 0.47 per 1,000,000 in the Japanese population and 0.16 per 100,000 in North-East England. Fewer than 100 families have been reported to date. ## Clinical description Clinical features overlap with many neurodegenerative syndromes and specifically, Huntington disease (see this term). ## Etiology SCA17 is caused by a CAG repeat expansion in the TATA box-binding protein gene TBP (6q27). ## Prognosis Prognosis is poor. More than 60% of patients present with dysphagia which frequently results in aspiration and death. Mean disease duration is less than 18 years and a few patients live beyond 60 years of age. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Spinocerebellar ataxia type 17

c1846707

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98759

{"gard": ["10469"], "mesh": ["C564616"], "omim": ["607136"], "umls": ["C1846707"], "icd-10": ["G11.8"], "synonyms": ["HDL4", "Huntington disease-like 4", "SCA17"]}

Livedo SpecialtyDermatology Livedo refers to a form of skin discoloration.[1] * Livedo reticularis * Livedo racemosa * Livedoid dermatitis * Livedoid vasculitis ## References[edit] 1. ^ "livedo" at Dorland's Medical Dictionary ## External links[edit] Classification D * ICD-10: R23.1 * ICD-9-CM: 782.61 * v * t * e Symptoms and signs relating to skin and subcutaneous tissue Disturbances of skin sensation * Hypoesthesia * Paresthesia * Formication * Hyperesthesia * Hypoalgesia * Hyperalgesia Circulation * Cyanosis * Pallor * Livedo * Livedo reticularis * Flushing * Petechia * Blanching Edema * Peripheral edema * Anasarca Other * Rash * Desquamation * Induration * Diaphoresis * Mass * Neck mass Skin * Asboe-Hansen sign * Auspitz's sign * Borsari's sign * Braverman's sign * Crowe sign * Dennie–Morgan fold * Darier's sign * Fitzpatrick's sign * Florid cutaneous papillomatosis * Gottron's sign * Hutchinson's sign * Janeway lesion * Kerr's sign * Koebner's phenomenon * Koplik's spots * Leser-Trelat sign * Nikolsky's sign * Pastia's sign * Russell's sign * Wickham striae * Wolf's isotopic response * Munro's microabscess Nails * Aldrich-Mees' lines * Beau's lines * Muehrcke's lines * Terry's nails 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

Livedo

c0332579

wikipedia

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

{"icd-9": ["782.61"], "icd-10": ["R23.1"], "wikidata": ["Q6658154"]}

Laing distal myopathy is a slowly progressive muscle disorder that tends to begin in childhood. Early symptoms include weakness in the feet and ankles, followed by weakness in the hands and wrists. Weakness in the feet leads to tightening of the Achilles tendon, an inability to lift the big toe, and a high-stepping walk. Weakness in the hands makes it more difficult to lift the fingers, especially the third and fourth fingers. As the muscle weakness slowly progresses over the course of many years, other muscles of the body (e.g., neck, face, legs, hips, and shoulders) weaken. Other findings include scoliosis and cardiomyopathy in up to one third of individuals. Most affected people remain mobile throughout life. Life expectancy is normal. Laing distal myopathy is caused by mutations in the MYH7 gene and is inherited in an autosomal dominant fashion. Treatment may include physiotherapy to prevent tightening of the Achilles tendon and splinting of the ankle. Annual neurologic examinations, evaluations for scoliosis, and regular assessments of cardiac and respiratory functions may be necessary. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Laing distal myopathy

c4552004

gard

https://rarediseases.info.nih.gov/diseases/10769/laing-distal-myopathy

{"mesh": ["D049310"], "omim": ["160500"], "orphanet": ["59135"], "synonyms": ["Distal myopathy type 1", "Myopathy distal, type 1", "Laing early-onset distal myopathy", "Gowers disease", "MPD1"]}

Impairment that can result from chemotherapy treatment Post-chemotherapy cognitive impairment (PCCI) (also known in the scientific community as "CRCIs or Chemotherapy-Related Cognitive Impairments" and in lay terms as chemotherapy-induced cognitive dysfunction or impairment, chemo brain, or chemo fog) describes the cognitive impairment that can result from chemotherapy treatment. Approximately 20 to 30% of people who undergo chemotherapy experience some level of post-chemotherapy cognitive impairment. The phenomenon first came to light because of the large number of breast cancer survivors who complained of changes in memory, fluency, and other cognitive abilities that impeded their ability to function as they had pre-chemotherapy.[1] Although the causes and existence of post-chemotherapy cognitive impairment have been a subject of debate, recent studies have confirmed that post-chemotherapy cognitive impairment is a real, measurable side effect of chemotherapy that appears in some patients.[2] While any cancer patient may experience temporary cognitive impairment while undergoing chemotherapy, patients with PCCI continue to experience these symptoms long after chemotherapy has been completed. PCCI is often seen in patients treated for breast cancer, ovarian cancer, prostate cancer, and other reproductive cancers,[3] as well as other types of cancers requiring aggressive treatment with chemotherapy.[4][5] The clinical relevance of PCCI is significant, considering the increasing number of long-term cancer survivors in the population, many of whom may have been treated with aggressive dosing of chemotherapeutic agents, or with chemotherapy as an adjuvant to other forms of treatment.[6] In some patients, fear of PCCI can impact treatment decisions. The magnitude of chemotherapy-related cognitive changes and their impact on the activities of daily living are uncertain.[7] ## Contents * 1 Signs and symptoms * 2 Proposed mechanisms * 3 Treatment * 4 Prognosis * 5 Incidence * 6 Research * 7 History * 8 See also * 9 Footnotes * 10 External links ## Signs and symptoms[edit] The systems of the body most affected by chemotherapy drugs include visual and semantic memory, attention and motor coordination.[8] These effects can impair a chemotherapy patient's ability to understand and make decisions regarding treatment, perform in school or employment and can reduce quality of life.[8] Survivors often report difficulty multitasking, comprehending what they have just read, following the thread of a conversation, and retrieving words.[9] Breast cancer survivors who were treated with chemotherapy may find it harder to perform tasks than survivors whose treatment was surgical. One study demonstrated that, a year after treatment, the brains of cancer survivors treated with chemotherapy (after surgery) had physically shrunk while those of people only treated surgically had not.[10] Post-chemotherapy cognitive impairment comes as a surprise to many cancer survivors. Often, survivors think their lives will return to normal when the cancer is gone, only to find that the lingering effects of post-chemotherapy cognitive impairment impede their efforts. Working, connecting with loved ones, carrying out day-to-day tasks—all can be very challenging for an impaired brain. Although post-chemotherapy cognitive impairment appears to be temporary, it can be quite long-lived, with some cases lasting 10 years or more.[11] ## Proposed mechanisms[edit] The details of PCCI's causes and boundaries are not well known.[6] Two major theories have been advanced:[3] the direct effect of chemotherapy drugs on the brain, and the role of hormones in nervous system health. PCCI is complex and factors other than the chemotherapeutic agents may impact cognitive functioning. Menopause, the biological impact of a surgical procedure with anesthesia, medications prescribed in addition to the chemotherapy, genetic predisposition, hormone therapy, emotional states (including anxiety, depression and fatigue), comorbid conditions and paraneoplastic syndrome may all co-occur and act as confounding factors in the study or experience of PCCI.[7] Chemotherapy drugs thalidomide, the epothilones such as ixabepilone, the vinca alkaloids vincristine and vinblastine, the taxanes paclitaxel and docetaxel, the proteasome inhibitors such as bortezomib, and the platinum-based drugs cisplatin, oxaliplatin and carboplatin often cause chemotherapy-induced peripheral neuropathy, a progressive and enduring tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs.[12][13][14] In most cases there is no known way of reducing the effects of chemotherapeutic agents related to taxanes, thalidomide and platinum-based compounds (oxaliplatin is a notable exception to the latter category—though it does cause PCCI its effects can be buffered by infusion of calcium and thought related to PCCI include the ability of the nerves to repair themselves, the ability of cells to excrete compounds, permeability of the blood–brain barrier, damage done to DNA including shortening of telomeres and cellular oxidative stress.[15] The importance of hormones, particularly estrogen, on cognitive function is underscored by the presence of cognitive impairment in breast cancer patients before chemotherapy is begun, the similarity of the cognitive impairments to several menopausal symptoms, the increased rate of PCCI in pre-menopausal women, and the fact that the symptoms can frequently be reversed by taking estrogen.[3] Other theories suggest vascular injury, inflammation, autoimmunity, anemia and the presence of the epsilon 4 version of the apolipoprotein E gene.[8] Fifty-six of the 132 chemotherapy agents approved by the FDA have been reported to induce oxidative stress.[16] The drug doxorubicin (adriamycin) has been investigated as a PCCI-causing agent due to its production of reactive oxygen species.[17] It has been investigated in an animal model with mice.[17][18] Mice were treated with the chemotherapeutic agent mitomycin C.[19] In the prefrontal cortex, this treatment resulted in an increase of the oxidative DNA damage 8-oxodG, a decrease in the enzyme OGG1 that ordinarily repairs such damage, and an increase in epigenetic alterations. These alterations, at the DNA level, may explain, at least in part, the impairments of cognitive function after chemotherapy.[20] Research has revealed that neural progenitor cells are particularly vulnerable to the cytotoxic effects of chemotherapy agents. 5-fluorouracil has been demonstrated to reduce the viability of neural progenitor cells by 55-70% at concentrations of 1 μM, whereas cancer cell lines exposed to 1 μM of 5-fluorouracil were unaffected.[21] Other chemotherapy agents such as BCNU, cisplatin, and cytarabine also displayed toxicity to progenitor cells in vivo and in vitro.[22] This is a concern because neural progenitor cells are the major dividing cell population in the brain, giving rise to neurons and glia. Due to the critical role the hippocampus plays in memory, it has been the focus of various studies involving post-chemotherapy cognitive impairment. The hippocampus is one of the rare areas of the brain that exhibits neurogenesis. These new neurons created by the hippocampus are important for memory and learning and require a brain-derived neurotrophic factor (BDNF) to form. 5-fluorouracil, a commonly used chemotherapy agent, has been shown to significantly reduce the levels of BDNF in the hippocampus of the rat.[23] Methotrexate, an agent widely used in the chemotherapy treatment of breast cancer, has also displayed a long-lasting dose dependent decrease in hippocampal cell proliferation in the rat following a single intravenous injection of the drug.[24] This evidence suggests that chemotherapy agent toxicity to cells in the hippocampus may be partially responsible for the memory declines experienced by some patients. Deficits in visuo-spatial, visual-motor, and visual memory functions are among the symptoms seen in post-chemotherapy patients.[25] There is evidence that this may be due to damage to the visual system rather than caused by cognitive deficits. In one study, 5-flouracil caused ocular toxicity in 25-38% of patients treated with the drug.[26] Methotrexate also caused ocular toxicity in 25% of patients within 2–7 days of initial chemotherapy regimen with the drug.[27] This evidence suggests that some of the visual-based cognitive deficits experienced by cancer survivors may be due to damage at the ocular level rather than cognitive processing, but most likely it is due to a synergistic effect on both systems. ## Treatment[edit] Hypothesized treatment options include the use of antioxidants, cognitive behavioral therapy, erythropoietin and stimulant drugs such as methylphenidate, though as the mechanism of PCCI is not well understood the potential treatment options are equally theoretical.[8] Modafinil, approved for narcolepsy, has been used off-label in trials with people with symptoms of PCCI. Modafinil is a wakefulness-promoting agent that can improve alertness and concentration, and studies have shown it to be effective at least among women treated for breast cancer.[28][29] While estrogen hormone supplementation may reverse the symptoms of PCCI in women treated for breast cancer,[3] this carries health risks, including possibly promoting the proliferation of estrogen-responsive breast cancer cells. ## Prognosis[edit] While frustrating, the ultimate outcome is very good: symptoms typically disappear in about four years, e.g., for breast cancer patients.[3] ## Incidence[edit] PCCI affects a subset of cancer survivors,[7] though the overall epidemiology and prevalence is not well known and may depend on many factors.[15] It generally affects about 10–40% of breast cancer patients, with higher rates among pre-menopausal women and patients who receive high-dose chemotherapy.[3] ## Research[edit] Research on PCCI is limited, and studies on the subject have often been conflicting in results, in part due to differing means of assessing and defining the phenomenon, which makes comparison and synthesis difficult.[7] Most studies have involved small samples, making generalization difficult. There has been a focus on PCCI in younger cancer patients. This makes it difficult to draw conclusions about PCCI in the elderly.[7] Several recent studies have advanced the field using neuroimaging techniques. In 2005, Dr. Masatoshi Inagaki used magnetic resonance imaging (MRI) to measure differences in brain volume between breast cancer patients exposed to chemotherapy and subjects unexposed. Subjects were tested at two periods: one year after surgery, and again at three years post-surgery. Results from the first year study found smaller volumes of gray and white matter in patients exposed to chemotherapy. However, in the three-year study, both groups of breast cancer survivors were observed to have similar gray and white matter volumes. Altered brain structure in chemotherapy patients provides explanation for cognitive impairment.[30] Another study in 2007 investigated the differences in brain structure between two adult, monozygotic twin females. One underwent chemotherapy treatment for breast cancer, while the other did not have cancer and was not treated with chemotherapy. MRI scans were taken of both twins' brain while taking part in a working memory task. Results found that twin A (exposed to chemotherapy) experienced a broader spatial extent of activation in her brain than twin B (not exposed to chemotherapy). Twin A also reported a greater difficulty than twin B in completing the memory activity. The authors of this study declare that commonly chemotherapy patients will self-report cognitive complaints, although they perform within normal limits on neuropsychological tasks. MRI scans may provide evidence for this occurrence. Chemotherapy patients may require greater volume of neural circuitry to complete neuropsychological tasks compared to others.[31] Positron Emission Tomography (PET) is also used to study post-chemotherapy cognitive impairment. In one study in 2007, scans were taken of patients exposed to adjuvant chemotherapy. Significantly altered blood flow in the brain was found, most notably in the frontal cortex and cerebellum. The most significant difference of blood flow was found in the inferior frontal gyrus. Authors report resting metabolism in this area is associated with performance on short term memory tasks.[32] While post-treatment studies suggest significant negative side effects of chemotherapy on cognition, other studies have indicated that there may be baseline vulnerability factors which could contribute to cognitive impairment development. Such factors may include menopausal status, surgery/anesthesia, stress, genetics and fatigue, among other suspected confounding variables.[33][34][35][36][37] ## History[edit] The symptoms of PCCI were recognized by researchers in the 1980s, who typically described it as mild cognitive impairment subsequent to successful cancer treatment.[3] Some authors say that it was identified primarily in breast cancer survivor and support groups as affecting a subset of individuals treated with chemotherapy, who attributed it to the effects of the medication taken to treat their cancers.[7] The term chemobrain appears in publications at least as early as 1997. ## See also[edit] * Cancer-related fatigue * Menopause-related cognitive impairment * Radiation induced cognitive decline ## Footnotes[edit] 1. ^ Tannock IF, Ahles TA, Ganz PA, Van Dam FS (2004). "Cognitive impairment associated with chemotherapy for cancer: report of a workshop". J. Clin. Oncol. 22 (11): 2233–9. doi:10.1200/JCO.2004.08.094. PMID 15169812.[permanent dead link] 2. ^ Hede K (2008). "Chemobrain is real but may need new name". J. Natl. Cancer Inst. 100 (3): 162–3, 169. doi:10.1093/jnci/djn007. PMID 18230787. 3. ^ a b c d e f g Matsuda T, Takayama T, Tashiro M, Nakamura Y, Ohashi Y, Shimozuma K (2005). "Mild cognitive impairment after adjuvant chemotherapy in breast cancer patients--evaluation of appropriate research design and methodology to measure symptoms". Breast Cancer. 12 (4): 279–87. doi:10.2325/jbcs.12.279. PMID 16286908. S2CID 36195323. Archived from the original on 2009-06-12. 4. ^ Ness KK, Gurney JG (2007). "Adverse late effects of childhood cancer and its treatment on health and performance". Annu Rev Public Health. 28 (1): 278–302. doi:10.1146/annurev.publhealth.28.021406.144049. PMID 17367288. 5. ^ Baudino B, et al. (December 2012). "The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients". Q J Nucl Med Mol Imaging. 56 (6): 559–568. PMID 23172518. 6. ^ a b Taillibert S, Voillery D, Bernard-Marty C (November 2007). "Chemobrain: is systemic chemotherapy neurotoxic?". Curr Opin Oncol. 19 (6): 623–7. doi:10.1097/CCO.0b013e3282f0e224. PMID 17906463. S2CID 9314670. 7. ^ a b c d e f Hurria A, Somlo G, Ahles T (September 2007). "Renaming "chemobrain"". Cancer Invest. 25 (6): 373–7. doi:10.1080/07357900701506672. PMID 17882646. S2CID 41200121. 8. ^ a b c d Nelson CJ, Nandy N, Roth AJ (September 2007). "Chemotherapy and cognitive deficits: mechanisms, findings, and potential interventions". Palliat Support Care. 5 (3): 273–80. doi:10.1017/S1478951507000442. PMID 17969831. 9. ^ Silverman, Dan; Davidson, Idelle (May 25, 2010). Your Brain After Chemo: A Practical Guide to Lifting the Fog and Getting Back Your Focus (1st ed.). Boston: Da Capo Lifelong Books. ISBN 978-0738213910. 10. ^ Inagaki M, Yoshikawa E, Matsuoka Y, et al. (2007). "Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy". Cancer. 109 (1): 146–56. doi:10.1002/cncr.22368. PMID 17131349. S2CID 33843091. 11. ^ Silverman DH, Dy CJ, Castellon SA, et al. (2007). "Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy". Breast Cancer Res. Treat. 103 (3): 303–11. doi:10.1007/s10549-006-9380-z. PMID 17009108. S2CID 9350024. 12. ^ del Pino BM. Chemotherapy-induced Peripheral Neuropathy. NCI Cancer Bulletin. Feb 23, 2010 [archived 2011-12-11];7(4):6. 13. ^ Grisold W, Oberndorfer S, Windebank AJ. Chemotherapy and polyneuropathies. European Association of Neurooncology Magazine. 2012;12(1). 14. ^ "Will you have Peripheral sensory neuropathy with Herceptin - eHealthMe". 15. ^ a b Kannarkat G, Lasher EE, Schiff D (December 2007). "Neurologic complications of chemotherapy agents". Curr. Opin. Neurol. 20 (6): 719–25. doi:10.1097/WCO.0b013e3282f1a06e. PMID 17992096. S2CID 25985136. 16. ^ Myers J. S., Pierce J., Pazdernik T. (2008). "Neurotoxicology of chemotherapy in relation to cyotkine release, the blood brain barrier, and cognitive impairment". Oncology Nursing Forum. 35 (6): 916–920. doi:10.1188/08.onf.916-920. PMID 18980922.CS1 maint: multiple names: authors list (link) 17. ^ a b Joshi G, Hardas S, Sultana R, St Clair DK, Vore M, Butterfield DA (February 2007). "Glutathione elevation by gamma-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin: Implication for chemobrain". J. Neurosci. Res. 85 (3): 497–503. doi:10.1002/jnr.21158. PMID 17171703. S2CID 2106229. 18. ^ Tangpong J, Cole MP, Sultana R, et al. (January 2007). "Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain". J. Neurochem. 100 (1): 191–201. doi:10.1111/j.1471-4159.2006.04179.x. PMID 17227439. S2CID 15386152. 19. ^ Kovalchuk A, Rodriguez-Juarez R, Ilnytskyy Y, Byeon B, Shpyleva S, Melnyk S, Pogribny I, Kolb B, Kovalchuk O (April 2016). "Sex-specific effects of cytotoxic chemotherapy agents cyclophosphamide and mitomycin C on gene expression, oxidative DNA damage, and epigenetic alterations in the prefrontal cortex and hippocampus - an aging connection". Aging (Albany NY). 8 (4): 697–711. doi:10.18632/aging.100920. PMC 4925823. PMID 27032448. 20. ^ Kovalchuk A, Kolb B (July 2017). "Chemo brain: From discerning mechanisms to lifting the brain fog-An aging connection". Cell Cycle. 16 (14): 1345–1349. doi:10.1080/15384101.2017.1334022. PMC 5539816. PMID 28657421. 21. ^ Han R, Dietrich J, Luebke A; et al. (2008). "Systematic 5-flouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system". Journal of Biology. 7 (4): 12. doi:10.1186/jbiol69. PMC 2397490. PMID 18430259.CS1 maint: multiple names: authors list (link) 22. ^ Dietrich J, Ruolan H, Yang Y, Margot MP, Noble M (2006). "CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo". Journal of Biology. 5 (7): 22. doi:10.1186/jbiol50. PMC 2000477. PMID 17125495.CS1 maint: multiple names: authors list (link) 23. ^ Mustafa S, Walker A, Bennett G, Wigmore PM (2008). "5-flouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus". The European Journal of Neuroscience. 28 (2): 323–330. doi:10.1111/j.1460-9568.2008.06325.x. PMID 18702703.CS1 maint: multiple names: authors list (link) 24. ^ Seigers R, Schagen SB, Beerling W, Boogerd W; et al. (2008). "Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat" (PDF). Behavioural Brain Research. 186 (2): 168–175. doi:10.1016/j.bbr.2007.08.004. PMID 17854921. S2CID 34942985.CS1 maint: multiple names: authors list (link) 25. ^ Raffa RB, Tallarida (2010). "Effects on the visual system might contribute to some of the cognitive deficits of cancer chemotherapy-induced 'chemo-fog'". Journal of Clinical Pharmacy and Therapeutics. 35 (3): 249–255. doi:10.1111/j.1365-2710.2009.01086.x. PMC 3249620. PMID 20831527. 26. ^ Khaw P. T., Sherwood M. B., MacKay S. L., Rossi M. J., Schultz G. (1992). "Five-minute treatments with fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenon's capsule fibroblasts". Archives of Ophthalmology. 110 (8): 1150–115. doi:10.1001/archopht.1992.01080200130040. PMID 1386726.CS1 maint: multiple names: authors list (link) 27. ^ Al-Tweigeri T, Nabholtz JM, Mackey JR (1996). "Ocular toxicity and cancer chemotherapy". Cancer. 78 (7): 1359–1373. doi:10.1002/(sici)1097-0142(19961001)78:7<1359::aid-cncr1>3.0.co;2-g.CS1 maint: multiple names: authors list (link) 28. ^ Doctors are finding it harder to deny "Chemobrain" Archived 2007-10-12 at the Wayback Machine The Virginian-Pilot October 2, 2007 29. ^ Modafinil Relieves Cognitive Chemotherapy Side Effects Psychiatric News, Stephanie Whyche, August 3, 2007 Volume 42 Number 15, page 31 30. ^ Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y; et al. (2006). "Smaller Regional Volumes of Brain Gray and White Matter Demonstrated in Breast Cancer Survivors Exposed to Adjuvant Chemotherapy". Cancer. 109 (1): 146–156. doi:10.1002/cncr.22368. PMID 17131349. S2CID 33843091.CS1 maint: multiple names: authors list (link) 31. ^ Ferguson RJ, McDonald BC, Saykin AJ, Ahles TA (2007). "Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy". Journal of Clinical Oncology. 25 (25): 3866–3870. doi:10.1200/jco.2007.10.8639. PMC 3329758. PMID 17761972.CS1 maint: multiple names: authors list (link) 32. ^ Silverman DH, Dy CJ, Castellon SA (2007). "Altered frontocortical cerebellar, and basal ganglia activity in adjuvant treated breast cancer survivors 5-10 years after chemotherapy". Breast Cancer Research and Treatment. 103 (3): 303–311. doi:10.1007/s10549-006-9380-z. PMID 17009108. S2CID 9350024.CS1 maint: multiple names: authors list (link) 33. ^ Cimprich B, Reuter-Lorenz P, Nelson J, Clark PM, Therrien B, Normolle D, Berman M, Hayes DF, Noll DC, Peltier S, Welsh RC (2009). "Pre-chemotherapy alterations in brain function in women with breast cancer". Journal of Clinical and Experimental Neuropsychology. 29: 1–8.CS1 maint: multiple names: authors list (link) 34. ^ Scherling C, Collins B, Mackenzie J, Bielajew C, Smith A (Nov 2011). "Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an FMRI study". Front Hum Neurosci. 5: 122. doi:10.3389/fnhum.2011.00122. PMID 22053153.CS1 maint: multiple names: authors list (link) 35. ^ Scherling C, Collins B, Mackenzie J, Bielajew C, Smith A (2012). "Prechemotherapy differences in response inhibition in breast cancer patients compared to controls: a functional magnetic resonance imaging study". J Clin Exp Neuropsychol. 34 (5): 543–60. doi:10.1080/13803395.2012.666227. PMID 22380580. S2CID 34748973.CS1 maint: multiple names: authors list (link) 36. ^ Scherling C, Collins B, Mackenzie J, Lepage C., Bielajew C, Smith A. (2012). "Structural Brain Differences in Breast Cancer Patients Compared to Matched Controls Prior to Chemotherapy". International Journal of Biology. 4 (2): 2. doi:10.5539/ijb.v4n2p3.CS1 maint: multiple names: authors list (link) 37. ^ Scherling C.S., Smith A. (2013). "Opening up the Window into 'Chemobrain': A Neuroimaging Review". Sensors. 13 (3): 3169–3203. doi:10.3390/s130303169. PMC 3658739. PMID 23467031. A full review of neuroimaging studies and chemobrain/chemofog. ## External links[edit] * "Chemo Brain". American Cancer Society. April 15, 2014. Retrieved November 27, 2015. * Mayo Clinic Staff (February 2, 2013). "Chemo Brain". Mayo Clinic. Retrieved November 27, 2015. * Brody, Jane (August 3, 2009). "The Fog That Follows Chemotherapy". Personal Health (column). The New York Times. p. D7. Retrieved November 27, 2015. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Post-chemotherapy cognitive impairment

None

wikipedia

https://en.wikipedia.org/wiki/Post-chemotherapy_cognitive_impairment

{"wikidata": ["Q1069589"]}

Fisher et al. (1979) described a family with a seemingly 'new' form of progressive choreoathetosis. Onset was infantile. The movements predominantly affected the legs and also impaired gait. No dementia, seizures, or rigidity was noted. It was designated 'inverted' because of the predominant involvement of the legs, an unusual feature among the choreas. Four generations, 5 sibships and 10 individuals were affected, with male-to-male transmission. The authors thought that it was distinguishable from benign hereditary chorea by its progressive nature; benign chorea remains static from early childhood and may even improve. In addition, pyramidal tract signs, demonstrated in some cases of the inverted form, have not been observed in benign chorea. In addition to benign hereditary chorea (118700) and Huntington disease (143100), familial choreoathetosis also occurs in a familial paroxysmal form (118800), which may be precipitated by sudden movements, i.e., kinesigenic (128200); with Lesch-Nyhan syndrome (308000); with Wilson disease (277900); with acanthocytosis (200150) and sometimes with familial basal ganglion calcification (114100). Misc \- Infantile onset Neuro \- Progressive choreoathetosis \- Impaired gait \- Predominant leg involvement \- Occasional pyramidal tract signs \- No dementia, seizures, or rigidity Inheritance \- Autosomal dominant ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

CHOREOATHETOSIS, FAMILIAL INVERTED

c1861569

omim

https://www.omim.org/entry/118750

{"mesh": ["C566127"], "omim": ["118750"], "synonyms": ["Alternative titles", "INFANTILE CHOREOATHETOSIS OF FISHER"]}

## Clinical Features Witkop (1979) reported 2 sibs born with white hair, some black locks, and depigmented skin with some brown spots on it. In addition, the infants were handicapped by nystagmus, photophobia, retinal depigmentation, and deafness. He called this disorder the black lock-albinism-deafness syndrome (BADS). O'Doherty and Gorlin (1988) presented photographs of a striking patient who had a nearly normal iris pigmentation but white hair and white eyebrows and eyelashes with scattered black tufts resembling ermine (the ermine is born with brown fur which changes at about age 9 months, when it grows its characteristic winter coat for camouflage in a snowy environment, but with the black tip of its tail always preserved). The patient had sensorineural hearing loss and mild mental retardation. On various areas of the body, there was depigmentation described as 'marked vitiligo.' There were no findings in the family that assisted with the possible inheritance. O'Doherty and Gorlin (1988) referred to descriptions of oculocutaneous albinism with black locks and congenital sensorineural hearing loss (BADS syndrome) occurring in the brother and sister described by Witkop (1979). They also referred to another pair of male and female sibs with normal pigmentation of the irides and eyegrounds and with depigmentation changes like those of vitiligo (193200). The latter was thought to represent an autoimmune disorder. The authors noted the association of vitiligo and deafness (see 606579, 221350) and of pigmentary abnormalities and deafness (as in 300700). Zarate et al. (2009) reported a 9-year-old girl, born to healthy nonconsanguineous parents, who had evenly pigmented fair skin and brown hair at birth but who developed skin patches of hyper- and hypopigmentation between 6 months and 12 months of age, as well as progressive replacement of her brown hair by white hair with black patches. She also exhibited developmental delay, microcephaly, and hypotonia; MRI at ages 7 months and 23 months revealed delayed myelination of the corpus callosum that showed improvement on the second MRI, decreased central white matter, and diffuse small calcifications within the periventricular white matter but no tubers or masses. In childhood she developed astigmatism requiring glasses, but ophthalmologic examination was otherwise normal. She had an abnormal hearing screen at 4 years of age, and audiogram at age 9 showed bilateral mild to moderate sensorineural hearing loss at all frequencies. At 9 years of age, her height, weight, and head circumference were all below the 5th centile for age, she had global developmental delay, and hypotonia was still present but less severe. She also had bilateral fifth finger clinodactyly, mild 2/3 toe syndactyly, a wide-based slow gait, mildly decreased muscle tone, and normal strength. On her skin there were multiple patches of well-demarcated hyper- and hypopigmentation covering the entire body that did not follow Blaschko lines and were randomly distributed. The pigmentation changes appeared to be quite stable over time, since some of the changes seen in photographs at age 18 months and 4 years were still identifiable at 9 years of age. Her hair was white with a few black patches but no alopecia. Microscopic examination of skin samples from hypopigmented, hyperpigmented, and normal skin showed melanin pigment in all samples but marked variation in the amount of pigment present; there was no inflammation and no pigmentary incontinence. Electron microscopy of epidermocytes and melanocytes showed that melanosomes in both cell types were smaller and more variable in size and shape than normal, and pigment was unevenly distributed in the granules; absent pigment incontinence in the dermis was confirmed. Muscle biopsy at age 29 months showed nonuniform myofiber atrophy and hypertrophy and was suggestive of chronic lower motor unit disorder, with normal muscle ultrastructure on electron microscopy. Mitochondrial functional studies from the muscle biopsy were normal. Zarate et al. (2009) noted that the phenotype in this patient was very similar to that described by O'Doherty and Gorlin (1988). Hair \- White hair with scattered black tufts \- White eyebrows and eyelashes HEENT \- Sensorineural hearing loss \- Normal iris pigmentation Inheritance \- Autosomal recessive Neuro \- Mild mental retardation Skin \- Vitiligo \- Patchy depigmentation ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

ERMINE PHENOTYPE

c1856899

omim

https://www.omim.org/entry/227010

{"mesh": ["C535508"], "omim": ["227010"], "orphanet": ["999"], "synonyms": ["Alternative titles", "PIGMENTARY DISORDER WITH HEARING LOSS"]}

A number sign (#) is used with this entry because of evidence that polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (PMGEDSV) is caused by homozygous or compound heterozygous mutation in the COL3A1 gene (120180) on chromosome 2q32. Heterozygous mutation in the COL3A1 gene causes the vascular type of Ehlers-Danlos syndrome (EDSVASC; 130050), which is an autosomal dominant disorder. Description Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome is an autosomal recessive disorder with a highly variable phenotype. Although all patients have polymicrogyria and other variable structural brain anomalies on imaging, only some show developmental delay and/or seizures. Similarly, only some patients have connective tissue defects that particularly affect the vascular system and can result in early death (summary by Vandervore et al., 2017). Clinical Features Plancke et al. (2009) reported an 11-year-old French girl, born of consanguineous parents, who was noted to have mildly delayed motor development (walking at age 30 months) and absence seizures in early childhood. She had normal language development. Brain imaging showed diffuse cortical dysplasia and dilated ventricles. She presented at age 10 with features of EDS, including easy bruising, thin skin with scars, varicose veins, and articular hypermobility. She had a long face with upslanting palpebral fissures, flat philtrum, and thin lips. She died of complications of small bowel occlusion, necrosis, and hemorrhagic bleeding. There was no family history of a similar disorder and the parents were clinically unaffected. Jorgensen et al. (2015) reported 2 sibs, born of unrelated parents, with a variant of vascular EDS. One died at age 15 years of vascular dissection, including dissection of the thoracic aorta and renal and femoral arteries. He had previously been noted to have clubfoot, crowded teeth, retrognathia, and long and slender fingers. At evaluations at ages 6 and 14 years, his sister had long slender fingers, small joint hypermobility, crowded teeth, prominent eyes, pinched nose, thin upper lip, and translucent skin with visible subcutaneous vessels. She later had exercise-induced connective tissue trauma. Brain imaging in the affected sister showed frontal and parietal polymicrogyria, but she had normal cognitive function and did not have seizures. Brain imaging in the deceased affected brother had not been performed. Family history revealed early death due to cerebral bleeding in the maternal grandfather, and photographs suggested the disorder. The mother of the sibs had subtle features of a connective tissue disorder, including small joint hypermobility, emphysema, aortic elasticity, and thin skin. The father had no clinical manifestations. Horn et al. (2017) reported a 3-year-old girl (patient 1), born of consanguineous Turkish parents, with clubfoot, joint laxity, long slender fingers, camptodactyly, widely spaced and deep-set eyes, retrognathia, prominent forehead hypotonia, and hyperopia. She had global developmental delay with inability to walk, poor speech, and poor overall growth. At 22 months, she had a spontaneous intracranial hemorrhage and brain imaging also showed frontoparietal cobblestone polymicrogyria, thin corpus callosum, vermian hypoplasia, cerebellar microcysts, pontine hypoplasia, and patchy signal abnormalities of the white matter. Family history was significant for a maternal grandfather who died of an aortic aneurysm, but the parents of the proband were unaffected. ### Clinical Variability Vandervore et al. (2017) reported 2 sibs, born of unrelated parents who originated from the same mountain village in Chechnya, who presented with global developmental delay in infancy. The girl achieved walking at age 4.5 years, had severely impaired intellectual development, and was only able to speak a few words. She developed seizures at age 5. The boy developed seizures at age 26 months, and he was unable to walk or speak at age 3, showing severely delayed intellectual development. He also had strabismus, hypermetropia, impaired ocular pursuit, and central visual impairment. Brain imaging showed cobblestone cortical changes in both patients, as well as abnormal white matter, cerebellar cysts, and brainstem and/or cerebellar vermis hypoplasia. Neither patient had significant connective tissue abnormalities, but the boy had mild hypermobility ankles; there was no family history of connective tissue abnormalities. Genetic analysis identified a homozygous missense mutation in the COL3A1 gene (P49A; 120180.0039) (see MOLECULAR GENETICS). Vandervore et al. (2017) noted that COL3A1 is a ligand for GPR56 (604110), and that the phenotype in these sibs was reminiscent of the phenotype associated with mutations in the GPR56 gene (see BFPP, 606854). Horn et al. (2017) reported 2 sibs (patients 2 and 3), born of unrelated parents from Chechnya and Ingushetia, who presented in infancy with seizures and later showed delayed motor development with walking at age 2 years and poor speech. The seizures were well-controlled and both were seizure-free at ages 5 and 3. Brain imaging in both patients showed cobblestone microgyria. Neither patient had connective tissue manifestations, except for talipes valgus in one. The parents were clinically unaffected. Genetic analysis identified the same homozygous missense mutation in the COL3A1 gene (P49A) that was identified by Vandervore et al. (2017). Inheritance The transmission pattern of PMGEDSV in the family reported by Plancke et al. (2009) was consistent with autosomal recessive inheritance. Molecular Genetics In an 11-year-old French girl, born of consanguineous parents, with PMGEDSV, Plancke et al. (2009) identified a homozygous frameshift mutation in the COL3A1 gene (c.479dupT; 120180.0034). The patient's unaffected parents were each heterozygous for the mutation, suggesting autosomal recessive inheritance. The mutation was shown to result in nonsense-mediated decay. The lack of phenotype in the parents was discussed by Plancke et al. (2009) in light of the study by Schwarze et al. (2001), who reported a severe phenotype resulting from haploinsufficiency for COL3A1 due to truncating mutations. Plancke et al. (2009) noted that heterozygous Col3a1-null mice have no phenotype (Liu et al., 1997), similar to the parents of their French patient. Plancke et al. (2009) also noted that the nonsense-mediated mRNA process is inefficient and, in the cases of Schwarze et al. (2001), could have resulted in the production of a small amount of protein with dominant-negative effects. In 2 sibs with PMGEDSV, Jorgensen et al. (2015) identified compound heterozygous mutations in the COL3A1 gene: a nonsense mutation (R596X; 120180.0035) and a substitution at a glycine residue (G1284E; 120180.0036). Patient fibroblasts showed a reduced amount of type III procollagen, the chains of which all had an abnormal electrophoretic mobility compared to controls, suggestive of overmodification of the protein possibly resulting from slow folding of the triple helical domain. Fibroblasts from the mother, who was heterozygous for the G1284E variant, showed a small amount of abnormal type III procollagen. The mother had subtle features of the disorder, including small joint hypermobility, aortic elasticity, emphysema, and thin, translucent skin. The father, who was heterozygous for the R596X variant, had no clinical features suggestive of EDS. In a 3-year-old girl with PMGEDSV, Horn et al. (2017) identified compound heterozygous loss-of-function mutations in the COL3A1 gene (120180.0037 and 120180.0038). Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to cause nonsense-mediated mRNA decay and an inability to contribute to a triple helix, consistent with a complete loss of function. Each unaffected parent was heterozygous for 1 of the mutations. In 2 sibs with polymicrogyria without vascular-type Ehlers-Danlos syndrome, who were born of unrelated parents from the same mountain village in Chechnya, Vandervore et al. (2017) identified a homozygous missense mutation in the COL3A1 gene (P49A; 120180.0039). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant is located in a von Willebrand factor C domain that may mediate interaction with GPR56 (604110) in the N terminus of the pro-COL3A1 chain; this region is usually cleaved from the intact type III collagen domain. Patient fibroblasts showed increased levels of COL3A1 mRNA, but normal amounts of the COL3A1 protein. Immunoprecipitation assays showed no significant differences in the COL3A1 interaction with GPR56, although there was a slight alteration of binding capacity. Vandervore et al. (2017) suggested that there may be tissue-specific effects of the mutation that may result in overstimulation of neuronal migration, or that the mutation may cause altered signaling patterns involved in pial basement membrane assembly. Horn et al. (2017) identified the same homozygous P49A mutation in 2 sibs, born of unrelated parents from Chechnya and Ingushetia, with polymicrogyria without vascular-type Ehlers-Danlos syndrome. Each unaffected parent was heterozygous for the mutation. Functional studies of the variant and studies of patient cells were not performed, but the variant was classified as pathogenic or likely pathogenic according to ACMG criteria. Animal Model Jeong et al. (2012) found that Col3a1-null mice had a cobblestone-like cortical malformation with breakdown of the pial basement membrane and marginal zone heterotopias. There was also neuronal overmigration and radial glial detachment. The defects started around embryonic day 11.5. The findings indicated an important role for collagen III in the developing brain. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor overall growth (in some patients) HEAD & NECK Face \- Long face \- Retrognathia \- Micrognathia \- Smooth philtrum \- Short philtrum Eyes \- Deep-set eyes \- Eye movement abnormalities \- Hypermetropia Nose \- Pinched nose Mouth \- Thin lips Teeth \- Crowded teeth CARDIOVASCULAR Heart \- Congenital heart defects \- Valvular defects Vascular \- Vascular fragility \- Aneurysms \- Aortic dissection \- Vascular dissection SKELETAL \- Small joint hypermobility Hands \- Long fingers \- Slender fingers \- Camptodactyly Feet \- Foot deformities \- Clubfoot SKIN, NAILS, & HAIR Skin \- Thin translucent skin \- Easy bruising \- Varicose veins \- Atrophic scars NEUROLOGIC Central Nervous System \- Delayed motor development (in some patients) \- Impaired intellectual development (in some patients) \- Seizures (in some patients) \- Speech delay (in some patients) \- Polymicrogyria \- Cobblestone-like malformation of the cortex \- Anterior to posterior gradient \- Enlarged ventricles \- Cerebellar hypoplasia \- Cerebellar cysts \- Brainstem hypoplasia \- Abnormal corpus callosum \- White matter abnormalities \- Reduction of white matter MISCELLANEOUS \- Highly variable phenotype \- Some patients may have normal development \- Some patients may not have connective tissue manifestations \- Onset in early childhood \- Early death due to vascular dissection may occur MOLECULAR BASIS \- Caused by mutation in the collagen, type III, alpha-1 gene (COL3A1, 120180.0034 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

POLYMICROGYRIA WITH OR WITHOUT VASCULAR-TYPE EHLERS-DANLOS SYNDROME

None

omim

https://www.omim.org/entry/618343

{"omim": ["618343"]}

## Summary ### Clinical characteristics. Individuals with MN1 C-terminal truncation (MCTT) syndrome have mild-to-moderate intellectual disability, severe expressive language delay, dysmorphic facial features (midface hypoplasia, downslanting palpebral fissures, hypertelorism, exophthalmia, short upturned nose, and small low-set ears), and distinctive findings on brain imaging (including perisylvian polymicrogyria and atypical rhombencephalosynapsis). Mild-to-moderate prelingual hearing loss (usually bilateral, conductive, and/or sensorineural) is common. Generalized seizures (observed in the minority of individuals) are responsive to antiepileptic drugs. There is an increased risk for craniosynostosis and, thus, increased intracranial pressure. To date, 25 individuals with MCTT syndrome have been identified. ### Diagnosis/testing. No consensus clinical diagnostic criteria for MCTT syndrome have been published. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in MN1 identified by molecular genetic testing. ### Management. Treatment of manifestations: Multidisciplinary specialists to help manage developmental delay / intellectual disability, feeding issues, seizures, hearing loss, and speech and language needs, especially alternative communication. Surveillance: Routine follow up by multidisciplinary specialists per their recommendations. ### Genetic counseling. MCTT syndrome is an autosomal dominant disorder typically caused by a de novo MN1 pathogenic variant. The risk to the sibs of a proband depends on the genetic status of the proband's parents: if the MN1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental somatic/germline mosaicism. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible once the MN1 pathogenic variant has been identified in an affected family member. ## Diagnosis No consensus clinical diagnostic criteria for MN1 C-terminal truncation (MCTT) syndrome have been published. ### Suggestive Findings MN1 C-terminal truncation (MCTT) syndrome should be suspected in individuals with the following clinical findings and brain MRI findings. Clinical findings * Intellectual disability (ID) with severe expressive language delay * Hypotonia * Delays in motor development * Hearing loss (conductive or sensorineural) * Distinctive craniofacial features (see Figure 1) #### Figure 1. Facial features of individuals with C-terminal truncating variants in MN1, illustrating how features evolve from before to after age five years. Frontal bossing may be more prominent at infancy, with a tall forehead at later stages. Skull shape anomalies (more...) Brain MRI findings. In MCTT syndrome, an atypical distinctive form of rhombencephalosynapsis is observed in which there is partial or complete loss of the cerebellar vermis landmarks with fusion of the cerebellar hemispheres characterized by abnormal midline crossing of cerebellar folia and white matter tracts. Other distinctive brain MRI findings are summarized in Table 1 (see Figure 2 and Figure 3). #### Figure 2. Partial rhombencephalosynapsis in patients with C-terminal truncating MN1 variants. Changes of the cerebellum include foliar dysplasia, abnormal folia crossing the midline, and small or almost absent vermis. For details, refer to Figure 4 of Mak et al (more...) #### Figure 3. Persistent trigeminal artery and prominent posterior clinoid process in patients with C-terminal truncating MN1 variants A. Carotid and basilar arteries (axial view): persistent trigeminal artery flow-voids (dark signal) connecting the carotid (C) and (more...) ### Table 1. Brain Imaging Features in Individuals with MCTT Syndrome View in own window FeaturePrevalence Perisylvian polymicrogyria 19/10 Rhombencephalosynapsis8/10 Persistent trigeminal artery7/10 Prominent posterior clinoid process7/10 Thick rostral corpus callosum6/11 Hypoplastic olfactory bulbs4/8 Ventriculomegaly3/11 Subcortical heterotopia2/11 Based on 11 MRIs reviewed at one center [Mak et al 2020] 1\. Observed in insula; can sometimes extend more broadly in perisylvian region. ### Establishing the Diagnosis The diagnosis of MN1 C-terminal truncation (MCTT) syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in MN1 identified by molecular genetic testing (see Table 2). Note: Identification of a heterozygous MN1 variant of uncertain significance does not establish or rule out the diagnosis of this disorder. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive craniofacial or brain MRI findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MCTT syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 Single-gene testing. Sequence analysis of MN1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. Typically, if no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, since MCTT occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is much less likely to identify a disease-causing variant given the current understanding. Note: To date all described variants have been C-terminal truncating variants at the 3' end of exon 1 or in exon 2. An intellectual disability multigene panel that includes MN1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Given that MCTT syndrome is quite rare and only recently identified, some intellectual disability panels may not include MN1. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 2. Molecular Genetic Testing Used in MN1 C-Terminal Truncation Syndrome View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method MN1Sequence analysis 324/24 4 Gene-targeted deletion/duplication analysis 5None reported 4 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Mak et al [2020], Miyake et al [2020] 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics ### Clinical Description To date, 25 individuals have been identified with a germline (de novo or inherited from a mosaic parent) pathogenic C-terminal variant in MN1 [Mak et al 2020, Miyake et al 2020]. Individuals with MN1 C-terminal truncation (MCTT) syndrome have intellectual disability, severe expressive language delay, dysmorphic facial features (see Figure 1), and distinctive findings on brain imaging (including perisylvian polymicrogyria and atypical rhombencephalosynapsis) (see Table 1). The summary of the phenotypic features associated with MCTT syndrome in Table 3 is based on these reports. ### Table 3. Clinical Features of MN1 C-Terminal Truncation Syndrome View in own window FeaturePersons w/Feature Intellectual disability19/20 (95%) Motor delay19/20 (95%) Speech delay21/23 (91%) Hypotonia19/21 (90%) Hearing loss16/20 (80%) Feeding difficulties14/21 (67%) Spinal anomalies8/12 (67%) Dental anomalies9/15 (60%) Ophthalmologic anomalies10/17 (59%) Cardiovascular anomalies6/20 (30%) Seizures6/22 (27%) Craniosynostosis3/22 (14%) Based on Mak et al [2020] and Miyake et al [2020] Developmental delay (DD) / intellectual disability (ID). Individuals with MCTT syndrome have mild-to-moderate intellectual disability and severe expressive language delay. The majority have nonverbal communication with notable exceptions. For example, one child was able to speak at age two years, and at age 14 years was able to function at the level of a seven-year-old. For others, single-word speech began between ages three and six years. Some can communicate in sign language with up to 50 signs [Mak et al 2020]. Delay in gross motor development included hypotonia; at least four of 22 children walked independently by age two to three years. Others required orthotics or a wheelchair for mobilization. As for fine motor and self-help skills, most individuals require help with writing, feeding, or dressing [Mak et al 2020]. Hearing loss, when present, is mild to moderate and prelingual. It is usually bilateral, conductive, and/or sensorineural. Dysplasia of the cochlea, semicircular canals, and bony structures of the middle ear (e.g., incus) has been reported. Feeding difficulties are more prominent early in infancy and may resolve after the first year of life. Hyperphagia has also been reported in three children [Miyake et al 2020]. Spinal anomalies include lordosis, scoliosis, or kyphosis, which may be detected clinically or by imaging. Dental anomalies can include conical teeth, crowded teeth, and serrated teeth. Malocclusion has also been reported. Ophthalmologic anomalies can include oculomotor defects, strabismus, and/or shallow orbits, giving the appearance of exorbitism. Cardiovascular anomalies include atrial septal defect or ventricular septal defects. Seizures are generalized and may be myoclonic in nature. Among the six individuals with seizures, the majority were isolated events and were responsive to antiepileptic drugs. While polymicrogyria may be associated with increased risk of seizures, more information is needed. Craniosynostosis. Individuals with MCTT syndrome are at increased risk for craniosynostosis with no specific pattern to the sutures affected. Although head circumference is normal in individuals with craniosynostosis, head shape is consistently affected. Skull shape anomalies that may be observed with or without underlying craniosynostosis include dolichocephaly, turricephaly, and/or bitemporal narrowing, plagiocephaly, and macrocephaly. Individuals with craniosynostosis are at increased risk for elevated intracranial pressure. Behavioral problems. While some affected individuals may experience frustration due to poor verbal communication, no consistent behavior problems have been reported. The natural history into adulthood has not yet been delineated. Growth. Growth parameters tend to remain within the normal range. Prognosis. It is unknown if life span is affected in MCTT syndrome. One individual is alive at age 21 years [Mak et al 2020]. An unreported male is well at age 39 years [Angela Lin, personal commmunication], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are unrecognized and underreported. ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ### Nomenclature MCTT syndrome is referred to as CEBALID (craniofacial defects, dysmorphic ears, structural brain abnormalities, expressive language delay, and impaired intellectual development) syndrome in OMIM (OMIM 618774). ### Prevalence To date, 25 individuals with MCTT syndrome have been reported [Mak et al 2020, Miyake et al 2020]. This disorder is expected to be rare; the prevalence among individuals with unexplained developmental disorders is estimated at 4.2:10,000 (see bioRxiv). ## Differential Diagnosis Gomez-Lopez-Hernandez syndrome (GLHS) (OMIM 601853). Like MN1 C-terminal truncation (MCTT) syndrome, GLHS is associated with turricephaly, midface hypoplasia, craniosynostosis, and rhombencephalosynapsis. Unlike MCTT syndrome, GLHS is also known to be associated with trigeminal anesthesia, scalp alopecia, corneal opacities, short stature, and ataxia. The genetic cause of GLHS is unknown. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with MN1 C-terminal truncation (MCTT) syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with MN1 C-Terminal Truncation Syndrome View in own window System/ConcernEvaluationComment ConstitutionalMeasure height, weight, & head circumference. Craniofacial * Dental eval * Oral-maxillofacial eval Incl: * Dental anomalies (e.g., conical teeth, crowded teeth, malocclusion) * Palate for submucous cleft assoc w/bifid uvula * Cranial exam & skull radiographs for craniosynostosis * CT if indicated There is ↑ risk for craniosynostosis & ↑ intracranial pressure. NeurologicNeurologic eval * Brain MRI to identify polymicrogyria (possibly assoc w/seizure risk) & persistent trigeminal artery (possible risks for neurosurgical procedures involving skull base & pituitary) * EEG, if seizures present DevelopmentDevelopmental assessment * Incl motor, adaptive, cognitive, & speech/language eval * Eval for early intervention / special education Speech & languageSpeech-language therapistAnticipate need for augmentative communication incl sign language. Psychiatric/ BehavioralAssessment by primary care provider * No consistent behavior problems reporte * Some may experience frustration due to poor verbal communication. MusculoskeletalOrthopedics / physical medicine & rehab / PT/OT evaluationIncl assessment of: * Spinal involvement (lordosis, scoliosis, kyphosis) * Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Gastrointestinal/ FeedingGastroenterology / nutrition / feeding team evalIncl eval of aspiration risk & nutritional status EyesOphthalmologic evalTo assess for ↓ vision, oculomotor defects, strabismus, or shallow orbits HearingAudiologic eval * Assess for conductive &/or sensorineural hearing loss. * If present, refer to otolaryngologist. CardiovascularCardiology evalFor congenital heart defects, most commonly ASD & VSD Genetic counselingBy genetics professionals 1To inform affected individuals & their families re nature, MOI, & implications of MCTT syndrome to facilitate medical & personal decision making Family support/ resourcesAssess: * Use of community or online resources such as Parent to Parent; * Need for social work involvement for parental support. ASD = atrial septal defect; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; VSD = ventricular septal defects 1\. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse ### Treatment of Manifestations ### Table 5. Treatment of Manifestations in Individuals with MN1 C-Terminal Truncation Syndrome View in own window Manifestation/ConcernTreatmentConsiderations/Other CraniofacialPer oral-maxillofacial & neurosurgical specialist Developmental delay / Intellectual disabilitySee Developmental Delay / Intellectual Disability Management Issues.W/emphasis on alternative (nonverbal) communication Speech & languageAlternative communication as needed EpilepsyStandardized treatment w/AEDs by experienced neurologist * Many AEDs may be effective; none demonstrated effective specifically for this disorder. * Education of parents/caregivers 1 Poor weight gain / Failure to thriveFeeding therapyLow threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia MusculoskeletalOrthopedics / physical medicine & rehab / PT/OT * Incl stretching to help avoid contractures & falls * Consider need for positioning & mobility devices, disability parking placard. Abnormal vision &/or strabismusStandard treatment(s) per ophthalmologist Hearing * Hearing aids may be helpful; per audiologist. * See also Hereditary Hearing Loss and Deafness Overview. Community hearing services through early intervention or school district CardiovascularPer treating cardiologist Family/Community * Ensure appropriate social work involvement to connect families w/local resources, respite, & support. * Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. AED = antiepileptic drug; OT = occupational therapy; PT = physical therapy 1\. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. #### Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider: * IEP services: * An IEP provides specially designed instruction and related services to children who qualify. * IEP services will be reviewed annually to determine whether any changes are needed. * As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. * Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. * PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. * As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. * A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). * Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it. #### Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive, self-injurious, or destructive behavior can be addressed by a pediatric psychiatrist, developmental pediatrician, or psychologist with particular interest in management of these types of behaviors. ### Surveillance ### Table 6. Recommended Surveillance for Individuals with MN1 C-Terminal Truncation Syndrome View in own window System/ConcernEvaluationFrequency FeedingMeasurement of growth parameters; eval of nutritional status & safety of oral intakeAt each visit NeurologicMonitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, & movement disorders.Per initial assessment or specialist advice DevelopmentMonitor developmental progress & educational needs.At each visit Psychiatric/ BehavioralBehavior assessment for anxiety, attention, & aggressive or self-injurious behaviorPer initial assessment or specialist advice MusculoskeletalPhysical medicine, OT/PT assessment of mobility, self-help skillsAt each visit HearingPer initial assessment or specialist advicePer initial assessment or specialist advice Risk for craniosynostosis Cardiovascular Miscellaneous/ OtherAssess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.At each visit OT = occupational therapy; PT = physical therapy ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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

MN1 C-Terminal Truncation Syndrome

None

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK560443/

{"synonyms": []}

Nose fetishism,[1] nose partialism, or nasophilia[2][3] is the partialism (or paraphilia) for the nose. This may include the sexual attraction to a specific form of physical variation of appearance (such as shape and size), or a specific area (for example; the bridge or nostrils). The fetish may manifest itself in a desire for actual physical contact and interaction, or specific fantasies such as the desire to penetrate the nostrils.[2] Other fantasies may include the desire to observe or experience a transformation of a nose with reference to an element of a fictional work such as Pinocchio, or ideas concerning the transformation of the nose into that of another creatures' like a pig's snout as a means of sexually humiliating a partner or acquaintance. These fantasies may be assisted with use of props, role-play or transformation fiction, in the form of writing, artwork, or modified photographs of people (known as morphing).[citation needed] Sigmund Freud interpreted the nose as a substitute for the penis.[4] ## References[edit] 1. ^ Magnus Hirschfeld Archive for Sexology. Variations in Sexual Behavior, Two Examples: 1. Fetishism, A Partial List of Fetishisms. Archived 2013-02-06 at Archive.today Retrieved 2007-12-15. 2. ^ a b Kick (2005) pp.125-6 3. ^ Love (1994) p.176 4. ^ Jay Geller, "On Freud's Jewish body: mitigating circumcisions", Fordham University Press, 2007, ISBN 0-8232-2782-0, p. 95-105 ## Sources[edit] * Russ Kick, "Everything You Know about Sex Is Wrong: The Disinformation Guide to the Extremes of Human Sexuality (and Everything in Between)", The Disinformation Company, 2005, ISBN 1-932857-17-6 * Brenda Love, "The Encyclopedia of Unusual Sex Practices", Barricade Books, 1994, ISBN 1-56980-011-1 (Online) ## Further reading[edit] * Anil Aggrawal, "Forensic and Medico-Legal Aspects of Sexual Crimes and Unusual Sexual Practices", CRC Press, 2008, ISBN 1-4200-4308-0, p. 110,377 * Eric W. Hickey, "Sex crimes and paraphilia", Pearson Education, 2006, ISBN 0-13-170350-1, p. 83 * Ronald M. Holmes, Stephen T. Holmes, "Sex crimes: patterns and behavior", Sage Publications, 2001, ISBN 0-7619-2417-5, p. 246 * Viren Swami, Adrian Furnham, The psychology of physical attraction, Routledge, 2008, ISBN 0-415-42250-7, p. 134 * v * t * e Sexual fetishism Actions, states * Aquaphilia * Autassassinophilia * Coprophilia * Cuckold / Cuckquean * Emetophilia * Erotic hypnosis * Erotic lactation * Erotic spanking * Exhibitionism * Forced seduction * Gaining and feeding * Medical fetishism * Omorashi * Paraphilic infantilism (adult baby) * Pregnancy * Smoking * Tickling * Total enclosure * Transvestic * Tightlacing * Tamakeri * Urolagnia * Vorarephilia * Wet and messy fetishism Body parts * Armpit * Breast * Belly * Buttocks * Eyeball * Fat * Feet * Hands * Height * Hair * Legs * Navels * Noses Clothing * Boots * Ballet boots * Boot worship * Thigh-high boots * Clothing * Corset * Diapers * Gloves * Pantyhose * Latex * Rubber and PVC * Shoes * Spandex * Underwear * Uniforms Objects * Balloons * Dolls * Latex and PVC * Robots * Spandex Controversial / illegal * Lust murder * Necrophilia * Rape fantasy * Zoophilia Culture / media * Artists * Fetish art * Fetish clubs * Fashion * Magazines * Models Race * Asian sexual fetishism * Ethnic pornography * Sexual racism Related topics * BDSM * FetLife * International Fetish Day * Kink * Leather subculture * Leather Pride flag * Sexual roleplay * Book * Category *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Nose fetishism

None

wikipedia

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

{"wikidata": ["Q3123486"]}

Severe achondroplasia-developmental delay-acanthosis nigricans syndrome is characterised by the association of severe achondroplasia with developmental delay and acanthosis nigricans. It has been described in four unrelated individuals. Structural central nervous system anomalies, seizures and hearing loss were also reported, together with bowing of the clavicle, femur, tibia and fibula in some cases. The syndrome is caused by a Lys650Met substitution in the kinase domain of fibroblast growth factor receptor 3 (encoded by the FGFR3 gene; 4p16.3). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Severe achondroplasia-developmental delay-acanthosis nigricans syndrome

c2674173

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85165

{"gard": ["9443"], "mesh": ["D000130"], "omim": ["616482"], "umls": ["C2674173"], "icd-10": ["Q77.4"], "synonyms": ["SADDAN"]}

This article is about pain in the patellofemoral region. For other uses, see Runner's knee. Patellofemoral pain syndrome Other namesPatellar overload syndrome, runner's knee,[1] retropatellar pain syndrome[1] Diagram of the bones of the lower extremity. Rough distribution of areas affected by PFPS highlighted in red: patella and distal femur. SpecialtyOrthopedics, sports medicine SymptomsPain in the front of the knee[1] Usual onsetGradual[2] CausesUnclear[1] Risk factorsTrauma, increased training, weak quadriceps muscle[1] Diagnostic methodBased on symptoms and examination[3] Differential diagnosisPatellar tendinopathy, infrapatellar bursitis, infrapatellar fat pad syndrome, chondromalacia patellae[2] TreatmentRest, physical therapy[3] PrognosisMay last for years[3] FrequencyRelatively common[2] Patellofemoral pain syndrome (PFPS; not to be confused with jumper's knee) is knee pain as a result of problems between the kneecap and the femur.[4] The pain is generally in the front of the knee and comes on gradually.[2][4] Pain may worsen with sitting, excessive use, or climbing and descending stairs.[1] While the exact cause is unclear, it is believed to be due to overuse.[1][2] Risk factors include trauma, increased training, and a weak quadriceps muscle.[1] It is particularly common among runners.[3] The diagnosis is generally based on the symptoms and examination.[3] If pushing the kneecap into the femur increases the pain, the diagnosis is more likely.[1][3] Treatment typically involves rest and physical therapy.[3] Runners may need to switch to activities such as cycling or swimming.[3] Insoles may help some people.[3] Symptoms may last for years despite treatment.[3] Patellofemoral pain syndrome is the most common cause of knee pain, affecting more than 20% of young adults.[1][2] It occurs about 2.5 times more often in females than males.[2] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Examination * 3.2 Classification * 3.3 Differential diagnosis * 4 Treatment * 4.1 Exercises * 4.2 Medication * 4.3 Braces and taping * 4.4 Insoles * 4.5 Surgery * 4.6 Alternative medicine * 5 Prognosis * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] The onset of the condition is usually gradual,[4] although some cases may appear suddenly following trauma.[3] The most common symptom is diffuse vague pain around the kneecap (peripatellar) and localized pain focused behind the kneecap (retropatellar). Affected individuals typically have difficulty describing the location of the pain. They may place their hands over the anterior patella or describe a circle around the patella. This is often called the "circle sign".[3] Pain is usually initiated when weight is put on the knee extensor mechanism, such as when ascending or descending stairs or slopes, squatting, kneeling, cycling, or running.[5][6][7] Pain during prolonged sitting is sometimes termed the "movie sign" or "theatre sign" because individuals might experience pain while sitting to watch a film or similar activity.[5] The pain is typically aching and occasionally sharp. Pain may be exacerbated by activities.[3][8] The knee joint may exhibit noises such as clicking.[5] However, this has no relation to pain and function.[9][10] Giving-way of the knee may be reported.[5] Reduced knee flexion may be experienced during activities.[11] ## Causes[edit] In most patients with PFPS an examination of their history will highlight a precipitating event that caused the injury. Changes in activity patterns such as excessive increases in running mileage, repetitions such as running up steps and the addition of strength exercises that affect the patellofemoral joint are commonly associated with symptom onset. Excessively worn or poorly fitted footwear may be a contributing factor. To prevent recurrence the causal behaviour should be identified and managed correctly.[3] The medical cause of PFPS is thought to be increased pressure on the patellofemoral joint.[5] There are several theorized mechanisms relating to how this increased pressure occurs: * Increased levels of physical activity[5] * Malalignment of the patella as it moves through the femoral groove[5] * Quadriceps muscle imbalance[5][12][13] * Tight anatomical structures, e.g. retinaculum or iliotibial band.[5] Causes can also be a result of excessive genu valgum and the above-mentioned repetitive motions leading to abnormal lateral patellar tracking. Individuals with genu valgum have larger than normal Q-angles causing the weight-bearing line to fall lateral to the centre of the knee causing overstretching of the MCL and stressing the lateral meniscus and cartilages.[citation needed] The cause of pain and dysfunction often results from either abnormal forces (e.g. increased pull of the lateral quadriceps retinaculum with acute or chronic lateral PF subluxation/dislocation) or prolonged repetitive compressive or shearing forces (running or jumping) on the PF joint. The result is synovial irritation and inflammation and subchondral bony changes in the distal femur or patella known as "bone bruises". Secondary causes of PF Syndrome are fractures, internal knee derangement, osteoarthritis of the knee and bony tumors in or around the knee.[14] ## Diagnosis[edit] ### Examination[edit] People can be observed standing and walking to determine patellar alignment.[15] The Q-angle, lateral hypermobility, and J-sign are commonly used determined to determine patellar maltracking.[16] The patellofemoral glide, tilt, and grind tests (Clarke's sign), when performed, can provide strong evidence for PFPS.[3][17] Lastly, lateral instability can be assessed via the patellar apprehension test, which is deemed positive when there is pain or discomfort associated with lateral translation of the patella.[3][15] Various clinical tests have been investigated for diagnostic accuracy. The Active Instability Test, knee pain during stair climbing, Clarke's test, pain with prolonged sitting, patellar inferior pole tilt, and pain during squatting have demonstrated the best accuracy.[18] However, careful consideration is still needed when using these tests to make a differential diagnosis of PFPS.[18] Individuals with PFP may be exhibit higher pain level and lower function.[19] Magnetic resonance imaging rarely can give useful information for managing patellofemoral pain syndrome and treatment should focus on an appropriate rehabilitation program including correcting strength and flexibility concerns.[20] In the uncommon cases where a patient has mechanical symptoms like a locked knee, knee effusion, or failure to improve following physical therapy, then an MRI may give more insight into diagnosis and treatment.[20] ### Classification[edit] PFPS is one of a handful of conditions sometimes referred to as runner's knee;[3] the other conditions being chondromalacia patellae, iliotibial band syndrome, and plica syndrome. Chondromalacia patellae is a term sometimes used synonymously with PFPS.[5] However, there is general consensus that PFPS applies only to individuals without cartilage damage,[5] thereby distinguishing it from chondromalacia patellae, a condition with softening of the patellar articular cartilage.[3] Despite this distinction, the diagnosis of PFPS is typically made based only on the history and physical examination rather than on the results of any medical imaging. Therefore, it is unknown whether most persons with a diagnosis of PFPS have cartilage damage or not, making the difference between PFPS and chondromalacia theoretical rather than practical.[5] It is thought that only some individuals with anterior knee pain will have true chondromalacia patellae.[3] ### Differential diagnosis[edit] Main article: Knee pain The diagnosis of patellofemoral pain syndrome is made by ruling out patellar tendinitis, prepatellar bursitis, plica syndrome, Sinding-Larsen and Johansson syndrome, and Osgood–Schlatter disease.[21] Currently, there is not a gold standard assessment to diagnose PFPS.[18] ## Treatment[edit] A variety of treatments for patellofemoral pain syndrome are available.[22] Most people respond well to conservative therapy.[22][23][12] ### Exercises[edit] Patellofemoral pain syndrome may also result from overuse or overload of the PF joint. For this reason, knee activity should be reduced until the pain is resolved.[24][25] There is consistent but low quality evidence that exercise therapy for PFPS reduces pain, improves function and aids long-term recovery.[26] However, there is insufficient evidence to compare the effectiveness of different types of exercises with each other, and exercises with other forms of treatment.[26] Exercise therapy is the recommended first line treatment of PFPS.[3] Various exercises have been studied and recommended.[27] Exercises are described according to 3 parameters:[6] * Type of muscle activity (concentric, eccentric or isometric) * Type of joint movement (dynamic, isometric or static) * Reaction forces (closed or open kinetic chain) The majority of exercise programs intended to treat PFPS are designed to strengthen the quadriceps muscles.[6] Quadriceps strengthening is considered to be the "gold" standard treatment for PFPS.[22] Quadriceps strengthening is commonly suggested because the quadriceps muscles help to stabilize the patella. Quadriceps weakness and muscle imbalance may contribute to abnormal patellar tracking.[22] If the strength of the vastus medialis muscle is inadequate, the usually larger and stronger vastus lateralis muscle will pull sideways (laterally) on the kneecap. Strengthening the vastus medialis to prevent or counter the lateral force of the vastus lateralis is one way of relieving PFPS. However, there is growing evidence that shows proximal factors play a much larger role than vastus medialis (VMO) strength deficits or quadriceps imbalance.[28] Hip abductor, extensor, and external rotator strengthening may help.[29] Emphasis during exercise may be placed on coordinated contraction of the medial and lateral parts of the quadriceps as well as of the hip adductor, hip abductor and gluteal muscles.[6] Many exercise programs include stretches designed to improve lower limb flexibility.[6] Electromyographic biofeedback allows visualization of specific muscle contractions and may help individuals performing the exercises to target the intended muscles during the exercise.[6] Neuromuscular electrical stimulation to strengthen quadracep muscles is sometimes suggested, however the effectiveness of this treatment is not certain.[30] Inflexibility has often been cited as a source of patellofemoral pain syndrome. Stretching of the lateral knee has been suggested to help.[31] Knee and lumbar joint mobilization are not recommended as primary interventions for PFPS. It can be used as combination intervention, but as we continue to promote use of active and physical interventions for PFPS, passive interventions such as joint mobilizations are not recommended.[32] ### Medication[edit] Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat PFPS; however, there is only very limited evidence that they are effective.[5] NSAIDs may reduce pain in the short term; overall, however, after three months pain is not improved.[33] There is no evidence that one type of NSAID is superior to another in PFPS, and therefore some authors have recommended that the NSAID with fewest side effects and which is cheapest should be used.[5] Glycosaminoglycan polysulfate (GAGPS) inhibits proteolytic enzymes and increases synthesis and degree of polymerization of hyaluronic acid in synovial fluid.[5] There is contradictory evidence that it is effective in PFPS.[5] ### Braces and taping[edit] There is no difference in pain symptoms between taping and non-taping in individuals with PFPS.[33] Although taping alone is not shown to reduce pain, studies show that taping in conjunction with therapeutic exercise can have a significant effect on pain reduction.[34] Knee braces are ineffective in treating PFPS.[33] The technique of McConnell taping involves pulling the patella medially with tape (medial glide). Findings from some studies suggest that there is limited benefit with patella taping or bracing when compared to quadriceps exercises alone.[22] There is a lack of evidence to show that knee braces, sleeves, or straps are effective.[35] ### Insoles[edit] Low arches can cause overpronation or the feet to roll inward too much increasing load on the patellofemoral joint. Poor lower extremity biomechanics may cause stress on the knees and can be related to the development of patellofemoral pain syndrome, although the exact mechanism linking joint loading to the development of the condition is not clear. Foot orthoses can help to improve lower extremity biomechanics and may be used as a component of overall treatment.[36][37] Foot orthoses may be useful for reducing knee pain in the short term,[38] and may be combined with exercise programs or physical therapy. However, there is no evidence supporting use of combined exercise with foot orthoses as intervention beyond 12 months for adults. Evidence for long term use of foot orthoses for adolescents is uncertain. No evidence supports use of custom made foot orthoses.[32] ### Surgery[edit] The scientific consensus is that surgery should be avoided except in very severe cases in which conservative treatments fail.[5] The majority of individuals with PFPS receive nonsurgical treatment.[6] ### Alternative medicine[edit] The use of electrophysical agents and therapeutic modalities are not recommended as passive treatments should not be the focus of the plan of care.[39] There is no evidence to support the use of acupuncture or low-level laser therapy.[40] Most studies claiming benefits of alternative therapies for PFPS were conducted with flawed experimental design, and therefore did not produce reliable results.[41] ## Prognosis[edit] Patellarfemoral pain syndrome can become a chronic injury, with an estimated 50% of people reporting persistent patellar-femoral pain after a year.[30] Risk factors for a prolonged recovery (or persistent condition) include age (older athletes), females, increased body weight, a reduction in muscle strength, time to seek care, and in those who experience symptoms for more than two months.[30] ## Epidemiology[edit] Patellofemoral pain syndrome is the most common cause of anterior knee pain in the outpatient.[3][42] Specific populations at high risk of primary PFPS include runners, bicyclists, basketball players, young athletes and females.[43] BMI did not significantly increase risk of developing PFPS in adolescents. However, adults with PFPS have higher BMI than those without. It is suggested that higher BMI is associated with limited physical activity in people with PFPS as physical activity levels decrease as a result of pain associated with the condition. However, no longitudinal studies are able to show that BMI can be a predictor of development or progression of the condition.[44] ## References[edit] 1. ^ a b c d e f g h i j Ferri, Fred F. (2016). Ferri's Clinical Advisor 2017 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 936.e6. ISBN 9780323448383. 2. ^ a b c d e f g Dutton, RA; Khadavi, MJ; Fredericson, M (February 2016). "Patellofemoral Pain". Physical Medicine and Rehabilitation Clinics of North America. 27 (1): 31–52. doi:10.1016/j.pmr.2015.08.002. PMID 26616176. 3. ^ a b c d e f g h i j k l m n o p q r s t u Dixit S, DiFiori JP, Burton M, Mines B (January 2007). "Management of patellofemoral pain syndrome". American Family Physician. 75 (2): 194–202. PMID 17263214. 4. ^ a b c Callaghan MJ, Selfe J (April 2012). "Patellar taping for patellofemoral pain syndrome in adults". The Cochrane Database of Systematic Reviews. 4 (4): CD006717. doi:10.1002/14651858.CD006717.pub2. PMID 22513943. 5. ^ a b c d e f g h i j k l m n o p q Heintjes E, Berger MY, Bierma-Zeinstra SM, Bernsen RM, Verhaar JA, Koes BW (2004). "Pharmacotherapy for patellofemoral pain syndrome". The Cochrane Database of Systematic Reviews (3): CD003470. doi:10.1002/14651858.CD003470.pub2. PMID 15266488. 6. ^ a b c d e f g van der Heijden RA, Lankhorst NE, van Linschoten R, Bierma-Zeinstra SM, van Middelkoop M (2013). "Exercise for treating patellofemoral pain syndrome (Protocol)". Cochrane Database of Systematic Reviews. 2: CD010387. doi:10.1002/14651858.CD010387. 7. ^ Smith TO, Drew BT, Meek TH, Clark AB (2013). "Knee orthoses for treating patellofemoral pain syndrome (Protocol)". Cochrane Database of Systematic Reviews. 5: CD010513. doi:10.1002/14651858.CD010513. 8. ^ Pazzinatto MF, de Oliveira Silva D, Barton C, Rathleff MS, Briani RV, de Azevedo FM (October 2016). "Female Adults with Patellofemoral Pain Are Characterized by Widespread Hyperalgesia, Which Is Not Affected Immediately by Patellofemoral Joint Loading". Pain Medicine. 17 (10): 1953–1961. doi:10.1093/pm/pnw068. PMID 27113220. 9. ^ de Oliveira Silva D, Pazzinatto MF, Priore LB, Ferreira AS, Briani RV, Ferrari D, Bazett-Jones D, Azevedo FM (September 2018). "Knee crepitus is prevalent in women with patellofemoral pain, but is not related with function, physical activity and pain". Physical Therapy in Sport. 33: 7–11. doi:10.1016/j.ptsp.2018.06.002. hdl:11449/179928. PMID 29890402. 10. ^ de Oliveira Silva D, Barton C, Crossley K, Waiteman M, Taborda B, Ferreira AS, Azevedo FM (September 2018). "Implications of knee crepitus to the overall clinical presentation of women with and without patellofemoral pain". Physical Therapy in Sport. 33: 89–95. doi:10.1016/j.ptsp.2018.07.007. hdl:11449/180174. PMID 30059950. 11. ^ Silva D, Briani RV, Pazzinatto MF, Ferrari D, Aragão FA, Azevedo FM (November 2015). "Reduced knee flexion is a possible cause of increased loading rates in individuals with patellofemoral pain". Clinical Biomechanics. 30 (9): 971–5. doi:10.1016/j.clinbiomech.2015.06.021. PMID 26169602. 12. ^ a b Briani RV, De Oliveira Silva D, Flóride CS, Aragão FA, de Albuquerque CE, Magalhães FH, de Azevedo FM (2018). "Quadriceps neuromuscular function in women with patellofemoral pain: Influences of the type of the task and the level of pain". PLOS ONE. 13 (10): e0205553. Bibcode:2018PLoSO..1305553B. doi:10.1371/journal.pone.0205553. PMC 6179260. PMID 30304030. 13. ^ Willy RW, et al. (2019). "Patellofemoral Pain: Clinical Practice Guidelines Linked to the International Classification of Functioning, Disability and Health From the Academy of Orthopaedic Physical Therapy of the American Physical Therapy Association". Journal of Orthopaedic & Sports Physical Therapy. 49 (9): CPG1–CPG95. doi:10.2519/jospt.2019.0302. PMID 31475628. 14. ^ Plamondon, Tom (12 Aug 2009). "Special tests in the clinical examination of patellofemoral syndrome". Doctors Lounge. 09 (8): 287. Retrieved 2012-08-20.[self-published source?] 15. ^ a b Sarwark JF (2010). Essentials of musculoskeletal care. Rosemont, Ill.: American Academy of Orthopaedic Surgeons. ISBN 9780892035793. OCLC 706805938. 16. ^ Sheehan FT, Derasari A, Fine KM, Brindle TJ, Alter KE (January 2010). "Q-angle and J-sign: indicative of maltracking subgroups in patellofemoral pain". Clinical Orthopaedics and Related Research. 468 (1): 266–75. doi:10.1007/s11999-009-0880-0. PMC 2795830. PMID 19430854. 17. ^ Malanga G, Nadler S (2006). Musculoskeletal physical examination : an evidence-based approach. Philadelphia, Penns.: Elsevier Mosby. pp. 302–304. ISBN 9781560535911. 18. ^ a b c Cook C, Mabry L, Reiman MP, Hegedus EJ (June 2012). "Best tests/clinical findings for screening and diagnosis of patellofemoral pain syndrome: a systematic review". Physiotherapy. 98 (2): 93–100. doi:10.1016/j.physio.2011.09.001. PMID 22507358. 19. ^ name=Amandaschenatto>Ferreira AS, Silva DO, Priore LB, Garcia CL, Ducatti MH, Botta AF, Waiteman MC, Azevedo FM (2018). "Differences in pain and function between adolescent athletes and physically active non-athletes with patellofemoral pain". Physical Therapy in Sport. 33: 70–75. doi:10.1016/j.ptsp.2018.07.005. hdl:11449/171444. PMID 30025378. 20. ^ a b American Medical Society for Sports Medicine (24 April 2014), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American Medical Society for Sports Medicine, retrieved 29 July 2014, which cites * Rixe JA, Glick JE, Brady J, Olympia RP (September 2013). "A review of the management of patellofemoral pain syndrome". The Physician and Sportsmedicine. 41 (3): 19–28. doi:10.3810/psm.2013.09.2023. PMID 24113699. S2CID 24177847. 21. ^ Prins MR, van der Wurff P (2009). "Females with patellofemoral pain syndrome have weak hip muscles: a systematic review". The Australian Journal of Physiotherapy. 55 (1): 9–15. doi:10.1016/S0004-9514(09)70055-8. PMID 19226237. 22. ^ a b c d e Bolgla LA, Boling MC (June 2011). "An update for the conservative management of patellofemoral pain syndrome: a systematic review of the literature from 2000 to 2010". International Journal of Sports Physical Therapy. 6 (2): 112–25. PMC 3109895. PMID 21713229. 23. ^ Earl JE, Vetter CS (August 2007). "Patellofemoral pain". Physical Medicine and Rehabilitation Clinics of North America. 18 (3): 439–58, viii. doi:10.1016/j.pmr.2007.05.004. PMID 17678761. 24. ^ Thomeé R, Renström P, Karlsson J, Grimby G (August 1995). "Patellofemoral pain syndrome in young women. I. A clinical analysis of alignment, pain parameters, common symptoms and functional activity level". Scandinavian Journal of Medicine & Science in Sports. 5 (4): 237–44. doi:10.1111/j.1600-0838.1995.tb00040.x. PMID 7552769. 25. ^ Tria AJ, Palumbo RC, Alicea JA (October 1992). "Conservative care for patellofemoral pain". The Orthopedic Clinics of North America. 23 (4): 545–54. PMID 1408039. 26. ^ a b van der Heijden RA, Lankhorst NE, van Linschoten R, Bierma-Zeinstra SM, van Middelkoop M (January 2015). "Exercise for treating patellofemoral pain syndrome". The Cochrane Database of Systematic Reviews. 1: CD010387. doi:10.1002/14651858.CD010387.pub2. PMID 25603546. 27. ^ van der Heijden, Rianne A; Lankhorst, Nienke E; van Linschoten, Robbart; Bierma-Zeinstra, Sita MA; van Middelkoop, Marienke; van Middelkoop, Marienke (2013). Van Middelkoop, Marienke (ed.). "Exercise for treating patellofemoral pain syndrome". Reviews. doi:10.1002/14651858.CD010387. 28. ^ de Oliveira Silva D, Barton CJ, Pazzinatto MF, Briani RV, de Azevedo FM (June 2016). "Proximal mechanics during stair ascent are more discriminate of females with patellofemoral pain than distal mechanics". Clinical Biomechanics. 35: 56–61. doi:10.1016/j.clinbiomech.2016.04.009. PMID 27128766. 29. ^ Powers, CM (February 2010). "The influence of abnormal hip mechanics on knee injury: a biomechanical perspective". The Journal of Orthopaedic and Sports Physical Therapy. 40 (2): 42–51. doi:10.2519/jospt.2010.3337. PMID 20118526. 30. ^ a b c Martimbianco, Ana Luiza C.; Torloni, Maria Regina; Andriolo, Brenda Ng; Porfírio, Gustavo Jm; Riera, Rachel (2017-12-12). "Neuromuscular electrical stimulation (NMES) for patellofemoral pain syndrome". The Cochrane Database of Systematic Reviews. 12: CD011289. doi:10.1002/14651858.CD011289.pub2. ISSN 1469-493X. PMC 6486051. PMID 29231243. 31. ^ Zaffagnini S, Dejour D, Arendt EA (2010). Patellofemoral pain, instability, and arthritis clinical presentation, imaging, and treatment. Berlin: Springer. p. 134. ISBN 9783642054242. 32. ^ a b Collins NJ, Barton CJ, van Middelkoop M, Callaghan MJ, Rathleff MS, Vicenzino BT, Davis IS, Powers CM, Macri EM, Hart HF, de Oliveira Silva D, Crossley KM (September 2018). "2018 Consensus statement on exercise therapy and physical interventions (orthoses, taping and manual therapy) to treat patellofemoral pain: recommendations from the 5th International Patellofemoral Pain Research Retreat, Gold Coast, Australia, 2017". British Journal of Sports Medicine. 52 (18): 1170–1178. doi:10.1136/bjsports-2018-099397. PMID 29925502. 33. ^ a b c Rodriguez-Merchan EC (March 2014). "Evidence Based Conservative Management of Patello-femoral Syndrome". The Archives of Bone and Joint Surgery. 2 (1): 4–6. PMC 4151435. PMID 25207305. 34. ^ Logan CA, Bhashyam AR, Tisosky AJ, Haber DB, Jorgensen A, Roy A, Provencher MT (September 2017). "Systematic Review of the Effect of Taping Techniques on Patellofemoral Pain Syndrome". Sports Health. 9 (5): 456–461. doi:10.1177/1941738117710938. PMC 5582697. PMID 28617653. 35. ^ Smith TO, Drew BT, Meek TH, Clark AB (December 2015). "Knee orthoses for treating patellofemoral pain syndrome" (PDF). The Cochrane Database of Systematic Reviews (12): CD010513. doi:10.1002/14651858.CD010513.pub2. PMID 26645724. 36. ^ Gross ML, Davlin LB, Evanski PM (1991). "Effectiveness of orthotic shoe inserts in the long-distance runner". The American Journal of Sports Medicine. 19 (4): 409–12. doi:10.1177/036354659101900416. PMID 1897659. S2CID 23550947. 37. ^ Eng JJ, Pierrynowski MR (February 1993). "Evaluation of soft foot orthotics in the treatment of patellofemoral pain syndrome". Physical Therapy. 73 (2): 62–8, discussion 68–70. doi:10.1093/ptj/73.2.62. PMID 8421719. S2CID 24645828. 38. ^ Hossain M, Alexander P, Burls A, Jobanputra P (January 2011). "Foot orthoses for patellofemoral pain in adults". The Cochrane Database of Systematic Reviews (1): CD008402. doi:10.1002/14651858.CD008402.pub2. PMID 21249707. 39. ^ Collins NJ, Barton CJ, van Middelkoop M, Callaghan MJ, Rathleff MS, Vicenzino BT, Davis IS, Powers CM, Macri EM, Hart HF, de Oliveira Silva D, Crossley KM (September 2018). "2018 Consensus statement on exercise therapy and physical interventions (orthoses, taping and manual therapy) to treat patellofemoral pain: recommendations from the 5th International Patellofemoral Pain Research Retreat, Gold Coast, Australia, 2017". British Journal of Sports Medicine. 52 (18): 1170–1178. doi:10.1136/bjsports-2018-099397. PMID 29925502. 40. ^ Crossley K, Bennell K, Green S, McConnell J (April 2001). "A systematic review of physical interventions for patellofemoral pain syndrome". Clinical Journal of Sport Medicine. 11 (2): 103–10. doi:10.1097/00042752-200104000-00007. PMID 11403109. S2CID 22097250. 41. ^ Bizzini M, Childs JD, Piva SR, Delitto A (January 2003). "Systematic review of the quality of randomized controlled trials for patellofemoral pain syndrome". The Journal of Orthopaedic and Sports Physical Therapy. 33 (1): 4–20. doi:10.2519/jospt.2003.33.7.F4. PMID 12570282. 42. ^ Lack S, Neal B, De Oliveira Silva D, Barton C (July 2018). "How to manage patellofemoral pain - Understanding the multifactorial nature and treatment options". Physical Therapy in Sport. 32: 155–166. doi:10.1016/j.ptsp.2018.04.010. hdl:11449/171014. PMID 29793124. 43. ^ Atanda A, Reddy D, Rice JA, Terry MA (November 2009). "Injuries and chronic conditions of the knee in young athletes". Pediatrics in Review. 30 (11): 419–28, quiz 429–30. doi:10.1542/pir.30-11-419. PMID 19884282. S2CID 23042353. 44. ^ Hart HF, Barton CJ, Khan KM, Riel H, Crossley KM (May 2017). "Is body mass index associated with patellofemoral pain and patellofemoral osteoarthritis? A systematic review and meta-regression and analysis". British Journal of Sports Medicine. 51 (10): 781–790. doi:10.1136/bjsports-2016-096768. PMID 27927675. S2CID 40935953. ## External links[edit] Classification D * ICD-10: M22.2 * ICD-9-CM: 719.46 * MeSH: D046788 * DiseasesDB: 33163 External resources * eMedicine: article/308471 * Patient UK: Patellofemoral pain syndrome * v * t * e Diseases of joints General * Arthritis * Monoarthritis * Oligoarthritis * Polyarthritis Symptoms * Joint pain * Joint stiffness Inflammatory Infectious * Septic arthritis * Tuberculosis arthritis Crystal * Chondrocalcinosis * CPPD (Psudogout) * Gout Seronegative * Reactive arthritis * Psoriatic arthritis * Ankylosing spondylitis Other * Juvenile idiopathic arthritis * Rheumatoid arthritis * Felty's syndrome * Palindromic rheumatism * Adult-onset Still's disease Noninflammatory * Hemarthrosis * Osteoarthritis * Heberden's node * Bouchard's nodes * Osteophyte * v * t * e Acquired musculoskeletal deformities Upper limb shoulder * Winged scapula * Adhesive capsulitis * Rotator cuff tear * Subacromial bursitis elbow * Cubitus valgus * Cubitus varus hand deformity * Wrist drop * Boutonniere deformity * Swan neck deformity * Mallet finger Lower limb hip * Protrusio acetabuli * Coxa valga * Coxa vara leg * Unequal leg length patella * Luxating patella * Chondromalacia patellae * Patella baja * Patella alta foot deformity * Bunion/hallux valgus * Hallux varus * Hallux rigidus * Hammer toe * Foot drop * Flat feet * Club foot knee * Genu recurvatum Head * Cauliflower ear General terms * Valgus deformity/Varus deformity * Joint stiffness * Ligamentous laxity * Medicine portal *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Patellofemoral pain syndrome

c0877149

wikipedia

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

{"mesh": ["D046788"], "umls": ["C0877149"], "icd-9": ["719.46"], "icd-10": ["M22.2"], "wikidata": ["Q7144437"]}

Kleefstra syndrome (KS) is a genetic disorder characterized by intellectual disability, childhood hypotonia, severe expressive speech delay and a distinctive facial appearance with a spectrum of additional clinical features. ## Epidemiology The prevalence is unknown. To date, 114 cases have been described. ## Clinical description Patients with KS have a distinctive facial appearance comprised of brachy-microcephaly, midface hypoplasia, unusual eyebrow shape, synophyrs, cupid bow upper lip, full everted lower lip, protruding tongue and prognathism. With age, facial features become coarser and dental anomalies, like retention of primary dentition, are seen. Birth weight is normal but half of children go on to suffer from obesity. Childhood hypotonia causes motor delay but most children walk independently by age 2 or 3. Most patients have moderate to severe intellectual disability with expressive speech delay and little speech development (nonverbal communication is possible). Additional features include congenital heart malformations (interauricular communication, ventricular septal defects, bicuspid aortic valve, pulmonary valve stenosis (see these terms)), genital defects in males (hypospadias, cryptorchidism, micropenis), renal defects (hydronephrosis, chronic renal insufficiency, renal cysts, vesico-ureteral reflux), epilepsy, recurrent infections, severe constipation and hearing problems. In adolescence/adulthood behavioral problems (aggressive/emotional outbursts, attention deficit problems, self-mutilation and severe sleep disturbances) can begin. Autistic-like behavior can be noted earlier in some children. Recurrent pulmonary infections, overweight and behavioral problems seem to be reported more often in those with KS due to a point mutation, whereas microcephaly, short stature, respiratory complications and tracheomalacia are more frequently seen in those with KS due to a 9q34 microdeletion. ## Etiology KS is caused by either a point mutation in the euchromatic histone-lysine N-methyltransferase 1 (EHMT1) gene (rarely) or by a microdeletion in the chromosome region 9q34.3 (seen in >85% of cases), leading to the loss of the entire gene. This gene encodes an enzyme that modifies histone function and is essential for normal development. Larger deletions (>1mb) are associated with more severe symptoms. ## Diagnostic methods Diagnosis of KS is determined by the presence of the characteristic clinical features and molecular genetic testing. A microarray detects any duplications/deletions. Fluorescent in situ hybridization (FISH) or multiplex ligation-dependent probe amplification (MLPA) can then be used to detect the specific 9q34.3 deletion seen in KS. Sequencing of the entire coding region of the EHMT1 gene can detect sequence variants. ## Differential diagnosis Differential diagnoses include Down, Pitt-Hopkins, Smith-Magenis, Rett and 2q23.1 microdeletion syndromes (see these terms). ## Antenatal diagnosis Antenatal diagnosis is offered to unaffected parents of a child with KS as they have a higher risk of having another child with this disorder. ## Genetic counseling Most reported cases have been de novo but familial recurrence has been seen. KS has a theoretical autosomal dominant transmission, but the majority of patients do not reproduce. ## Management and treatment Treatment requires a multidisciplinary team, specializing in patients with intellectual deficiencies. Special education and vocational training along with speech therapy, physical and occupational therapy and sensory integration therapy are recommended from an early age. Standard treatment is necessary for those with renal, cardiac and urologic issues and for hearing loss. Psychiatric care along with behavioral intervention therapy may be needed. Cardiac screening (for the presence of arrhythmias) as well as intestinal and renal/urologic monitoring is recommended. Medical follow-up is life-long. ## Prognosis The prognosis of KS is variable but in most cases it is not a life-threatening disease. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Kleefstra syndrome

c0795833

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=261494

{"gard": ["8672"], "mesh": ["C563043"], "omim": ["610253"], "umls": ["C0795833"], "icd-10": ["Q87.8"]}

This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Cryoglobulinemic vasculitis" – news · newspapers · books · scholar · JSTOR (April 2009) (Learn how and when to remove this template message) Cryoglobulinemic vasculitis Other namesEssential mixed cryoglobulinemia, Primary cryoglobulinemia[1] Cryoglobulinemic vasculitis is inherited in an autosomal dominant manner SpecialtyDermatology Cryoglobulinemic vasculitis is a form of inflammation affecting the blood vessels caused by the deposition of abnormal proteins called cryoglobulins in the blood vessels. Cryoglobulinemic vasculitis affects the skin and causes a rash in roughly 15% of people with detectable circulating cryoglobulin proteins.[2]:835 Additionally, the kidneys may be affected by this form of vasculitis resulting in membranoproliferative glomerulonephritis. Fevers, painful muscles and joints, and peripheral nerve damage are other common manifestations of cryoglobulinemic vasculitis. Due to deposition of complement (in particular, C4), low levels of circulating complement factors may be seen. ## See also[edit] * Cryoglobulinemia * Cutaneous small-vessel vasculitis * Skin lesion ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Cryoglobulinemic vasculitis". www.orpha.net. Retrieved 19 April 2019. 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. ## External links[edit] Classification D * ICD-10: D89.1 * OMIM: 123550 * MeSH: C565141 External resources * Orphanet: 91138 * v * t * e Immunoproliferative immunoglobulin disorders PCDs/PP * Plasmacytoma * Multiple myeloma (Plasma cell leukemia) * MGUS * IgM (Macroglobulinemia/Waldenström's macroglobulinemia) * heavy chain (Heavy chain disease) * light chain (Primary amyloidosis) Other hypergammaglobulinemia * Cryoglobulinemia 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

Cryoglobulinemic vasculitis

c0543697

wikipedia

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

{"mesh": ["C565141"], "umls": ["C0543697", "C0340992"], "orphanet": ["91138"], "wikidata": ["Q5190533"]}

An extremely rare congenital limb malformation syndrome, described in only 3 patients to date,characterized by the association of hypoplasia or aplasia of the hand and foot phalanges, hemivertebrae and various urogenital and/or intestinal abnormalities (i.e. dysgenesis of the urogenital tract and rectum). There have been no further descriptions in the literature since 1991. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Aphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome

c1859754

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1112

{"gard": ["3051"], "mesh": ["C535881"], "omim": ["207620"], "umls": ["C1859754"], "icd-10": ["Q87.8"], "synonyms": ["Johnson-Munson syndrome"]}

Distal monosomy 15q is a rare chromosomal anomaly syndrome characterized by pre- and postnatal growth restriction, developmental delay, variable degrees of intellectual disability, hand and foot anomalies (e.g. brachy-/clinodactyly, talipes equinovarus, nail hypoplasia, proximally placed digits) and mild craniofacial dysmorphism (incl. microcephaly, triangular face, broad nasal bridge, micrognathia). Neonatal lymphedema, heart malformations, aplasia cutis congenita, aortic root dilatation, and autistic spectrum disorder have also been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Distal monosomy 15q

c2675463

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1596

{"mesh": ["C567232"], "omim": ["612626"], "umls": ["C2675463"], "icd-10": ["Q93.5"], "synonyms": ["15q26 deletion syndrome", "Distal 15q deletion syndrome", "Monosomy 15q26", "Telomeric 15q deletion syndrome"]}

A number sign (#) is used with this entry because of evidence that autosomal dominant myotonia congenita (Thomsen disease) is caused by heterozygous mutation in the gene encoding skeletal muscle chloride channel-1 (CLCN1; 118425) on chromosome 7q34. Autosomal recessive myotonia congenita, or Becker disease (255700), is also caused by mutation in the CLCN1 gene. Description Autosomal dominant myotonia congenita is a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction (Sun et al., 2001). Thomsen disease is less common and less severe than Becker disease. See also paramyotonia congenita (PMC; 168300) and potassium-aggravated myotonia (608390), overlapping phenotypes caused by mutations in the SCN4A gene (603967). Clinical Features Myotonia congenita was first described by the Danish physician Julius Thomsen (1876) in his own family. A follow-up report (Thomasen, 1948) identified 64 affected persons in 7 consecutive generations. The pedigree of Birt (1908), who, like Thomsen, was himself affected, showed skipped generations. Isaacs (1959) reported a mother and son with myotonia congenita. Quinine, local procaine, procainamide, insulin, injections of 50% magnesium sulfate, curarization, sodium loading and sodium depletion had no effect on the mother's myotonia. However, marked improvement occurred when potassium depletion was achieved with cortisone and chlorothiazide. The son improved when treated with chlorothiazide only. Pasternack and Lindqvist (1962) described 6 cases in 3 generations, and personally examined 4. Celesia et al. (1967) reported monomelic myotonia congenita, which may have been due to somatic mutation. Sanders (1976) reported a family with dominant inheritance of myotonia congenita. Two affected family members had painful muscle contractions and hypothyroidism; they showed improvement after thyroid replacement therapy. Becker (1977) provided a classification of the myotonias, and suggested 3, and perhaps 5, different varieties of dominant myotonia. Type I was classic Thomsen disease. Type II, represented by 4 families in Becker's series, was characterized by muscle pain and a fluctuating course. In type III, a marked relationship of myotonia to cold was noted, especially in the muscles around the eyes, nose, and mouth. It differed from paramyotonia congenita (168300) by the lack of cold-induced paralysis. Types IV and V, although not clearly distinct, were characterized by lack of involvement of facial muscles and isolated percussion myotonia of the tongue, respectively. Lehmann-Horn et al. (1995) commented that Becker had found that many forms of autosomal dominant myotonia exhibited a clinical picture that did not fit the classic form of Thomsen disease. These disorders were later found to be caused by mutations in the gene encoding the alpha subunit of the muscle sodium channel (SCN4A; 603967). These atypical Thomsen cases, now classified as potassium-aggravated myotonias (608390), are more common than Thomsen disease. Dupre et al. (2009) reported 9 French Canadian patients from 4 unrelated families with autosomal dominant myotonia caused by heterozygous CLCN1 mutations (see, e.g., S189F; 118425.0018). The mean age of onset was 13 years (range, 2 to 20). The most common clinical features included percussion myotonia (44%), handgrip myotonia (56%), warm-up phenomenon (100%), generalized hypertrophy (78%), generalized muscle stiffness (78%), and exacerbation with cold temperatures (56%). Less common features included lid lag (11%), lid myotonia (22%), tongue myotonia (22%), and muscle pain (11%). None had weakness, and none had sought to use medications to alleviate their symptoms. About half of affected females reported aggravation of symptoms during menstruation or pregnancy, and alleviation of symptoms after menopause. Some also reported symptom improvement with alcohol. Electrophysiologic studies showed less severe myotonia and less severe CMAP decrements compared to patients with recessive CLCN1 mutations, but similar results compared to patients with dominant SCN4A (603967) mutations. ### Myotonia Levior Myotonia levior, a mild form of autosomal dominant myotonia, was first described by de Jong (1966). Siciliano et al. (1988) reported 2 families with myotonia levior. Affected individuals had isolated myotonia without muscle weakness, hypotrophy, or hypertrophy. They suggested that myotonia levior was a 'low expressivity variant' of Thomsen disease. Lehmann-Horn et al. (1995) reported a family in which 2 brothers and their mother had myotonia levior. The brothers had onset at age 5 years of impeded muscle relaxation which was pronounced during exercise. Physical examination showed normotrophic skeletal muscles, lid lag, percussion myotonia, mild myotonia most pronounced in the forearm muscles, 'warm-up' phenomenon, and no muscle weakness. EMG showed myotonic runs. Muscle biopsy and CT scans of thigh and leg muscles were normal. Diagnosis Among 22 patients with paramyotonia congenita (PMC; 168300), 14 with sodium channel myotonia (608390), and 18 myotonia patients with mutations in the CLCN1 gene, Fournier et al. (2006) found that cold temperature was able to exaggerate electromyographic findings in a way that enabled a clear correlation between EMG findings and genetic defects. Those with PMC showed a clear worsening of compound muscle action potential with cold temperature. Those with sodium channel myotonia tended not to show a decline in compound action muscle potentials, whereas those with myotonia due to CLCN1 mutations tended to show improvement of the muscle potential with exercise, concomitant with the clinical warm-up phenomenon. Clinical Management Hughes and Wilson (1991) reported apparent benefit from antihistaminics, specifically antazoline and trimeprazine, in myotonia congenita. Pathogenesis Lipicky and Bryant (1973) found that sarcolemmal chloride conductance was significantly reduced in intercostal muscle biopsies of patients with myotonia congenita, suggesting a defect in a chloride channel. Ptacek et al. (1993) discussed the genetics and physiology of the myotonic muscular disorders: the sodium-channel disorders resulting from mutations in the SCN4A gene (603967) on chromosome 17; disorders of the chloride channel; and myotonic dystrophy (DM1; 160900) caused by mutation in the DMPK gene (605377) on 19q13. Mapping Because of the similarities between myotonia congenita and the mouse disorder Adr, which maps to mouse chromosome 7, Abdalla et al. (1992) looked for linkage to the human TCRB gene (see 186930) on the homologous region 7q35. In 4 pedigrees, they found a maximum cumulative lod score of 3.963 at a recombination fraction of 0.10 (1-lod support interval = 0.048-0.275). Abdalla et al. (1992) excluded linkage of myotonia congenita from at least 24 cM on either side of the CFTR gene (602421) on 7q31, and from the SCN4A and GH1 genes (139250) on 17q. In 4 families with Thomsen disease, Koch et al. (1992) found linkage to the CLCN1 gene on 7q35 (maximum multipoint lod score of 4.58 at theta = 0.0). Molecular Genetics In affected members of 3 unrelated families with autosomal dominant myotonia congenita, George et al. (1993) identified a heterozygous mutation in the CLCN1 gene (G230E; 118425.0002). The findings indicated that Thomsen disease and Becker disease are allelic. In affected members of Thomsen's own family (Thomasen, 1948) with autosomal dominant myotonia congenita, Steinmeyer et al. (1994) identified a heterozygous mutation in the CLCN1 gene (P480L; 118425.0006). After identifying mutations in the CLCN1 gene in patients with autosomal recessive myotonia congenita, Koch et al. (1992) concluded that mutations in the CLCN1 gene can cause either dominant or recessive myotonia congenita. A recessive form was explicable on the basis of total loss of function. A mutation acting dominantly in producing Thomsen disease could be explained by a homomultimeric structure of the channel, whereby the channel subunit encoded by the mutated gene associates with and inactivates the functional subunits encoded by the normal allele. In affected members of 18 unrelated families from Norway and Sweden with both autosomal dominant (5 families) and autosomal recessive (13 families) inheritance of myotonia congenita, Sun et al. (2001) identified 8 different mutations, including 3 novel mutations, in the CLCN1 gene. Fifteen probands had mutations in both alleles; 2 had mutations in a single allele, and 2 had no CLCN1 mutations. The majority of the patients were compound heterozygous with all possible mutational combinations, even in families with a dominant pattern of inheritance. Families with apparently dominant segregation of myotonia congenita may actually represent recessive inheritance with undetected heterozygous individuals married-in as a consequence of a high population carrier frequency of some mutations. The findings, together with the very variable clinical presentation, challenged the classification into dominant Thomsen or recessive Becker disease. Sun et al. (2001) suggested that most cases of myotonia congenita show recessive inheritance with some modifying factors or genetic heterogeneity. ### Myotonia Levior In 2 brothers with myotonia levior, Lehmann-Horn et al. (1995) identified a heterozygous mutation in the CLNC1 gene (118425.0007). The findings indicated the myotonia levior is a variant or allelic form of Thomsen disease due to a mutation leading to low clinical expressivity. Population Genetics Sun et al. (2001) stated that the worldwide prevalence of myotonic congenita, both dominant and recessive forms, is 1:100,000. In the northern Norwegian population, Sun et al. (2001) found a prevalence of about 9:100,000, which was comparable to the Finnish experience. Animal Model Beck et al. (1996) noted that the current hypotheses regarding the pathophysiology of autosomal dominant myotonia congenita, or Thomsen disease, were initially formulated from studies of the myotonic goat, an unusual breed afflicted with severe autosomal dominant congenital myotonia that closely resembles the human disease clinically and in its mode of inheritance. Beck et al. (1996) demonstrated that the phenotype of the myotonic goat was due to a heterozygous mutation in the Clcn1 gene, confirming that it is an animal model for Thomsen disease. History Myotonia with muscular hypertrophy and hyperirritability was described in 3 generations, with male-to-male transmission, by Torbergsen (1975), who maintained that the disorder was distinct from Thomsen myotonia congenita; see rippling muscle disease (606072). Studies by Iaizzo et al. (1991) implicated sodium channel dysfunction as the primary defect in Thomsen disease. Koch et al. (1989) excluded myotonia congenita from a distance within 9 cM of the myotonic dystrophy locus (160900) on chromosome 19, indicating that the 2 disorders are not allelic. Ptacek et al. (1992) excluded linkage of myotonia congenita to the SCN4A sodium channel gene (603967) on 17q. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Eyelid myotonia \- Lid lag Mouth \- Tongue myotonia MUSCLE, SOFT TISSUES \- Myotonia (usually occurs during rapid voluntary muscle movements after a period of rest) \- Myotonia is most pronounced in the extremities \- Muscle stiffness \- Muscle pain (less common) \- Percussion myotonia \- Handgrip myotonia \- Delayed relaxation of muscle fibers after contraction \- Myotonia improves with continued activity ('warm-up phenomenon') \- Muscle hypertrophy \- No muscle weakness \- EMG shows spontaneous, repetitive electrical activity ('myotonic runs') MISCELLANEOUS \- Onset in childhood, adolescence \- Highly variable phenotype and severity \- Cold temperatures exacerbate symptoms \- Warm weather and alcohol are alleviating factors \- Affected females report aggravation of symptoms during menstrual periods and pregnancy, with alleviation after menopause \- Worldwide prevalence of 1/100,000 \- Increased prevalence in Northern Finland (7.3/100,000) \- See also autosomal recessive form ( 255700 ), which is more common and more severe MOLECULAR BASIS \- Caused by mutation in the skeletal muscle chloride channel-1 gene (CLCN1, 118425.0002 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

MYOTONIA CONGENITA, AUTOSOMAL DOMINANT

c2936781

omim

https://www.omim.org/entry/160800

{"doid": ["2106"], "mesh": ["D009224"], "omim": ["160800"], "icd-10": ["G71.12"], "orphanet": ["614"], "synonyms": ["Alternative titles", "THOMSEN DISEASE"], "genereviews": ["NBK1355"]}

A number sign (#) is used with this entry because of evidence that Ullrich congenital muscular dystrophy-1 (UCMD1) can be caused by mutation in any of 3 genes encoding the subunits of collagen type VI (COL6A1, 120220; COL6A2, 120240; and COL6A3, 120250). Both recessive (homozygous) and dominant (heterozygous) mutations have been reported. See also Bethlem myopathy-1 (BTHLM1; 158810), an allelic disorder that shows autosomal dominant inheritance and a milder phenotype. Description Ullrich congenital muscular dystrophy is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (summary by Kirschner, 2013). ### Genetic Heterogeneity of Ullrich Congenital Muscular Dystrophy UCMD2 (616470) is caused by mutation in the COL12A1 gene (120320) on chromosome 6q. Nomenclature At the 229th ENMC international workshop, Straub et al. (2018) classified Ullrich congenital muscular dystophy caused by mutation in one of the collagen VI genes, which they called recessive Bethlem myopathy, as a form of limb-girdle muscular dystrophy (LGMDR22). Clinical Features Ullrich (1930) described a congenital muscular dystrophy that he called 'scleroatonic muscular dystrophy.' In most cases, muscle weakness and multiple contractures were noted at birth or in early infancy. Furukawa and Toyokura (1977) described affected sibs. The limitation of motion in axial and proximal joints suggested a rigid spine syndrome. The patients often have hyperextensibility in distal joints, suggesting the Ehlers-Danlos syndrome (see 130000). Ricci et al. (1988) described brother and sister with relatively late onset of manifestations. The sister was found to have bilateral hip dislocation at 16 months and difficulty climbing stairs at 3 years. The patient died at age 13 years of recurrent bronchopneumonia. The brother was noted to have a clumsy gait and difficulty climbing stairs at the age of 3 years. Contractures at the elbows were evident at age 12 and the spine appeared rigid. De Paillette et al. (1989) found reports of other affected sibs as well as several instances of first-cousin parents. Proximal contractures, distal hyperextensibility, and hyperhidrosis were commented on. Wiedemann (1991) stated that about 20 cases were known. Mercuri et al. (2002) described 15 patients with Ullrich congenital muscular dystrophy. All of the patients presented within the first months of life with hypotonia, contractures, torticollis, or hip dislocation. Eight of the patients acquired ambulation or had only mild motor delay, whereas 7 had severe motor disability. Most patients had characteristic round facies and long, thin extremities with wasting of the muscles. All had generalized weakness, rigidity of the spine, and respiratory insufficiency with tendency toward recurrent chest infections. Lampe and Bushby (2005) provided a review of collagen VI-related muscle disorders. Nadeau et al. (2009) reported the natural history of 13 patients with UCMD. The mean age at symptom onset was 12 months, with delayed motor development and proximal weakness, but 6 patients had a congenital presentation with variable combinations of congenital hip dislocation (2), hypotonia (3), contractures (4), torticollis (2), scoliosis (1), and feeding difficulties (2). Eight patients (61.5%) acquired independent ambulation, none ever ran, and 9 were wheelchair-dependent at a mean age of 11 years. All patients developed multiple joint contractures in the first decade of life, including of the long finger flexors. Twelve patients had scoliosis, 6 had kyphosis, and many had rigid spine. All patients developed progressive respiratory insufficiency from age 6 years on, and most required nocturnal ventilation; 2 died of respiratory failure at ages 10.8 and 15.1 years. Eight patients were underweight and 7 described chewing difficulties; 3 required gastrostomy. Eight patients had follicular hyperkeratosis and 3 had abnormal scarring with keloid formation. Serum creatine kinase was mildly increased, and staining for collagen VI was abnormal in all patients examined. All patients had normal cognitive abilities and cardiac function. Overall, most patients had rapid deterioration of respiratory function in the first decade of life, but this deterioration was not correlated with age or severity at presentation. Pathogenesis In a boy with Ullrich disease, Ishikawa et al. (2002) identified compound heterozygosity in the COL6A2 gene (120240) and complete deficiency of collagen VI by immunohistochemistry in the patient's muscle biopsy. Expression of collagen IV (see 120130), a major component of the basal lamina, was normal. Electron microscopy showed a total absence of microfibrils, which are usually seen in the interstitium associated with collagen fibrils. Ishikawa et al. (2002) suggested that loss of anchoring between the basal lamina and the interstitium may be the molecular mechanism of muscular dystrophy. Angelin et al. (2007) identified significantly increased apoptosis in skeletal muscle biopsies and myoblast cultures from 5 unrelated patients with variable severity of Ullrich congenital muscular dystrophy. Addition of oligomycin, a selective mitochondrial inhibitor, resulted in mitochondrial depolarization of myoblasts from UCMD patients but not from healthy controls. Electron microscopy showed abnormal mitochondrial morphology, including less elongation, increased size, and hypodense matrix with absence of cristae. Plating on collagen VI or treatment with cyclosporin A or calcium chelators normalized all of these findings and decreased apoptosis. The response to cyclosporin A suggested an inappropriate opening defect in the permeability transition pore, since the drug desensitizes the pore. Angelin et al. (2007) concluded that mitochondrial dysfunction is involved in the pathogenesis of Ullrich congenital muscular dystrophy. Kawahara et al. (2007) observed sarcolemmal-specific collagen VI deficiency in muscle biopsies from patients with a heterozygous COL6A1 G284R mutation (120220.0012) in the N-terminal region in the triple helical domain. Collagen VI was present in the interstitium but was barely detectable in the sarcolemma; patients with compound heterozygous COL6A1 mutations had complete absence of the protein. Electron microscopy showed that collagen VI microfibrils did not bind to the basement membrane. Further studies showed that fibroblasts with the mutation assembled and secreted normal collagen VI microfibrils. However, cell adhesion of heterozygous G284R fibroblasts was markedly decreased, similar to that of collagen VI-deficient cells, but could be rescued by the addition of normal collagen VI. Kawahara et al. (2007) concluded that heterozygous mutations in the COL6A1 gene result in decreased binding of collagen VI to the extracellular matrix. Voermans et al. (2007) reported a patient with Ehlers-Danlos syndrome (EDS; 606408) who had a homozygous mutation in the TNXB gene (600985.0002). In addition to classic clinical features of EDS, such as mild joint hypermobility, skin hyperextensibility, and easy bruising since childhood, she also had progressive generalized muscle weakness and distal contractures beginning at about age 40. She was unable to walk up stairs, had limited walking endurance of 1 hour, and had reduced gripping force. Needle biopsy of the quadriceps muscle did not show significant myopathic changes, but there was absence of immunostaining to tenascin XB and decreased endomysial staining for collagen VI. Voermans et al. (2007) noted that disruption of the TNXB gene, which is part of the extracellular matrix in skeletal muscle, results in decreased expression of type VI collagen. Thus, some patients with EDS due to tenascin deficiency may show myopathic features of collagen VI-related myopathies, such as Ullrich congenital muscular dystrophy. Kirschner et al. (2005) had previously suggested an overlap in ultrastructural connective tissue abnormalities between patients with UCMD and EDS, namely, changes in collagen fibril morphology and increased ground substance. All 5 UCMD patients examined by Kirschner et al. (2005) had distal joint hypermobility, and some patients had abnormal scar formation, poor wound healing, and velvety skin texture as observed in EDS. Pace et al. (2008) reported 8 patients with UCMD caused by heterozygous glycine mutations toward the N-terminal of the triple helix of the collagen VI molecule. Studies of patient fibroblasts showed that all the mutations compromised intracellular assembly and disulfide bonding of the collagen VI tetramers. The mutations produced 2 assembly phenotypes that reflected severity. In the mild group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The more severe group had more severe collagen assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced. These data indicate that collagen VI glycine mutations can impair the assembly pathway in different ways that correlate with disease severity. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate to severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. Clinical Management Merlini et al. (2008) found that treatment of 4 UCMD patients with 2 divided doses of orally administered cyclosporin A resulted in decreased mitochondrial dysfunction and apoptosis in skeletal muscle biopsies 1 month later. Cellular signs of muscle regeneration were also observed. Clinical response could not be assessed because of the limited time frame, but the study provided a proof of principle and suggested that mitochondrial dysfunction may play a role in the pathogenesis of the disorder. Cyclosporine A acts as an inhibitor of opening of the mitochondrial permeability transition pore (PTP). Opening of the PTP allows equilibration of the ionic charge between the mitochondrial matrix and the intermembrane space, causing depolarization of the electrochemical gradient used to generate ATP and prompting apoptosis. Hicks et al. (2009) found evidence for PTP dysregulation in muscle cell lines, but not fibroblasts, from 2 UCMD patients. PTP dysregulation was also observed in LGMD2B (253601) myoblasts, but not in myoblasts from patients with several other muscular dystrophies. Further studies led Hicks et al. (2009) to conclude that PTP dysregulation may be a characteristic of cells in culture and not specific to a collagen VI defect, calling into question the results of Merlini et al. (2008). In a reply, Bernardi et al. (2009) noted that the findings of Hicks et al. (2009) actually supported their original results (Merlini et al., 2008), since they had studied myoblasts, not fibroblasts. Bernardi et al. (2009) cited the studies of Angelin et al. (2007), who found that cyclosporin A normalized mitochondrial dysfunction in myoblasts, and of Irwin et al. (2003), who demonstrated that treatment of Col6a1 -/- mice with cyclosporin A rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. Heterogeneity ### Genetic Heterogeneity Mercuri et al. (2002) sought abnormalities in collagen VI in 15 affected patients. Muscle biopsy examination for collagen VI in 11 patients showed 5 with a marked reduction, 1 with a mild reduction, and 5 with normal expression of collagen VI. Genetic linkage analysis of 6 families linked 3 with collagen VI loci (COL6A1, 120220; COL6A2, 120240; and COL6A3, 120250) and excluded 3 families. In sum, 6 of 15 patients had evidence of primary collagen VI involvement. The clinical features were similar in both groups, and did not segregate with collagen VI status. Mercuri et al. (2002) concluded that although collagen VI involvement is common in this disease, the role of this molecule was excluded in a number of cases, suggesting genetic heterogeneity of UCMD. Lampe et al. (2005) sequenced all 3 COL6 genes from genomic DNA in 79 patients with UCMD or Bethlem myopathy, and found putative mutations in 1 of the COL6 genes in 62% of patients. Some patients showed changes in more than one of the COL6 genes, and some UCMD patients appeared to have dominant rather than recessive disease. Lampe et al. (2005) concluded that these findings may explain some or all of the cases of UCMD that are unlinked to the COL6 gene under a recessive model and noted that the large number of SNPs generated in this study may be of importance in determining the major phenotypic variability seen in this group of disorders. Molecular Genetics Camacho Vanegas et al. (2001) demonstrated recessive mutations in COL6A2 as the cause of UCMD (see, e.g., 120240.0002-120240.0004). Demir et al. (2002) stated that UCMD behaving as an autosomal recessive disorder and characterized by generalized muscle weakness, contractures of multiple joints, and distal hyperextensibility could also be caused by homozygous mutations in the COL6A3 gene (see, e.g., 120250.0002 and 120250.0003). Pan et al. (2003) identified a de novo heterozygous deletion near a minisatellite DNA sequence in intron 8 of the COL6A1 gene that removed 1.1 kb of genomic DNA encompassing exons 9 and 10 (120220.0006), resulting in a severe form of classic UCMD. In 3 unrelated patients with UCMD, all born of consanguineous parents, Giusti et al. (2005) identified homozygous mutations in the COL6A1 gene (120220.0009-120220.0011). Among 13 patients from 11 families with UCMD, Nadeau et al. (2009) found that 4 patients, including 2 sibs, were heterozygous for a COL6A1 mutation (see, e.g., 120220.0012); 2 were heterozygous for a COL6A2 mutation (see, e.g., 120240.0013), 4, including 2 cousins, were homozygous for a COL6A2 mutation (see, e..g, 120240.0012), and 2 were heterozygous for a COL6A3 mutation (120250.0004). One patient was compound heterozygous for mutations in COL6A1 (G281R; 120220.0014) and COL6A2 (R498H; 120240.0014), consistent with digenic inheritance. No genotype/phenotype correlations were noted. Foley et al. (2011) reported large genomic deletions of chromosome 21q22.3 involving the COL6A1 and/or COL6A2 genes in 2 unrelated individuals with UCMD. One patient was compound heterozygous for a splice site mutation in COL6A2 and a 69-kb deletion involving COL6A2, whereas the other was compound heterozygous for a 47-kb deletion involving COL6A2 and a 1.61-Mb deletion involving COL6A1, COL6A2, and several surrounding genes. The 4 asymptomatic parents were each heterozygous for 1 of the molecular defects. Skin biopsies from the second patient and his asymptomatic mother who was heterozygous for the 1.61-Mb deletion showed absent and decreased collagen VI staining, respectively. A third patient with global developmental delay and axial hypotonia, but not frank UCMD, was heterozygous for a 1.09-Mb deletion involving the COL6A1 and COL6A2 genes inherited from his asymptomatic father. Foley et al. (2011) emphasized that the heterozygous carrier parents were asymptomatic, indicating that haploinsufficiency of these genes is not a disease mechanism for Bethlem myopathy, despite the finding of decreased collagen VI deposition. Genotype/Phenotype Correlations Baker et al. (2005) studied 5 patients with a clinical diagnosis of UCMD. Three patients had heterozygous in-frame deletions in the N-terminal region of the triple helical domain of type VI collagen (see, e.g., COL6A2 120240.0008 and COL6A3 120250.0004). Protein biosynthesis and assembly studies showed that these mutations acted in a dominant-negative fashion and resulted in severe collagen VI matrix deficiencies. One patient had recessive amino acid changes in the C2 subdomain of COL6A2, which prevented collagen VI assembly. No collagen VI mutations were found in a fifth patient. Baker et al. (2005) concluded that dominant mutations may be common in UCMD and that mutation detection remains critical for accurate genetic counseling. In 2 patients with UCMD, Giusti et al. (2005) identified heterozygous missense mutations in the COL6A1 gene (120220.0012 and 120220.0013). The mutations occurred at glycine residues in exons 9 and 10, respectively, the same exons deleted in the patient reported by Pan et al. (2003). Both patients had a milder phenotype than that seen in classic cases, as well as reduced but not absent collagen VI protein in muscle cells and fibroblasts. The findings confirmed that dominant mutations in the COL6A1 gene can result in UCMD. Brinas et al. (2010) classified 49 patients with muscular dystrophy due to mutations in 1 of the 3 COL6A genes into 3 clinical groups: 9 (18%) had a severe phenotype with contractures and never achieved ambulation, 26 (53%) had a moderate phenotype and were initially able to walk but tended to lose ambulation later in childhood, and 14 (29%) had a milder course and remained ambulatory at a mean age of 20 years. All patient fibroblasts showed absent or reduced COL6A secretion, with frequent intracellular retention, and the decreased levels correlated with increased disease severity. Genetic analysis showed equal distribution of mutations across the cohort: 17 (30%) in COL6A1, 26 (46%) in COL6A2, and 13 (23%) in COL6A3. Thirty patients (61%) had dominant de novo mutations, and 18 had recessive mutations. Fourteen patients (28.5%) had truncating mutations. Homozygous truncating mutations before or within the triple helix (TH) domain were associated with the most severe phenotypes. The moderate phenotype was associated with heterozygous mutations resulting in the skipping of part of the TH domains or affecting the glycine residue of the Gly-X-Y domain. RT-PCR analysis was helpful in defining the effect of splice site mutations. Substitutions in the conserved Gly-X-Y motif in the triple helix (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies, accounting for almost one-third of all pathogenic mutations. Butterfield et al. (2013) analyzed genotype/phenotype correlations of 194 individuals with Gly substitutions in the TH domain of the COL6A1, COL6A2, or COL6A3 genes. The cohort included 97 newly reported cases and 97 published cases. In all 3 genes, 89% of the mutations clustered in the N-terminal regions before the 17th Gly-X-Y triplet (TH17). This important landmark is delineated by cysteine residues in the COL6A3 chain, which form disulfide bonds stabilizing tetramers. Patients with mutations inside the critical region of Gly-X-Y triplets 10-15 tended to have a more severe phenotype than those with mutations outside this critical region. However, identical glycine substitutions were associated with both severe and mild phenotypes. The most commonly observed mutation was G284R in the COL6A1 gene (120220.0012), found in 28 cases with variable phenotypes. Glycine substitutions in the TH domain were dominantly acting in 96% of cases, and recessive mutations tended to occur in the C-terminal end of the TH domain. Butterfield et al. (2013) concluded that the clustering of glycine substitutions in this region is not based on features of the primary sequence, but rather reflects a functional importance of this domain. Population Genetics Okada et al. (2007) determined that primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan after Fukuyama congenital muscular dystrophy (FCMD), now designated muscular dystrophy-dystroglycanopathy type A4 (MDDGA4; 253800). Collagen VI deficiency accounted for 26 (7.2%) of 362 Japanese patients with a clinical diagnosis of congenital muscular dystrophy. There were no genotype/phenotype correlations. History Wiedemann (1991) gave an account of Otto Ullrich (1894-1957) that included information on his teacher, von Pfaundler, his career, his personality, and 'his' syndromes. INHERITANCE \- Autosomal recessive \- Autosomal dominant GROWTH Weight \- Low weight due to poor feeding Other \- Failure to thrive \- Slender build HEAD & NECK Face \- Facial weakness, mild \- Round face Ears \- Prominent ears Mouth \- High-arched palate Neck \- Torticollis \- Neck weakness RESPIRATORY \- Respiratory insufficiency due to muscle weakness often requiring ventilatory assistance \- Nocturnal hypoventilation \- Recurrent chest infections SKELETAL \- Proximal joint contractures \- Distal joint laxity Spine \- Spinal rigidity \- Scoliosis \- Kyphosis Pelvis \- Hip dislocation Limbs \- Long, thin limbs \- Increased laxity of wrists \- Increased laxity of ankles Hands \- Increased laxity of fingers Feet \- Talipes equinovarus \- Calcaneal protrusion SKIN, NAILS, & HAIR Skin \- Hyperhidrosis \- Follicular hyperkeratosis MUSCLE, SOFT TISSUES \- Hypotonia, neonatal \- Muscle weakness, proximal greater than distal \- Generalized muscle atrophy \- Delayed motor milestones \- Delayed ambulation \- Some patients never achieve ambulation \- Muscle biopsy shows increased variation in fiber size \- Muscle biopsy shows type 1 fiber predominance \- Muscle biopsy shows merosin ( 156225 )-positive muscle fibers \- Absence of collagen VI immunostaining \- Increased endo- and perimysial connective tissue \- Muscle fiber necrosis \- Muscle fiber regeneration NEUROLOGIC Central Nervous System \- Normal intelligence Peripheral Nervous System \- Decreased or absent reflexes due to muscle weakness LABORATORY ABNORMALITIES \- Normal to mildly increased serum creatine kinase MISCELLANEOUS \- Onset in infancy \- Variable severity \- Progressive disorder \- Bethlem myopathy ( 158810 ) is an allelic disorder with a milder phenotype and autosomal dominant inheritance \- A subset of patients have heterozygous mutations consistent with a dominant-negative effect MOLECULAR BASIS \- Caused by mutation in the collagen VI, alpha-1 polypeptide gene (COL6A1, 120220.0007 ) \- Caused by mutation in the collagen VI, alpha-2 polypeptide gene (COL6A2, 120240.0002 ) \- Caused by mutation in the collagen VI, alpha-3 polypeptide gene (COL6A3, 120250.0002 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1

c0410179

omim

https://www.omim.org/entry/254090

{"doid": ["0050558"], "mesh": ["C537521"], "omim": ["254090"], "orphanet": ["75840"], "synonyms": ["Alternative titles", "ULLRICH CONGENITAL MUSCULAR DYSTROPHY", "MUSCULAR DYSTROPHY, SCLEROATONIC", "ULLRICH DISEASE", "ULLRICH SCLEROATONIC MUSCULAR DYSTROPHY", "MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 22"], "genereviews": ["NBK1503"]}

A number sign (#) is used with this entry because choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP) is caused by heterozygous mutation in the NKX2-1 gene (600635) on chromosome 14q13. See also benign hereditary chorea (118700), an allelic disorder with less severe manifestations. Description Choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP) is an autosomal dominant disorder characterized by onset of this triad of features in infancy. Movement abnormalities begin with muscular hypotonia followed by the development of chorea, athetosis, dystonia, ataxia, and dysarthria. Some patients show neonatal respiratory distress and developmental delay. The phenotype is variable both between and within families (summary by Thorwarth et al., 2014). Clinical Features Pohlenz et al. (2002) described a boy with neonatal respiratory distress requiring mechanical ventilation and mildly increased serum thyrotropin (TSH; 188540) with normal serum thyroxine. He was hypotonic, showed delayed development, and staggering gait later in childhood. By age 4.5 years, he had choreiform hyperkinesia. Brain MRI was normal. Krude et al. (2002) described 5 patients with variable degrees of congenital hypothyroidism with choreoathetosis, muscular hypotonia, and neonatal respiratory distress with recurrent pulmonary infections. Three patients had hypoplasia of the thyroid gland on imaging and 1 had thyroid gland agenesis apparent in the neonatal period. All had increased serum TSH and decreased thyroxin. Four patients aged 3 to 16 years had severe choreoathetosis and 1 showed muscle hypotonia at age 1.5 years. In 1 of the patients, cytogenetic studies identified an interstitial deletion of chromosomal region 14q11.2-q13.3, including the TITF1 locus. Krude et al. (2002) concluded that the neurologic dysfunction in these patients was most likely related to TITF1 gene deficiency in the thyroid and brain rather than to the consequence of hypothyroidism since all patients were adequately treated with thyroxine. Asmus et al. (2005) reported a German family in which a mother and 3 of her children, all born of different fathers, had congenital hypothyroidism, neonatal respiratory distress, and choreoathetosis. The proband was born prematurely at 31 weeks' gestation and developed pneumonia and apneic episodes at birth. She had a small thyroid gland, increased serum TSH, and delayed motor development. At age 48 months, she was unable to walk unassisted for more than a few steps because of marked muscular hypotonia, hyperextendable knee joints, and muscular atrophy of the lower limbs. She also had rapid choreatic and athetotic movements of the limbs and trunk. Her 2 affected half sibs had respiratory insufficiency at birth, pneumonia, congenital hypothyroidism necessitating thyroxine replacement, muscular hypotonia and choreoathetotic movements developing within the first 2 years of life. All children showed delayed motor development and ataxia and cerebellar symptoms. The mother had hypothyroidism, ataxic gait, and choreoathetosis; information about her neonatal respiratory function was not available. Two of the affected children had a favorable response to levodopa treatment. Doyle et al. (2004) reported a 3-generation family in which 4 members had congenital hypothyroidism, neonatal respiratory distress, and ataxia. The probands, who were maternal half sibs, both had neonatal respiratory distress requiring prolonged mechanical ventilation and compensated hypothyroidism with increased serum TSH and normal T4. Both showed a normal thyroid gland on ultrasound. During infancy, each child showed global developmental delay and later developed ataxia, choreoathetosis, and dysarthria. The mother had required mechanical ventilation as a neonate, had delayed motor development, and was diagnosed with hypothyroidism at age 18 years. She demonstrated ataxia and dysarthria. The maternal grandmother had a twin who died at birth of respiratory distress. The grandmother had pneumonia as a child, fell frequently, had dysarthria, and was diagnosed with hypothyroidism at age 52 years. Carre et al. (2009) reported that the clinical spectrum of 46 patients from 28 families with NKX2-1 mutations. Half of the patients developed the complete triad of brain-lung-thyroid syndrome, whereas 14 (30%) of 46 had brain and thyroid disease, 6 (13%) of 46 had chorea only, and 3 (7%) of 46 had no neurologic signs with lung and thyroid disease or thyroid disease only. Thyroid morphology was normal in 17 (55%) of 31 patients by ultrasound or scintigraphy. In 28 patients with documented peripheral thyroid hormone values, compensated hypothyroidism was more prevalent than overt hypothyroidism (61% vs 39%). Lung disease occurred in 25 (54%) of 46 patients, with infant respiratory distress syndrome present at term in 19 (76%) patients and recurrent pulmonary infections in 6 (24%). On follow-up, 5 (20%) of 25 developed severe chronic interstitial lung disease, and 4 (16%) of 25 died from respiratory failure or infant respiratory distress syndrome. Thorwarth et al. (2014) identified 25 unrelated patients with NKX2-1 mutations (17) or deletions involving the NKX2-1 gene (8). All patients had muscular hypotonia in infancy followed by choreoathetosis and other movement abnormalities, including ataxia in 7, and dystonia in 6. Dysarthria was present in 23 patients. All but 2 patients had thyroid defects, including congenital hypothyroidism (11), hyperthyrotropinemia (12), and thyroid dysgenesis (14). The lungs were affected in 22 patients; 13 had neonatal respiratory distress and 15 had recurrent respiratory infections. Some family members reportedly had asthma. Several patients showed symptoms of possible hypothalamic dysfunction, such as unexplained fever and disturbed hunger, thirst, or sleep. Seven patients had congenital cardiac septal defects that did not require surgery. All but 2 of 17 patients with point mutations had truncating mutations. Two additional patients with a similar phenotype had deletions that excluded the NKX2-1 gene, but affected the neighboring MBIP gene (609431), which was shown to have a similar expression pattern as NKX2-1 in mouse embryonic brain, thyroid, and lung. However, direct sequencing of the MBIP gene did not identify mutations in 79 other patients. Molecular Genetics Devriendt et al. (1998) identified deletion of the TITF1 gene in an infant with neonatal thyroid dysfunction, respiratory failure, hypotonia, and ataxia. Iwatani et al. (2000) reported deletion of the TITF1 gene in 2 sibs with hypothyroidism and respiratory failure. In 5 unrelated patients with choreoathetosis, hypothyroidism, and respiratory distress, Krude et al. (2002) identified 4 different mutations in the TITF1 gene (see, e.g., 600635.0005 and 600635.0006) and 1 deletion of the TITF1 gene. Pohlenz et al. (2002) identified a 1-bp insertion in the TITF1 gene (600635.0010) in a boy with choreoathetosis, hypothyroidism, and neonatal respiratory distress. Doyle et al. (2004) identified a heterozygous mutation in the TITF1 gene (376-2A-G; 600635.0011) in 4 affected members of a family with autosomal dominant inheritance of this disorder. In 4 affected members of a German family with congenital hypothyroidism, neonatal respiratory distress, and choreoathetosis, Asmus et al. (2005) identified a heterozygous mutation in the TITF1 gene (600635.0008). INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Congenital septal defects (in some patients) RESPIRATORY \- Respiratory distress, neonatal \- Recurrent respiratory infections \- Asthma (in some patients) NEUROLOGIC Central Nervous System \- Delayed motor development \- Global developmental delay \- Difficulty walking in childhood \- Choreoathetosis \- Hypotonia \- Ataxia \- Dysarthria \- Dystonia \- Symptoms of hypothalamic disturbances (in some patients) \- Sleep disturbances (in some patients) \- Hunger and thirst disturbances (in some patients) METABOLIC FEATURES \- Unexplained fever (in some patients) ENDOCRINE FEATURES \- Hypothyroidism, congenital \- Hypoplasia of the thyroid gland in some patients LABORATORY ABNORMALITIES \- Increased serum thyroid-stimulating hormone (TSH) \- Serum thyroxine may be decreased or normal \- 'Compensated hypothyroidism' with increased TSH and normal T4 MISCELLANEOUS \- Onset at birth \- Allelic disorder to benign hereditary chorea ( 118700 ), which is less severe MOLECULAR BASIS \- Caused by mutation in the thyroid transcription factor 1 gene (TITF1, 600635.0005 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH OR WITHOUT PULMONARY DYSFUNCTION

c1970269

omim

https://www.omim.org/entry/610978

{"mesh": ["C567034"], "omim": ["610978"], "orphanet": ["209905"], "synonyms": ["Alternative titles", "BRAIN-LUNG-THYROID SYNDROME"], "genereviews": ["NBK185066"]}

Hot spot on a Golden Retriever Pyotraumatic dermatitis, also known as a hot spot or acute moist dermatitis, is a common infection of the skin surface of dogs, particularly those with thick or long coats.[1] It occurs following self-inflicted trauma of the skin.[1] Pyotraumatic dermatitis rarely affects cats.[1] ## Contents * 1 Signs * 2 Cause * 3 Treatment * 4 References ## Signs[edit] The dog persistently licks, chews, scratches or rubs at a focal area of skin,[2] which quickly causes hair loss.[1] The skin becomes red, moist and weeps.[1] The affected area is obviously defined and separate from the surrounding healthy skin and coat.[1] Usually only one area of the skin is affected.[1] The size of the affected area is variable.[3] If the area is difficult for the dog to scratch, or if the disease is caught early, hair may still be present.[3] Areas commonly affected include the rump above the tail, the head and neck near the ears, and the top and sides of the lumbar area.[3] ## Cause[edit] Pyotraumatic dermatitis is caused by self-inflicted trauma to the skin, which is incited by pain or irritation, such as infestation with fleas or lice,[4] irritation from clippers,[3] allergic skin diseases,[4] diseases of the anal sacs,[4] inflammation of the ear canal,[4] foreign bodies or irritants within the coat,[4] or pain in muscles or joints.[4] Skin maceration from repeated wetting of the coat or moisture in the fur can also be an inciting cause.[3] Flea infestations are the most common inciting factor.[1] The inciting factor causes the dog to traumatize a small area of skin.[2] The affected skin weeps (that is, it exudes serum),[3] and this moist surface layer of skin can become colonized by bacteria, although the skin itself is not infected.[4] The affected area is usually painful, as nerve endings are exposed when the surface of the skin is eroded.[5] Hair which remains in the affected area holds in the moisture and further irritates the skin surface.[6] Continued itching by the dog can cause the affected area to enlarge rapidly in only a few hours.[4] Pyotraumatic dermatitis is more common when the dog's environment is hot and humid.[3] Dogs with thick undercoats or long fur are most commonly affected,[1] but pyotraumatic dermatitis can occur in any dog.[4] Commonly affected breeds include the Airedale Terrier, Akita, Basset Hound, Golden Retriever, Great Pyrenees, Labrador Retriever, Leonberger, Peruvian Inca Orchid (Peruvian Hairless Dog), Shiba Inu, and Xoloitzcuintle (Mexican hairless dog)[7] as well as the German Shepherd and St. Bernard.[4] ## Treatment[edit] There are several aspects to treatment: breaking the "itch-scratch" cycle by clipping the fur and cleaning the skin;[5] addressing the underlying painful or itchy condition which initially caused the animal to begin scratching;[2] and relieving the dog's discomfort, for example with steroid medications.[3] The hair in and around the affected area is clipped before the skin is cleaned with an antiseptic, rinsed, and dried.[3] The dog may require sedation before the fur is clipped, as skin affected by pyotraumatic dermatitis can be painful.[3] With treatment, pyotraumatic dermatitis resolves in 3–7 days, but can recur if the inciting factor is not addressed.[3] ## References[edit] 1. ^ a b c d e f g h i Hnilica, Keith A.; Patterson, Adam P. (2016). "Chapter 3. Bacterial skin diseases. Pyotraumatic dermatitis". Small Animal Dermatology: A Color Atlas and Therapeutic Guide (4th ed.). St. Louis, Missouri: Elsevier. pp. 49–50. ISBN 978-0-323-37651-8. 2. ^ a b c Lewis, Diane T. (2016). "Chapter 18 Dermatologic disorders. Pyotraumatic dermatitis". In Schaer, Michael; Gaschen, Frederic P. (eds.). Clinical Medicine of the Dog and Cat (3rd ed.). CRC Press. p. 779. ISBN 9781482226072. 3. ^ a b c d e f g h i j k Tim, Nuttall; Harvey, Richard G.; McKeever, Patrick J. (2009). "Chapter 1: Pruritic dermatoses. Pyotraumatic dermatitis". Skin Diseases of the Dog and Cat a Colour Handbook (2nd ed.). London: CRC Press. p. 18. ISBN 978-1-84076-539-7. 4. ^ a b c d e f g h i j Miller, William H., Jr.; Griffin, Craig E.; Campbell, Karen L. (2013). "Pyotraumatic dermatitis". Muller & Kirk's Small Animal Dermatology (7th ed.). St. Louis, Missouri: Elsevier. pp. 677–678. ISBN 9781416000280. 5. ^ a b Moriello, Karen A. (2011). Small Animal Dermatology (6th, rev. ed.). London: CRC Press. p. 90. ISBN 9781840766356. 6. ^ Susan M. Ewing. Poodles For Dummies. Retrieved December 29, 2012. 7. ^ Dodds, W. Jean (2011). "Guide to Congenital and heritable Disorders in Dogs: Includes Genetic Predispositions to Diseases" (PDF). Retrieved March 6, 2020. * Dog Hot Spot Treatment *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Pyotraumatic dermatitis

c0263214

wikipedia

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

{"wikidata": ["Q1568766"]}

## Summary ### Clinical characteristics. Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor or only mildly delayed development in the first year of life, followed by slowly progressive neurologic impairment manifest as ataxia, spasticity (brisk tendon reflexes and bilateral extensor plantar responses), and mild-to-moderate cognitive impairment. Dysarthria and truncal hypotonia are observed. Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur. Cataracts may be absent in some individuals. ### Diagnosis/testing. The diagnosis of HCC can be established in individuals with typical clinical findings, characteristic abnormalities on brain MRI, and biallelic pathogenic variants in FAM126A identified by molecular genetic testing. ### Management. Treatment of manifestations: Cataract extraction usually in the first months of life. Therapy support for developmental delays; special education; physical medicine and rehabilitation for spasticity and ataxia. Consider pharmacologic agents for spasticity; antiepileptic drugs as needed. Treatment for scoliosis and contractures per orthopedist; feeding therapy and or gastrostomy tube as needed. Surveillance: Eye examinations if cataracts were not identified in neonatal period. Developmental, neurologic, and musculoskeletal assessments at each visit. Growth measurement, nutrition assessment, and assessment of family need for social work support and care coordination at each visit. ### Genetic counseling. HCC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a FAM126A pathogenic variant, each sib of an affected individual has at conception 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 FAM126A pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. ## Diagnosis ### Suggestive Findings Hypomyelination and congenital cataract (HCC) should be suspected in individuals with the following clinical findings [Biancheri et al 2007] and characteristic abnormalities on brain MRI [Rossi et al 2008]. Clinical findings * Bilateral congenital cataracts. One individual had juvenile cataract [Ugur & Tolun 2008]; one individual had only a mild lens opacity, noted at age three years [Biancheri et al 2011]. * Nystagmus present from the first few weeks of life * Classic presentation shows normal or mildly delayed psychomotor development in the first year of life, followed by slowly progressive neurologic impairment manifest as: * Ataxia * Spasticity * Loss of the ability to walk * Mild-to-moderate cognitive impairment * Uncommon presentations [Biancheri et al 2011] * Early-onset severe variant. Hypotonia and feeding difficulties in the neonatal period, developmental delay in the first months of life, and wheelchair dependency in early childhood * Late-onset mild variant. Normal development in the first two years of life with subsequent sudden motor regression MRI findings * Diffusely abnormal supratentorial white matter in all individuals * Abnormal white matter signal behavior consistent with hypomyelination: * Hyperintense on T2-weighted images (intermediate hyperintensity between that of myelinated white matter and CSF) (Figure 1) * Isointense to slightly hypointense on T1-weighted images (Figure 2) * Areas of higher T2-weighted signal intensity with corresponding low-signal intensity on T1-weighted images consistent with areas of increased white matter water content of variable extension in some individuals (Figure 3) * White matter bulk loss in older individuals (Figure 4) * Medullary centers of the cerebellar hemispheres showing mildly increased T2-weighted signal intensity, paralleling that of the adjacent cortical gray matter and resulting in a "blurred" gray-white matter interface in some individuals (Figure 5) * Sparing of the cortical and deep gray matter structures #### Figure 1. Axial T2-weighted image shows diffuse hyperintensity of supratentorial white matter consistent with hypomyelination. #### Figure 2. Axial T1-weighted image shows diffusely isointense white matter with poor demarcation from adjacent gray matter, consistent with hypomyelination. #### Figure 3. Axial T1-weighted image (panel A) and axial T2-weighted image (panel B) show areas of increased water content involving the deep frontal white matter. #### Figure 4. Axial T2-weighted image in a 15-year-old shows enlargement of ventricles and subarachnoid spaces consistent with cerebral atrophy. The periventricular white matter is more hyperintense than the subcortical white matter, suggesting superimposed gliosis. (more...) #### Figure 5. Coronal T2-weighted image shows poor gray-white matter demarcation at the level of the medullary centers of the cerebellum, suggesting abnormal myelination of the cerebellar white matter. ### Establishing the Diagnosis The diagnosis of HCC is established in a proband with suggestive findings and biallelic pathogenic variants in FAM126A identified by molecular genetic testing (see Table 1). Note: Identification of biallelic FAM126A variants of uncertain significance (or identification of one known FAM126A pathogenic variant and one FAM126A variant of uncertain significance) does not establish or rule out a diagnosis of this disorder. Molecular testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with cataracts and/or leukodystrophy are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 Single-gene testing. Sequence analysis of FAM126A is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. A multigene panel that includes FAM126A 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. #### Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by cataracts and/or leukodystrophy, comprehensive genomic testing (which does not require the clinician to determine which gene is likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Hypomyelination and Congenital Cataract View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method FAM126ASequence analysis 316/17 4 Gene-targeted deletion/duplication analysis 5One family 6 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Missense and splice-site variants in all probands were identified by sequence analysis of the entire coding region and the exon-intron boundaries of FAM126A [Zara et al 2006, Biancheri et al 2011, Traverso et al 2013a, Traverso et al 2013b]. 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\. One such analysis involving FAM126A identified a homozygous deletion in a proband from a large consanguineous Turkish family [Ugur & Tolun 2008]. ## Clinical Characteristics ### Clinical Description Hypomyelination and congenital cataract (HCC) phenotype is quite consistent in the affected individuals described to date. ### Table 2. Hypomyelination and Congenital Cataract: Frequency of Select Features View in own window FeatureProportion of Persons w/FeatureComment Bilateral congenital cataracts26/30 Developmental delay30/30 Intellectual disability30/30 Dysarthria26/26 Truncal hypotonia26/26 Brisk tendon reflexes & bilateral extensor plantar responses30/30 Cerebellar signs11/25Truncal titubation, intention tremor Peripheral neuropathy22/24Muscle weakness, muscle wasting of the legs Seizures4/28Seizures may be prolonged & w/fever. Prenatal/perinatal. All affected individuals have normal prenatal and perinatal histories. Ophthalmologic. Bilateral congenital cataracts identified at birth or within the first month of life are the first clinical sign. All children underwent ocular surgery in the first months of life with the exception of the one child who had adolescent-onset cataracts [Ugur & Tolun 2008]. Psychomotor development is normal up until the end of the first year of life, when developmental delays appear [Biancheri et al 2007]. The ability to walk with support is achieved between ages 12 and 24 months. Independent walking is not achieved in all individuals. Slowly progressive neurologic impairment then becomes apparent with gradual loss of the ability to walk. Most individuals become wheelchair bound between ages eight and nine years [Biancheri et al 2007]. Feeding issues occur due to neurologic impairment. Swallowing may become difficult, and growth may be affected by suboptimal intake. Cognitive skills. All individuals have mild-to-moderate intellectual disability without deterioration in cognitive ability over time. Neurologic findings. Clinical examination reveals the following from the onset of the disease course: * Dysarthria * Truncal hypotonia * Pyramidal signs and spasticity. Tendon reflexes may be decreased or lost due to peripheral neuropathy. * Cerebellar signs/ataxia (including truncal titubation and intention tremor) * Peripheral neuropathy, present in most individuals, manifest as muscle weakness, wasting of the legs and ataxia. Peripheral neuropathy is absent in individuals with a milder form of the disorder (see Genotype-Phenotype Correlations). Seizures including those triggered by fever may occur, but are not a predominant clinical feature. Neurophysiologic investigations show the following from the onset of the disease course: * Motor nerve conduction velocity. Slightly to markedly slowed in most individuals, with lower values in older persons * Compound muscle action potentials. Reduced amplitude * Electromyography. Signs of denervation in the absence of spontaneous activity * Waking EEG. Irregular background activity; multifocal epileptiform discharges may be recorded. * Brain stem auditory evoked potentials. Increased I-V interpeak conduction time in individuals older than age two years * Electroretinogram. Normal Neuropathologic findings * Sural nerve biopsy of individuals with peripheral neuropathy shows a slight-to-severe reduction in density of myelinated fibers, with several axons surrounded by a thin myelin sheath or devoid of myelin. * Uncompaction of the myelin sheath, which in some fibers appears redundant and irregularly folded, is occasionally seen. * Electron microscopy confirms the presence of axons devoid of myelin, together with thinly myelinated fibers, sometimes surrounded by few Schwann cells processes, forming small onion bulbs. Orthopedic issues. A slowly progressive scoliosis appears concurrently with the loss of the ability to walk [Biancheri et al 2007]. Life expectancy is unknown; the oldest living affected individual is age 34 years. ### Genotype-Phenotype Correlations Pathogenic variants leading to the complete absence of FAM126A protein expression are associated with the full phenotype of bilateral cataract, central nervous system hypomyelination, and peripheral nerve hypomyelination. Pathogenic variants leading to a partial protein deficiency are associated with the milder form without peripheral nervous system involvement. An individual with deletion of exons 8 and 9 did not have congenital cataracts; cataracts developed at age nine years. A second individual had congenital unilateral cataract. However, of the four children in this family who survived beyond age two years, none was able to walk even with support after age six years [Ugur & Tolun 2008]. Because of the limited number of individuals with HCC described so far, these correlations should be further confirmed. ### Penetrance Penetrance is complete. ### Prevalence HCC is likely a rare disorder. No epidemiologic studies are available. ## Differential Diagnosis The association of congenital cataract and CNS hypomyelination is typical of hypomyelination and congenital cataract (HCC). However, the differential diagnosis with other hypomyelinating disorders should include the disorders summarized in Table 3. MRI usually shows areas with an even higher T2-weighted signal in HCC, whereas the white matter signal is homogeneously hyperintense in other hypomyelinating disorders. ### Table 3. Hypomyelinating Disorders of Interest in the Differential Diagnosis of Hypomyelination and Congenital Cataract View in own window Gene(s)DiffDx DisorderMOIFeatures of DiffDx Disorder Overlapping w/HCCDistinguishing from HCC PLP1Pelizaeus-Merzbacher disease (See PLP1 Disorders.)XLSpasticity/ataxia; nystagmus; hypomyelinationNo congenital cataracts; pure hypomyelination on MRI; peripheral neuropathy rare; X-linked inheritance GJC2Hypomyelinating leukodystrophy 2 (OMIM 608804)ARSpasticity/ataxia; nystagmus; hypomyelination, peripheral neuropathy, epilepsyNo congenital cataracts; hypomyelinating MRI pattern different TUBB4ATUBB4A-related leukodystrophyADSpasticity/ataxia; nystagmus; hypomyelinationHypomyelination, cerebellar atrophy, & (in most cases) atrophy of the basal ganglia on MRI POLR1C POLR3A POLR3B POLR3KPOLR3-related leukodystrophyARAtaxia, hypodontia, hypogonadotropic hypogonadism, high myopiaSpecific pattern of hypomyelination & cerebellar atrophy on MRI AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; HCC = hypomyelination and congenital cataract; MOI = mode of inheritance; XL = X-linked ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hypomyelination and congenital cataract (HCC), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Hypomyelination and Congenital Cataract View in own window System/ConcernEvaluationComment CataractsOphthalmologic exam Developmental delayDevelopmental assessment * Incl motor, adaptive, cognitive, & speech/language eval for dysarthria * Eval for early intervention / special education NeurologicNeurologic eval for evidence of spasticity, ataxia, seizuresConsider EEG if seizures are a concern. MusculoskeletalOrthopedics / physical medicine & rehabilitation / PT/OT evalTo incl assessment of: * Gross motor & fine motor skills * Contractures, clubfoot, & kyphoscoliosis * Mobility, activities of daily living, & need for adaptive devices * Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Gastrointestinal/ FeedingGastroenterology / nutrition / feeding team eval * To incl eval of aspiration risk & nutritional status * Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. Genetic counselingBy genetics professionals 1To inform patients & their families re nature, MOI, & implications of HCC in order to facilitate medical & personal decision making Family support/ resourcesAssess: * Use of community or online resources such as Parent to Parent; * Need for social work involvement for parental support; * Need for home nursing referral. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy 1\. Medical geneticist, certified genetic counselor, certified advanced genetic nurse ### Treatment of Manifestations ### Table 5. Treatment of Manifestations in Individuals with Hypomyelination and Congenital Cataract View in own window Manifestation/ ConcernTreatmentConsiderations/Other CataractCataract extractionUsually in the first months of life DD/ID * Adjuvant therapies incl PT, OT, & speech therapy for persons w/identified DDs * Individualized education plans for learning disorders & school performance issues Spasticity * Pharmacologic agents (e.g., baclofen, incl intrathecal baclofen) * Orthopedics / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & falls Consider need for positioning & mobility devices, disability parking placard. AtaxiaPhysical medicine & rehab EpilepsyStandardized treatment w/AEDs by experienced neurologist * Many AEDs may be effective; none has been demonstrated effective specifically for HCC. * Education of parents/caregivers 1 Scoliosis & contracturesPrevention/treatment per orthopedist FeedingFeeding therapy; gastrostomy tube placement may be required for persistent feeding issues.Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia AED = antiepileptic drug; DD = developmental delay; HCC = hypomyelination and congenital cataract; ID = intellectual disability; OT = occupational therapy; PT = physical therapy 1\. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. ### Surveillance ### Table 6. Recommended Surveillance for Individuals with Hypomyelination and Congenital Cataract View in own window System/ConcernEvaluationFrequency CataractsEye exam if cataracts were not identified in the neonatal period DevelopmentMonitor developmental progress & educational needs.At each visit NeurologicMonitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, movement disorders. MusculoskeletalPhysical medicine, OT/PT assessment of mobility, self-help skills Feeding * Measurement of growth parameters * Eval of nutritional status & safety of oral intake Family/ CommunityAssess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination. OT = occupational therapy; PT = physical therapy ### Agents/Circumstances to Avoid None are known. Some individuals are prone to febrile seizures. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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

Hypomyelination and Congenital Cataract

c1864663

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK2587/

{"mesh": ["C567166"], "synonyms": []}

Cryptogenic cirrhosis is a condition that impairs liver function. People with this condition develop irreversible liver disease caused by scarring of the liver (cirrhosis), typically in mid- to late adulthood. The liver is a part of the digestive system that helps break down food, store energy, and remove waste products, including toxins. Minor damage to the liver can be repaired by the body. However, severe or long-term damage can lead to the replacement of normal liver tissue with scar tissue. In the early stages of cryptogenic cirrhosis, people often have no symptoms because the liver has enough normal tissue to function. Signs and symptoms become apparent as more of the liver is replaced by scar tissue. Affected individuals can experience fatigue, weakness, loss of appetite, weight loss, nausea, swelling (edema), enlarged blood vessels, and yellowing of the skin and whites of the eyes (jaundice). People with cryptogenic cirrhosis may develop high blood pressure in the vein that supplies blood to the liver (portal hypertension). Cryptogenic cirrhosis can lead to type 2 diabetes, although the mechanism is unclear. Some people with cryptogenic cirrhosis develop cancer of the liver (hepatocellular cancer). ## Frequency Cirrhosis affects more than 600,000 people in the United States; cryptogenic cirrhosis likely accounts for 5 to 30 percent of these cases. ## Causes Unlike most cases of cirrhosis, cryptogenic cirrhosis is not caused by the hepatitis C or B virus or chronic alcohol use. A diagnosis of cryptogenic cirrhosis is typically given when all other causes of cirrhosis have been ruled out. When a disorder occurs without an apparent underlying reason, it is described as cryptogenic. Research has shown that many cases of cryptogenic cirrhosis likely result from a condition called non-alcoholic fatty liver disease (NAFLD). In NAFLD, fat accumulates in the liver, impairing its function. If the fat buildup leads to inflammation and damage to liver tissue, NAFLD progresses to a condition called non-alcoholic steatohepatitis (NASH). Long term inflammation in people with NASH can cause the formation of scar tissue and a decrease in fat buildup. As a result, individuals progress from NASH to cirrhosis. Cryptogenic cirrhosis may also develop from autoimmune hepatitis, which is a condition that occurs when the body's immune system malfunctions and attacks the liver, causing inflammation and liver damage. In very rare cases, cryptogenic cirrhosis has been associated with mutations in genes that provide instructions for making certain keratin proteins. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, nails, and similar tissues. People with these keratin gene mutations are more likely to have fibrous deposits in their livers than individuals without the mutations. These deposits impair liver function, leading to cirrhosis. Mutations in these genes have also been found in people with other liver disorders. In many cases, the cause of cryptogenic cirrhosis is unknown. Many people with predisposing conditions do not develop cirrhosis. Researchers are working to discover the causes of cryptogenic cirrhosis as well as to find out why some people seem to be protected from developing cirrhosis and others seem to be susceptible. ## Inheritance Pattern Most cases of cryptogenic cirrhosis are not inherited. However, people with a family history of liver disease or autoimmune disease are at an increased risk of developing these diseases themselves, and possibly cirrhosis. In individuals with an associated keratin gene mutation, the risk of developing cryptogenic cirrhosis appears to have an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means that one copy of an altered gene in each cell is sufficient to increase the risk of developing cryptogenic cirrhosis. In these families, people inherit an increased risk of cryptogenic cirrhosis, not the disease itself. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Cryptogenic cirrhosis

c0268074

medlineplus

https://medlineplus.gov/genetics/condition/cryptogenic-cirrhosis/

{"mesh": ["C562580"], "omim": ["215600"], "synonyms": []}

A number sign (#) is used with this entry because of the finding that this form of autosomal recessive deafness, DFNB30, is caused by mutations in the myosin IIIA gene (MYO3A; 606808). Clinical Features Walsh et al. (2002) studied a family that traced its ancestry to the Jewish community of Mosul, Iraq. This community dated to 586 B.C. and was highly endogamous, with considerable emigration but little immigration, for more than 2,500 years. Most remaining Jewish residents of Mosul, including this family, migrated to Israel in 1950-1951. Three generations of the family had experienced bilateral progressive hearing loss, which first affected the high frequencies. Hearing loss began in the second decade, and by age 50, was severe in high and middle frequencies and moderate at low frequencies. Vision and balance of all affected individuals were normal. Inheritance of deafness in this family was likely recessive with age-dependent penetrance, although dominant inheritance could not be excluded. Mapping By genomewide linkage analysis, Walsh et al. (2002) identified a locus for DFNB30 on chromosome 10p in 23 members of an Israeli family that can be traced to the Jewish community of Mosul, Iraq. They found evidence of linkage to an interval between D10S1749 and D10S1654 with a lod score of 4.3. Fine mapping by SNPs revealed no subregion homozygous in all affected relatives, leading to the conclusion that multiple alleles (or even multiple genes) were likely to be responsible for deafness in this family. The critical region for the myosin IIIA gene (606808) seemed to be an excellent candidate for DFNB30, because 4 other myosins had been associated with hearing loss: MYO7A (276903), MYH9 (160775), MYO6 (600970), and MYO15A (602666). Molecular Genetics Walsh et al. (2002) determined that DFNB30 is caused by mutations in the MYO3A gene (606808). Genotype/Phenotype Correlations Three mutations in MYO3A fully explained the hearing loss in the family described by Walsh et al. (2002), in that there was complete concordance of MYO3A genotypes and hearing loss. All homozygotes and compound heterozygotes were deaf; all simple heterozygotes were carriers with normal hearing. Variability in age of onset of hearing loss could be explained. Between age 25 and 50 years, hearing across all frequencies was significantly poorer among individuals homozygous for the nonsense mutation than among individuals heterozygous for the nonsense mutation in combination with either of the splice mutations. Hearing loss was equally severe in all affected individuals by the sixth decade. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing loss, sensorineural, progressive (moderate to severe) MISCELLANEOUS \- Onset in the second decade and by age 50 is severe in high and middle frequencies and moderate at low frequencies \- Based on a family from an endogamous Jewish community of Mosul, Iraq (last curated August 2015) MOLECULAR BASIS \- Caused by mutation in the myosin IIIA gene (MYO3A, 606808.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

DEAFNESS, AUTOSOMAL RECESSIVE 30

c1846784

omim

https://www.omim.org/entry/607101

{"doid": ["0110489"], "mesh": ["C564624"], "omim": ["607101"], "orphanet": ["90636"], "synonyms": ["Autosomal recessive isolated neurosensory deafness type DFNB", "Autosomal recessive isolated sensorineural deafness type DFNB", "Autosomal recessive non-syndromic neurosensory deafness type DFNB"], "genereviews": ["NBK1434"]}

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by agenesis of the corpus callosum, borderline or mild intellectual disability, macrocephaly, and dysmorphic facial features (broad forehead, widely spaced eyes). Chiari type I malformation has also been reported in association. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Corpus callosum agenesis-macrocephaly-hypertelorism syndrome

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=459074

{"icd-10": ["Q04.0"], "synonyms": ["7q36.3 microduplication syndrome", "Dup(7)(q36.3)"]}

## Summary ### Clinical characteristics. Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid β-oxidation. Fatty acid β-oxidation fuels hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. MCAD deficiency is the most common disorder of fatty acid β-oxidation and one of the most common inborn errors of metabolism. Most children are now diagnosed through newborn screening. Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma triggered by a common illness. Hepatomegaly and liver disease are often present during an acute episode. Children appear normal at birth and – if not identified through newborn screening – typically present between age three and 24 months, although presentation even as late as adulthood is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged periods of fasting. ### Diagnosis/testing. The diagnosis of MCAD deficiency is established in a proband with confirmatory biochemical testing results and biallelic pathogenic variants in ACADM identified on molecular genetic testing. Diagnostic testing is typically initiated after either a positive newborn screening result or suggestive biochemical testing in a previously healthy individual who develops symptoms. Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without needing provocative tests. Assays to determine residual enzyme activity are possible but not routinely necessary and not clinically available in many regions. ### Management. Treatment of manifestations: The most important intervention is giving simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV if needed to reverse catabolism and sustain anabolism. Prevention of primary manifestations: The mainstay is avoidance of fasting: infants require frequent feedings; toddlers could be placed on a relatively low-fat diet (e.g., <30% of total energy from fat) and could receive 2 g/kg of uncooked cornstarch at bedtime to ensure sufficient glucose overnight. Agents/circumstances to avoid: Hypoglycemia (e.g., from excessive fasting); infant formulas that contain medium-chain triglycerides as the primary source of fat. Evaluation of relatives at risk: If the ACADM pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs and offspring of the proband. If the ACADM pathogenic variants in the family are not known, plasma acylcarnitine and urine acylglycine analysis can be used to clarify the disease status. ### Genetic counseling. MCAD deficiency is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual are at a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. Because of the high carrier frequency for the ACADM c.985A>G pathogenic variant in individuals of northern European origin, carrier testing should be discussed with reproductive partners of individuals with MCAD deficiency. Once both ACADM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for MCAD deficiency are possible. ## Diagnosis Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common fatty acid β-oxidation disorder. Fatty acid β-oxidation fuels hepatic ketogenesis, a major source of energy for peripheral tissues after glycogen stores are depleted during prolonged fasting and periods of higher energy demands. ### Suggestive Findings MCAD deficiency should be suspected in: * An infant with a positive newborn screening result; * A previously healthy individual who becomes symptomatic and has supportive clinical and laboratory findings; or * A case of sudden and unexpected death. #### Positive Newborn Screening (NBS) Result NBS for MCAD deficiency is primarily based on the results of a quantitative acylcarnitine profile on dried blood spot (DBS) cards. Elevations of C8-acylcarnitine with lesser elevations of C6-, and C10-acylcarnitine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing. The cut-off values for C8 differ by NBS program and may be combined with elevated secondary markers including C0, C2, and C10:1, and the ratios of C8/C2 and C8/C10 in presumptive positive cases to aid in NBS sensitivity. (Mayo Clinic CLIR, accessed 6-18-20). Follow-up testing includes: plasma acylcarnitine analysis, urine organic acid analysis, and urine acylglycine analysis. If the test results support the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis (see Establishing the Diagnosis). The American College of Medical Genetics and Genomics ACT Sheet and Diagnostic Algorithm (pdfs) for follow up of an abnormal NBS result suggestive of MCAD deficiency should be reviewed. The positive predictive value for elevations of C8-acylcarnitines is currently considered to be very high with the use of tandem mass spectrometry (MS/MS). False positives for elevations of C8-acylcarnitines are not common but can be seen in term infants who are appropriate for gestational age and heterozygous for the common c.985A>G pathogenic variant (see Table 1), and premature infants [McCandless et al 2013]. False negatives have been reported in newborns with low free carnitine levels, such as infants born to a mother with low free carnitine levels, including previously undiagnosed mothers with MCAD deficiency, maternal carnitine transporter deficiency, or nutritional carnitine deficiency [Leydiker et al 2011, Aksglaede et al 2015]. Note: A newborn whose blood sample has been submitted for NBS may become symptomatic before the screening results are available. Severe lethal presentations in the first week of life (i.e., before NBS results are available) have been reported [Ensenauer et al 2005, Wilcken et al 2007, Lindner et al 2011, Andresen et al 2012, Lovera et al 2012, Tal et al 2015]. Published reports on NBS outcomes document that individuals identified and treated presymptomatically can be saved from metabolic decompensations and relevant sequelae [Wilcken et al 2007, Lindner et al 2011, Catarzi et al 2013, Tal et al 2015]. However, these reports also show that some individuals with MCAD deficiency present (sometimes fatally) within the first few days of life, making it impossible to obtain NBS results prior to their initial clinical manifestation [McCandless et al 2013] Implementation of NBS has seen improvements in mortality rates from >20% to 3.5%-10% [Nennstiel-Ratzel et al 2005, Grosse et al 2006, Wilcken et al 2007, Feuchtbaum et al 2018]. #### A Previously Healthy Individual Who Becomes Symptomatic Symptoms in a previously healthy individual may include: * Hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma triggered by a common illness; * Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver). Historically, prior to NBS, the first acute episode would typically occur before age two years; however, affected individuals may present at any age including adulthood [Raymond et al 1999, Schatz & Ensenauer 2010]. Late-onset presentations have been described in adults after prolonged fasting, including after fasting for surgery, or with alcohol intoxication [Lang 2009]. Rapid clinical deterioration that is disproportionate in the setting of a common and generally benign infection should raise the suspicion of MCAD deficiency or other fatty acid β-oxidation disorders, and should prompt initiation of treatment simultaneously with additional diagnostic testing. #### Sudden and Unexpected Death Most FAO disorders including MCAD deficiency frequently manifest with sudden and unexpected death [Rinaldo et al 2002]. The following information supports the possibility of MCAD deficiency: * Evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death * Breast-fed infant (rather than bottle-fed) [Ahrens-Nicklas et al 2016] * Adult following an episode of fasting or alcohol consumption [Lang 2009] * A family history of sudden death or Reye syndrome in sibs [Bzduch et al 2001] * Findings at autopsy of cerebral edema and fatty infiltration of the liver, kidneys, and heart [Boles et al 1998] Note: Postmortem acylcarnitine analysis for MCAD deficiency may be performed on original NBS DBS cards, which can be stored at 4-8°C for up to at least a decade [Kaku et al 2018]. ### Establishing the Diagnosis The diagnosis of MCAD deficiency is established in a proband with Suggestive Findings (see above) by confirmatory biochemical testing and identification of biallelic pathogenic variants in ACADM on molecular genetic testing (see Table 1). Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without using provocative tests. Assays to determine residual enzyme activity are possible but not routinely necessary and not clinically available in many regions. Note: Confirmatory postmortem testing is possible in the individual with sudden and unexpected death if MCAD deficiency is suspected. #### Biochemical Testing Testing should include plasma acylcarnitine analysis with proper interpretation. Urine organic acid analysis and urine acylglycine analysis may provide supporting evidence and have been used for diagnosis prior to the advent of widely available molecular testing, or when molecular testing is not readily available. Plasma acylcarnitine analysis. The acylcarnitine profile of individuals with MCAD deficiency is characterized by the prominent accumulation of C8- (octanoylcarnitine), with lesser elevations of C6-, C10-, and C10:1-acylcarnitines [Millington et al 1990, Chace et al 1997, Smith et al 2010]. Secondary decreased levels of free carnitine (C0) and acetylcarnitine (C2) may be seen with carnitine deficiency. The C8/C2 and C8/C10 ratios have also been used for interpretation of primary elevations of C8. Sole reliance on plasma acylcarnitine analysis may not be sufficient, and either urine organic acids or acylglycines (ideally collected during an acute episode of metabolic decompensation as these, as well as acylcarnitines, could normalize when the individual is not under metabolic stress) should be analyzed to reach a correct biochemical diagnosis. Note: When clinical suspicion of MCAD deficiency remains high and plasma acylcarnitine testing is not diagnostic, low free carnitine levels should be considered during the evaluation. Secondary carnitine deficiency may cause lower elevations of C8-, C6-, and C10 -acylcarnitines, or even normal acylcarnitine profiles [Clayton et al 1998; Leydiker et al 2011]. Some laboratories report acylcarnitine profiles with low C0 and C2-acylcarnitines, and while nonspecific, these findings may indicate an underlying metabolic disorder such as maternal MCAD deficiency, maternal carnitine transporter deficiency, or nutritional carnitine deficiency [Aksglaede et al 2015; Leydiker et al 2011]. Urine organic acid analysis. In symptomatic individuals, medium-chain dicarboxylic acids are elevated with a characteristic pattern – hexanoylglycine (C6) > octanoylglycine (C8) > decanoylglycine (C10) – while ketones are inappropriately low. During acute episodes, suberylglycine and dicarboxylic acids (adipic, suberic, sebacic, dodecanedioic, and tetradecanedioic) may be elevated, and represent additional biochemical markers of MCAD deficiency [Niwa 1995, Rinaldo et al 1998]. * Standard urine organic acid profiles are often uninformative in individuals with MCAD deficiency who are clinically stable and not fasting [Rinaldo et al 2001]. Under these conditions, the urinary excretion of the three acylglycines is often <10 mmol/mol creatinine – levels not readily detectable by routine organic acid analysis. * Individuals receiving medium-chain triglyceride (MCT) oil supplements or MCT-containing foods (e.g., MCT-supplemented infant formulas, coconut oil) may demonstrate elevated concentrations of octanoic acid and decanoic acid, but have normal cis-4 decenoic acid and should not be interpreted as possibly having MCAD deficiency. * Low levels of ketones may be seen (see Clinical Description, Hypoketotic hypoglycemia). Urine acylglycine analysis will detect urinary n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine. This test is more sensitive and specific for the identification of asymptomatic individuals and those with mild or intermittent biochemical phenotypes that may be missed by organic acid analysis alone [Rinaldo et al 1988, Rinaldo et al 2001]. * During acute episodes, large amounts of hexanoylglycine and suberylglycine are present (which are also readily detectable by urine organic acid analysis). * Acylglycine analysis is informative in newborns and is the preferred test in persons who are clinically asymptomatic or who have mild or intermittent biochemical phenotypes. * The test, requiring only a random urine sample from asymptomatic individuals and no provocative tests, is informative immediately after birth [Bennett et al 1991]. Note: Integrated analysis, post-analytic interpretation, and differential diagnosis of acylcarnitine and acylglycine results deemed to be abnormal could be aided by tools developed through the Collaborative Laboratory Integrated Reports (CLIR) project. #### Molecular Genetic Testing Molecular genetic testing approaches, which are determined by the clinical findings, can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (typically exome sequencing and exome array). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Infants with positive NBS and confirmatory follow-up testing are likely to be diagnosed using gene-targeted testing (see Option 1), whereas symptomatic individuals with nonspecific supportive clinical and laboratory findings (who had not undergone NBS or had normal NBS results in the past) in whom the diagnosis of MCAD deficiency has not been considered are more likely to be diagnosed using comprehensive genomic testing (see Option 2). #### Option 1 When NBS results and other laboratory findings suggest the diagnosis of MCAD deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. Single-gene testing. Sequence analysis of ACADM detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon-level or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * Targeted analysis for common northern European pathogenic variants may be performed first in individuals of northern European background: * c.985A>G (p.Lys329Glu) * c.199T>C (p.Tyr67His) * Targeted analysis for common Japanese pathogenic variants may be performed first in individuals of Japanese ancestry. These variants account for about 60% of alleles examined in the Japanese population [Tajima et al 2016]: * c.449_452delCTGA (p.Thr150ArgfsTer4) * c.50G>A (p.Arg17His) * c.1085G>A (p.Gly362Glu) * c.157C>T (p.Arg53Cys) * c.843A>T (p.Arg281Ser) A multigene panel that includes ACADM and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. #### Option 2 When the diagnosis of MCAD deficiency has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. 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 Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency View in own window Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method ACADMTargeted analysisc.985A>G (p.Lys329Glu) 3 Sequence analysis 498% 5 Gene-targeted deletion/duplication analysis 64 reported 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\. The c.985A>G pathogenic variant accounts for between 56% and 91% of MCAD deficiency-causing alleles [Rhead 2006, Gramer et al 2015]. 4\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5\. HGMD (accessed 3/14/19) 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. [Morris et al [1995], Arnold et al [2010], Searle et al [2013], Abulí et al [2016] #### Enzyme Activity Analysis Analysis of fatty acid β-oxidation in cultured fibroblasts involves acylcarnitine analysis of culture medium or a mix of culture medium and disrupted cells following the incubation of fibroblast cultures with labeled or non-labeled palmitic acid and non-labeled L-carnitine [Schmidt-Sommerfeld et al 1998]. The accumulation of C6-C10 acylcarnitines as described for plasma analysis confirms the diagnosis [Matern 2014]. Noninvasive testing using palmitate in individuals with suspected fatty-acid oxidation defects. Identification of disease-specific acylcarnitine patterns can help establish the diagnosis [Janzen et al 2017]. Measurement of MCAD enzyme activity (currently not available in the United States) in cultured fibroblasts or other tissues (leukocytes, liver, heart, skeletal muscle, or amniocytes) by the ETF reduction assay reveals that individuals with MCAD deficiency usually exhibit MCAD enzymatic activity that is <10% of normal [Hale et al 1990]. Similar enzyme deficiency was seen in a different assay using an HPLC method [Wanders et al 2010]. Another study investigating enzyme activity in fibroblasts found <35% activity in individuals with MCAD deficiency [Bouvier et al 2017]. * Derks et al [2007] suggested that when residual MCAD enzyme activity in leukocytes is >10% of normal, prevention of fasting is not necessary for otherwise healthy individuals older than age six months [Touw et al 2013]. According to Sturm et al [2012], however, residual MCAD enzyme activity <30% requires treatment and follow up. * It is uncertain whether variability in MCAD enzyme activity assays plays a role in these different conclusions. * MCAD enzyme activity is routinely measured in The Netherlands and may guide NBS risk stratification [Jager et al 2019]. #### Confirmatory Postmortem Testing Collect postmortem blood [Chace et al 2001] and bile [Rashed et al 1995] spots on filter paper cards of the type used for NBS for subsequent acylcarnitine analysis. Collection of both specimens provides a better chance of detecting affected individuals and independently confirming the diagnosis. Molecular genetic testing of ACADM using the postmortem blood spot or NBS blood spot retrieved from the screening laboratory can help confirm the diagnosis. Note: States store leftover dried blood spot samples for variable lengths of time following NBS testing. These samples may be retrievable with parent/patient consent for retrospective biochemical or molecular genetic testing. See Baby's First Test for US state-by-state NBS laboratory contact information. Note: Although postmortem biochemical and/or molecular genetic testing of tissues and cultured skin fibroblasts is possible [Rinaldo et al 2002], it is logistically impractical and thus rarely performed. ## Clinical Characteristics ### Clinical Description Fatty acid β-oxidation fuels hepatic ketogenesis, a major source of energy for peripheral tissues once glycogen stores become depleted during prolonged fasting and/or periods of higher energy demands (see Pathophysiology). The frequent feeding schedule of infants typically precludes the need for alternative energy sources, but as the interval between feeds increases, reliance on fatty acid catabolism commensurately increases. This may manifest in preprandial hypoglycemia symptoms such as lethargy, irritability, jitteriness, seizures, or hypoglycemic crisis. MCAD deficiency is a known cause of sudden infant death syndrome (SIDS) [Roe et al 1986]. #### MCAD Deficiency Individuals with MCAD deficiency appear normal at birth and historically have presented between age three and 24 months; presentations in adulthood have also been reported [Duran et al 1986, Raymond et al 1999, Lang 2009]. Hypoketotic hypoglycemia. Affected individuals tend to present in response to either prolonged fasting (e.g., weaning the infant from nighttime feedings) or intercurrent and common infections (e.g., viral gastrointestinal or upper respiratory tract infections), which typically cause loss of appetite and increased energy requirements when fever is present. * Hypoglycemic episodes may also begin with or be accompanied by seizures. * In a cohort of non-diabetic adults, MCAD deficiency was diagnosed in some individuals presenting with fasting hypoglycemia [Douillard et al 2012]. * Such instances of metabolic stress lead to vomiting and lethargy, which may quickly progress to coma and death. * The presence of low levels of ketones on urinalysis, urine organic acids, or serum beta-hydroxybutyrate should not be taken as evidence against MCAD deficiency ("hypoketotic" as compared to nonketotic), as ketones may be detected during times of acute metabolic decompensation. Hepatomegaly may be present during an acute decompensation, which is also characterized by hypoketotic hypoglycemia, increased anion gap, hyperuricemia, elevated liver transaminases, and hyperammonemia. Sudden death. Sudden and unexpected death was historically common as the first manifestation of MCAD deficiency [Iafolla et al 1994, Rinaldo et al 1999, Chace et al 2001] and still may occur as late as adulthood (e.g., precipitated by times of increased metabolic stress such as surgery or prolonged fasting) [Raymond et al 1999]. * If the diagnosis of MCAD has not been previously established, at least 18% and up to 25% of affected individuals die during their first metabolic crisis [Iafolla et al 1994]. * Early death before the return of newborn screening (NBS) results still occurs. * Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys, and heart [Boles et al 1998]. Neurologic findings. Individuals with MCAD deficiency who have suffered the effects of an uncontrolled metabolic decompensation are at risk of losing developmental milestones and acquiring aphasia and attention-deficit disorder, which are thought to be secondary to brain injury sustained during the acute metabolic event. Muscular concerns. Individuals with MCAD deficiency who have suffered the effects of uncontrolled metabolic decompensation may be at risk for chronic muscle weakness, as observed in 18% of individuals who experienced several episodes of metabolic decompensation [Iafolla et al 1994]. In a long-term study of individuals with MCAD deficiency diagnosed prior to NBS, many reported fatigue, muscle pain, and reduced exercise tolerance. No abnormality in cardiac function was identified to explain these symptoms [Derks et al 2006]. Growth. Children with MCAD deficiency are at risk for obesity after initiation of treatment, likely due to the frequency of feeding. Arrhythmia. Cardiac symptoms in MCAD deficiency are rare but have been reported in sporadic case reports. Prolongation of the QTc interval has been reported in an infant with MCAD deficiency [Wiles et al 2014]. A girl age 16 years presented with hepatic, renal, and cardiac failure after an alcoholic binge and subsequent period of starvation [Mayell et al 2007]. An adult with MCAD deficiency also developed supraventricular tachycardia, ventricular tachycardia, and ultimately ventricular fibrillation resulting in cardiac arrest after presenting with vomiting and headaches in the setting of hyperammonemia and hypoglycemia [Feillet at al 2003]. Renal disease. Some studies have suggested that individuals with MCAD deficiency and other fatty acid disorders may be at risk for chronic kidney disease as they age. Renal proximal tubules contain high concentration of mitochondria that express fatty acid enzymes, which may be affected in individuals with fatty acid oxidation defects. Autopsy findings associated with MCAD deficiency have identified fatty infiltration of the kidney [Boles et al 1998]. Individuals with tubulointerstitial fibrosis have also been demonstrated to have lower expression of some fatty acid oxidation enzymes, leading to ATP depletion, apoptosis, and intracellular lipid deposition [Kang et al 2015]. #### "Mild" MCAD Deficiency Often referred to as "asymptomatic" MCAD deficiency, this designation is not entirely accurate. The expansion of NBS programs using tandem mass spectrometry (MS/MS) led to the identification of affected individuals with milder abnormalities in their acylcarnitine profiles (see Genotype-Phenotype Correlations). * Individuals with MCAD deficiency may remain asymptomatic, although whether this is attributable to early awareness of the disease, early initiation of treatment and resulting prevention of symptoms, or to a higher residual MCAD enzymatic activity remains to be determined [Zschocke et al 2001]. * Individuals with a "milder" biochemical phenotype can still develop life-threatening symptoms [Dessein et al 2010]. * All individuals with MCAD deficiency should be considered at risk of developing clinical manifestations and should receive long-term follow up and management [Arnold et al 2010]. ### Pathophysiology Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid β-oxidation. Fatty acid β-oxidation releases energy and provides acetyl-CoA for hepatic ketogenesis. Once glycogen stores are depleted during prolonged fasting and periods of higher energy demands, peripheral tissues switch to using energy from fatty acid oxidation to preserve glucose for utilization by the brain. The brain can also use ketone bodies derived from fatty acids. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to CoA esters in the mitochondrial matrix. Fatty acid β-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the β-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH+, and NADH2. MCAD deficiency impairs the energy supply to peripheral tissues through ketogenesis and increases glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine- and acylcarnitine-esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage [Derks et al 2014]. ### Genotype-Phenotype Correlations Inclusion of MCAD deficiency in NBS programs has led to the identification of individuals with less pronounced abnormalities in their acylcarnitine profiles who are compound heterozygotes either for the common European ACADM pathogenic variant c.985A>G (p.Lys329Glu), previously known as p.Lys304Glu), and another pathogenic variant, or for two non-c.985A>G pathogenic variants [Albers et al 2001, Andresen et al 2001, Zschocke et al 2001, Maier et al 2005, Smith et al 2010]. * Most individuals are compound heterozygous for the c.985A>G pathogenic variant and another deletion or pathogenic variant, or homozygous for c.985A>G. * Individuals homozygous for the common c.985A>G variant had the highest C8 newborn screen values and were most likely to have neonatal symptoms [Waddell et al 2006, Arnold et al 2010, Bentler et al 2016]. * Individuals with compound heterozygous pathogenic variants c.985A>G and c.600-18G>A have a mild phenotype and may not be detected by NBS due to residual MCAD enzyme activity [Grünert et al 2015]. * A collaborative retrospective analysis of a cohort of 221 affected individuals identified by NBS in the United States showed that C8 level and genotype were significant predictors of neonatal symptoms. Individuals with neonatal symptoms had significantly higher C8 values [Bentler et al 2016]. The c.199T>C pathogenic variant has an allele frequency of approximately 6% in MCAD-deficient newborns [Andresen et al 2001, Maier et al 2005, Waddell et al 2006, Nichols et al 2008] and is associated with some residual MCAD enzymatic activity [Andresen et al 2001]. Individuals who are heterozygous for the c.199T>C variant and another pathogenic variant may have lower acylcarnitine levels but still be at risk for metabolic crisis [Gramer et al 2015]. While it appears that residual enzyme activity levels better correlate with phenotype [Touw et al 2013], it is reasonable to assume that environmental factors (e.g., diet, stress, or intercurrent illnesses) are critical in determining the natural history of this disorder. For several presumably mild pathogenic variants identified only presymptomatically through NBS, expression studies that may aid in risk assessment have also been conducted to evaluate the effect of the variant on protein folding, temperature sensitivity, and enzyme activity [Jank et al 2014, Koster et al 2014]. ### Nomenclature MCAD deficiency was first described in individuals presenting with a Reye-like phenotype and urine organic acid analysis that revealed overexcretion of medium-chain dicarboxylic acids and hexanoylglycine in the absence of significant ketosis [Kølvraa et al 1982, Roe et al 1986, Bzduch et al 2001]. Accordingly, it is likely that prior to MCAD deficiency having been better delineated, affected individuals were misdiagnosed as having Reye syndrome. Note that historical nomenclature begins amino acid numbering at p.1 of the mature protein, whereas current nomenclature begins amino acid numbering at p.1 of the pro-protein. Therefore, the common pathogenic variant encoded by c.985A>G (p.Lys329Glu) was historically known as p.Lys304Glu. ### Prevalence The overall prevalence of MCAD deficiency is 5.3 (4.1-6.7, 99% CI) per 100,000 births across a variety of ethnic groups [Feuchtbaum et al 2012]. MCAD deficiency is prevalent in individuals of (especially northern) European descent. The carrier frequency for the c.985A>G pathogenic variant in ACADM is between 1:40 and 1:100 in northern Europeans, suggestive of a founder effect [Gregersen et al 1993, Tanaka et al 1997]. A similar prevalence has been observed among Portuguese with Gypsy ancestry [Rocha et al 2014] and Native Americans of California [Feuchtbaum et al 2012]. The number of newborns detected with MCAD deficiency through NBS programs exceeds that expected based on the population frequency of the common c.985A>G pathogenic variant [Andresen et al 2001, Maier et al 2005, Wilcken et al 2009, Vilarinho et al 2010, Andresen et al 2012, Touw et al 2012]. The c.449_452delCTGA deletion is more prevalent in Asian (i.e., Taiwanese, Japanese, and Korean) populations [Woo et al 2011, Chien et al 2013, Hara et al 2016, Tajima et al 2016]. Based on NBS programs or pilot studies worldwide, the incidence of MCAD deficiency has been determined as follows: * Asia * Japan. 1:51,000 live births [Shigematsu et al 2002]. There has also been a significant increase in the diagnosis of MCAD deficiency in Japanese individuals, with most having at least one novel pathogenic variant [Hara et al 2016, Tajima et al 2016]. * Saudi Arabia. 1:18,000 live births [Al-Hassnan et al 2010] * Taiwan. 1:263,500 live births [Chien et al 2013] * Australia. New South Wales. 1:19,000 live births [Wilcken et al 2009] * Europe. The prevalence in live births in Europe has ranged from a high of 1:4,900 in northern Germany [Sander et al 2001] to a low of 1:24,900 in Austria [Kasper et al 2010] or 1:23,000 in central Italy. * North America. Prevalence has ranged from 1:23,400 live births in Canada [Prasad et al 2012] to ranges of 1:13,000 to 1:19,000 in various states aross the United States [Chace et al 2002, Frazier et al 2006, Hsu et al 2008, Nichols et al 2008, Anderson et al 2012, Feuchtbaum et al 2012]. Historically, MCAD deficiency was considered less common in the Hispanic, African American, and Native American populations in the USA. More recent analysis of data from California demonstrated that MCAD deficiency may be as prevalent in Native Americans (1:7,500 live births) as in northern Europeans. Prevalences are similar among newborns of Hispanic, black, and Middle Eastern origin (1:23,000 live births) [Feuchtbaum et al 2012]. ## Differential Diagnosis All causes of a Reye-like syndrome (i.e., acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver) need to be considered in the differential diagnosis of MCAD deficiency, including other disorders of fatty acid β-oxidation, defects in ketogenesis, urea cycle disorders, organic acidurias, respiratory chain defects, and inborn errors of carbohydrate metabolism (e.g., hereditary fructose intolerance). Disorders of fatty acid β-oxidation. Because of the nonspecific clinical presentation of MCAD deficiency, distinguishing it from other mitochondrial fatty acid β-oxidation disorders requires biochemical and molecular testing. Medium-chain acyl-coenzyme A dehydrogenase belongs to the acyl-CoA dehydrogenase (ACAD) gene family, which includes three other dehydrogenases involved in the fatty acid β-oxidation pathway [Swigonová et al 2009]: short-chain-specific acyl-CoA dehydrogenase (SCAD) encoded by ACADS, long-chain-specific acyl-CoA dehydrogenase (LCAD) encoded by ACADL, and very long-chain-specific acyl-CoA dehydrogenase (VLCAD) encoded by ACADVL, long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD), and trifunctional protein (TFP) encoded by HADHA and HADHB. Additional enzymes with homology to MCAD are isovaleryl-CoA dehydrogenase encoded by IVD, short-/branched-chain-specific acyl-CoA dehydrogenase acyl-CoA dehydrogenase encoded by ACADSB [Alfardan et al 2010], isobutyryl-CoA dehydrogenase encoded by ACAD8 [Pedersen et al 2006], and mitochondrial acyl-CoA dehydrogenase family member 9 encoded by ACAD9 [Haack et al 2010]. Disorders to consider in the differential diagnosis: * Multiple acyl-CoA dehydrogenase deficiency (also known as MADD or glutaric acidemia type II [GA II]) is a complex disorder with presentations ranging from neonatal with complex congenital abnormalities and dysmorphism to hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis in later-onset presentations. Acylcarnitines demonstrate variable elevations of C4-, C5-, C5DC-, C6-, C8-, C10:1-, C12-, C14-, C14:1-, C16-, C16:1-, C16-OH-, C16:1-OH-, C18-, C18:1-, C18-OH-, and C18:1-OH-acylcarnitines. Additionally, elevations of diagnostic biochemical markers may include glutaric acid, 3-hydroxyisovaleric acid, lactic acid, medium- and long-chain dicarboxylic acids, and glycine species such as isovalerylglycine, isobutyrylglycine, and 2-methylbutyrylglycine. However, ketone bodies including acetoacetic acid and 3-hydroxybutyric acids will be minimal or undetectable, distinguishing GA II from MCAD deficiency. MADD is associated with biallelic pathogenic variants in one of three genes: EFTA, EFTB, or ETFDH. * Short-chain acyl-CoA dehydrogenase (SCAD) deficiency (SCAD deficiency) is associated with biallelic pathogenic variants in ACADS. Most infants with SCAD deficiency identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria have been reported. Thus, SCAD deficiency is now viewed as a clinically benign biochemical phenotype rather than a disease. Acylcarnitines will demonstrate elevations of C4-acylcarnitines (butyrylcarnitine), distinguishing SCAD deficiency from MCAD deficiency. * Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency may present similarly to MCAD deficiency with hypoketotic hypoglycemia, liver dysfunction, and liver failure, but VLCAD deficiency is clinically distinct with the presence of significant rhabdomyolysis and cardiomyopathy not seen in MCAD deficiency. Plasma acylcarnitines demonstrate elevations of C14-, C14:1-, C16- and C16:1-acylcarnitines, distinguishing VLCAD deficiency from MCAD deficiency. VLCAD deficiency is caused by biallelic pathogenic variants in ACADVL. * Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (OMIM 609016) and trifunctional protein (TFP) deficiency (OMIM 609015) may present similarly to MCAD deficiency with hypoketotic hypoglycemia, liver dysfunction, and liver failure, but LCHAD and TFP deficiencies are clinically distinct with the presence of significant rhabdomyolysis and cardiomyopathy as well as peripheral neuropathy and retinopathy not seen in MCAD deficiency. Plasma acylcarnitines demonstrate elevations of C16-OH-, C16:1-OH-, C18-OH-, and C18:1-OH-acylcarnitines, distinguishing LCHAD deficiency and TFP deficiency from MCAD deficiency. LCHAD and TFP deficiencies are caused by biallelic variants in HADHA and HADHB, respectively. * The carnitine transport disorders are very closely related to the fatty acid β-oxidation disorders as they are involved in long-chain fatty acid transport across the mitochondrial inner membrane. These disorders clinically present with a similar combination of hypoketotic hypoglycemia and liver dysfunction as seen in MCAD deficiency. Recurrent rhabdomyolysis, skeletal myopathy, and cardiomyopathy may also develop. These disorders include the following. * Systemic primary carnitine deficiency (also known as carnitine uptake defect) is caused by biallelic pathogenic variants in SLC22A5. Plasma total and free carnitine levels are low, distinguishing systemic primary carnitine deficiency from MCAD deficiency. * Carnitine palmitoyltransferase 1A (CPT 1A) deficiency is caused by biallelic pathogenic variants in CPT1A and does not present with cardiomyopathy or skeletal myopathy. Plasma total and free carnitine levels are elevated, with decreased levels of long-chain acylcarnitines and an elevated C0/(C16+C18) ratio, distinguishing CPT 1A deficiency from MCAD deficiency. * Carnitine palmitoyltransferase II (CPT II) deficiency is caused by biallelic pathogenic variants in CPT2, and in addition to the more commonly known adult form, individuals may develop a severe infantile hepatocardiomuscular form of the disorder. Plasma acylcarnitine analysis will demonstrate elevations of C16-OH-, C16:1-, C18-, and C18:1-acylcarnitines, distinguishing CPT II deficiency from MCAD deficiency. * Carnitine-acylcarnitine translocase (CACT) deficiency (OMIM 212138) is caused by biallelic pathogenic variants in SLC25A20. CACT deficiency may be indistinguishable from CPT II deficiency clinically and biochemically. CACT deficiency and CPTII have identical elevations on plasma acylcarnitines of C16-OH-, C16:1-, C18-, and C18:1-acylcarnitines, distinguishing both from MCAD deficiency. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease in an asymptomatic individual with a diagnosis of medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency or an abnormal newborn screen, the following evaluations are recommended: * Plasma acylcarnitine analysis * Plasma free and total carnitine levels * Urine acylglycine analysis * Urine organic acid analysis * Consultation with a biochemical geneticist, clinical geneticist, and/or genetic counselor In a symptomatic individual diagnosed with MCAD deficiency, the following additional laboratory studies should be considered when clinically appropriate: * Blood glucose concentration * Liver function tests (i.e., AST, ALT, alkaline phosphatase, prothrombin time, partial thromboplastin time, total bilirubin, albumin) * Blood gas analysis * Ammonia (collected in a sodium-heparin tube, placed on ice immediately, and sent STAT to the lab on ice) * Lactic acid * CBC with differential * Electrolytes * Blood cultures (in case of fever) ### Treatment of Manifestations The acute illness places the infant with MCAD deficiency at high risk for metabolic crisis. Metabolic crisis should be considered a medical emergency and implementation of treatment is essential. Consultation with a biochemical geneticist should be obtained as soon as possible. * Early initiation of investigation of the underlying cause of the metabolic stress and initiation of appropriate treatment is necessary. * Treatment recommendations are available but should be implemented in consultation with a biochemical geneticist [Aldubayan et al 2017]. See New England Consortium of Metabolic Programs and Genetic Metabolic Dietitians International. The most important aspect of treating symptomatic individuals is reversal of catabolism and prevention of hypoglycemia by providing simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or intravenous fluids if the individual is unable to receive sufficient oral intake to maintain anabolism. IV administration of glucose should be initiated immediately with a bolus of 2 mL/kg 25% dextrose, followed by 10% dextrose with appropriate electrolytes at a rate of 1.5 times maintenance rate or at 10-12 mg glucose/kg/minute to achieve and maintain a blood glucose level higher than 5 mmol/L, or between 120 and 170 mg/dL [Saudubray et al 1999]. Emergency letter. All affected individuals should have a frequently updated "emergency" letter that may be given, if needed, to health care providers who may not be familiar with MCAD deficiency. This letter should include a detailed explanation of the management of acute metabolic decompensation, emphasizing the importance of preventive measures (e.g., intravenous glucose regardless of "normal" laboratory results, overnight in-hospital observation), and the telephone numbers of the individual's metabolic specialist. * A MedicAlert bracelet may be helpful. * The New England Metabolic Consortium of Metabolic Programs website provides an example of a post-emergency management letter for MCAD (pdf); see Acute Illness Protocol, page 4. ### Prevention of Primary Manifestations #### Avoidance of Fasting Avoidance of fasting is the mainstay in treatment of MCAD deficiency. Derks et al [2007] studied the length of time that MCAD-deficient but asymptomatic individuals should be able to fast. In the absence of an intercurrent infection with fever or other stressing conditions, they recommend the following maximum fasting times: * Up to eight hours in infants between ages six and 12 months * Up to ten hours during the second year of life * Up to 12 hours after age two years Others have recommended a general rule of thumb: to avoid fasting for longer than four hours between birth and age four months, then add an additional hour of fasting for each month of age up to 12 months (see Genetic Metabolic Dietitians International). To avoid excessive fasting: * Infants require frequent feedings (every 2-3 hours), as is the practice with unaffected newborn infants. * Overnight feedings, a bedtime snack, or 2 g/kg of uncooked cornstarch as a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight have also been used. If an individual does not have an illness, this supplemental feeding may not be necessary. * A normal, healthy diet containing no more than 30% of total energy from fat may be followed. Breastmilk or standard infant formulas are appropriate to meet nutritional needs during infancy, with introduction of solids per standard infant feeding guidelines [Frazier 2008]. * Individuals with MCAD deficiency do not need extra calories; overfeeding should be avoided because of the risk for obesity. Prolonged fasting is not recommended, especially during times of illness when individuals with MCAD deficiency are at risk for metabolic crisis. #### L-Carnitine Supplementation L-carnitine supplementation is controversial. Individuals with MCAD deficiency may develop a secondary carnitine deficiency as excess acylcarnitines bind to free carnitine and are renally excreted. * Several authors recommend oral supplementation with 100 mg/kg/day of carnitine to correct the frequently observed secondary carnitine deficiency and to enhance the elimination of toxic metabolites [Roe & Ding 2001]. * A NBS follow-up study from Spain and Portugal also reported the need for higher-dose carnitine supplementation due to the findings of low C0 levels associated with homozygosity for c.985A>G at diagnosis [Couce et al 2013]. * Two exercise studies of individuals with MCAD deficiency before and after L-carnitine supplementation suggested improved exercise tolerance with supplementation of 100 mg/kg/day [Lee et al 2005] and statistically insignificant benefit with supplementation of 50 mg/kg/day [Huidekoper et al 2006]. Low-intensity exercise for one hour on a cycle ergometer showed reduced fatty acid oxidation rates in affected individuals vs controls that were not improved by carnitine administration (100 mg/kg/day), while carnitine concentrations in muscle and plasma increased among those receiving carnitine supplementation [Madsen et al 2013]. * Carnitine-mediated detoxification of medium-chain fatty acids, assessed by urinary excretion of medium-chain acylcarnitines, is quantitatively negligible in individuals who have MCAD deficiency [Rinaldo et al 1993]. Under controlled circumstances, carnitine supplementation also did not improve the response to a fasting challenge [Treem et al 1989]. * The cost of long-term supplementation with carnitine could be significant. Furthermore, while no severe untoward effects of L-carnitine have been reported in individuals with MCAD deficiency [Potter et al 2012], some individuals have complained about nausea, diarrhea, abdominal pain, and a fishy odor when treated with 100 mg/kg/day of L-carnitine [Madsen et al 2013]. Given this information, the authors recommend the use of low-dose L-carnitine supplementation when free carnitine levels are below the normal range. Consensus as to whether additional carnitine is detrimental or efficacious has not been established. ### Surveillance A medical or clinical biochemical geneticist or similarly qualified metabolic specialist should be consulted immediately during concurrent illness, especially when it involves fever and/or poor caloric intake. During the first months of life, monthly visits should be considered to ensure that families understand and are comfortable with treatment while the infant is otherwise well. A metabolic dietician (see gmdi.org) should be involved to ensure proper nutrition in terms of quality and quantity. The frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers. Long-term outcome studies revealed that persons treated for MCAD deficiency are prone to excessive weight gain [Derks et al 2006]. Prepubertal children may become overweight given the frequent feeding as part of treatment, especially with the increasing incidence of obesity in pediatric and general populations worldwide. Growth parameters should be monitored carefully at each clinic visit. Accordingly, follow up should include weight control measures such as regular education about proper nutrition and recommended physical exercise. Although development is typically normal for individuals treated prospectively, those who experience metabolic decompensations requiring hospitalization often demonstrate developmental and neurologic disabilities. Neurodevelopmental assessments and intervention should be considered for such individuals [Derks et al 2006]. ### Agents/Circumstances to Avoid Hypoglycemia must be avoided by frequent feedings to avoid catabolism – if necessary, by intravenous administration of glucose. Infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat are contraindicated in MCAD deficiency. Popular high-fat/low-carbohydrate diets are not appropriate in MCAD deficiency. Alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), often elicits metabolic decompensation in individuals with MCAD deficiency [Lang 2009]. Aspirin has been demonstrated to exacerbate MCAD deficiency by increasing mitochondrial fatty acid oxidation and long-chain fatty acid flux, and inhibiting peroxisomal fatty acid oxidation, which normally serves as a lipitoxic buffer [Uppala et al 2017]. ### Evaluation of Relatives at Risk It is appropriate to evaluate the older and younger sibs and offspring of a proband in order to identify as early as possible those who would benefit from treatment and preventive measures. * If the ACADM pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs and offspring of a proband. * If the ACADM pathogenic variants in the family are not known, plasma acylcarnitine and urine acylglycine analysis can be used to clarify the disease status of at-risk sibs and offspring of a proband. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Pregnant women who have MCAD deficiency must avoid catabolism. This is supported by several case reports describing carnitine deficiency, acute liver failure, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnant women with MCAD deficiency [Nelson et al 2000, Santos et al 2007, Leydiker et al 2011]. ### Therapies Under Investigation A Phase I clinical trial examining the use of glycerol phenylbutyrate (Ravicti®) at 2, 4, and 6 g/m2/day in four adults with MCAD deficiency who had at least one copy of the c.985A>G pathogenic variant was completed in 2017. The primary outcome was changes in the assessment of metabolic stress pre- and post-dosing with Ravicti®. There were no serious adverse events. Previous molecular modeling has suggested that the MCAD enzyme may be able to utilize phenylbutyryl-CoA as a substrate [Kormanik et al 2012]. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

c0220710

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK1424/

{"mesh": ["C536038"], "synonyms": ["MCAD Deficiency"]}

A number sign (#) is used with this entry because of evidence that susceptibility to neonatal pulmonary hypertension (PHN) is associated with variation in the CPS1 gene (608307) on chromosome 2q34. Molecular Genetics In a study of 31 neonates with persistent pulmonary hypertension, 6 cases of which were idiopathic, Pearson et al. (2001) found an association (p = 0.05) between PHN and a T1405N polymorphism in the carbamoyl phosphate synthetase I gene (608307.0006). The authors suggested that the functional status of carbamoyl phosphate synthetase, an enzyme that controls the rate-limiting step of the urea cycle, has a role in the cardiorespiratory transition at birth. Canter et al. (2007) prospectively evaluated a consecutive modeling cohort of 131 children with congenital heart defects requiring surgery to determine key factors associated with increased postoperative pulmonary artery pressure (PAP), which was defined as a mean PAP above 20 mm Hg for at least 1 hour during the 48 hours following surgery measured by an indwelling pulmonary artery catheter. Multiple dimensionality reduction (MDR) was used to both internally validate observations and develop optimal 2-variable through 5-variable models that were tested prospectively in a validation cohort of 41 children. Unconditional logistic regression analysis of the modeling chohort revealed that age (OR = 0.92, p = 0.01), CPS1 T1405N (608307.0006) genotype (AC vs AA: OR = 4.08, p = 0.04; CC vs AA: OR = 5.96, p = 0.01), and Down syndrome (OR = 5.25, p = 0.04) were independent predictors of this complex phenotype. MDR predicted that the best 2-variable model consisted of age and CPS1 T1405N genotype (p less than 0.001). This 2-variable model correctly predicted 73% of the outcomes from the validation cohort. A 5-variable model that added race, gender, and Down syndrome was not significantly better than the 2-variable model. Canter et al. (2007) concluded that the CPS1 T1405N genotype appears to be an important risk factor for predicting susceptibility to increased PAP following surgical repair of congenital cardiac defects in children. Solomon et al. (2011) reported a neonate with VACTERL association (see 192350) who experienced severe pulmonary artery hypertension following heart surgery on his second day of life. Exome sequencing in the infant and his healthy monozygotic twin revealed a novel heterozygous mutation in the CPS1 gene (G530V; 608307.0012), which was not found in 100 ethnically matched control chromosomes. Both twins were also found to carry the CPS1 T1405N polymorphism. Both mutations were inherited from their father. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

PULMONARY HYPERTENSION, NEONATAL, SUSCEPTIBILITY TO

c3714958

omim

https://www.omim.org/entry/615371

{"omim": ["615371"]}

A number sign (#) is used with this entry because of evidence that many genes are involved in the origin and/or progression of this neoplasm. ### Genetic Heterogeneity of Susceptibility to Prostate Cancer See HPC1 (601518), associated with variation in the RNASEL gene on chromosome 1q25; HPC2 (614731), associated with variation in the ELAC2 gene (605367) on chromosome 17p12; HPC3 (608656), mapped to chromosome 20q13; HPC4 (608658), mapped to chromosome 7p11-q21; HPC5 (609299), mapped to chromosome 3p26; HPC6 (609558), mapped to chromosome 22q12; HPC7 (610321), mapped to chromosome 15q12; HPC8 (602759), mapped to chromosome 1q42.2-q43; HPC9 (610997), associated with variation in the HOXB13 gene (604607) on chromosome 17q21-q22; HPC10 (611100), mapped to chromosome 8q24; HPC11 (611955), mapped to chromosome 17q12; HPC12 (611868), associated with variation in the EHBP1 gene (609922) on chromosome 2p15; HPC13 (611928), associated with variation in the MSMB gene (611928) on chromosome 10q11; HPC14 (611958), mapped to chromosome 11q13; HPC15 (611959), mapped to chromosome 19q13; HPCX1 (300147), mapped to chromosome Xq27-q28; and HPCX2 (300704), mapped to chromosome Xp11. Somatic mutations in several genes have been found in prostate cancer tumors, including PTEN (601728), MAD1L1 (602686), ATBF1 (ZFHX3; 104155), and KLF6 (602053). Somatic mutations in the EPHB2 gene (600997) are associated with susceptibility to prostate cancer/brain cancer (603688). A prostate cancer aggressiveness quantitative trait locus (HPCQTL19; 607592) has been mapped to chromosome 19q. Also see MOLECULAR GENETICS. Clinical Features The aggressiveness of prostate cancer varies widely. Some tumors progress to invasive, potentially life-threatening disease, whereas others stay latent for the remainder of an individual's lifetime. Inheritance Studies by Woolf (1960), Cannon et al. (1982), Meikle et al. (1985) and others suggested the significance of familial factors in prostate cancer. Steinberg et al. (1990) investigated the frequency of prostate cancer in the relatives of 691 men with prostate cancer and 640 of their spouses. In 15% of the cases, but only 8% of the controls, it was a father or brother affected with prostate cancer (P less than 0.001). Men with a father or brother affected were twice as likely to develop prostate cancer as men with no relatives affected. There was a trend of increasing risk with increasing number of affected family members, such that men with 2 or 3 first-degree relatives affected had a 5- and 11-fold increased risk of developing prostate cancer, respectively. Carter et al. (1992) found in the 691 prostate cancer families that early onset of disease in the proband was also an important determinant of risk. Complex segregation analysis led to the conclusion that the family clustering was best explained by autosomal dominant inheritance of a rare (q = 0.0030) high-risk allele leading to an early onset of prostate cancer. The estimated cumulative risk of prostate cancer for carriers showed that the allele was highly penetrant; by age 85, 88% of carriers compared to only 5% of noncarriers were projected to be affected with prostate cancer. Twin studies support the existence of a significant genetic factor (Walsh, 1992). To determine whether family history is associated with an increased prevalence of prostate cancer in an unselected group of men attending a hospital-based screening clinic, Narod et al. (1995) inquired about affected relatives before prostate cancer screening in 6,390 men, aged 50 to 80 years, in the region of Quebec City. Of these 6,390 men, 1,563 (24.5%) had a positive test by either rectal examination or blood test for prostate-specific antigen (APS; 176820). Among the 6,390 men, 264 were found to have prostate cancer (4.13%). The prevalence was increased in those men with any first-degree relative affected (prevalence = 6.7%; relative risk = 1.72 as compared with men with no first-degree relative affected; prevalence = 3.89; relative risk = 1.00). Most of the increase in relative risk was contributed by affected brothers (prevalence = 10.2%; relative risk = 2.62; P = 0.0002). Schaid et al. (1998) performed a family history cancer survey on 5,486 men who underwent radical prostatectomy at the Mayo Clinic for clinically localized prostate cancer; 4,288 men responded to the survey. The best-fitting model that explained familial aggregation was a rare autosomal dominant susceptibility gene, and this model fit best when probands were diagnosed under 60 years of age. The model predicted that the frequency of a susceptibility gene in the population is 0.006 and that the risk of prostate cancer by age 85 years is 89% among carriers of the gene and 3% among noncarriers. Genetic heterogeneity was suggested by the study. Other evidence suggesting genetic complexity included the significantly elevated age-adjusted risk of prostate cancer among brothers of probands, compared with their fathers. Cui et al. (2001) conducted single- and 2-locus segregation analyses of data from 1,476 men with prostate cancer diagnosed under the age of 70 years and ascertained through population registers in Australia, together with brothers, fathers, and both maternal and paternal lineal uncles. All 2-locus models gave better fits than did single-locus models, even if lineal uncles were excluded. The best-fitting genetic models included a dominantly inherited increased risk that was greater, in multiplicative terms, at younger ages, as well as a recessively inherited or X-linked increased risk that was greater, in multiplicative terms, at older ages. Penetrance to age 80 years was approximately 70% for the dominant effect and virtually 100% for the recessive and X-linked effects. Nieder et al. (2003) suggested that major risk factors for developing prostate cancer, including positive family history and African American ethnicity, can be quantified for genetic counseling. Factors increasing familial risk for prostate cancer are closer degree of kinship, number of affected relatives, and early age of onset (under 50 years) among the affected relatives. Genetic testing may be useful for modification of risk, but at the time of writing, Nieder et al. (2003) suggested that genetic testing should be performed only within the context of a well-designed research study that will determine penetrance and genotype-phenotype correlation of specific mutations. Even in the absence of genetic testing, African American men and men with a strong family history of prostate cancer may opt to initiate screening by prostate-specific antigen and digital rectal examination at age 40 years. Valeri et al. (2003) stated that recent linkage analyses had led to the detection of at least 8 prostate cancer predisposing genes, suggesting complex inheritance and genetic heterogeneity. They conducted segregation analysis in 691 prostate cancer patients, recruited from 3 French hospitals and unselected with respect to age at diagnosis, clinical stage, or family history. Segregation analyses were carried out using the logistic hazard regressive model, as incorporated in the REGRESS program, which can accommodate a major gene effect, residual familial dependences of any origin (genetic and/or environmental), and covariates, while including survival analysis concepts. Segregation analysis showed evidence for the segregation of an autosomal dominant gene (allele frequency 0.03%) with an additional brother-brother dependence. The estimated cumulative risks of prostate cancer by age 85 years, among subjects with the at-risk genotype, were 86% in the fathers' generation and 99% in the probands' generation. The study supported the model of mendelian transmission of a rare autosomal dominant gene with high penetrance, and demonstrated that additional genetic and/or common sib environmental factors are involved to account for the familial clustering of prostate cancer. Pakkanen et al. (2007) performed segregation analysis in 2 cohorts of 557 early-onset and 989 late-onset nuclear Finnish families in which the father had histologically confirmed prostate cancer. Their findings suggested that inheritance of prostate cancer in the Finnish population is best explained by a mendelian recessive model with a significant paternal regressive coefficient that is indicative of a polygenic multifactorial component. Mapping To investigate genetic factors involved in the variability of prostate cancer aggressiveness, Witte et al. (2000) conducted a genomewide linkage analysis of 513 brothers with prostate cancer, using the Gleason score, which reflects tumor histology, as a quantitative measure of prostate cancer aggressiveness. To their knowledge, this was the first time that a measure of prostate cancer aggressiveness had been directly investigated as a quantitative trait in a genomewide scan. Candidate regions were found on 5q, 7q, and 19q (see 607592). Gibbs et al. (2000) found evidence of linkage of susceptibilty to prostate cancer at multiple sites in a genomewide scan. Stratification by a variety of factors appeared to improve the chances of identifying relevant genes. Ostrander and Stanford (2000) reviewed the search for prostate cancer genes. Peters and Ostrander (2001) presented a tabulation of the cytogenetic location of 16 mapped prostate cancer susceptibility loci and candidate genes. Oba et al. (2001) studied the significance of the loss of heterozygosity (LOH) frequently observed on chromosome 8p in prostate cancer. By fluorescence in situ hybridization (FISH) in 42 prostate cancers, they found a deletion for at least 1 locus on 8p in 29 (69%) tumors. A significantly higher frequency of the deletion on 8p21.2-p21.1 was observed in advanced prostate cancer than in localized prostate cancer. They concluded that deletions on 8p22-p21.3 play an important role in tumor differentiation, while 8p21.2-p21.1 deletion plays a role in progression of prostate cancer. Xu et al. (2001) undertook a systematic evaluation of linkage across chromosome 1 using 50 microsatellite markers in 159 hereditary prostate cancer families, including 79 families analyzed in the original report by Smith et al. (1996) describing HPC1 linkage. The results of the new study were consistent with the heterogeneous nature of hereditary prostate cancer and the existence of multiple loci on chromosome 1 for this disease. Goddard et al. (2001) detected linkage near 3 locations for prostate cancer: 1q24-q25, 1q42.2-q43, and near Xq12-q13, the AR (313700) locus. Six other locations gave lod scores greater than 2.5. Xu et al. (2001) performed linkage analysis using 24 markers from 8p in 159 pedigrees with hereditary prostate cancer. In 79 families with an average age at diagnosis of greater than 65 years, an allele-sharing lod score of 2.64 (P = 0.0005) was observed. Of note, the small number (11) of Ashkenazi Jewish pedigrees analyzed in this study contributed disproportionately to this linkage. Mutation screening in hereditary prostate cancer probands and association analyses in case subjects and unaffected control subjects was carried out for a putative prostate cancer susceptibility gene, which they called PG1, previously localized to the 8p22-p23 region. (PG1 had been cloned in a haplotype-based association study conducted by Geneset by Daniel Cohen and described only in a US patent dated August 31, 1999.) Xu et al. (2001) concluded that evaluation of PG1 and other candidate genes in the region appeared warranted. Cancel-Tassin et al. (2001) examined evidence for linkage to the HPC1, HPC8, CAPB, and HPCX loci in 64 families from southern and western Europe with at least 3 affected individuals with prostate cancer. No significant evidence of linkage to HPC1, CAPB, or HPCX was found. Results in favor of linkage to HPC8 were observed and homogeneity analysis gave an estimated proportion of families with linkage to this locus up to 50%. Schaid et al. (2004) compared genome linkage scans for prostate cancer susceptibility loci using microsatellites with those using SNPs, performed in 467 men with prostate cancer from 167 families. The highest lod scores were found for chromosome 6 (4.2) and chromosome 12 (3.9), but these were judged difficult to interpret because they occurred only at the extreme ends of the chromosomes. The greatest gain provided by the SNP markers was a large increase in the linkage information content, with an average information content of 61% for the SNPs versus an average of 41% for the microsatellite markers. Paris et al. (2004) analyzed a cohort of 64 prostate cancer patients (half of whom had postoperative recurrence) using array comparative genomic hybridization (aCGH). Analysis of the aCGH profiles revealed numerous recurrent genomic copy number aberrations. Specific loss at 8p23.2 was associated with advanced stage disease, and gain at 11q13.1 was found to be predictive of postoperative recurrence independent of stage and grade. Moreover, comparison with an independent set of metastases revealed approximately 40 candidate markers associated with metastatic potential. The authors proposed that copy number aberrations at these loci may define metastatic genotypes. Xu et al. (2005) performed genomewide linkage analysis of 269 prostate cancer families with at least 5 affected members and found significant linkage at 22q12 (lod score, 3.57; HPC6; 609558). They also found 'suggestive' linkage (lod score of 1.86 or greater) at 1q25, 8q13, 13q14, 16p13, and 17q21 in these families. In 606 families with prostate cancer with a mean age at diagnosis of 65 years or less, 4 additional suggestive linkages were found: 3p24, 5q35, 11q22, and Xq12. Thomas et al. (2008), in a genomewide association study (GWAS) of prostate cancer, confirmed 3 previously reported loci: 2 independent SNPs at 8q24 (HPC10; 611100) and 1 in HNF1B (189907) on 17q (HPC11; 611955). In addition, loci on chromosomes 7, 10 (2 loci), and 11 (HPC14; 611958) were highly significant. Loci on chromosome 10 (see HPC13, 611928) included MSMB (157145), which encodes beta-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2 (602619), a gene with antiapoptotic activity. The locus on chromosome 7 was at JAZF1 (606246), a transcriptional repressor that is fused by chromosome translocation to SUZ12 (606245) in endometrial cancer. Of the 9 loci that showed highly suggestive associations, 4 best fit a recessive model and included candidate susceptibility genes: CPNE3 (604207), IL16 (603035), and CDH13 (601364). The findings pointed to multiple loci with moderate affects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals. Eeles et al. (2008) conducted a genomewide association study using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA; 176820) concentration (less than 0.5 ng/ml). They analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. They identified 7 loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11 (HPC14), 19 (HPC15; 611959), and X. They confirmed previous reports of common loci associated with prostate cancer at 8q24 (HPC10; 611100) and 17q (HPC11; 611955). Three of the newly identified loci contained candidate susceptibility genes: MSMB (157145) on 10q11.2, LMTK2 (610989) on 7q21.3-q22.1 and KLK3 (176820) on 19q13.4. Eeles et al. (2009) extended the study of Eeles et al. (2008) to evaluate promising associations in a second stage in which they genotyped 43,671 SNPs in 3,650 prostate cancer cases and 3,940 controls, and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, Eeles et al. (2009) identified 7 new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)). The strongest association was found with a G/A SNP at chromosome 11p15, rs7127900 (position 2,190,150; per-allele OR = 1.22, 95% CI = 1.17-1.27, P = 2.7 x 10(-33)). Kote-Jarai et al. (2011) extended the multistage genomewide association study of Eeles et al. (2008, 2009) and reported the results of stage 3, in which they evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. They followed up 10 new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, they identified 7 new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p12, 12q13, and Xq12 (p = 4.0 x 10(-8) to p = 2.7 x 10(-24)). Kote-Jarai et al. (2011) identified a SNP in TERT (187270) on chromosome 5p15 (rs2242652, p = 4.4 x 10(-11)) that was more strongly associated with prostate cancer than the previously reported rs401681 and rs2736098 (Rafnar et al., 2009). Kote-Jarai et al. (2011) concluded that more than 40 prostate cancer susceptibility loci, explaining approximately 25% of the familial risk in this disease, have been identified. Gudmundsson et al. (2009) reported a prostate cancer genomewide association follow-up study and discovered 4 variants associated with susceptibility to prostate cancer in several European populations: rs10934853A (OR = 1.12, P = 2.9 x 10(-10)) on 3q21.3; 2 SNPs on chromosome 8q24.21, as described in HPC10 (611100); and rs8102476C (odds ratio = 1.12, P = 1.6 x 10(-11)) on 19q13.2. Gudmundsson et al. (2009) also refined a previous association signal on 11q13 (see HPC14, 611958). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, Gudmundsson et al. (2009) estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population. Cytogenetics Tomlins et al. (2005) used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG (165080) and ETV1 (600541), were identified as outliers in prostate cancer. Tomlins et al. (2005) identified recurrent gene fusions of the 5-prime untranslated region of TMPRSS2 (602060) to ERG or ETV1 in prostate cancer tissues with outlier expression. By using FISH, Tomlins et al. (2005) demonstrated that 23 of 29 prostate cancer samples harbored rearrangements in ERG or ETV1. Cell line experiments suggested that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer. Chang et al. (2006) performed 2-locus conditional linkage analysis to identify possible gene-gene interactions in a genomewide scan of 426 families with prostate cancer. Suggestive evidence for an epistatic interaction was found for 6 sets of loci: 11q13 and 13q32; 22q13 and 21q22; 12q24 and 16p13; 8q24 and 7q21; 20p13 and 16q21; and 5p13 and 16p12. Tomlins et al. (2007) explored the mechanism of ETV1 outlier expression in human prostate tumors and prostate cancer cell lines. They identified previously unknown 5-prime fusion partners in prostate tumors with ETV1 outlier expression, including untranslated regions from a prostate-specific androgen-induced gene (SLC45A3; 605097) and an endogenous retroviral element, HERV-K_22q11.23, a prostate-specific androgen-repressed gene (C15ORF21; 611314), and a strongly expressed housekeeping gene (HNRNPA2B1; 600124). To study aberrant activation of ETV1, Tomlins et al. (2007) identified 2 prostate cancer cell lines that had ETV1 outlier expression. Through distinct mechanisms, the entire ETV1 locus (7p21) is rearranged to a 1.5-Mb prostate-specific region at 14q13.3-q21.1 in both cell lines, in one by cryptic insertion and in the other by balanced translocation. Because the common factor of these rearrangements is aberrant ETV1 overexpression, Tomlins et al. (2007) recapitulated this event in vitro and in vivo, demonstrating that ETV1 overexpression in benign prostate cells and in mouse prostate confers neoplastic phenotypes. Identification of distinct classes of ETS gene rearrangements demonstrated that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci. Using dual-color FISH in LNCaP prostate cancer cells, which are androgen-sensitive but lack the TMPRSS2-ERG fusion gene, Mani et al. (2009) observed that stimulation with the AR ligand dihydrotestosterone (DHT) for 60 minutes induced proximity between the TMPRSS2 and ERG genomic loci. The effect was dependent upon AR, as the same proximity was not induced in an androgen-insensitive prostate cancer cell line. To determine whether the induced proximity facilitates formation of these gene fusions, Mani et al. (2009) treated LNCaP cells with DHT for 12 hours and then irradiated the cells to induce DNA double-strand breaks. TMPRSS2-ERG fusions were detected in 25% of clones treated with 3-Gy irradiation but in only 2.3% of those treated with 1-Gy. Mani et al. (2009) speculated that androgen signaling colocalizes the 5- and 3-prime gene fusion partners, thereby increasing the probability of a gene fusion when subjected to agents that cause DNA double-strand breaks. The TMPRS22 and ERG genes are arranged tandemly on chromosome 21q22. The TMPRSS2/ERG fusion joins TMPRSS2 exons 1 or 2 usually to ERG exons 2, 3 or 4, which results in activation of the ERG transcription factor. This fusion separates the ERG 3-prime centromeric regions from the 5-prime telomeric ends; deletions of this region can also occur. Attard et al. (2008) performed FISH studies of the TMPRS22/ERG genes in 445 prostate cancers from patients who had been managed conservatively. The authors identified an alteration, called 2+Edel, characterized by duplication of the TMPRS22/ERG fusion (detected as duplication of 3-prime ERG sequence) together with interstitial deletion of 5-prime ERG sequences. The alteration was found in 6.6% of cancers and was associated with very poor clinical outcome compared to cancers with normal ERG loci (25% vs 90% survival at 8 years). Cancers with 1 copy of 3-prime ERG (1Edel) did not have a worse clinical outcome. The findings were consistent with the hypothesis that overexpression of ERG that results from the fusion of 5-prime TMPRSS2 to 3-prime ERG is responsible for driving cancer progression. Attard et al. (2008) suggested that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, may allow stratification of prostate cancer into distinct survival categories. Berger et al. (2011) presented the complete sequence of 7 primary human prostate cancers and their paired normal counterparts. Several tumors contained complex chains of balanced (i.e., 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor (AR; 313700), and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2/ERG, but inversely correlated with these regions in tumors lacking ETS fusions. Berger et al. (2011) suggested that this observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumors contained rearrangements that disrupted CADM2 (609938), and 4 harbored events disrupting either PTEN (unbalanced events), a prostate tumor suppressor, or MAGI2 (606382) (balanced events), a PTEN-interacting protein not previously implicated in prostate tumorigenesis. Berger et al. (2011) concluded that genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms. Population Genetics Seidman et al. (1985) estimated that 9% of white males and 10% of black males in the US will develop clinical prostate cancer in their lifetime. Silverberg (1987) stated that in American men, prostate cancer is the most common malignancy and the second most common cause of cancer deaths. Over 100,000 cases of prostate cancer had occurred annually in the United States in previous years, with 20,000 of these cases occurring in men under the age of 65 years. In Los Angeles County, California, prostate cancer incidence differs considerably among the various racial-ethnic groups: highest in African Americans (116 per 1,000 person-years), intermediate in non-Hispanic whites (71 per 100,000 person-years), and lowest among Asians (Japanese at 39 per 100,000 person-years and Chinese at 28 per 100,000 person-years). In 940 Ashkenazi Israelis with prostate cancer, Giusti et al. (2003) tested DNA obtained from paraffin sections for the 3 Jewish founder mutations: 185delAG (113705.0003) and 5382insC (113705.0018) in BRCA1 and 6174delT (600185.0009) in BRCA2. They estimated that there is a 2-fold increase in BRCA mutation-related prostate cancer among Ashkenazi Israelis. No differences were noted between the histopathologic features of cases with or without founder mutations, and no difference was found in the mean age at diagnosis between cases with or without a founder mutation. Pathogenesis Karhadkar et al. (2004) found that activity of the hedgehog (see 600725) signaling pathway, which has essential roles in developmental patterning, was required for regeneration of prostate epithelium, and that continuous pathway activation transformed prostate progenitor cells and rendered them tumorigenic. Elevated pathway activity furthermore distinguished metastatic from localized prostate cancer, and pathway manipulation modulated invasiveness and metastasis. Pathway activity was triggered in response to endogenous expression of hedgehog ligands, and was dependent upon the expression of Smoothened (601500), which is not expressed in benign prostate epithelial cells. Karhadkar et al. (2004) concluded that monitoring and manipulating hedgehog pathway activity may offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential. Seligson et al. (2005) used immunohistochemical staining of primary prostatectomy tissue samples to determine the percentage of cells that stained for the histone acetylation and dimethylation of 5 residues in histones H3 (see 142780) and H4 (see 602822). Grouping of samples with similar patterns of modifications identified 2 disease subtypes with distinct risks of tumor recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumor stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, Seligson et al. (2005) concluded that widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behavior in cancer patients. Luo et al. (2007) examined IKK-alpha (CHUK; 600664) involvement in prostate cancer and its progression. They demonstrated that a mutation that prevents IKK-alpha activation slowed down prostate cancer growth and inhibited metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin (154790), the ablation of which restored metastatic activity. IKK-alpha activation by RANK ligand (RANKL; 602642) inhibited Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription required nuclear translocation of active IKK-alpha. The amount of active nuclear IKK-alpha in mouse and human prostate cancer correlated with metastatic progression, reduced Maspin expression, and infiltration of prostate tumors with RANKL-expressing inflammatory cells. Luo et al. (2007) proposed that tumor-infiltrating RANKL-expressing cells lead to nuclear IKK-alpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype. Using a combination of high-throughput liquid and gas chromatography-based mass spectrometry, Sreekumar et al. (2009) profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer, and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that is highly increased during prostate cancer progression to metastasis and can be detected noninvasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase (606628), the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase (604455), induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor (AR; 313700) and the ERG (165080) gene fusion product (see 165080) coordinately regulate components of the sarcosine pathway. Sreekumar et al. (2009) concluded that by profiling the metabolomic alterations of prostate cancer progression, they revealed sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity. Ammirante et al. (2010) found that prostate cancer progression is associated with inflammatory infiltration and activation of IKK-alpha (600664), which stimulates metastasis by an NF-kappa-B (see 164011)-independent cell-autonomous mechanism (Luo et al., 2007). Ammirante et al. (2010) showed that androgen ablation causes infiltration of regressing androgen-dependent tumors with leukocytes, including B cells, in which IKK-beta (603258) activation results in production of cytokines that activate IKK-alpha and STAT3 (102582) and prostate cancer cells to enhance hormone-free survival. Goldstein et al. (2010) showed that basal cells from primary benign human prostate tissue could initiate prostate cancer in immunodeficient mice. The cooperative effects of AKT (164730), ERG, and AR in basal cells recapitulated the histologic and molecular features of human prostate cancer, with loss of basal cells and expansion of luminal cells expressing PSA and alpha-methylacyl-CoA racemase (AMACR; 604489). Goldstein et al. (2010) concluded that the histologic characterization of cancers does not necessarily correlate with the cellular origins of the disease. Studying mouse models, Ku et al. (2017) demonstrated that Rb1 (604041) loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten (601728) mutation. Additional loss of Tp53 caused resistance to antiandrogen therapy. Gene expression profiling indicated that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibited increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2 (184429). Clinically relevant Ezh2 inhibitors restored Ar expression and sensitivity to antiandrogen therapy. Ku et al. (2017) concluded that their findings uncovered genetic mutations that enable prostate cancer progression, identified mouse models for studying prostate cancer lineage plasticity, and suggested an epigenetic approach for extending clinical responses to antiandrogen therapy. Molecular Genetics Using cDNA microarrays, Dhanasekaran et al. (2001) examined gene expression profiles of more than 50 normal and neoplastic prostate specimens and 3 common prostate cancer cell lines. Signature expression profiles of normal adjacent prostate, benign prostatic hypertrophy, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Dhanasekaran et al. (2001) established many associations between genes and prostate cancer. They assessed 2 of these genes, hepsin (142440), a transmembrane serine protease, and PIM1 (164960), a serine/threonine kinase, at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate cancer specimens. Expression of hepsin and PIM1 proteins was significantly correlated with measures of clinical outcome. To explore potential molecular variation underlying the broad range of clinical behavior of prostate cancer from relatively indolent to aggressive metastatic disease, Lapointe et al. (2004) profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and 9 lymph node metastases, using cDNA microarrays containing approximately 26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified 3 subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among 2 of the 3 subtypes, 1 of which also included most lymph node metastases. To characterize further the clinical relevance of tumor subtypes, Lapointe et al. (2004) evaluated as surrogate markers 2 genes differentially expressed among tumor subgroups using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1 (158340), a gene highly expressed in the 2 subgroups with 'aggressive' clinicopathologic features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1 (194460), a gene highly expressed in the third subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative levels of prostate-specific antigen (PSA; 176820). The results suggested that prostate tumors can be classified according to their gene expression patterns. Barbieri et al. (2012) sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 (300188) and FOXA1 (602294). Pritchard et al. (2016) screened 20 DNA repair genes for germline mutation in 692 men with metastatic prostate cancer and identified 84 pathogenic mutations in 82 men (11.8%). This frequency was significantly higher than the rate of germline mutations in these genes in men with localized prostate cancer (4.6% among 499 men, p less than 0.001) or the prevalence among individuals in the ExAC browser (2.7% among 53,105 individuals without a known cancer diagnosis). Pathogenic variants were identified in 16 genes, including BRCA2 (600185) (37 men; 5.3%); ATM (607585) (11 men; 1.6%); CHEK2 (604373) (10 men; 1.9% of 534 men with data); BRCA1 (113705) (6 men, 0.9%), and RAD51D (602954) and PALB2 (610355) (each in 3 men, 0.4%). ### Association with the SRD5A2 Gene on Chromosome 2p23 Nam et al. (2001) investigated the val89-to-leu polymorphism (V89L) of the SRD5A2 gene (607306) in 320 men undergoing evaluation for prostate cancer, and found that the adjusted odds ratio for having prostate cancer for men with at least 1 V allele was 2.53 compared to men with the L/L genotype (95% CI, 1.11-5.78; p = 0.03). When stratified for ethnic background, the effect of the V89L polymorphism did not vary among whites, blacks, and Asians. In a separate cohort of 318 men with known prostate cancer, Nam et al. (2001) found that the odds ratio for progression for men with at least 1 V allele was 3.32 compared to men with the L/L genotype (95% CI, 1.67-6.62; p = 0.0006). In a genotype/haplotype association study involving a case-control sample of 1,117 brothers from 506 sibships with prostate cancer, Loukola et al. (2004) detected positive associations between prostate cancer risk and 2 single-nucleotide polymorphisms (SNPs) in SRD5A2 (V89L and -3001G-A) and observed an inverse association between high aggressiveness of prostate cancer and SRD5A2_Hap3. The authors could not confirm a previously reported association between prostate cancer and the SRD5A2 A49T polymorphism (607306.0012). ### Association with the LMTK2 Gene on Chromosome 7q21-q22 For discussion of a possible association of prostate cancer with mutation in the LMTK2 gene (610989), see HPC4 (608658). ### Association with the CYP3A4 Gene on Chromosome 7q22 Loukola et al. (2004) detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 (124010) SNPs and a CYP3A4 haplotype; they noted that both the CYP3A4*1B allele and the CYP3A4_Hap4 haplotype were inversely associated with low disease aggressiveness. ### Association with the KLF6 Gene on Chromosome 10p14 Narla et al. (2001) identified loss of heterozygosity of 1 KLF6 (602053) allele in 77% of primary prostate tumors. Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors. See 602053.0001-602053.0005. Functional studies confirmed that whereas wildtype KLF6 upregulates p21 (WAF1/CIP1; 116899) in a p53-independent manner and significantly reduces cell proliferation, tumor-derived KLF6 mutants do not. ### Association with the MXI1 Gene on Chromosome 10q25 Eagle et al. (1995) demonstrated that mutation in the MXI1 gene (600020) is involved in either the pathogenesis or the neoplastic evolution of some prostate cancer. The MXI1 protein negatively regulated MYC oncoprotein (190080) activity and thus potentially serves a tumor suppressor function. Furthermore, MXI1 maps to chromosome 10q25, a region that is deleted in some cases of prostate cancer. Eagle et al. (1995) detected mutations in the retained MXI1 allele in 4 primary prostate tumors with 10q24-q25 deletions, thus satisfying the Knudson hypothesis. ### Association with the CD82 Gene on Chromosome 11p11 For discussion of the possible role of the KAI1 (CD82) gene in suppression of metastatic potential in prostate cancer, see 600623. ### Association with the CDKN1B Gene on Chromosome 12p13 Chang et al. (2004) analyzed the CDKN1B gene (600778) in 188 families with hereditary prostate cancer and found a significant association between the SNP -79C/T (rs34330) and prostate cancer. The -79C allele was overtransmitted from parents to affected offspring, an association that was observed primarily in offspring whose age at diagnosis was less than 65 years. Chang et al. (2004) suggested that germline variants of this gene play a role in prostate cancer susceptibility. ### Association with the CDH1 Gene on Chromosome 16q22 In a Swedish population, Jonsson et al. (2004) demonstrated an association between the -160C/A promoter polymorphism in the CDH1 gene (192090.0018) and risk of hereditary prostate cancer. In an independent replication study population, Lindstrom et al. (2005) confirmed the association. ### Association with the HNF1B Gene on Chromosome 17q12 For discussion of a possible association of prostate cancer with variation in the HNF1B gene (189907) gene, see HPC11 (611955). ### Association with the ZNF652 Gene on Chromosome 17q21 In a genomewide association study of 3,425 African Americans with prostate cancer and 3,290 African American controls with follow-up in 1,844 cases and 3,269 controls of African ancestry, Haiman et al. (2011) identified a risk variant on chromosome 17q21 (rs7210100, odds ratio per allele of 1.51, p = 3.4 x 10(-13) for the combined cohorts). The frequency of the risk allele was about 5% in men of African descent, whereas it was rare in other populations (less than 1%). The variant rs7210100 is located in intron 1 of the ZNF652 gene (613907). ### Association with the SPOP Gene on Chromosome 17q21 Barbieri et al. (2012) sequenced the exomes of 112 prostate tumor and normal tissue pairs. SPOP (602650) was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6 to 15% of tumors across multiple independent cohorts. Prostate tumors with mutant SPOP lacked ETS family (see 164720) gene rearrangements and showed a distinct pattern of genomic alterations. Barbieri et al. (2012) concluded that SPOP mutations may define a novel molecular subtype of prostate cancer. Zuhlke et al. (2014) identified a heterozygous missense mutation in the SPOP gene in a patient with familial prostate cancer showing linkage to chromosome 17 (602650.0001). ### Association with the CHEK2 gene on Chromosome 22q12 For discussion of the role of the CHEK2 Gene in the development of prostate cancer, see 604373. ### Association with the AR Gene on Chromosome Xq12 One of the critical functions of the product of the androgen receptor gene (AR; 313700) is to activate the expression of target genes. This transactivation activity resides in the N-terminal domain of the protein, which is encoded in exon 1 and contains polymorphic CAG and GGC repeats (microsatellites). A smaller size of the CAG repeat is associated with a higher level of receptor transactivation function, thereby possibly resulting in a higher risk of prostate cancer. Schoenberg et al. (1994) demonstrated contraction in this microsatellite from 24 to 18 CAG units in an adenocarcinoma of the prostate, and the affects of the shorter allele were implicated in the development of the tumor. Edwards et al. (1992) and Irvine et al. (1995) showed that the prevalence of short CAG alleles was highest in African American males with the highest risk for prostate cancer, intermediate in intermediate-risk non-Hispanic whites, and lowest in Asians at very low risk for prostate cancer. Irvine et al. (1995) found that high-risk African Americans also had the lowest frequency of the GGC allele. Consistent with the interracial variation in CAG and GGC distributions, there was an excess of white patients with short CAG repeats relative to white controls. Irvine et al. (1995) found a statistically significant negative association between the number of CAG and GGC repeats among the prostate cancer patients. Overall, the data were interpreted to suggest a possible association between the microsatellites of the AR gene and the development of prostate cancer. ### Castration-Resistant Prostate Cancers Grasso et al. (2012) sequenced the exomes of 50 lethal, heavily pretreated metastatic castration-resistant prostate cancers (CRPC) obtained at rapid autopsy (including 3 different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. Grasso et al. (2012) identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 (602118) that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, Grasso et al. (2012) demonstrated that ETS2 (164740), which is deleted in one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, they identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (602113) (mutated in 8.6% of prostate cancers), and demonstrated interaction of the MLL complex with the AR, which is required for AR-mediated signaling. Grasso et al. (2012) identified novel recurrent mutations in the AR collaborating factor FOXA1 (602294) in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signaling and increases tumor growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (300128), and ASXL1 (612990), were found to be mutated in CRPC. Grasso et al. (2012) concluded that their study described the mutational landscape of a heavily treated metastatic cancer, identified novel mechanisms of AR signaling deregulated in prostate cancer, and prioritized candidates for future study. Xu et al. (2012) found that the oncogenic function of EZH2 (601573) in cells of castration-resistant prostate cancer is independent of its role as a transcriptional repressor. Instead, it involves the ability of EZH2 to act as a coactivator for critical transcription factors including the androgen receptor. This functional switch is dependent on phosphorylation of EZH2 and requires an intact methyltransferase domain. To elucidate mechanisms of castration resistance, Lunardi et al. (2013) performed an integrated analysis that leveraged data from treatment of genetic mouse models of prostate cancer with clinical data from patients. The authors found that castration counteracted tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response was bypassed with deletion of either Trp53 (191170) or Zbtb7a (605878) together with Pten, leading to the development of castration-resistant prostate cancer. Mechanistically, the integrated acquisition of data from mouse models and patients identified the expression patterns of XAF1 (606717), XIAP (300079), and SRD5A1 (184753) as a predictive and actionable signature for castration-resistant prostate cancer. Lunardi et al. (2013) showed that combined inhibition of the XIAP, SRD5A1, and AR (313700) pathways overcomes castration resistance. Using in vitro and in vivo human prostate cancer models, Mu et al. (2017) showed that prostate tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor-dependent luminal epithelial cells to androgen receptor-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2 and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, Mu et al. (2017) mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching. Yang et al. (2013) reported that 2 long noncoding RNAs (lncRNAs) highly overexpressed in aggressive prostate cancer, PRNCR1 (615452) and PCGEM1 (605443), bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated AR on enhancers and its association with DOT1L (607375) appear to be required for recruitment of the second lncRNA, PCGEM1, to the AR amino terminus, which is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus-2 (PYGO2; 606903) PHD domain enhances selective looping of AR-bound enhancers to target gene promoters in these cells. In resistant prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumor xenograft growth in vivo. Yang et al. (2013) concluded that these overexpressed lncRNAs can potentially serve as a required component of castration resistance in prostatic tumors. Zhang et al. (2018) identified ARLNC1 (618053) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling, and prostate cancer growth in vitro and in vivo, suggesting that ARLNC1 has a role in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression. Zhang et al. (2018) found that ARLNC1 has elevated expression in cancer and that knockdown resulted in increased cytoplasmic levels of AR transcripts. Knockdown of ARNLC1 also resulted in increased apoptosis in AR-positive prostate cancer cells. These results translated to effects in vivo, as cells expressing shRNA targeting ARLNC1 formed smaller tumors in mice when compared to cells expressing nontargeting shRNA, suggesting that ARLNC1 is an important survival factor for AR-dependent prostate cancer. Calcinotto et al. (2018) identified IL23 (605580)-produced myeloid-derived suppressor cells (MDSCs) as a driver of castration-resistant prostate cancer (CRPC) in mice and patients with CRPC. Mechanistically, IL23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumor cells, promoting cell survival and proliferation in androgen-deprived conditions. Intratumor MDSC infiltration and IL23 concentration are increased in blood and tumor samples from patients with CRPC. Antibody-mediated inactivation of IL23 restored sensitivity to androgen-deprivation therapy in mice. Calcinotto et al. (2018) concluded that MDSCs promote CRPC by acting in a non-cell-autonomous manner. ### Exclusion Studies In the Ashkenazi-Jewish population, 3 founder mutations, 185delAG (113705.0003) and 5382insC (113705.0018) in the BRCA1 gene and 6174delT (600185.0018) in the BRCA2 gene, exist at a relatively high frequency as predisposing mutations for breast cancer and ovarian cancer. Hubert et al. (1999) reasoned that if germinal mutations in the BRCA1 and BRCA2 genes increased the risk of prostate cancer in carriers, it would be expected that the carrier frequency in prostate cancer patients would be higher than in the general population, as documented in female patients diagnosed with breast cancer and ovarian cancer. However, they found no evidence for an increased frequency of prostate cancer in association with these mutations in Ashkenazi males. Animal Model Green tea, a popular beverage consumed worldwide, has been shown to possess cancer chemopreventive effects in a wide range of target organs in rodent carcinogenesis models. The effects have been attributed to the biochemical and pharmacologic activities of its polyphenolic constituents. Epidemiologic studies, although inconclusive, suggest a protective effect on some cancer types in humans. People who consume tea regularly may have a lower risk of prostate cancer. The Japanese and Chinese populations who regularly consume tea, especially green tea, have one of the lowest incidences of prostate cancer in the world. Gupta et al. (2001) used the TRAMP (transgenic adenocarcinoma of the mouse prostate) mouse as a model for testing the effect of green tea in this cancer. In this model, expression of the SV40 early genes are driven by the prostate-specific promoter probasin that leads to cell transformation within the prostate. One-hundred percent of male TRAMP mice develop cancer of the prostate without any chemical or hormonal treatment. Gupta et al. (2001) found that oral infusion of a polyphenolic fraction isolated from green tea causes significant inhibition in the development, progression, and metastasis of prostate cancer to distant organ sites in these mice. Prostate cancer may become resistant to treatment with androgen deprivation therapy (ADT). Niu et al. (2008) demonstrated that the prostate AR (313700) may function as both a suppressor and a proliferator of prostate cancer metastasis, depending on its tissue location. Coculture of human stromal prostate WPMY1 cells with human AR-null epithelial prostate cancer PC3 cells showed that knockdown of AR in WPMY1 cells or restoration of AR in PC3 cells suppressed prostate cancer metastasis. Furthermore, in bone lesion assays and in vivo mouse models of prostate cancer, restoration of the AR in PC3 epithelial cells resulted in decreased tumor invasion. Knockdown of the AR in epithelial ADT-resistant prostate cancer cells resulted in increased cell invasion in vitro and in vivo. Transgenic mice lacking the prostate epithelial AR showed increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells, which coincided with larger and more invasive metastatic tumors and earlier death compared to wildtype mice. An evaluation of human prostate tumors showed a significant difference in AR expression between primary (91.75%) and metastatic (67.86%) prostate tumors. Together, these results indicated that AR functions in epithelial cells as a tumor suppressor of prostate cancer metastasis, whereas AR acts in stromal cells as a stimulator of prostate cancer progression. In a screen for endogenous tumor-associated T-cell responses in a primary mouse model of prostatic adenocarcinoma, Savage et al. (2008) identified a naturally arising CD8+ (186910) T cell response that is reactive to a peptide derived from histone H4 (602822). Despite the ubiquitous nature of histones, T cell recognition of histone H4 peptide was specifically associated with the presence of prostate cancer in these mice. Thus, Savage et al. (2008) concluded that the repertoire of antigens recognized by tumor-infiltrating T cells is broader than previously thought and includes peptides derived from ubiquitous self antigens that are normally sequestered from immune detection. Ding et al. (2011) exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumors and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonic pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGF-beta (190180)/BMP-SMAD4 (600993) signaling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic, and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathologic and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumors identified cell proliferation and invasion as 2 cardinal tumor biologic features in the metastatic Smad4/Pten-null prostate cancer model. Follow-on pathologic and functional assessment confirmed cyclin D1 (168461) and SPP1 (166490) as key mediators of these biologic processes, which together with PTEN and SMAD4 form a 4-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human prostate cancer. Ding et al. (2011) concluded that this model-informed progression analysis, together with genetic, functional, and translational studies, established SMAD4 as a key regulator of prostate cancer progression in mice and humans. INHERITANCE \- Somatic mutation \- Autosomal dominant NEOPLASIA \- Early onset prostate cancer ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

PROSTATE CANCER

c2931456

omim

https://www.omim.org/entry/176807

{"doid": ["10283"], "mesh": ["C537243"], "omim": ["176807"], "icd-9": ["185"], "icd-10": ["C61"], "orphanet": ["1331"]}

Acheiria /əˈkɪəriə/ is the congenital absence of one or both hands.[1][2] ## Causes[edit] It can occur in a number of situations which include:[1] * Amniotic band syndrome, particularly if unilateral * Cornelia de Lange syndrome * Fetal hydantoin syndrome * Incontinentia pigmenti ## References[edit] 1. ^ a b Weerakkody, Dr Yuranga; et al. "Acheiria". Radiopedia. Retrieved 4 December 2012. 2. ^ "Acheiria". TheFreeDictionary.com. Retrieved 4 December 2012. ## External links[edit] * Case Histories and sonograms on TheFetus.net[permanent dead link] *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Acheiria

c0265594

wikipedia

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

{"umls": ["C0265594"], "orphanet": ["294983"], "wikidata": ["Q4673591"]}

Familial partial lipodystrophy type Köbberling is a rare subtype of early-onset familial partial lipodystrophy (FPL), characterized by fat loss in the lower limbs and abnormal fat increase in other areas. The symptoms are similar to those seen in familial partial lipodystrophy, Dunnigan type (the most common type of FPL). However, only arms and legs have fat loss, and there is a normal or slightly increased fat distribution on the face, neck, and trunk, with excess of belly fat (central obesity). Metabolic abnormalities including insulin resistance, high blood pressure (hypertension), and high levels of fat in the blood (hypertriglyceridemia) have also been reported. This form of FPL has only been reported in women. Inheritance seems to be autosomal dominant, but the exact cause is not known. Treatment includes medication for the metabolic problems, diet and exercises, and in some cases, surgical procedures. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Familial partial lipodystrophy type Köbberling

c1720859

gard

https://rarediseases.info.nih.gov/diseases/12598/familial-partial-lipodystrophy-type-kobberling

{"mesh": ["D052496"], "omim": ["608600"], "orphanet": ["79084"], "synonyms": ["Familial partial lipodystrophy type 1", "FPLD1", "Familial partial lipodystrophy, Köbberling type"]}

A rare neuroendocrine neoplasm of pancreas characterized by a high-grade malignant epithelial tumor with neuroendocrine differentiation. Based on histopathologic appearance, a small cell (composed of diffuse sheets of cells) and a large cell type (showing a nesting/trabecular pattern) are distinguished. Synaptophysin and chromogranin are positive on immunohistochemistry. The Ki-67 proliferation index is typically very high (>60 - 80%). Patients present with back pain, jaundice, and/or non-specific abdominal symptoms. Serum hormone activity is unusual. The tumor is highly aggressive with poor prognosis. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Neuroendocrine carcinoma of pancreas

c2205506

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=506098

{"synonyms": ["Pancreatic NEC", "Pancreatic neuroendocrine carcinoma", "Poorly-differentiated NEN of pancreas", "Poorly-differentiated neuroendocrine neoplasm of pancreas", "Poorly-differentiated pancreatic NEN", "Poorly-differentiated pancreatic neuroendocrine neoplasm"]}

Intraoperative floppy iris syndrome SpecialtyOphthalmology Intraoperative floppy iris syndrome (IFIS) is a complication that may occur during cataract extraction in certain patients. This syndrome is characterized by a flaccid iris which billows in response to ordinary intraocular fluid currents, a propensity for this floppy iris to prolapse towards the area of cataract extraction during surgery, and progressive intraoperative pupil constriction despite standard procedures to prevent this.[1] IFIS has been associated with tamsulosin (e.g., Flomax), a medication widely prescribed for urinary symptoms associated with benign prostatic hyperplasia (BPH). Tamsulosin is a selective alpha blocker that works by relaxing the bladder and prostatic smooth muscle. As such, it also relaxes the iris dilator muscle by binding to its postsynaptic nerve endings.[2][3] Various alpha-blockers are associated with IFIS, but tamsulosin has a stronger association than the others.[4] A joint statement of two ophthalmologic societies states that "the other major class of drugs to treat BPH — 5-alpha reductase inhibitors — do not appear to cause IFIS to any significant degree."[4][5] 5-ARIs include finasteride, a medication typically used as first line therapy for BPH and androgenic alopecia. The medication is also associated with cataract formation.[6][7] IFIS may also be associated with other causes of small pupil like synechiae, pseudoexfoliation and other medications (used for conditions such as glaucoma, diabetes and high blood pressure). IFIS does not usually cause significant changes in postoperative outcomes. Patients may experience more pain, a longer recovery period, and less improvement in visual acuity than a patient with an uncomplicated cataract removal. The severity of the condition is not linked to the duration of tamsulosin intake.[8] ## References[edit] 1. ^ Chang, D.; Campbell, J. (April 2005). "Intraoperative floppy iris syndrome associated with tamsulosin". J Cataract Refract Surg. 31 (4): 664–73. doi:10.1016/j.jcrs.2005.02.027. PMID 15899440. 2. ^ Schwinn, D.; Afshari, N. (2006). "α1-Adrenergic Receptor Antagonists and the Iris: New Mechanistic Insights into Floppy Iris Syndrome". Survey of Ophthalmology. 51 (5): 501–512. doi:10.1016/j.survophthal.2006.06.011. PMID 16950249. 3. ^ Pärssinen, O.; Leppänen, E.; Keski-Rahkonen, P.; Mauriala, T.; Dugué, B.; Lehtonen, M. (2006). "Influence of Tamsulosin on the Iris and Its Implications for Cataract Surgery". Investigative Ophthalmology & Visual Science. 47 (9): 3766–3771. doi:10.1167/iovs.06-0153. PMID 16936084. 4. ^ a b American Society of Cataract and Refractive Surgery; American Academy of Ophthalmology (2014), Alpha-Blocker Patient Advisory: ASCRS and AAO Information Statement (PDF), retrieved 2017-05-12. 5. ^ Chang, DF; et al. (2008), "ASCRS White Paper: clinical review of intraoperative floppy-iris syndrome", J Cataract Refract Surg, 34 (12): 2153–2162, doi:10.1016/j.jcrs.2008.08.031, PMID 19027575. 6. ^ Wong, A. C. M.; Mak, S. T. (2011). "Finasteride-associated cataract and intraoperative floppy-iris syndrome". Journal of Cataract & Refractive Surgery. 37 (7): 1351–1354. doi:10.1016/j.jcrs.2011.04.013. PMID 21555201. 7. ^ Issa, S. A.; Dagres, E. (2007). "Intraoperative floppy-iris syndrome and finasteride intake". Journal of Cataract & Refractive Surgery. 33 (12): 2142–2143. doi:10.1016/j.jcrs.2007.07.025. PMID 18053919. 8. ^ Cheung, C.; Awan, M.; Sandramouli, S. (August 2006). "Prevalence and clinical findings of tamsulosin-associated intraoperative floppy-iris syndrome". J Cataract Refract Surg. 32 (8): 1336–9. doi:10.1016/j.jcrs.2006.03.034. PMID 16863971. ## External links[edit] Classification D * ICD-9-CM: 364.81 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Intraoperative floppy iris syndrome

c1688637

wikipedia

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

{"icd-9": ["364.81"], "wikidata": ["Q3825451"]}

A number sign (#) is used with this entry due to evidence that this form of retinitis pigmentosa, designated RP18, is caused by heterozygous mutation in the PRPF3 gene (607301) on chromosome 1q21. For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000. Clinical Features Xu et al. (1996) studied a large Danish family of 7 generations in which autosomal dominant retinitis pigmentosa segregated. Clinical diagnosis was based on a history of night blindness and ocular fundus findings typical of retinitis pigmentosa and included peripheral bone spicule formation, severe constriction of retinal arterioles, and progressive visual field defects beginning as midperipheral ring scotomas. Pathologic dark adaptation did not occur until the end of the first decade. Mapping In a 7-generation Danish family with autosomal dominant retinitis pigmentosa, Xu et al. (1996) found linkage without recombination between RP18 and D1S498, which maps to chromosome 1q near the centromere. Analysis of multiple informative meioses suggests that in this family D1S534 and D1S305 flank RP18 in interval 1p13-q23. Xu et al. (1998) refined the genetic mapping of RP18 to a 2-cM region between D1S442 and D1S2858 on 1q. Inglehearn et al. (1998) reported an English family with autosomal dominant retinitis pigmentosa mapping to this locus. Haplotype analysis placed the locus proximal to D1S1664. This marker is proximal to D1S2346, which is genetically indistinguishable from D1S2858; furthermore, 3 CEPH YACs containing D1S1664 did not contain either D1S2858 or D1S2346. Inglehearn et al. (1998) therefore concluded that their analysis further refined the distal boundary of the RP18 interval. Molecular Genetics Chakarova et al. (2002) screened the PRPF3 gene, which they called HPRP3, in 3 chromosome 1q-linked RP families. Two different missense mutations in 2 English families, a Danish family, and in 3 RP individuals were identified. One of the mutations (T494M; 607301.0001) was seen repeatedly in apparently unlinked families, raising the possibility of a mutation hotspot. Haplotype analysis with PRPF3 SNPs supported multiple origins for the mutation. The altered amino acids, which are highly conserved in all known PRPF3 orthologs, suggested a major function of that domain in the splicing process. Although PRPF3 appears to be ubiquitously expressed, the authors speculated that a retina-specific splicing element may interact with PRPF3 and generate the rod photoreceptor-specific phenotype. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Night blindness \- Peripheral fundus bone spicule formation \- Constricted retinal arterioles \- Progressive visual field defects \- Mid-peripheral ring scotomas MOLECULAR BASIS \- Caused by mutation in the pre-mRNA processing factor 3 gene ( 607301.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

RETINITIS PIGMENTOSA 18

c0035334

omim

https://www.omim.org/entry/601414

{"doid": ["0110356"], "mesh": ["D012174"], "omim": ["601414"], "orphanet": ["791"], "genereviews": ["NBK1417"]}

A rare congenital non-syndromic heart malformation characterized by an imperforate or absent mitral valve. In most cases, there is a univentricular atrioventricular connection to a dominant right ventricle via a tricuspid valve, and a hypoplastic left ventricle. Morphologic heterogeneity is considerable, and hemodynamic picture and clinical manifestation depend on the type and severity of associated cardiovascular anomalies (such as ventricular septal defect or aortic atresia). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Mitral atresia

c0344760

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1205

{"gard": ["3685"], "umls": ["C0344760"], "icd-10": ["Q23.2"]}

Fundus pulverulentus is a rare form of patterned dystrophy of the retinal pigment epithelium characterized by a granular appearance in the macula, with coarse and punctiform mottling of the retinal pigment epithelium within the macular region. Association with choroidal neovascularization has been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Fundus pulverulentus

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99004

{"icd-10": ["H35.5"]}

Isolated ectopia lentis is a condition that affects the eyes, specifically the positioning of the lens. The lens is a clear structure at the front of the eye that helps focus light. In people with isolated ectopia lentis, the lens in one or both eyes is not centrally positioned as it should be but is off-center (displaced). Isolated ectopia lentis usually becomes apparent in childhood. The lens may drift further off-center over time. Vision problems are common in isolated ectopia lentis. Affected individuals often have nearsightedness (myopia) and can have an irregular curvature of the lens or a structure that covers the front of the eye (the cornea), which causes blurred vision (astigmatism). They may also develop clouding of the lenses (cataracts) or increased pressure in the eyes (glaucoma) at an earlier age than other adults. In a small number of people with isolated ectopia lentis, tearing of the back lining of the eye (retinal detachment) occurs, which can lead to further vision problems and possible blindness. In individuals with isolated ectopia lentis, each eye can be affected differently. In addition, the eye problems vary among affected individuals, even those within the same family. Ectopia lentis is classified as isolated when it occurs alone without signs and symptoms affecting other body systems. Ectopia lentis can also be classified as syndromic, when it is part of a syndrome that affects multiple parts of the body. Ectopia lentis is a common feature of genetic syndromes such as Marfan syndrome and Weill-Marchesani syndrome. ## Frequency The prevalence of isolated ectopia lentis is unknown. In Denmark, an estimated 6.4 per 100,000 individuals have ectopia lentis, but a large proportion of these cases (about 75 percent) are syndromic. ## Causes Mutations in the FBN1 or ADAMTSL4 gene cause isolated ectopia lentis. These genes provide instructions for making proteins that are necessary for the formation of threadlike filaments called microfibrils. Microfibrils provide support to many tissues, including the lenses of the eyes, which are held in position by these filaments. Mutations in the FBN1 or ADAMTSL4 gene impair protein function and lead to a decrease in microfibril formation or result in the formation of impaired microfibrils. Without functional microfibrils to anchor the lens in its central position at the front of the eye, the lens becomes displaced. The displaced lens cannot focus light correctly, contributing to the vision problems that are common in people with isolated ectopia lentis. ### Learn more about the genes associated with Isolated ectopia lentis * ADAMTSL4 * FBN1 ## Inheritance Pattern When isolated ectopia lentis is caused by mutations in the FBN1 gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. When isolated ectopia lentis is caused by mutations in the ADAMTSL4 gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Isolated ectopia lentis

c3541518

medlineplus

https://medlineplus.gov/genetics/condition/isolated-ectopia-lentis/

{"gard": ["12251"], "omim": ["129600", "225100"], "synonyms": []}

## Description In most vertebrates, including pigs and mice, 2 major L-threonine degradation pathways exist. Tdh catalyzes the first step in 1 of these pathways, wherein L-threonine is converted to glycine and acetyl-CoA. However, in humans, TDH is an expressed pseudogene that produces nonfunctional proteins (Edgar, 2002). Cloning and Expression Using exon trapping to identify genes in the critical region for keratolytic winter erythema (KWE; 148370) on chromosome 8, followed by RT-PCR of lymphoblastoid cells, Appel et al. (2002) identified 3 splice variants of TDH. The open reading frames contain 280, 250, and 231 codons, and the deduced proteins share significant similarity with murine Tdh. RT-PCR detected TDH expression in leukocytes, muscle, testis, lung, and small intestine, in addition to the lymphoblastoid cell line. Expression was not detected in primary keratinocytes, skin, heart, spleen, brain, liver, kidney, ovary, prostate, and HeLa cells. Using the murine Tdh sequence to search a human genomic database, followed by PCR of liver and lung cDNA libraries, Edgar (2002) cloned human TDH. However, SNP database analysis revealed 3 major polymorphisms that disrupt transcription and translation of the TDH gene, including loss of acceptor splice sites preceding exons 4 and 6 and an in-frame stop codon in exon 6. Translation of all human mRNAs would generate truncated proteins ranging from 157 to 230 residues, some of which would also contain deletions of residues 96 to 146. These proteins were predicted to lack dehydrogenase activity due to an inability to make appropriate contacts with the substrates, L-threonine and NAD+. RT-PCR detected TDH expression in all normal tissues examined and in a number of human cell lines. Edgar (2002) noted that there is no evidence of alternative splicing in pig and mouse Tdh. Using quantitative PCR, in situ hybridization, and immunohistochemical analysis, Wang et al. (2009) found that mouse Tdh mRNA and protein were highly expressed in embryonic stem (ES) cells and in the inner cell mass of blastocysts. Lower expression was detected following differentiation of ES cells into embryoid bodies. Tdh localized to mitochondria. RT-PCR of human fetal liver showed TDH transcripts that lacked exon 4 and either lacked or showed aberrant splicing of exon 6. Wang et al. (2009) concluded that human TDH is incapable of producing an active enzyme. They noted that all other metazoans, including chimpanzees, appear to contain an intact TDH gene. Gene Function Mouse ES cells show a more rapid growth rate than human ES cells in culture. By depleting specific amino acids, Wang et al. (2009) showed that threonine alone supported rapid growth in mouse ES cells. Threonine had little effect on growth of mouse embryonic fibroblasts, 3T3 mouse fibroblasts, or HeLa cells. Inhibitor studies revealed that both glycine and acetyl-CoA were required for rapid growth in mouse ES cells. Gene Structure Appel et al. (2002) determined that the TDH gene contains 9 exons and spans 30 kb. Its 5-prime end is associated with a 70% GC-rich CpG island. Edgar (2002) identified 8 exons in the human TDH gene and found that it spans 10 kb. Mapping By constructing a physical and transcriptional map of the KWE critical region on chromosome 8, Appel et al. (2002) mapped the TDH gene to chromosome 8p23-p22. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

L-THREONINE DEHYDROGENASE, PSEUDOGENE

c3888000

omim

https://www.omim.org/entry/615174

{"omim": ["615174"]}

Stomach disease that is an inflammation of the lining of the stomach Gastritis Micrograph showing gastritis. H&E stain. SpecialtyGastroenterology SymptomsUpper abdominal pain, nausea, vomiting, bloating, loss of appetite, heartburn[1][2] ComplicationsBleeding, stomach ulcers, stomach tumors, pernicious anemia[1][3] DurationShort or long term[1] CausesHelicobacter pylori, NSAIDs, alcohol, smoking, cocaine, severe illness, autoimmune problems[1] Diagnostic methodEndoscopy, upper gastrointestinal series, blood tests, stool tests[1] Differential diagnosisMyocardial infarction, inflammation of the pancreas, gallbladder problems, peptic ulcer disease[2] TreatmentAntacids, H2 blockers, proton pump inhibitors, antibiotics[1] Frequency~50% of people[4] Deaths50,000 (2015)[5] Gastritis is inflammation of the lining of the stomach.[1] It may occur as a short episode or may be of a long duration.[1] There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain.[1] Other possible symptoms include nausea and vomiting, bloating, loss of appetite and heartburn.[1][2] Complications may include stomach bleeding, stomach ulcers, and stomach tumors.[1] When due to autoimmune problems, low red blood cells due to not enough vitamin B12 may occur, a condition known as pernicious anemia.[3] Common causes include infection with Helicobacter pylori and use of nonsteroidal anti-inflammatory drugs (NSAIDs).[1] Less common causes include alcohol, smoking, cocaine, severe illness, autoimmune problems, radiation therapy and Crohn's disease.[1][6] Endoscopy, a type of X-ray known as an upper gastrointestinal series, blood tests, and stool tests may help with diagnosis.[1] The symptoms of gastritis may be a presentation of a myocardial infarction.[2] Other conditions with similar symptoms include inflammation of the pancreas, gallbladder problems, and peptic ulcer disease.[2] Prevention is by avoiding things that cause the disease.[4] Treatment includes medications such as antacids, H2 blockers, or proton pump inhibitors.[1] During an acute attack drinking viscous lidocaine may help.[7] If gastritis is due to NSAIDs these may be stopped.[1] If H. pylori is present it may be treated with a combination of antibiotics such as amoxicillin and clarithromycin.[1] For those with pernicious anemia, vitamin B12 supplements are recommended either by mouth or by injection.[3] People are usually advised to avoid foods that bother them.[8] Gastritis is believed to affect about half of people worldwide.[4] In 2013 there were approximately 90 million new cases of the condition.[9] As people get older the disease becomes more common.[4] It, along with a similar condition in the first part of the intestines known as duodenitis, resulted in 50,000 deaths in 2015.[5] H. pylori was first discovered in 1981 by Barry Marshall and Robin Warren.[10] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Helicobacter pylori * 2.2 Critical illness * 2.3 Diet * 3 Pathophysiology * 3.1 Acute * 3.2 Chronic * 3.2.1 Metaplasia * 4 Diagnosis * 5 Treatment * 6 History * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] A peptic ulcer may accompany gastritis. Endoscopic image. Many people with gastritis experience no symptoms at all. However, upper central abdominal pain is the most common symptom; the pain may be dull, vague, burning, aching, gnawing, sore, or sharp.[11] Pain is usually located in the upper central portion of the abdomen,[12] but it may occur anywhere from the upper left portion of the abdomen around to the back. Other signs and symptoms may include the following: * Nausea * Vomiting (may be clear, green or yellow, blood-streaked or completely bloody depending on the severity of the stomach inflammation) * Belching (does not usually relieve stomach pain if present) * Bloating * Early satiety[11] * Loss of appetite * Unexplained weight loss ## Cause[edit] Common causes include Helicobacter pylori and NSAIDs. Less common causes include alcohol, cocaine, severe illness and Crohn's disease, among others.[1] ### Helicobacter pylori[edit] Helicobacter pylori colonizes the stomachs of more than half of the world's population, and the infection continues to play a key role in the pathogenesis of a number of gastroduodenal diseases. Colonization of the gastric mucosa with Helicobacter pylori results in the development of chronic gastritis in infected individuals, and in a subset of patients chronic gastritis progresses to complications (e.g., ulcer disease, stomach cancers, some distinct extragastric disorders).[13] However, over 80 percent of individuals infected with the bacterium are asymptomatic and it has been postulated that it may play an important role in the natural stomach ecology.[14] ### Critical illness[edit] Gastritis may also develop after major surgery or traumatic injury ("Cushing ulcer"), burns ("Curling ulcer"), or severe infections. Gastritis may also occur in those who have had weight loss surgery resulting in the banding or reconstruction of the digestive tract. ### Diet[edit] Evidence does not support a role for specific foods including spicy foods and coffee in the development of peptic ulcers.[15] People are usually advised to avoid foods that bother them.[8] ## Pathophysiology[edit] ### Acute[edit] Acute erosive gastritis typically involves discrete foci of surface necrosis due to damage to mucosal defenses.[16] NSAIDs inhibit cyclooxygenase-1, or COX-1, an enzyme responsible for the biosynthesis of eicosanoids in the stomach, which increases the possibility of peptic ulcers forming.[17] Also, NSAIDs, such as aspirin, reduce a substance that protects the stomach called prostaglandin. These drugs used in a short period are not typically dangerous. However, regular use can lead to gastritis.[18] Additionally, severe physiologic stress ("stress ulcers") from sepsis, hypoxia, trauma, or surgery, is also a common etiology for acute erosive gastritis. This form of gastritis can occur in more than 5% of hospitalized patients. Also, note that alcohol consumption does not cause chronic gastritis. It does, however, erode the mucosal lining of the stomach; low doses of alcohol stimulate hydrochloric acid secretion. High doses of alcohol do not stimulate secretion of acid.[19] ### Chronic[edit] Chronic gastritis refers to a wide range of problems of the gastric tissues.[16] The immune system makes proteins and antibodies that fight infections in the body to maintain a homeostatic condition. In some disorders the body targets the stomach as if it were a foreign protein or pathogen; it makes antibodies against, severely damages, and may even destroy the stomach or its lining.[18] In some cases bile, normally used to aid digestion in the small intestine, will enter through the pyloric valve of the stomach if it has been removed during surgery or does not work properly, also leading to gastritis. Gastritis may also be caused by other medical conditions, including HIV/AIDS, Crohn's disease, certain connective tissue disorders, and liver or kidney failure. Since 1992, chronic gastritis lesions are classified according to the Sydney system.[20] #### Metaplasia[edit] Mucous gland metaplasia, the reversible replacement of differentiated cells, occurs in the setting of severe damage of the gastric glands, which then waste away (atrophic gastritis) and are progressively replaced by mucous glands. Gastric ulcers may develop; it is unclear if they are the causes or the consequences. Intestinal metaplasia typically begins in response to chronic mucosal injury in the antrum, and may extend to the body. Gastric mucosa cells change to resemble intestinal mucosa and may even assume absorptive characteristics. Intestinal metaplasia is classified histologically as complete or incomplete. With complete metaplasia, gastric mucosa is completely transformed into small-bowel mucosa, both histologically and functionally, with the ability to absorb nutrients and secrete peptides. In incomplete metaplasia, the epithelium assumes a histologic appearance closer to that of the large intestine and frequently exhibits dysplasia.[16] ## Diagnosis[edit] Often, a diagnosis can be made based on the patient's description of their symptoms, but other methods which may be used to verify gastritis include: * Blood tests: * Blood cell count * Presence of H. pylori * Liver, kidney, gallbladder, or pancreas functions * Urinalysis * Stool sample, to look for blood in the stool * X-rays * Endoscopy, to check for stomach lining inflammation and mucous erosion * Stomach biopsy, to test for gastritis and other conditions[21] ## Treatment[edit] Antacids are a common treatment for mild to medium gastritis.[22] When antacids do not provide enough relief, medications such as H2 blockers and proton-pump inhibitors that help reduce the amount of acid are often prescribed.[22][23] Cytoprotective agents are designed to help protect the tissues that line the stomach and small intestine.[24] They include the medications sucralfate and misoprostol. If NSAIDs are being taken regularly, one of these medications to protect the stomach may also be taken. Another cytoprotective agent is bismuth subsalicylate[citation needed]. Several regimens are used to treat H. pylori infection. Most use a combination of two antibiotics and a proton pump inhibitor. Sometimes bismuth is added to the regimen. ## History[edit] In 1,000 A.D, Avicenna first gave the description of stomach cancer. In 1728, German physician Georg Ernst Stahl first coined the term "gastritis". Italian anatomical pathologist Giovanni Battista Morgagni further described the characteristics of gastric inflammation. He described the characteristics of erosive or ulcerative gastritis and erosive gastritis. Between 1808 and 1831, French physician François-Joseph-Victor Broussais gathered information from the autopsy of the dead French soldiers. He described chronic gastritis as "Gastritide" and erroneously believed that gastritis was the cause of ascites, typhoid fever, and meningitis. In 1854, Charles Handfield Jones and Wilson Fox described the microscopic changes of stomach inner lining in gastritis which existed in diffuse and segmental forms. In 1855, Baron Carl von Rokitansky first described hypetrophic gastritis. In 1859, British physician, William Brinton first described about acute, subacute, and chronic gastritis. In 1870, Samuel Fenwick noted that pernicious anemia causes glandular atrophy in gastritis. German surgeon, Georg Ernst Konjetzny noticed that gastric ulcer and gastric cancer are the result of gastric inflammation. Shields Warren and Willam A. Meissner described the intestinal metaplasia of the stomach as a feature of chronic gastritis.[25] ## See also[edit] * Gastroenteritis * Esophagitis ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r "Gastritis". The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). November 27, 2013. Archived from the original on 6 March 2015. Retrieved 1 March 2015. 2. ^ a b c d e Rosen & Barkin's 5-Minute Emergency Medicine Consult (4 ed.). Lippincott Williams & Wilkins. 2012. p. 447. ISBN 9781451160970. Archived from the original on 2015-04-02. 3. ^ a b c Varbanova, M.; Frauenschläger, K.; Malfertheiner, P. (Dec 2014). "Chronic gastritis - an update". Best Pract Res Clin Gastroenterol. 28 (6): 1031–42. doi:10.1016/j.bpg.2014.10.005. PMID 25439069. 4. ^ a b c d Fred F. Ferri (2012). Ferri's Clinical Advisor 2013,5 Books in 1, Expert Consult - Online and Print,1: Ferri's Clinical Advisor 2013. Elsevier Health Sciences. p. 417. ISBN 9780323083737. Archived from the original on 2016-03-05. 5. ^ a b GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903. PMID 27733281. 6. ^ Hauser, Stephen (2014). Mayo Clinic Gastroenterology and Hepatology Board Review. Oxford University Press. p. 49. ISBN 9780199373338. Archived from the original on 2016-03-05. 7. ^ Adams (2012). "32". Emergency Medicine: Clinical Essentials. Elsevier Health Sciences. ISBN 9781455733941. Archived from the original on 2016-08-15. 8. ^ a b Webster-Gandy, Joan; Madden, Angela; Holdsworth, Michelle, eds. (2012). Oxford handbook of nutrition and dietetics (2nd ed.). Oxford: Oxford University Press, USA. p. 571. ISBN 9780199585823. Archived from the original on 2017-09-08. 9. ^ Global Burden of Disease Study 2013, Collaborators (22 August 2015). "Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 386 (9995): 743–800. doi:10.1016/s0140-6736(15)60692-4. PMC 4561509. PMID 26063472. 10. ^ Wang, AY; Peura, DA (October 2011). "The prevalence and incidence of Helicobacter pylori-associated peptic ulcer disease and upper gastrointestinal bleeding throughout the world". Gastrointestinal Endoscopy Clinics of North America. 21 (4): 613–35. doi:10.1016/j.giec.2011.07.011. PMID 21944414. 11. ^ a b "Gastritis Symptoms". eMedicineHealth. 2008. Archived from the original on 2008-12-06. Retrieved 2008-11-18. 12. ^ "Gastritis". National Digestive Diseases Information Clearinghouse. National Institute of Diabetes and Digestive and Kidney Diseases. December 2004. Archived from the original on 2008-10-11. Retrieved 2008-10-06. 13. ^ Kandulski A, Selgrad M, Malfertheiner P (August 2008). "Helicobacter pylori infection: a clinical overview". Digestive and Liver Disease. 40 (8): 619–26. doi:10.1016/j.dld.2008.02.026. PMID 18396114. 14. ^ Blaser, M. J. (2006). "Who are we? Indigenous microbes and the ecology of human diseases" (PDF). EMBO Reports. 7 (10): 956–60. doi:10.1038/sj.embor.7400812. PMC 1618379. PMID 17016449. Archived (PDF) from the original on 2012-11-05. 15. ^ Raphael Rubin; David S. Strayer; Emanuel Rubin, eds. (2012). Rubin's pathology : clinicopathologic foundations of medicine (Sixth ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 623. ISBN 9781605479682. Archived from the original on 2015-04-02. 16. ^ a b c "Gastritis". Merck. January 2007. Archived from the original on 2009-01-25. Retrieved 2009-01-11. 17. ^ Dajani EZ, Islam K (August 2008). "Cardiovascular and gastrointestinal toxicity of selective cyclo-oxygenase-2 inhibitors in man" (PDF). J Physiol Pharmacol. 59 Suppl 2: 117–33. PMID 18812633.[permanent dead link] 18. ^ a b Siegelbaum, Jackson (2006). "Gastritis". Jackson Siegelbaum Gastroenterology. Archived from the original on 2008-12-16. Retrieved 2008-11-18. 19. ^ Wolff G (1989). "[Effect of alcohol on the stomach]" [Effect of alcohol on the stomach]. Gastroenterol J (in German). 49 (2): 45–9. PMID 2679657. 20. ^ Mayo Clinic Staff (April 13, 2007). "Gastritis". MayoClinic. Archived from the original on December 8, 2008. Retrieved 2008-11-18. 21. ^ "Exams and Tests". eMedicinHealth. 2008. Archived from the original on 2008-12-11. Retrieved 2008-11-18. 22. ^ a b Zajac, P; Holbrook, A; Super, ME; Vogt, M (March–April 2013). "An overview: Current clinical guidelines for the evaluation, diagnosis, treatment, and management of dyspepsia". Osteopathic Family Physician. 5 (2): 79–85. doi:10.1016/j.osfp.2012.10.005. 23. ^ Boparai V, Rajagopalan J, Triadafilopoulos G (2008). "Guide to the use of proton pump inhibitors in adult patients". Drugs. 68 (7): 925–47. doi:10.2165/00003495-200868070-00004. PMID 18457460. S2CID 29732662. 24. ^ Fashner, J; Gitu, AC (15 February 2015). "Diagnosis and Treatment of Peptic Ulcer Disease and H. pylori Infection". American Family Physician. 91 (4): 236–42. PMID 25955624. 25. ^ Gyula, Mozsik (16 January 2013). "Chapter 1: Diagnosis of Gastritis – Review from Early Pathological Evaluation to Present Day Management" (PDF). Current Topics in gastritis. University of Pécs. pp. 1–19. ISBN 978-953-51-0907-5. Retrieved 10 July 2018. ## External links[edit] Classification D * ICD-10: K29.0-K29.7 * ICD-9-CM: 535.0-535.5 * MeSH: D005756 * DiseasesDB: 34500 External resources * MedlinePlus: 001150 * eMedicine: emerg/820 med/852 * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum * v * t * e Alcohol and health Alcohol use Alcohol-related crimes * Drunk drivers * Alcohol-related traffic crashes in the United States * Driving under the influence (DUI) * Drunk driving in the United States * Public intoxication * Rum-running * Adulterated moonshine/Denatured alcohol * List of methanol poisoning incidents Alcoholism * Alcohol and Native Americans * Alcoholism in adolescence * Alcoholism in family systems * Collaborative Study on the Genetics of Alcoholism * College student alcoholism * Disease theory of alcoholism * High-functioning alcoholic (HFA) * Seeing pink elephants Chemistry * Beer chemistry * Congener * Alcohol congener analysis * Ethanol * Blood alcohol content * Breathalyzer * Fusel alcohol * Wine chemistry Effects * Short-term effects of alcohol consumption * Long-term effects of alcohol * On memory * Subjective response to alcohol Interactions * Aging * Brain * Cancer * breast cancer * Cortisol * Pregnancy * Sleep * Tolerance/intolerance * Weight * Beverage-specific * Beer: Potomania * Red wine: Red wine headache Social issues * Alcohol advertising * on college campuses * Sex * Alcohol myopia * Alcohol abuse among college students * Binge drinking * Epidemiology * Blackout (alcohol-related amnesia) * Blackout Wednesday * Drinking game * list * pregaming * Drinking in public * Drunk dialing * Drunk walking * Drunkorexia * Dry drunk * French paradox * Hair of the dog * Nightcap * Pantsdrunk * Passive drinking * Binge drinking devices * Beer bong * Yard of ale * Routes of administration * Alcohol enema * Alcohol inhalation * Sconcing * Surrogate alcohol * Related issues * Balconing * Suicide History * Dionysian Mysteries * Dipsomania * Gin Craze * List of deaths through alcohol * Rum ration * Speakeasy General * Beer day * Drinking culture * Apéritif and digestif * Hangover remedies * Health effects of wine * Wine and food matching * Long-distance race involving alcohol * List of countries by alcohol consumption per capita * Alcohol consumption by youth in the United States * Nip joint Alcohol control Alcohol law * Administrative license suspension (ALS) * Alcohol packaging warning messages * Drunk driving law by country * DWI court * Field sobriety testing * Hip flask defence * Ignition interlock device 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intake of alcoholic beverages Addiction medicine * Disulfiram-like drugs: disulfiram, calcium carbimide, cyanamide. Sulfonic acids: Acamprosate Religion and alcohol * Christian views on alcohol * alcohol in the Bible * Islam and alcohol History * Bratt System Related * Index of alcohol-related articles * Austrian syndrome * Ban on caffeinated alcoholic beverages * Brief intervention * Gateway drug effect * Last call * Mood disorder * Non-alcoholic fatty liver disease * Self-medication * Spins * Sober companion * Sober living houses * Sobering center * Town drunk * Category Authority control * The LNB id 174445 is not valid. * NDL: 00563898 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Gastritis

c0017152

wikipedia

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

{"mesh": ["D005756"], "umls": ["C0017152"], "icd-9": ["535.0"], "wikidata": ["Q183130"]}

A number sign (#) is used with this entry because of evidence that susceptibility to microvascular complications of diabetes-4 (MVCD4) is associated with variation in the IL1RN gene (147679) on chromosome 2q14. Molecular Genetics Blakemore et al. (1996) studied the IL1RN*2 allele (147679.0001) in 128 patients with type 1 (IDDM; 222100) and 125 patients with type 2 (NIDDM; 125853) diabetes and found significant association between IL1RN*2 and diabetic nephropathy (corrected p less than 0.0012). The association was significant in both types of diabetes, but the observed increase was highest in NIDDM, rising to double the control levels. Noting that the IL1RN*2 allele had been found to be associated with more severe clinical outcome in several chronic inflammatory diseases, the authors suggested that IL1RN*2 might be a novel genetic marker of severity of inflammatory complications of disease rather than a marker of disease susceptibility. In a study of 95 Korean patients with type 2 diabetes and nephropathy and 126 patients with type 2 diabetes and normal renal function, Lee et al. (2004) found an association between nephropathy and the IL1RN*2 polymorphism and the -511C-T polymorphism ('IL1B2') in the IL1B gene (147720), with the risk of kidney failure highest in those carrying both IL1RN*2 and IL1B2 (odds ratio, 3.90). Lee et al. (2004) concluded that the IL1B2 and IL1RN*2 genotypes of the IL1 cluster genes are associated with diabetic nephropathy in Korean patients with type 2 diabetes. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

MICROVASCULAR COMPLICATIONS OF DIABETES, SUSCEPTIBILITY TO, 4

c2675112

omim

https://www.omim.org/entry/612628

{"omim": ["612628"], "synonyms": ["Alternative titles", "NEPHROPATHY, DIABETIC, SUSCEPTIBILITY TO"]}

A number sign (#) is used with this entry because of evidence that lateral meningocele syndrome (LMNS) is caused by heterozygous mutation in the NOTCH3 gene (600276) on chromosome 19p13. Description Lateral meningocele syndrome is a rare disorder characterized by distinctive facial features, hyperextensibility, hypotonia, and characteristic lateral meningoceles, which can result in neurologic complications such as bladder dysfunction and neuropathy. Dysmorphic features include dolichocephaly, hypertelorism, ptosis, microretrognathia, high-arched palate, long, flat philtrum, and low-set ears. Multiple additional variable features may also be observed, including cryptorchidism, vertebral anomalies, and connective tissue abnormalities. Early motor development is delayed, but cognition is usually normal (summary by Gripp et al., 2015). Clinical Features Lehman et al. (1977) reported a 14-year-old girl with generalized osteosclerosis, distinctive craniofacial features, and multiple thoracic and lateral meningoceles. She had downslanting palpebral fissures, high-arched palate, mandibular and facial bone hypoplasia, a large sella turcica and spacious foramen magnum, platybasia, basilar impression, widened spinal cord, and scalloping of the posterior surfaces of the vertebral bodies. Radiographic studies suggested maldevelopment of the spinal cord, cerebellum, and cerebral cortex. Her asymptomatic mother showed similar craniofacial skeletal features. Katz et al. (1978) reported an isolated case. Merle et al. (1979) may have described the same disorder in 2 sisters, aged 6 and 9 years. They had short stature and facial dysmorphism similar to that reported by Lehman et al. (1977). Other features included enlarged sella turcica and enlargement of the optic foramina and internal auditory meatus. The mother had a large sella. Merle et al. (1979) suggested a general dysplastic syndrome rather than a local disease. Philip et al. (1995) reported a 19-year-old boy with facial dysmorphism, skeletal anomalies, and multiple lateral meningoceles. He had increased bone density of the skull base and sutures. Intelligence was normal. Electron microscopy of skin showed nonspecific abnormalities suggesting a connective tissue disorder. The clinical features closely resembled those reported by Lehman et al. (1977). Gripp et al. (1997) described 1 female and 2 male patients with multiple lateral meningoceles. One patient had thickened calvaria, and 2 had prominent metopic sutures. Other shared features included wormian bones, malar hypoplasia, downslanting palpebral fissures, a high narrow palate, keloid formation, and cryptorchidism in males. One had a hypoplastic posterior arch of the atlas and an enlarged sella, as reported by Lehman et al. (1977). Chen et al. (2005) reported 3 additional cases of LMS, including an affected mother and daughter. The daughter presented at the age of 10 years for neurosurgery for increasing lower back pain, which was treated by L4-L5 and S1 laminectomy and excision of an extradural arachnoid cyst. Multiple abnormalities had been demonstrated by MRI, including a Chiari I malformation (CM1; 118420) and a large dorsal extradural arachnoid cyst expanding the canal and extending from the lower thoracic spine into the sacrum. Facies showed hypertelorism, mildly downslanting palpebral fissures, and ptosis. There was mild micrognathia and a high narrow palate. In the mother, bilateral flank masses and an umbilical hernia were noted at birth. She had had multiple surgeries to correct malformed auditory ossicles. At the age of 33 years she was found to have dural ectasia and multiple lateral meningoceles. At that time the mother's height was 143 cm (50th centile for a 10-year-old child). She had the appearance of hypertelorism, mildly downslanting palpebral fissures, ptosis, and micrognathia. All features were strikingly similar to those of the daughter. The affected male reported by Chen et al. (2005) had telecanthus and micrognathia, bilateral inguinal hernias, and multiple lateral meningoceles in the thoracic and lumbar regions. Chen et al. (2005) suggested that lateral meningocele syndrome may be a connective tissue disorder. Avela et al. (2011) reported a 6-year-old boy, born of unrelated Finnish parents, with dolichocephaly, hypertelorism, epicanthal folds, high-arched palate,, micrognathia, and scoliosis. He was hypotonic and learned to walk at age 24 months; cognition was normal. Spine MRI, performed due to progressive kyphoscoliosis, showed extensive multilobar ductal ectasia resulting in hydronephrosis, as well as erosion of the thoracic and lumbar vertebral pedicles and abnormal vertebral bony elements. Additional features included coarse hair, ptosis, posteriorly angulated ears, nasal voice, and slender long bones with biochemical evidence of osteolysis. Avela et al. (2011) suggested that the diagnosis in this patient was consistent with Hajdu-Cheney syndrome (HJCYS; 102500). However, Gripp (2011) concluded that the patient reported by Avela et al. (2011) had lateral meningocele syndrome, although she noted that the 2 disorders have overlapping features and may either be allelic or caused by mutations in genes in the same pathway. Alves et al. (2013) reported a 6-year-old boy with lateral meningocele syndrome. He presented at birth with feeding difficulties and hypotonia, and was noted to have dysmorphic features, including ptosis, microretrognathia, long and smooth philtrum, low-set ears, and cryptorchidism. Echocardiography showed a bicuspid aortic valve. During the next few years, he developed sleep apnea, conductive hearing loss, hypertelorism, pectus excavatum, hyperextensibility, and skin keloid scarring. At age 6 years, he had normal motor and cognitive development. Imaging of the spine showed scoliosis with expansion of the spinal canal and intervertebral foramina with scalloping of the posterior wall of the vertebrae. There was no evidence of acroosteolysis or wormian bones. Genetic analysis excluded mutations in the PLOD1 (153454), FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes. Alves et al. (2013) emphasized the connective tissue defects often observed in lateral meningocele syndrome. Gripp et al. (2015) reported a boy with lateral meningocele syndrome who developed acute back pain, urinary incontinence, worsening stool incontinence, and abnormal gait around 5 years of age. Prior to that, he was noted to have dysmorphic facial features, hypotonia, pectus excavatum, and delayed motor development. Imaging studies at age 5 showed multiple lateral meningoceles and a tethered cord, which was surgically repaired. He also developed neuropathic pain. Inheritance Chen et al. (2005) suggested autosomal dominant inheritance, but noted that X-linked inheritance could not be completely excluded. Of the 9 reported cases, 5 were male and 4 female, and the males did not appear to be more severely affected than the females, making autosomal dominant inheritance most likely. Molecular Genetics In 6 unrelated patients with LMNS, including 5 patients reported by Gripp et al. (1997), Chen et al. (2005), Avela et al. (2011), and Alves et al. (2013), Gripp et al. (2015) identified 5 different de novo heterozygous truncating mutations in exon 33 of the NOTCH3 gene (600276.0013-600276.0017). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Studies of the cells of 1 patient showed decreased expression of the NOTCH3 protein as well as expression of the truncated transcript. The truncated NOTCH3 proteins predicted to result from these mutations would lack a functional PEST domain, which could prolong the half-life and thus increase signaling effects. Gripp et al. (2015) postulated that the de novo mutations in exon 33 would result in a dominant gain-of-function effect. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Head \- Dolichocephaly Face \- Micrognathia \- Malar hypoplasia \- Long, smooth philtrum Ears \- Hearing loss, conductive \- Low-set ears \- Posteriorly rotated ears \- Malformed ossicles Eyes \- Downslanting palpebral fissures \- Hypertelorism \- Ptosis Nose \- Short nasal bridge Mouth \- High-arched palate Teeth \- Dental crowding Neck \- Short neck CARDIOVASCULAR Heart \- Bicuspid aortic valve (1 patient) Vascular \- Patent ductus arteriosus CHEST External Features \- Pectus excavatum ABDOMEN External Features \- Umbilical hernia \- Inguinal hernia GENITOURINARY External Genitalia (Male) \- Cryptorchidism SKELETAL \- Joint hyperextensibility Skull \- Platybasia \- Sclerosis of the skull base \- Wormian bones Spine \- Vertebral fusion \- Scalloping of vertebral bodies \- Scoliosis \- Kyphosis SKIN, NAILS, & HAIR Skin \- Keloid formation Hair \- Coarse hair MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed motor development \- Meningoceles, multiple, lateral \- Syringomyelia \- Arachnoid cyst \- Dural ectasia \- Widening of the spinal canal \- Chiari I malformation VOICE \- High nasal voice MISCELLANEOUS \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the homolog of the Drosophila NOTCH gene 3 (NOTCH3, 600276.0013 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

LATERAL MENINGOCELE SYNDROME

c0344487

omim

https://www.omim.org/entry/130720

{"doid": ["0111343"], "omim": ["130720"], "orphanet": ["2789"], "synonyms": ["Alternative titles", "LMS", "LEHMAN SYNDROME"], "genereviews": ["NBK368476"]}

A rare aortic malformation characterized by the narrowing of the aorta lumen (close to its origin) associated or not with stenosis of other arteries (branch pulmonary arteries, coronary arteries). This narrowing of the aorta or pulmonary branches may impede blood flow, resulting in heart murmur and ventricular hypertrophy (left ventricle in case of aorta involvement, right ventricle in case of pulmonary artery involvement). ## Epidemiology The incidence of supravalvular aortic stenosis (SVAS) is estimated at approximately 1 in 25 000 births and the mean prevalence in the general population at 1/7 500. ## Clinical description Clinical manifestations of SVAS include ejection systolic murmur and, in some cases, symptoms of chest pain or syncope. The electrocardiogram may indicate signs of a repolarisation disorder at rest and/or signs of ischemia after a stress test. ## Etiology The narrowing results from a thickening of the artery wall, which is not related to atherosclerosis. SVAS is caused by a mutation in the elastin gene (ELN), which is located on chromosome 7q11.23. In nearly all cases, ELN mutations disrupt elastin protein synthesis, resulting in a production deficit. ## Diagnostic methods The discovery of a systolic murmur may prompt a cardiological examination, potentially showing ventricular hypertrophy. Echocardiogram may indicate a progressive ''hourglass'' narrowing of the aorta and/or pulmonary artery lumen, specific to SVAS. Angiography by retrograde femoral arterial catheterization would allow a more precise diagnosis but it may be associated with risk if the stenosis is significant. Thus, in such cases scanning is preferred. CT scan can show the location and the severity of aorta narrowing. ## Differential diagnosis SVAS can be part of the Williams-Beuren syndrome caused by microdeletion of the 7q11-q23 region, including the elastin and many contiguous genes. SVAS associated with Williams-Beuren syndrome is identical to isolated SVAS, however Williams-Beuren syndrome is also associated with a characteristic face, behavioral disorders and hypercalcemia. ## Antenatal diagnosis In a family affected by SVAS, the progressive nature of the disease makes the identification of mutation carriers important for follow-up. Prenatal ultrasound examination can allow detection of the aortic or pulmonary supravalvular stenosis. ## Genetic counseling Except for the cases with Williams-Beuren syndrome, the disease is either sporadic or familial. In familial cases it is transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity within members of the same family. ## Management and treatment Regular follow-up is recommended (every 6 months for infants and each year in children) in order to monitor the evolution of the stenosis, which can be removed by surgery. Surgical repair is indicated only for significant stenosis. ## Prognosis The prognosis of SVAS depends on the severity of the lesion and on potential associated anomalies located on the aortic valve or coronary arteries. Predictors of worse outcomes and frequent surgical intervention are the presence of diffuse lesions compared to discrete stenosis or presence of associated aortic valve disease. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Supravalvular aortic stenosis

c0003499

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3193

{"gard": ["743"], "mesh": ["D021921"], "omim": ["185500"], "umls": ["C0003499", "C1305147"], "icd-10": ["Q25.3"], "synonyms": ["SVAS"]}

Microcephaly-microcornea syndrome, Seemanova type is characterised by microcephaly and brachycephaly, eye anomalies (microphthalmia, microcornea, congenital cataract), hypogenitalism, severe intellectual deficit, growth retardation and progressive spasticity. It has been described in two patients (a male and his sister's son). Both patients also presented with facial dysmorphism, including upslanting palpebral fissures, epicanthal folds, highly arched palate, microstomia, and retrognathia. This syndrome is transmitted as an X-linked trait. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Microcephaly-microcornea syndrome, Seemanova type

c2931524

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2528

{"gard": ["3627"], "mesh": ["C537536", "C537539"], "umls": ["C0796151", "C2931524"], "icd-10": ["Q87.8"], "synonyms": ["Seemanova-Lesny syndrome"]}

Isolated agammaglobulinemia (IA) is the non-syndromic form of agammaglobulinemia, a primary immunodeficiency disease, and is characterized by deficient gamma globulins and associated predisposition to frequent and recurrent infections from infancy. ## Epidemiology Prevalence is estimated to be about 1/250,000 to 1/500/000. Isolated agammaglobulinemia has been reported worldwide in all ethnic groups. ## Clinical description Two forms of IA have been described based on the pattern of inheritance of the genetic defects underlying the disorder: X-linked agammaglobulinemia (XLA) which represents approximately 85% of the affected patients, and autosomal agammaglobulinemia (see these terms) which includes recessive and dominant cases but is far less frequent. The clinical signs of the two forms are very similar and include recurrent bacterial infections (otitis media, pneumonia, and sinusitis), diarrhea and skin infections with onset in infancy. Late-onset agammaglobulinemia is known as common variable immunodeficiency (CVID; see this term). ## Etiology Defects in B lymphocyte development and maturation appear to underlie agammaglobulinemia. Mutations in seven genes have been reported to be related to IA: BTK (Xq21.33-q22), BLNK (10q23.2-q23.33), CD79A (19q13.2), CD79B (17q23), IGHM(14q32.33), IGLL1 (22q11.23), PIK3R1 (5q13.1) and TCF3 (19p13.3). ## Genetic counseling X-linked, autosomal recessive and autosomal dominant cases are reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Isolated agammaglobulinemia

c0086438

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=229717

{"mesh": ["D000361"], "omim": ["300310", "300755", "601495", "612692", "613500", "613501", "613502", "613506", "615214", "616941"], "umls": ["C0001768", "C0086438"], "icd-10": ["E80.0"], "synonyms": ["Isolated hypogammaglobulinemia"]}

Persistent adrenarche syndrome Other namesAdrenal SAHA syndrome[1] SpecialtyDermatology Persistent adrenarche syndrome is a cutaneous condition seen typically in thin young women who report great psychological and physical stress in their lives.[1] ## See also[edit] * SAHA syndrome * List of cutaneous conditions ## References[edit] 1. ^ a b Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Persistent adrenarche syndrome

None

wikipedia

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

{"wikidata": ["Q7170402"]}

Cancer of the cells that produce cerebrospinal fluid in the ventricles of the brain 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: "Choroid plexus tumor" – news · newspapers · books · scholar · JSTOR (January 2010) (Learn how and when to remove this template message) Choroid plexus tumors are a rare type of cancer that occur from the brain tissue called choroid plexus of the brain.[1] These tumors usually occur in children younger than 2 years and are classified according to the WHO classification of the tumors of the central nervous system: ## Contents * 1 Presentation * 2 Diagnosis * 2.1 Classification * 3 Treatment * 4 See also * 5 References * 6 External links ## Presentation[edit] Symptoms vary depending on the size and location of the tumor and typically include headaches, nausea and vomiting, irritability, and decreased energy. [2] ## Diagnosis[edit] ### Classification[edit] * Choroid plexus carcinoma (WHO grade III) * Choroid atypical plexus papilloma (WHO grade II) * Choroid plexus papilloma (WHO grade I) ## Treatment[edit] In order to remove it completely, surgery may be an option. It relieves the hydrocephalus (excess water in the brain) about half of the time. Another treatment is chemotherapy, recommended for patients with severe problem.[3] ## See also[edit] * Brain tumor ## References[edit] 1. ^ McEvoy AW, Harding BN, Phipps KP, et al. (April 2000). "Management of choroid plexus tumours in children: 20 years experience at a single neurosurgical centre". Pediatr Neurosurg. 32 (4): 192–9. doi:10.1159/000028933. PMID 10940770. S2CID 20244382. 2. ^ "Choroid Plexus Tumor". Retrieved 2017-12-13. 3. ^ "Choroid Plexus | American Brain Tumor Association". www.abta.org. Archived from the original on 2016-12-20. Retrieved 2016-12-03. ## External links[edit] * Choroid plexus tumor in the NCI Dictionary of Cancer Terms * v * t * e Tumours of the nervous system Endocrine Sellar: * Craniopharyngioma * Pituicytoma Other: * Pinealoma CNS Neuroepithelial (brain tumors, spinal tumors) Glioma Astrocyte * Astrocytoma * Pilocytic astrocytoma * Pleomorphic xanthoastrocytoma * Subependymal giant cell astrocytoma * Fibrillary astrocytoma * Anaplastic astrocytoma * Glioblastoma multiforme Oligodendrocyte * Oligodendroglioma * Anaplastic oligodendroglioma Ependyma * Ependymoma * Subependymoma Choroid plexus * Choroid plexus tumor * Choroid plexus papilloma * Choroid plexus carcinoma Multiple/unknown * Oligoastrocytoma * Gliomatosis cerebri * Gliosarcoma Mature neuron * Ganglioneuroma: Ganglioglioma * Retinoblastoma * Neurocytoma * Dysembryoplastic neuroepithelial tumour * Lhermitte–Duclos disease PNET * Neuroblastoma * Esthesioneuroblastoma * Ganglioneuroblastoma * Medulloblastoma * Atypical teratoid rhabdoid tumor Primitive * Medulloepithelioma Meninges * Meningioma * Hemangiopericytoma Hematopoietic * Primary central nervous system lymphoma PNS: * Nerve sheath tumor * Cranial and paraspinal nerves * Neurofibroma * Neurofibromatosis * Neurilemmoma/Schwannoma * Acoustic neuroma * Malignant peripheral nerve sheath tumor Other * WHO classification of the tumors of the central nervous system Note: Not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastasis). This article incorporates public domain material from the U.S. National Cancer Institute document: "Dictionary of Cancer Terms". This oncology article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Choroid plexus tumor

c0085138

wikipedia

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

{"mesh": ["D016545"], "umls": ["C0085138"], "orphanet": ["251896"], "wikidata": ["Q5105211"]}

## Description Hyperhomocysteinemia refers to above-normal concentrations of plasma/serum homocysteine. Plasma/serum homocysteine is the sum of the thiol-containing amino acid homocysteine and the homocysteinyl moiety of the disulfides homocystine and cysteine-homocysteine, whether free or bound to proteins (Malinow and Stampfer, 1994). Hyperhomocysteinemia in isolation may be associated with an increased risk of atherosclerosis and recurrent arterial and venous thrombosis usually in the third or fourth decade of life (review by Welch and Loscalzo, 1998). Homocysteinemia is also a feature of several inherited metabolic disorders, including homocystinuria (236200), due to mutation in the CBS gene (613381), and N(5,10)-methylenetetrahydrofolate reductase deficiency (236250), caused by mutation in the MTHFR gene (607093). Homocysteinemia/homocystinuria and megaloblastic anemia can result from defects in vitamin B12 (cobalamin; cbl) metabolism, which have been classified according to complementation groups of cells in vitro; see cblE (236270) and cblG (250940). See also the various forms of combined methylmalonic aciduria (MMA) and homocystinuria due to disorders of cobalamin: cblC (277400), cblD (277410), and cblF (277380). Clinical Features Wilcken and Wilcken (1976) studied methionine loading in males under age 50 with angiographic evidence of ischemic heart disease but free of known risk factor. Of 25 such persons, 7 had peak postmethionine concentrations of homocysteine-cysteine elevated in the heterozygous range, whereas only 1 of 22 controls had such an elevation. Genest et al. (1991) had estimated that 14% of coronary artery disease patients had familial hyperhomocysteinemia. Other data suggested a relationship to cerebrovascular and peripheral arterial disease. The studies showing elevated basal homocysteine levels as correlated among family members of patients with coronary vascular disease and juvenile venous thrombosis suggested the possibility of an inherited basal mild hyperhomocysteinemia. Rees and Rodgers (1993) summarized clinical data linking vascular disease with homocysteinemia. Falcon et al. (1994) determined the prevalence of hyperhomocysteinemia before and 4 hours after methionine load in 80 patients who had had at least one verified episode of venous thromboembolism before the age of 40 years and in 51 healthy control subjects. According to their criteria, hyperhomocysteinemia was found in 15 patients (18.8%) and in 1 control subject (1.9%). Family history for venous thromboembolism was positive in 7 of the 15 patients. Family studies, performed for 8 kindreds, showed that for more than half of the studied probands the abnormality was inherited. Wu et al. (1994) found hyperhomocysteinemia in at least 12% of 85 families with 2 or more sibs affected by early coronary artery disease. Boushey et al. (1995) and Motulsky (1996) concluded from a metaanalysis of 27 relevant publications that homocysteine is an independent risk factor for arteriosclerotic vascular disease unrelated to hyperlipidemia, hypertension, diabetes, and smoking. As with cholesterol levels, the risk is graded, i.e., the risk rises with increasing homocysteine levels. They calculated that 10% of the population's risk for coronary artery disease is attributable to elevated homocysteine levels. In 269 patients with a first, objectively diagnosed episode of deep-vein thrombosis and in 269 healthy controls matched to the patients according to age and sex, den Heijer et al. (1996) measured plasma homocysteine levels and concluded that high plasma homocysteine is a risk factor for deep-vein thrombosis in the general population. Welch and Loscalzo (1998) reviewed the topic of homocysteine and atherothrombosis beginning with the clinical observations of McCully (1969). By the time of the review, multiple prospective and case-control studies had shown that a moderately elevated plasma homocysteine concentration is an independent risk factor for atherothrombotic vascular disease. They stated that it was not yet clear whether homocysteine itself or a related metabolite or cofactor is primarily responsible for the atherothrombogenic effects of hyperhomocysteinemia in vivo. In a 2-year prospective study in an Asian Indian population, Narayanasamy et al. (2007) found that 15 (51.7%) of 29 consecutive patients (mean age, 30 +/- 6 years) with central retinal vein occlusion (CRVO) exhibited significantly elevated homocysteine levels compared with those of healthy control subjects. The increased homocysteine level in CRVO cases was associated with decreased methionine and decreased B-12 levels. Other Features Recurrent early spontaneous abortion was linked to hyperhomocysteinemia by Steegers-Theunissen et al. (1992) and Wouters et al. (1993). Owen et al. (1997) found hyperhomocysteinemia in 6 of 21 women with unexplained abruptio placentae. They presented data suggesting that homocysteinemia in these women is not caused by a block in the transsulfuration pathway but could be due to defective remethylation of homocysteine into methionine. Selhub et al. (1995) concluded that high plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid artery stenosis in the elderly. The Framingham (Massachusetts) Study cohort has been evaluated biennially since 1948. In a sample of 1,092 subjects (mean age, 76 years) from this cohort, Seshadri et al. (2002) analyzed the relation of the plasma total homocysteine level measured at baseline and that measured 8 years earlier to the risk of newly diagnosed dementia on follow-up. They used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E (107741) genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Over a median follow-up period of 8 years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer disease (AD; 104300). The multivariable-adjusted relative risk of dementia was 1.4 for each increase of 1 standard deviation in the log-transformed homocysteine value either at baseline or 8 years earlier. The relative risk of Alzheimer disease was 1.8 per increase of 1 SD at baseline and 1.6 per increase of 1 SD 8 years before baseline. With a plasma homocysteine level greater than 14 micromoles per liter, the risk of Alzheimer disease nearly doubled. Seshadri et al. (2002) concluded that an increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer disease. Axer-Siegel et al. (2004) found an association between an elevated plasma level of homocysteine and exudative neovascular age-related macular degeneration (ARMD; see 603075) but not dry ARMD. Very high plasma homocysteine levels are characteristic of classic homocystinuria (236200), a rare autosomal recessive disorder accompanied by the early onset of generalized osteoporosis. The increased prevalence of osteoporosis in homocystinuria suggests that a high serum homocysteine concentration may weaken bone by interfering with collagen crosslinking, thereby increasing the risk of osteoporotic fracture. Van Meurs et al. (2004) and McLean et al. (2004) reported findings in the Netherlands and the Framingham (Massachusetts) Study, respectively, suggesting that homocysteine concentration is a strong and independent risk factor for osteoporotic fractures in older persons. Inheritance Franken et al. (1996) studied homocysteine levels after fasting as well as after methionine load among 96 family members of 21 postload hyperhomocysteinemic vascular index patients: 6 parents, 27 offspring, 38 sibs, 19 uncles and aunts, and 6 cousins. In 15 of 21 screened families, postload mild hyperhomocysteinemia was established in at least 1 family member. Both fasting and postload hyperhomocysteinemia were observed in 21% of screened family members and 32% of screened family members, respectively. Franken et al. (1996) concluded that both fasting and postload hyperhomocysteinemia are inherited in the majority of instances. In 306 individuals from 51 Dutch families, den Heijer et al. (2005) found that heritability for homocysteine levels after methionine-loading was greater (67.5%) than that for fasting homocysteine levels (21.6%). However, the heritability of postload homocysteine levels was not strongly affected by the MTHFR C677T genotype (607093.0003), in contrast to fasting homocysteine levels, which were affected. The findings were consistent with a model in which the capacity for methionine handling is dependent on genetically determined enzyme activity. Clinical Management Rees and Rodgers (1993) reviewed therapeutic measures for homocysteinemic patients. Stampfer and Malinow (1995) argued that the 'time is ripe for randomized clinical trials' of folate supplementation. To avoid masking pernicious anemia, the supplement could include oral vitamin B12 in doses that would circumvent the lack of intrinsic factor. Motulsky (1996) stated 'On the basis of our assessment of the role of folic acid in reduction of raised homocysteine levels, and on the basis of the quantitative effects of homocysteine elevations on the pathogenesis of coronary artery disease, we have calculated that 9% of male and 5.4% of female coronary artery deaths in the United States (approximately 50,000 total deaths/year) could be prevented by fortification of flour and cereal products by using 350 micro g folic acid/100 g food.' (An erratum pointed out that the editorial by Motulsky (1996) stated: '54% of female coronary artery deaths,' whereas the correct figure is 5.4%.) Wiklund et al. (1996) described results of a double-blind study using N-acetylcysteine (NAC) or placebo on 11 subjects with high plasma lipoprotein(a) levels (greater than 0.3 g/l). Main outcome measures were treatment effects on Lp(a) and plasma amino thiols (homocysteine, cysteine, and cysteinyl glycine). They reported that there was no significant effect on plasma Lp(a) levels with NAC: homocysteine was reduced by 45% (p less than 0.0001), cysteinyl glycine by 24% (p less than 0.0001), and cysteine by 11% (p = 0.0002). Wiklund et al. (1996) noted that the reduction of homocysteine levels seen with NAC was considerable and might be of clinical significance in cases with high plasma homocysteine levels, since even moderately high plasma levels of homocysteine are associated with atherosclerosis and thrombotic events. Although vitamin supplementation decreases or even normalizes plasma homocysteine concentrations in most cases, prospective, randomized clinical trials will be necessary to determine the effect of vitamin supplementation on cardiovascular morbidity and mortality. The Food and Drug Administration (FDA) recommended that cereal-grain products be fortified with folic acid to prevent congenital neural tube defects. Since folic acid supplementation reduces levels of plasma homocysteine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, Malinow et al. (1998) hypothesized that folic acid fortification of food might reduce plasma homocyst(e)ine levels. To test this hypothesis, they assessed the effects of breakfast cereals fortified with 3 levels of folic acid, as well as the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. The results suggested that folic acid fortification at levels higher than that recommended by the FDA may be warranted for the prevention of atherothrombotic disease. Schnyder et al. (2001) found that treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduced homocysteine levels and decreased the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. They proposed that this inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty. Pathogenesis Fryer et al. (1993) demonstrated that homocysteine can induce tissue factor procoagulant activity in cultured human endothelial cells. Several reports, including those of Kang et al. (1986) and Chao et al. (1999), indicated a likely role for homocysteine in the pathogenesis of atherosclerosis. Malinow and Stampfer (1994) reviewed the role of plasma homocysteine in arterial occlusive diseases. To understand the role of homocysteine in the pathogenesis of atherosclerosis, Tsai et al. (1994) examined the effect of homocysteine on the growth of both vascular smooth muscle cells and endothelial cells at concentrations similar to those observed clinically. As little as 0.1 mM homocysteine caused a 25% increase in DNA synthesis, and homocysteine at 1 mM increased DNA synthesis by 4.5-fold in rat aortic smooth muscle cells. In contrast, homocysteine caused a dose-dependent decrease in DNA synthesis in human umbilical vein endothelial cells. Homocysteine increased mRNA levels of cyclin D1 (168461) and cyclin A (123835) in aortic smooth muscle cells by 3- and 15-fold, respectively, indicating that homocysteine induced the mRNA of cyclins important for the reentry of quiescent smooth muscle cells into the cell cycle. The growth-promoting effect of homocysteine on vascular smooth muscle cells, together with its inhibitory effect on endothelial cell growth, may explain homocysteine-induced atherosclerosis. Kraus et al. (1986) demonstrated that mean activity of cystathionine synthase (CBS; 613381), which is on chromosome 21, is 166% in cultured fibroblasts from Down syndrome patients compared with controls. Brattstrom et al. (1987) suggested that if cystathionine synthase deficiency is involved in the pathophysiology of arteriosclerosis, Down syndrome patients might be protected against arteriosclerosis. Indeed, Murdoch et al. (1977) found that arteriosclerosis was rare in Down syndrome and referred to this disorder as an 'atheroma-free model.' Brattstrom et al. (1987) likewise found a remarkable freedom from arteriosclerosis in Down syndrome. In cultured human hepatocytes and vascular endothelial and aortic smooth muscle cells, Werstuck et al. (2001) found that homocysteine-induced endoplasmic reticulum (ER) stress activated both the unfolded protein response and sterol regulatory element-binding proteins (SREBPs). Activation of the SREBPs was associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake, and with intracellular accumulation of cholesterol. Mice with diet-induced hyperhomocysteinemia had significantly increased cholesterol and triglycerides in liver, but not plasma, due to increased lipid biosynthesis, not impaired hepatic export of lipids. The findings suggested a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides., which contribute to hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia. Jakubowski et al. (2008) found that patients with homocysteinemia due to MTHFR deficiency or CBS deficiency had increased plasma levels of N-homocysteine (Hcy)-linked proteins, including the prothrombotic N-Hcy-fibrinogen (134820). N-Hcy-proteins are detrimental by contributing to both thrombogenesis and immune activation. The authors suggested that increased levels of N-Hcy-fibrinogen may explain the increased susceptibility to thrombogenesis in these individuals. Population Genetics Chandalia et al. (2003) investigated whether Asian Indians have high plasma homocysteine compared with Caucasians in the United States in the era of folate fortification, and whether low vitamin B12 or insulin resistance may account for possible interethnic differences in plasma homocysteine. A total of 227 Asian Indians and 155 Caucasians participated in the study. Asian Indians were found to have significantly higher plasma homocysteine than Caucasians (median of 12.6 and 8.0 micromol/liter, P less than 0.0001, respectively) and lower plasma concentrations of B6 (median 49 vs 70 nmol/liter, P = 0.05, respectively). Plasma folate was relatively high and similar in both ethnic groups. Plasma vitamin B12 was significantly lower in Asian Indians than in Caucasians. Vitamin B12 correlated significantly with plasma homocysteine. When vitamin B12 was between 150 and 379 pmol/liter, the regression curve between vitamin B12 and homocysteine had a significantly different slope in the 2 ethnic groups (P less than 0.05) and Asian Indians had significantly higher homocysteine for any level of vitamin B12. Chandalia et al. (2003) concluded that Asian Indians living in the United States have significant elevation of plasma homocysteine concentrations despite normal plasma folate. Molecular Genetics In an editorial, Motulsky (1996) reviewed evidence that polymorphism of the MTHFR gene (C677T; 607093.0003) may be an important factor in atherosclerotic vascular disease. Polymorphic mutations in the MTHFR and MTR (156570) genes, both of which cause recessively inherited increased homocysteine levels, explain only a small proportion of the observed variation in homocysteine level. To investigate additional genetic influences, Jee et al. (2002) examined environmental, familial, and genetic influences on serum homocysteine levels in 661 family members of 112 probands who underwent elective coronary arteriography. Estimated mean homocysteine levels for the 3 putative genotypes (designated LL, LH, and HH) were 8.0, 10.1, and 15.9 micromol per liter, respectively, with relative frequencies of 56.8%, 37.2%, and 6%, respectively. Analysis suggested the presence of a codominantly expressed major gene, in addition to the effects of the MTHFR C677T mutation. The results of the study supported multifactorial inheritance more strongly than mendelian inheritance alone. Retinal artery occlusion is a common vision-threatening disease, primarily affecting patients older than 60 years. Because hyperhomocysteinemia has been established as an important risk factor for cardiovascular disease, Weger et al. (2002) investigated whether hyperhomocysteinemia and/or homozygosity for the C677T mutation (607093.0003) in the MTHFR gene were associated with an increased risk for retinal artery occlusion. They found that mean plasma homocysteine levels were significantly higher in patients with retinal artery occlusion compared with normal controls. However, the prevalence of the homozygous genotype of the MTHFR C677T mutation did not differ significantly between patients and controls. Lange et al. (2010) performed a genomewide association study for plasma homocysteine (Hcy) in 1,786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated single-nucleotide polymorphism (SNP), rs7422339 (p = 4.7 x 10(-13)), encodes thr1405 to asn in CPS1 (608307.0006) and explained 3.0% of variation in the Hcy level. The widely studied MTHFR C677T SNP (rs1801133; 607093.0003) was also highly significant (p = 8.7 x 10(-10)) and explained 1.6% of the trait variation. In a follow-up genotyping of these 2 SNPs in 1,679 CLHNS young adult offspring, the MTHFR C677T SNP was strongly associated (p = 1.9 x 10(-26)) with Hcy and explained 5.1% of the variation in gender-combined offspring. In contrast, the CPS1 variant was significant only in females. Combined analysis of all samples confirmed that the MTHFR variant was more strongly associated with Hcy in the offspring. Although there was evidence for a positive synergistic effect between the CPS1 and MTHFR SNPs in the offspring, there was no significant evidence for an interaction in the mothers. The authors suggested that genetic effects on Hcy may differ across developmental stages. Nomenclature Genest et al. (1991) introduced the term 'familial hyperhomocysteinemia.' Hyperhomocysteinemia is sometimes written as hyperhomocyst(e)inemia to emphasize the pathogenetic significance of the sulfhydryl homocysteine as opposed to the disulfide homocystine. Mudd and Levy (1995) urged use of the term hyperhomocyst(e)inemia to describe the composite of homocysteine-derived moieties usually measured in the plasma in either sulfhydryl or disulfide form, since in speech it is difficult to distinguish 'homocyst(e)ine' from 'homocysteine.' They suggested that an alternative useful in communicating orally is to substitute 'total Hcy' for homocyst(e)ine, spelling out the 'Hcy.' The term 'homocyst(e)ine' with parentheses around the 'e' in the middle of the word is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. Animal Model Nishinaga et al. (1993) presented results from experiments in cultured porcine aortic endothelial cells suggesting that inhibited expression of anticoagulant heparan sulfate may contribute to the thrombogenic property resulting from the homocysteine-induced endothelial cell perturbation. To investigate the mechanism whereby folate supplementation protects against heart and neural tube defects, Rosenquist et al. (1996) tested the effects of homocysteine on chick embryos and the effect of added folate. The hypothesis was that homocysteine may be the teratogenic agent, since serum homocysteine increases in folate depletion. Of embryos treated with homocysteine or homocysteine thiolactone, 27% showed neural tube defects. A high frequency of ventricular septal defects and neural tube defects was observed. Also, a ventral closure defect was found in a high percentage of day 9 embryos. The teratogenic dose was shown to raise serum homocysteine to over 150 nmol/ml, compared with a normal level of about 10 nmol/ml. Folate supplementation kept the rise in serum homocysteine to approximately 45 nmol/ml and prevented the teratogenic effect. Rosenquist et al. (1996) concluded that homocysteine per se causes dysmorphogenesis of the heart and neural tube, as well as of the ventral wall. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency (236250), Chen et al. (2001) generated Mthfr knockout mice. Plasma total homocysteine levels in heterozygous and homozygous knockout mice were 1.6- and 10-fold higher than those in wildtype littermates, respectively. Both heterozygous and homozygous knockouts had either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appeared normal, whereas the homozygotes were smaller and showed developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice. Troen et al. (2008) found that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. There was also a decrease in brain microglia. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies and with plasma total homocysteine. Feeding mice a methionine-rich diet produced similar but less pronounced effects. The findings suggested that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

HOMOCYSTEINEMIA

c3495426

omim

https://www.omim.org/entry/603174

{"mesh": ["C566403"], "omim": ["603174"], "synonyms": ["Alternative titles", "HYPERHOMOCYSTEINEMIA"]}

Typical pulmonary carcinoid tumour Other namesTypical lung carcinoid tumour, lung carcinoid, typical lung carcinoid Micrograph of a typical pulmonary carcinoid tumour. SpecialtyOncology Typical pulmonary carcinoid tumour is a subtype of pulmonary carcinoid tumour. It is an uncommon low-grade malignant lung mass that is most often in the central airways of the lung.[1] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Signs and symptoms[edit] Lung carcinoids typically present with a cough or hemoptysis.[2] Findings may closely mimic malignant tumours of the lung, i.e. lung cancer. ## Diagnosis[edit] CT-guided biopsy of peripheral typical carcinoid tumor The definitive diagnosis is rendered by a microscopic examination, after excision. Typical carcinoids have cells with stippled chromatin and a moderate quantity of cytoplasm. They typically have few mitoses and lack necrosis. By definition, they are greater than 4 mm in largest dimension; smaller lesions are referred to as pulmonary carcinoid tumourlets. The differential diagnosis of typical pulmonary carcinoid tumour includes: atypical pulmonary carcinoid tumour, pulmonary carcinoid tumourlet and lung adenocarcinoma. * Very high magnification * With prominent rosettes ## Treatment[edit] Typical carcinoids are usually treated with surgical excision. ## See also[edit] * Pulmonary tumor * Lung cancer * Atypical pulmonary carcinoid tumour * Pulmonary neuroendocrine tumor ## References[edit] 1. ^ Meisinger, QC.; Klein, JS.; Butnor, KJ.; Gentchos, G.; Leavitt, BJ. (Nov 2011). "CT features of peripheral pulmonary carcinoid tumors". AJR Am J Roentgenol. 197 (5): 1073–80. doi:10.2214/AJR.10.5954. PMID 22021498. 2. ^ Gungor, S.; Damadoglu, E.; Aybatli, A.; Yilmaz, A.; Kir, A.; Akkaya, E. (Jul 2006). "Typical pulmonary carcinoid tumors: presentation and outcome of 24 cases". Med Sci Monit. 12 (7): CR315–8. PMID 16810137. ## External links[edit] Classification D * Lung carcinoids (cancer.org) * v * t * e Cancer involving the respiratory tract Upper RT Nasal cavity Esthesioneuroblastoma Nasopharynx Nasopharyngeal carcinoma Nasopharyngeal angiofibroma Larynx Laryngeal cancer Laryngeal papillomatosis Lower RT Trachea * Tracheal tumor Lung Non-small-cell lung carcinoma * Squamous-cell carcinoma * Adenocarcinoma (Mucinous cystadenocarcinoma) * Large-cell lung carcinoma * Rhabdoid carcinoma * Sarcomatoid carcinoma * Carcinoid * Salivary gland–like carcinoma * Adenosquamous carcinoma * Papillary adenocarcinoma * Giant-cell carcinoma Small-cell carcinoma * Combined small-cell carcinoma Non-carcinoma * Sarcoma * Lymphoma * Immature teratoma * Melanoma By location * Pancoast tumor * Solitary pulmonary nodule * Central lung * Peripheral lung * Bronchial leiomyoma Pleura * Mesothelioma * Malignant solitary fibrous tumor *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Typical pulmonary carcinoid tumour

c1708788

wikipedia

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

{"umls": ["C1708788"], "wikidata": ["Q3658376"]}

Cheilitis glandularis is a rare inflammatory disorder of the lip. It is mainly characterized by swelling of the lip with hyperplasia of the salivary glands; secretion of a clear, thick mucus; and variable inflammation. Enlargement and chronic exposure of the mucous membrane on the lower lip becomes affected by the environment, leading to erosion, ulceration, crusting, and, occasionally, infection. Cheilitis glandularis is more common in adult males, although cases have been described in women and children. In Caucasians, it is associated with a relatively high incidence of squamous cell carcinoma of the lip. Although there may be a genetic susceptibility, no definitive cause has been established. Treatment may include surgical excision by vermilionectomy (sometimes called a lip shave), but treatment varies for each individual. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Cheilitis glandularis

c0267034

gard

https://rarediseases.info.nih.gov/diseases/412/cheilitis-glandularis

{"mesh": ["C535921"], "omim": ["118330"], "umls": ["C0267034"], "orphanet": ["1221"], "synonyms": []}

Popliteal pterygium syndrome is a condition that affects the development of the face, skin, and genitals. Most people with this disorder are born with a cleft lip and/or a cleft palate. Other symptoms may include depressions (pits) near the center of the lower lip, small mounds of tissue on the lower lip, or missing teeth. Other features may include webs of skin on the backs of the legs across the knee joint (popliteal pterygium), webbing or fusion of the fingers or toes (syndactyly), triangular shaped folds of skin over the nails of the large toes, and tissue connecting the upper and lower eyelids or the upper and lower jaw. Affected people may also have abnormal genitals. There is no growth delay and intelligence is usually normal. Inheritance is autosomal dominant. It is caused by mutations in the IRF6 gene. Treatment may include reconstructive surgery for the oral defects, such as the cleft lip and cleft palate, and for other defects such as the popliteal pterygium or abnormal genitalia. Popliteal pterygium syndrome is part of the IRF6-related disorders which also include Van der Woude syndrome 2. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Popliteal pterygium syndrome

c0265259

gard

https://rarediseases.info.nih.gov/diseases/3242/popliteal-pterygium-syndrome

{"mesh": ["C562509"], "omim": ["119500"], "orphanet": ["1300"], "synonyms": ["Facio-genito-popliteal syndrome", "Popliteal web syndrome", "Cleft lip/palate paramedian mucous cysts of the lower lip popliteal pterygium digital and genital anomalies", "PPS", "Faciogenitopopliteal syndrome"]}

A severe form of otopalatodigital syndrome spectrum disorder, and is characterized by dysmorphic facies, severe skeletal dysplasia affecting the axial and appendicular skeleton, extraskeletal anomalies (including malformations of the brain, heart, genitourinary system, and intestine) and poor survival. ## Epidemiology To date, more than 40 cases of Otopalatodigital syndrome type 2 (OPD2) have been described in the literature. ## Clinical description OPD2 is a congenital disorder. Intrauterine growth is usually normal and affected infants have large anterior fontanels, and facial dysmorphism including broad forehead and lateral fullness of the supraorbital ridge, hypertelorism, downslanting palpebral fissures, stubby nose with a flat root, midfacial hypoplasia, microstomia (with typical down turned bow of the upper lip), micrognathia, Pierre Robin sequence, posterior cleft palate (submucosal cleft palate or cleft velum), glossoptosis, malformed and/or apparently low-set ears. Additional features include skeletal anomalies: pectus deformity, short limbs, campomelia, fibular agenesis, flexion contractures of elbows, knees, rocker bottom or equinovarus feet, syndactyly (usually involving fingers III and IV in the hands and toes II to V in the feet), camptodactyly of fingers, and absent halluces. Extraskeletal malformations include malformations of the central nervous system (myelomeningocele /encephalocele, cerebellar hypoplasia, hydrocephalus), heart (congenital valvular heart defects), intestine, genitourinary system (hydronephrosis ± urethral valve/reflux, hypospadias, epispadias). Congenital corneal opacities, bilobed tongue, deafness, and Dandy-Walker malformation have been reported in a minority of OPD2 cases. Congenital glaucoma and cataracts have been described in one patient. Psychomotor development varies from normal to mild intellectual disability. Carrier females with OPD2 can be asymptomatic or exhibit a phenotype that can extend from a mild subclinical osteodysplasia to a presentation indistinguishable from that of affected males. Prognosis of OPD2 is poor and perinatal death is common, secondary to cardio respiratory failure. ## Etiology OPD2 is caused by gain of function mutations in the gene FLNA (Xq28) that encodes filamin A. However the pathogenesis is still elusive. OPD2 is allelic with 4 other skeletal dysplasias (OPD1, Melnick-Needles syndrome (MNS), terminal osseous dysplasia - pigmentary defects (TOD) and frontometaphyseal dysplasia (FMD)). ## Genetic counseling OPD2 is inherited in an X-linked dominant manner. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation are less severely affected. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template

Otopalatodigital syndrome type 2

c1844696

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=90652

{"gard": ["5802"], "mesh": ["C538089"], "omim": ["304120"], "umls": ["C1844696"], "icd-10": ["Q87.0"], "synonyms": ["OPD II syndrome", "OPD syndrome 2"]}

Skin condition Pachydermatous eosinophilic dermatitis SpecialtyDermatology Pachydermatous eosinophilic dermatitis is a skin condition observed in South African black teenage girls and characterized by generalized pruritic papules, hypertrophic genital lesions and peripheral eosinophilia.[1] ## See also[edit] * Keloid morphea * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 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

Pachydermatous eosinophilic dermatitis

None

wikipedia

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

{"wikidata": ["Q7122118"]}

"Tourette" redirects here. For other uses, see Tourette (disambiguation). Neurodevelopmental disorder involving motor and vocal tics Tourette syndrome Other namesTourette's syndrome, Tourette's disorder, Gilles de la Tourette syndrome (GTS), combined vocal and multiple motor tic disorder [de la Tourette] Georges Gilles de la Tourette (1857–1904), namesake of Tourette syndrome SpecialtyPediatrics, neurology SymptomsTics[1] Usual onsetTypically in childhood[1] DurationLong term[2] CausesGenetic with environmental influence[2] Diagnostic methodBased on history and symptoms[1] MedicationUsually none, occasionally neuroleptics and noradrenergics[1] PrognosisImprovement to disappearance of tics beginning in late teens[2] FrequencyAbout 1%[3] Tourette syndrome or Tourette's syndrome (abbreviated as TS or Tourette's) is a common neurodevelopmental disorder that begins in childhood or adolescence. It is characterized by multiple movement (motor) tics and at least one vocal (phonic) tic. Common tics are blinking, coughing, throat clearing, sniffing, and facial movements. These are typically preceded by an unwanted urge or sensation in the affected muscles, can sometimes be suppressed temporarily, and characteristically change in location, strength, and frequency. Tourette's is at the more severe end of a spectrum of tic disorders. The tics often go unnoticed by casual observers. Tourette's was once regarded as a rare and bizarre syndrome and has popularly been associated with coprolalia (the utterance of obscene words or socially inappropriate and derogatory remarks). It is no longer considered rare; about 1% of school-age children and adolescents are estimated to have Tourette's,[1] and coprolalia occurs only in a minority. There are no specific tests for diagnosing Tourette's; it is not always correctly identified, because most cases are mild, and the severity of tics decreases for most children as they pass through adolescence. Therefore, many go undiagnosed or may never seek medical attention. Extreme Tourette's in adulthood, though sensationalized in the media, is rare, but for a small minority, severely debilitating tics can persist into adulthood. Tourette's does not affect intelligence or life expectancy. There is no cure for Tourette's and no single most effective medication. In most cases, medication for tics is not necessary, and behavioral therapies are the first-line treatment. Education is an important part of any treatment plan, and explanation alone often provides sufficient reassurance that no other treatment is necessary.[1] Among those who are referred to specialty clinics, other conditions like attention deficit hyperactivity disorder (ADHD) and obsessive–compulsive disorder (OCD) are more likely than in the broader population of persons with Tourette's. These co-occurring diagnoses often cause more impairment to the individual than the tics; hence it is important to correctly distinguish co-occurring conditions and treat them. Tourette syndrome was named by French neurologist Jean-Martin Charcot for his intern, Georges Gilles de la Tourette, who published in 1885 an account of nine patients with a "convulsive tic disorder". While the exact cause is unknown, it is believed to involve a combination of genetic and environmental factors. The mechanism appears to involve dysfunction in neural circuits between the basal ganglia and related structures in the brain. ## Contents * 1 Classification * 2 Characteristics * 2.1 Tics * 2.2 Onset and progression * 2.3 Co-occurring conditions * 2.4 Neuropsychological function * 3 Causes * 4 Mechanism * 5 Diagnosis * 5.1 Assessment and screening for other conditions * 6 Management * 6.1 Psychoeducation and social support * 6.2 Behavioral * 6.3 Medication * 6.4 Other * 6.5 Pregnancy * 7 Prognosis * 7.1 Quality of life * 8 Epidemiology * 9 History * 10 Society and culture * 11 Research directions * 12 Notes * 13 References * 13.1 Book sources * 14 Further reading * 15 External links ## Classification Tourette syndrome is classified as a motor disorder (a disorder of the nervous system that causes abnormal and involuntary movements). It is listed in the neurodevelopmental disorder category of the fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published in 2013.[5] Tourette's is at the more severe end of the spectrum of tic disorders; its diagnosis requires multiple motor tics and at least one vocal tic to be present for more than a year. Tics are sudden, repetitive, nonrhythmic movements that involve discrete muscle groups,[6] while vocal (phonic) tics involve laryngeal, pharyngeal, oral, nasal or respiratory muscles to produce sounds.[7][8] The tics must not be explained by other medical conditions or substance use.[9] Other conditions on the spectrum include persistent (chronic) motor or vocal tics, in which one type of tic (motor or vocal, but not both) has been present for more than a year; and provisional tic disorder, in which motor or vocal tics have been present for less than one year.[10][11] The fifth edition of the DSM replaced what had been called transient tic disorder with provisional tic disorder, recognizing that "transient" can only be defined in retrospect.[12][13][14] Some experts believe that TS and persistent (chronic) motor or vocal tic disorder should be considered the same condition, because vocal tics are also motor tics in the sense that they are muscular contractions of nasal or respiratory muscles.[4][11] Tic disorders are defined only slightly differently by the World Health Organization (WHO);[3] in its ICD-10, the International Statistical Classification of Diseases and Related Health Problems, TS is described as "combined vocal and multiple motor tic disorder [de la Tourette]", code F95.2 in chapter V, mental and behavioural disorders,[15] equivalent to 307.23 in DSM-5, Tourette's disorder.[5] Most published research on TS originates in the United States, and in international research the DSM is preferred over the WHO classification.[12] Genetic studies indicate that tic disorders cover a spectrum that is not recognized by the clear-cut distinctions in the current diagnostic framework.[9] Studies have suggested since 2008 that Tourette's is not a unitary condition with a distinct mechanism as described in the existing classification systems; the studies suggest instead that subtypes should be recognized to distinguish "pure TS" from TS that is accompanied by attention deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD) or other disorders.[3][9][10] Elucidation of these subtypes awaits fuller understanding of the genetic and other causes of tic disorders (similar to the subtypes established for other conditions, for example, in distinguishing type 1 and type 2 diabetes).[12] ## Characteristics ### Tics Play media Examples of tics Tics are movements or sounds that take place "intermittently and unpredictably out of a background of normal motor activity",[16] having the appearance of "normal behaviors gone wrong".[17] The tics associated with Tourette's wax and wane; they change in number, frequency, severity and anatomical location, and each person experiences a unique pattern of fluctuation in their severity and frequency. Tics may also occur in "bouts of bouts", which also vary among people.[18] The variation in tic severity may occur over hours, days, or weeks.[10] Tics may increase when someone is experiencing stress, fatigue, anxiety, or illness,[9][19] or when engaged in relaxing activities like watching TV. They sometimes decrease when an individual is engrossed in or focused on an activity like playing a musical instrument.[9][20] In contrast to the abnormal movements associated with other movement disorders such as choreas, dystonias, myoclonus, and dyskinesias, the tics of Tourette's are nonrhythmic, temporarily suppressible, and often preceded by an unwanted urge.[18][21] The ability to suppress tics varies among individuals, and may be more developed in adults than children.[22] People with tics are sometimes able to suppress them for limited periods of time, but doing so often results in tension or mental exhaustion.[1][23] People with Tourette's may seek a secluded spot to release the suppressed urge, or there may be a marked increase in tics after a period of suppression at school or work.[10][17] Children may suppress tics while in the doctor's office, so they may need to be observed when not aware of being watched.[24] Over time, about 90% of individuals with Tourette's feel an urge preceding the tic,[10] similar to the urge to sneeze or scratch an itch. The urges and sensations that precede the expression of a tic are referred to as premonitory sensory phenomena or premonitory urges. These urges may be physical or mental.[25] People describe the urge to express the tic as a buildup of tension, pressure, or energy[26][27] which they ultimately choose consciously to release, as if they "had to do it"[28] to relieve the sensation[26] or until it feels "just right".[28][29] Examples of this urge are the feeling of having something in one's throat, or a localized discomfort in the shoulders, which lead to the need to clear one's throat or shrug the shoulders. The actual tic may be felt as relieving this tension or sensation, similar to scratching an itch or blinking to relieve an uncomfortable feeling in the eye. Because of the urges that precede them, tics are described as semi-voluntary or "unvoluntary",[1][16] rather than specifically involuntary; they may be experienced as a voluntary, suppressible response to the unwanted premonitory urge.[18][20] Some people with Tourette's may not be aware of the premonitory urge associated with tics. Children may be less aware of it than are adults,[10] but their awareness tends to increase with maturity;[16] by the age of ten, most children recognize the premonitory urge.[20] Complex tics related to speech include coprolalia, echolalia and palilalia. Coprolalia is the spontaneous utterance of socially objectionable or taboo words or phrases. Although it is the most publicized symptom of Tourette's, only about 10% of people with Tourette's exhibit it, and it is not required for a diagnosis.[1][30] Echolalia (repeating the words of others) and palilalia (repeating one's own words) occur in a minority of cases.[31] Complex motor tics include copropraxia (obscene or forbidden gestures, or inappropriate touching), echopraxia (repetition or imitation of another person's actions) and palipraxia (repeating one's own movements).[22] ### Onset and progression There is no typical case of Tourette syndrome,[32] but the age of onset and the severity of symptoms follow a fairly reliable course. Although onset may occur anytime before eighteen years, the typical age of onset of tics is from five to seven, and is usually before adolescence.[1] A 1998 study from the Yale Child Study Center showed that tic severity increased with age until it reached its highest point between ages eight and twelve.[33] Severity declines steadily for most children as they pass through adolescence, when half to two-thirds of children see a dramatic decrease in tics.[34] The first tics to appear usually affect the head, face, and shoulders, and include blinking, facial movements, sniffing and throat clearing.[10] Vocal tics often appear months or years after motor tics but can appear first.[11][12] Among people who experience more severe tics, complex tics may develop, including "arm straightening, touching, tapping, jumping, hopping and twirling".[10] There are different movements in contrasting disorders (for example, the autism spectrum disorders), such as self-stimulation and stereotypies. These stereotyped movements typically have an earlier age of onset; are more symmetrical, rhythmical and bilateral; and involve the extremities (for example, flapping the hands).[35] The severity of symptoms varies widely among people with Tourette's, and many cases may be undetected.[1][3][11][31] Most cases are mild and almost unnoticeable;[36][37] many people with TS may not realize they have tics. Because tics are more commonly expressed in private, Tourette syndrome may go unrecognized,[38] and casual observers might not notice tics.[30][39][40] Most adults with TS have mild symptoms and do not seek medical attention.[1] While tics subside for the majority after adolescence, some of the "most severe and debilitating forms of tic disorder are encountered" in adults.[41] In some cases, what appear to be adult-onset tics can be childhood tics re-surfacing.[41] ### Co-occurring conditions André Malraux (center) was a French Minister of Culture, author and adventurer who may have had Tourette syndrome.[42][43][44] Because people with milder symptoms are unlikely to be referred to specialty clinics, studies of Tourette's have an inherent bias towards more severe cases.[45] When symptoms are severe enough to warrant referral to clinics, ADHD and OCD are often also found.[1] In specialty clinics, 30% of those with TS also have mood or anxiety disorders or disruptive behaviors.[10][46] In the absence of ADHD, tic disorders do not appear to be associated with disruptive behavior or functional impairment,[47] while impairment in school, family, or peer relations is greater in those who have more comorbid conditions.[17][48] When ADHD is present along with tics, the occurrence of conduct disorder and oppositional defiant disorder increases.[10] Aggressive behaviors and angry outbursts in people with TS are not well understood; they are not associated with severe tics, but are connected with the presence of ADHD.[49] ADHD may also contribute to higher rates of anxiety, and aggression and anger control problems are more likely when both OCD and ADHD co-occur with Tourette's.[41] Compulsions that resemble tics are present in some individuals with OCD; "tic-related OCD" is hypothesized to be a subgroup of OCD, distinguished from non-tic related OCD by the type and nature of obsessions and compulsions.[50] Compared to the more typical compulsions of OCD without tics that relate to contamination, tic-related OCD presents with more "counting, aggressive thoughts, symmetry and touching" compulsions.[10] Compulsions associated with OCD without tics are usually related to obsessions and anxiety, while those in tic-related OCD are more likely to be a response to a premonitory urge.[10] There are increased rates of anxiety and depression in those adults with TS who also have OCD.[41] Among individuals with TS studied in clinics, between 2.9% and 20% had autism spectrum disorders,[51] but one study indicates that a high association of autism and TS may be partly due to difficulties distinguishing between tics and tic-like behaviors or OCD symptoms seen in people with autism.[52] Not all people with Tourette's have ADHD or OCD or other comorbid conditions, and estimates of the rate of pure TS or TS-only vary from 15% to 57%;[a] in clinical populations, a high percentage of those under care do have ADHD.[29][53] Children and adolescents with pure TS are not significantly different from their peers without TS on ratings of aggressive behaviors or conduct disorders, or on measures of social adaptation.[3] Similarly, adults with pure TS do not appear to have the social difficulties present in those with TS plus ADHD.[3] Among those with an older age of onset, more substance abuse and mood disorders are found, and there may be self-injurious tics. Adults who have severe, often treatment-resistant tics are more likely to also have mood disorders and OCD.[41] Coprolalia is more likely in people with severe tics plus multiple comorbid conditions.[22] ### Neuropsychological function There are no major impairments in neuropsychological function among people with Tourette's, but conditions that occur along with tics can cause variation in neurocognitive function. A better understanding of comorbid conditions is needed to untangle any neuropsychological differences between TS-only individuals and those with comorbid conditions.[48] Only slight impairments are found in intellectual ability, attentional ability, and nonverbal memory—but ADHD, other comorbid disorders, or tic severity could account for these differences. In contrast with earlier findings, visual motor integration and visuoconstructive skills are not found to be impaired, while comorbid conditions may have a small effect on motor skills. Comorbid conditions and severity of tics may account for variable results in verbal fluency, which can be slightly impaired. There might be slight impairment in social cognition, but not in the ability to plan or make decisions.[48] Children with TS-only do not show cognitive deficits. They are faster than average for their age on timed tests of motor coordination, and constant tic suppression may lead to an advantage in switching between tasks because of increased inhibitory control.[3][55] Learning disabilities may be present, but whether they are due to tics or comorbid conditions is controversial; older studies that reported higher rates of learning disability did not control well for the presence of comorbid conditions.[56] There are often difficulties with handwriting, and disabilities in written expression and math are reported in those with TS plus other conditions.[56] ## Causes Main article: Causes and origins of Tourette syndrome The exact cause of Tourette's is unknown, but it is well established that both genetic and environmental factors are involved.[9][10][57] Genetic epidemiology studies have shown that Tourette's is highly heritable,[58] and 10 to 100 times more likely to be found among close family members than in the general population.[59] The exact mode of inheritance is not known; no single gene has been identified, and hundreds of genes are likely involved.[58][59][60] Genome-wide association studies were published in 2013[1] and 2015[10] in which no finding reached a threshold for significance.[1] Twin studies show that 50 to 77% of identical twins share a TS diagnosis, while only 10 to 23% of fraternal twins do.[9] But not everyone who inherits the genetic vulnerability will show symptoms.[61][62] A few rare highly penetrant genetic mutations have been found that explain only a small number of cases in single families (the SLITRK1, HDC, and CNTNAP2 genes).[63] Psychosocial or other non-genetic factors—while not causing Tourette's—can affect the severity of TS in vulnerable individuals and influence the expression of the inherited genes.[3][32][57][59] Pre-natal and peri-natal events increase the risk that a tic disorder or comorbid OCD will be expressed in those with the genetic vulnerability. These include paternal age; forceps delivery; stress or severe nausea during pregnancy; and use of tobacco, caffeine, alcohol,[3] and cannabis during pregnancy.[1] Babies who are born premature with low birthweight, or who have low Apgar scores, are also at increased risk; in premature twins, the lower birthweight twin is more likely to develop TS.[3] Autoimmune processes may affect the onset of tics or exacerbate them. Both OCD and tic disorders may arise in a subset of children as a result of a post-streptococcal autoimmune process.[36] Its potential effect is described by the controversial hypothesis called PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), which proposes five criteria for diagnosis in children.[64][65] PANDAS and the newer PANS (pediatric acute-onset neuropsychiatric syndrome) hypotheses are the focus of clinical and laboratory research, but remain unproven. There is also a broader hypothesis that links immune-system abnormalities and immune dysregulation with TS.[10][36] Some forms of OCD may be genetically linked to Tourette's,[29] although the genetic factors in OCD with and without tics may differ.[9] The genetic relationship of ADHD to Tourette syndrome, however, has not been fully established.[55][66][46] A genetic link between autism and Tourette's has not been established as of 2017.[41] ## Mechanism The basal ganglia and thalamus are implicated in Tourette syndrome. The exact mechanism affecting the inherited vulnerability to Tourette's is not well established.[9] Tics are believed to result from dysfunction in cortical and subcortical brain regions: the thalamus, basal ganglia and frontal cortex.[67] Neuroanatomic models suggest failures in circuits connecting the brain's cortex and subcortex;[32] imaging techniques implicate the frontal cortex and basal ganglia.[60] In the 2010s, neuroimaging and postmortem brain studies, as well as animal and genetic studies,[48][68] made progress towards better understanding the neurobiological mechanisms leading to Tourette's.[48] These studies support the basal ganglia model, in which neurons in the striatum are activated and inhibit outputs from the basal ganglia.[49] Cortico-striato-thalamo-cortical (CSTC) circuits, or neural pathways, provide inputs to the basal ganglia from the cortex. These circuits connect the basal ganglia with other areas of the brain to transfer information that regulates planning and control of movements, behavior, decision-making, and learning.[48] Behavior is regulated by cross-connections that "allow the integration of information" from these circuits.[48] Involuntary movements may result from impairments in these CSTC circuits,[48] including the sensorimotor, limbic, language and decision making pathways. Abnormalities in these circuits may be responsible for tics and premonitory urges.[69] The caudate nuclei may be smaller in subjects with tics compared to those without tics, supporting the hypothesis of pathology in CSTC circuits in Tourette's.[48] The ability to suppress tics depends on brain circuits that "regulate response inhibition and cognitive control of motor behavior".[68] Children with TS are found to have a larger prefrontal cortex, which may be the result of an adaptation to help regulate tics.[68] It is likely that tics decrease with age as the capacity of the frontal cortex increases.[68] Cortico-basal ganglia (CBG) circuits may also be impaired, contributing to "sensory, limbic and executive" features.[10] The release of dopamine in the basal ganglia is higher in people with Tourette's, implicating biochemical changes from "overactive and dysregulated dopaminergic transmissions".[57] Histamine and the H3 receptor may play a role in the alterations of neural circuitry.[10][70][71][72] A reduced level of histamine in the H3 receptor may result in an increase in other neurotransmitters, causing tics.[73] Postmortem studies have also implicated "dysregulation of neuroinflammatory processes".[9] ## Diagnosis According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Tourette's may be diagnosed when a person exhibits both multiple motor tics and one or more vocal tics over a period of one year. The motor and vocal tics need not be concurrent. The onset must have occurred before the age of 18 and cannot be attributed to the effects of another condition or substance (such as cocaine).[5] Hence, other medical conditions that include tics or tic-like movements—for example, autism or other causes of tics—must be ruled out.[74] There are no specific medical or screening tests that can be used to diagnose Tourette's;[29] the diagnosis is usually made based on observation of the individual's symptoms and family history,[30] and after ruling out secondary causes of tic disorders.[75] Tics that may appear to mimic those of Tourette's—but are associated with disorders other than Tourette's—are known as tourettism.[76] Most of these conditions, including dystonias, choreas, and other genetic conditions, are rarer than tic disorders and a thorough history and examination may be enough to rule them out without medical or screening tests.[1][32][76] Delayed diagnosis often occurs because professionals mistakenly believe that TS is rare, always involves coprolalia, or must be severely impairing.[77] The DSM has recognized since 2000 that many individuals with Tourette's do not have significant impairment;[12][74][78] diagnosis does not require the presence of coprolalia or a comorbid condition, such as ADHD or OCD.[30][77] Tourette's may be misdiagnosed because of the wide expression of severity, ranging from mild (in the majority of cases) or moderate, to severe (the rare but more widely recognized and publicized cases).[33] About 20% of people with Tourette syndrome do not realize that they have tics.[32] Tics that appear early in the course of TS are often confused with allergies, asthma, vision problems, and other conditions. Pediatricians, allergists and ophthalmologists are among the first to identify a child as having tics,[31] although the majority of tics are first identified by the child's parents.[77] Coughing, blinking, and tics that mimic unrelated conditions such as asthma are commonly misdiagnosed.[30] In the UK, there is an average delay of three years between symptom onset and diagnosis.[3] ### Assessment and screening for other conditions Main screening and assessment tools[79][80] * Yale Global Tic Severity Scale (YGTSS), recommended in international guidelines to assess "frequency, intensity, complexity, distribution, interference and impairment" of or due to tics * Tourette Syndrome Clinical Global Impression (TS–CGI) and Shapiro TS Severity Scale (STSS), for a briefer assessment of tics than YGTSS * Tourette's Disorder Scale (TODS), to assess tics and comorbidities * Premonitory Urge for Tics Scale (PUTS), for individuals over age ten * Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey (MOVES), to evaluate complex tics and other behaviors * Autism—Tics, AD/HD, and other Comorbities (A–TAC), to screen for other conditions Patients referred for a tic disorder are assessed based on their family history of tics, vulnerability to ADHD, obsessive–compulsive symptoms, and a number of other chronic medical, psychiatric and neurological conditions.[81][82] In individuals with a typical onset and a family history of tics or OCD, a basic physical and neurological examination may be sufficient.[83] If another condition might better explain the tics, tests may be done; for example, if there is diagnostic confusion between tics and seizure activity, an EEG may be ordered. An MRI can rule out brain abnormalities,[81] but such brain imaging studies are not usually warranted.[81] Measuring thyroid-stimulating hormone blood levels can rule out hypothyroidism, which can be a cause of tics. In teenagers and adults presenting with a sudden onset of tics and other behavioral symptoms, a urine drug screen for cocaine and stimulants might be necessary. If there is a family history of liver disease, serum copper and ceruloplasmin levels can rule out Wilson's disease.[83] Although not all those with Tourette's have comorbid conditions, most presenting for clinical care exhibit symptoms of other conditions along with their tics.[55] ADHD and OCD are the most common, but autism spectrum disorders or anxiety, mood, personality, oppositional defiant, and conduct disorders may also be present.[7] Learning disabilities and sleep disorders may be present;[30] higher rates of sleep disturbance and migraine than in the general population are reported.[84] A thorough evaluation for comorbidity is called for when symptoms and impairment warrant,[82][83] and careful assessment of people with TS includes comprehensive screening for these conditions.[7][59] Comorbid conditions such as OCD and ADHD can be more impairing than tics, and cause greater impact on overall functioning.[4][32] Disruptive behaviors, impaired functioning, or cognitive impairment in individuals with comorbid Tourette's and ADHD may be accounted for by the ADHD, highlighting the importance of identifying comorbid conditions.[10][29][30][85] Children and adolescents with TS who have learning difficulties are candidates for psychoeducational testing, particularly if the child also has ADHD.[81][82] ## Management Main article: Management of Tourette syndrome There is no cure for Tourette's.[86] There is no single most effective medication,[1] and no one medication effectively treats all symptoms. Most medications prescribed for tics have not been approved for that use, and no medication is without the risk of significant adverse effects.[4][30][87] Treatment is focused on identifying the most troubling or impairing symptoms and helping the individual manage them.[30] Because comorbid conditions are often a larger source of impairment than tics,[81] they are a priority in treatment.[88] The management of Tourette's is individualized and involves shared decision-making between the clinician, patient, family and caregivers.[88][89] Practice guidelines for the treatment of tics were published by the American Academy of Neurology in 2019.[88] Education, reassurance and psychobehavioral therapy are often sufficient for the majority of cases.[1][30][90] In particular, psychoeducation targeting the patient and their family and surrounding community is a key management strategy.[91][92] Watchful waiting "is an acceptable approach" for those who are not functionally impaired.[88] Symptom management may include behavioral, psychological and pharmacological therapies. Pharmacological intervention is reserved for more severe symptoms, while psychotherapy or cognitive behavioral therapy (CBT) may ameliorate depression and social isolation, and improve family support.[30] The decision to use behavioral or pharmacological treatment is "usually made after the educational and supportive interventions have been in place for a period of months, and it is clear that the tic symptoms are persistently severe and are themselves a source of impairment in terms of self-esteem, relationships with the family or peers, or school performance".[80] ### Psychoeducation and social support Further information: Management of Tourette syndrome § Psychoeducation and social support Knowledge, education and understanding are uppermost in management plans for tic disorders,[30] and psychoeducation is the first step.[93] A child's parents are typically the first to notice their tics;[77] they may feel worried, imagine that they are somehow responsible, or feel burdened by misinformation about Tourette's.[93] Effectively educating parents about the diagnosis and providing social support can ease their anxiety. This support can also lower the chance that their child will be unnecessarily medicated[94] or experience an exacerbation of tics due to their parents' emotional state.[7] People with Tourette's may suffer socially if their tics are viewed as "bizarre". If a child has disabling tics, or tics that interfere with social or academic functioning, supportive psychotherapy or school accommodations can be helpful.[75] Even children with milder tics may be angry, depressed or have low self-esteem as a result of increased teasing, bullying, rejection by peers or social stigmatization, and this can lead to social withdrawal. Some children feel empowered by presenting a peer awareness program to their classmates.[59][89][95] It can be helpful to educate teachers and school staff about typical tics, how they fluctuate during the day, how they impact the child, and how to distinguish tics from naughty behavior. By learning to identify tics, adults can refrain from asking or expecting a child to stop ticcing,[23][95] because "tic suppression can be exhausting, unpleasant, and attention-demanding and can result in a subsequent rebound bout of tics".[23] Adults with TS may withdraw socially to avoid stigmatization and discrimination because of their tics.[96] Depending on their country's healthcare system, they may receive social services or help from support groups.[97] ### Behavioral Further information: Management of Tourette syndrome § Behavioral Behavioral therapies using habit reversal training (HRT) and exposure and response prevention (ERP) are first-line interventions in the management of Tourette syndrome,[98] and have been shown to be effective.[9] Because tics are somewhat suppressible, when people with TS are aware of the premonitory urge that precedes a tic, they can be trained to develop a response to the urge that competes with the tic.[10][98] Comprehensive behavioral intervention for tics (CBIT) is based on HRT, the best researched behavioral therapy for tics.[98] TS experts debate whether increasing a child's awareness of tics with HRT/CBIT (as opposed to ignoring tics) can lead to more tics later in life.[98] When disruptive behaviors related to comorbid conditions exist, anger control training and parent management training can be effective.[3][99][100] CBT is a useful treatment when OCD is present.[10] Relaxation techniques, such as exercise, yoga and meditation may be useful in relieving the stress that can aggravate tics. Beyond HRT, the majority of behavioral interventions for Tourette's (for example, relaxation training and biofeedback) have not been systematically evaluated and are not empirically supported.[101] ### Medication Further information: Management of Tourette syndrome § Medication Clonidine is one of the medications typically tried first when medication is needed for Tourette's.[102] It is available as a pill or a transdermal (skin) patch. Children with tics typically present when their tics are most severe, but because the condition waxes and wanes, medication is not started immediately or changed often.[32] Tics may subside with education, reassurance and a supportive environment.[1][59] When medication is used, the goal is not to eliminate symptoms. Instead, the lowest dose that manages symptoms without adverse effects is used, because adverse effects may be more disturbing than the symptoms being treated with medication.[32] The classes of medication with proven efficacy in treating tics—typical and atypical neuroleptics—can have long-term and short-term adverse effects.[59] Some antihypertensive agents are also used to treat tics; studies show variable efficacy but a lower side effect profile than the neuroleptics.[9][102] The antihypertensives clonidine and guanfacine are typically tried first in children; they can also help with ADHD symptoms,[59][102] but there is less evidence that they are effective for adults.[1] The neuroleptics risperidone and aripiprazole are tried when antihypertensives are not effective,[4][59] and are generally tried first for adults.[1] The most effective medication for tics is haloperidol, but it has a higher risk of side effects.[59] Methylphenidate can be used to treat ADHD that co-occurs with tics, and can be used in combination with clonidine.[10][59] Selective serotonin reuptake inhibitors are used to manage anxiety and OCD.[10] ### Other Further information: Management of Tourette syndrome § Other Complementary and alternative medicine approaches, such as dietary modification, neurofeedback and allergy testing and control have popular appeal, but they have no proven benefit in the management of Tourette syndrome.[103][104] Despite this lack of evidence, up to two-thirds of parents, caregivers and individuals with TS use dietary approaches and alternative treatments and do not always inform their physicians.[19][89] There is low confidence that tics are reduced with tetrahydrocannabinol,[4] and insufficient evidence for other cannabis-based medications in the treatment of Tourette's.[88] There is no good evidence supporting the use of acupuncture or transcranial magnetic stimulation; neither is there evidence supporting intravenous immunoglobulin, plasma exchange, or antibiotics for the treatment of PANDAS.[3] Deep brain stimulation (DBS) has become a valid option for individuals with severe symptoms that do not respond to conventional therapy and management.[57] Selecting candidates who may benefit from DBS is challenging, and the appropriate lower age range for surgery is unclear.[7] The ideal brain location to target has not been identified as of 2019.[88][105] ### Pregnancy A quarter of women report that their tics increase before menstruation, however studies have not shown consistent evidence of a change in frequency or severity of tics related to pregnancy.[106][107] Overall, symptoms in women respond better to haloperidol than they do for men,[106] and one report found that haloperidol was the preferred medication during pregnancy,[107] to minimize the side effects in the mother, including low blood pressure, and anticholinergic effects.[108] Most women find they can withdraw from medication during pregnancy without much trouble.[107] ## Prognosis Tim Howard, described in 2019 by a staff writer for the Los Angeles Times as the "greatest goalkeeper in U.S. soccer history",[109] attributes his success in the sport to his Tourette's.[110] Tourette syndrome is a spectrum disorder—its severity ranges from mild to severe.[75] Symptoms typically subside as children pass through adolescence.[57] In a group of ten children at the average age of highest tic severity (around ten or eleven), almost four will see complete remission by adulthood. Another four will have minimal or mild tics in adulthood, but not complete remission. The remaining two will have moderate or severe tics as adults, but only rarely will their symptoms in adulthood be more severe than in childhood.[34] Regardless of symptom severity, individuals with Tourette's have a normal life span. Symptoms may be lifelong and chronic for some, but the condition is not degenerative or life-threatening.[111] Intelligence among those with pure TS follows a normal curve, although there may be small differences in intelligence in those with comorbid conditions.[56] The severity of tics early in life does not predict their severity in later life.[30] There is no reliable means of predicting the course of symptoms for a particular individual,[84] but the prognosis is generally favorable.[84] By the age of fourteen to sixteen, when the highest tic severity has typically passed, a more reliable prognosis might be made.[96] Tics may be at their highest severity when they are diagnosed, and often improve as an individual's family and friends come to better understand the condition. Studies report that almost eight out of ten children with Tourette's experience a reduction in the severity of their tics by adulthood,[10][34] and some adults who still have tics may not be aware that they have them. A study that used video to record tics in adults found that nine out of ten adults still had tics, and half of the adults who considered themselves tic-free displayed evidence of mild tics.[10][112] ### Quality of life People with Tourette's are affected by both the consequences of living with tics as well as efforts to suppress them.[113] Head and eye tics can interfere with reading or lead to headaches, and forceful tics can lead to repetitive strain injury.[114] Severe tics can lead to pain or injuries; as an example, a rare cervical disc herniation was reported from a neck tic.[41][59] Some people may learn to camouflage socially inappropriate tics or channel the energy of their tics into a functional endeavor.[31] A supportive family and environment generally give those with Tourette's the skills to manage the disorder.[113][115][116] Outcomes in adulthood are associated more with the perceived significance of having severe tics as a child than with the actual severity of the tics. A person who was misunderstood, punished or teased at home or at school is likely to fare worse than a child who enjoyed an understanding environment.[31] The long-lasting effects of bullying and teasing can influence self-esteem, self-confidence, and even employment choices and opportunities.[113][117] Comorbid ADHD can severely affect the child's well-being in all realms, and extend into adulthood.[113] Factors impacting quality of life change over time, given the natural fluctuating course of tic disorders, the development of coping strategies, and a person's age. As ADHD symptoms improve with maturity, adults report less negative impact in their occupational lives than do children in their educational lives.[113] Tics have a greater impact on adults' psychosocial function, including financial burdens, than they do on children.[96] Adults are more likely to report a reduced quality of life due to depression or anxiety;[113] depression contributes a greater burden than tics to adults' quality of life compared to children.[96] As coping strategies become more effective with age, the impact of OCD symptoms seems to diminish.[113] ## Epidemiology Tourette syndrome is a common but underdiagnosed condition that reaches across all social, racial and ethnic groups.[3][29][30][118] It is three to four times more frequent in males than in females.[53] Observed prevalence rates are higher among children than adults because tics tend to remit or subside with maturity and a diagnosis may no longer be warranted for many adults.[33] Up to 1% of the overall population experiences tic disorders, including chronic tics and transient (provisional or unspecified) tics in childhood.[47] Chronic tics affect 5% of children and transient tics affect up to 20%.[53][100] Most individuals with tics do not seek a diagnosis, so epidemiological studies of TS "reflect a strong ascertainment bias" towards those with co-occurring conditions.[60] The reported prevalence of TS varies "according to the source, age, and sex of the sample; the ascertainment procedures; and diagnostic system",[29] with a range reported between 0.15% and 3.0% for children and adolescents.[53] Sukhodolsky, et al. wrote in 2017 that the best estimate of TS prevalence in children was 1.4%.[53] Both Robertson[36] and Stern state that the prevalence in children is 1%.[1] According to turn of the century census data, these prevalence estimates translate to half a million children in the US with TS and half a million people in the UK with TS, although symptoms in many older individuals would be almost unrecognizable.[b] Tourette syndrome was once thought to be rare: in 1972, the US National Institutes of Health (NIH) believed there were fewer than 100 cases in the United States,[119] and a 1973 registry reported only 485 cases worldwide.[120] However, numerous studies published since 2000 have consistently demonstrated that the prevalence is much higher.[121] Recognizing that tics may often be undiagnosed and hard to detect,[c] newer studies use direct classroom observation and multiple informants (parents, teachers and trained observers), and therefore record more cases than older studies.[90][124] As the diagnostic threshold and assessment methodology have moved towards recognition of milder cases, the estimated prevalence has increased.[121] ## History Main article: History of Tourette syndrome Jean-Martin Charcot was a French neurologist and professor who named Tourette syndrome for his intern, Georges Gilles de la Tourette. In A Clinical Lesson at the Salpêtrière (1887), André Brouillet portrays a medical lecture by Charcot (the central standing figure) and shows de la Tourette in the audience (seated in the first row, wearing an apron). A French doctor, Jean Marc Gaspard Itard, reported the first case of Tourette syndrome in 1825,[125] describing the Marquise de Dampierre, an important woman of nobility in her time.[126] In 1884, Jean-Martin Charcot, an influential French physician, assigned his student[127] and intern Georges Gilles de la Tourette, to study patients with movement disorders at the Salpêtrière Hospital, with the goal of defining a condition distinct from hysteria and chorea.[128] In 1885, Gilles de la Tourette published an account in Study of a Nervous Affliction of nine people with "convulsive tic disorder", concluding that a new clinical category should be defined.[129][130] The eponym was bestowed by Charcot after and on behalf of Gilles de la Tourette, who later became Charcot's senior resident.[24][131] Following the 19th-century descriptions, a psychogenic view prevailed and little progress was made in explaining or treating tics until well into the 20th century.[24] The possibility that movement disorders, including Tourette syndrome, might have an organic origin was raised when an encephalitis lethargica epidemic from 1918 to 1926 was linked to an increase in tic disorders.[24][132] During the 1960s and 1970s, as the beneficial effects of haloperidol on tics became known, the psychoanalytic approach to Tourette syndrome was questioned.[133] The turning point came in 1965, when Arthur K. Shapiro—described as "the father of modern tic disorder research"[134]—used haloperidol to treat a person with Tourette's, and published a paper criticizing the psychoanalytic approach.[132] In 1975, The New York Times headlined an article with "Bizarre outbursts of Tourette's disease victims linked to chemical disorder in brain", and Shapiro said: "The bizarre symptoms of this illness are rivaled only by the bizarre treatments used to treat it."[135] During the 1990s, a more neutral view of Tourette's emerged, in which a genetic predisposition is seen to interact with non-genetic and environmental factors.[24][136][137] The fourth revision of the DSM (DSM-IV) in 1994 added a diagnostic requirement for "marked distress or significant impairment in social, occupational, or other important areas of functioning", which led to an outcry from TS experts and researchers, who noted that many people were not even aware they had TS, nor were they distressed by their tics; clinicians and researchers resorted to using the older criteria in research and practice.[12] In 2000, the American Psychiatric Association revised its diagnostic criteria in the fourth text revision of the DSM (DSM-IV-TR) to remove the impairment requirement,[74] recognizing that clinicians often see people who have Tourette's without distress or impairment.[78] ## Society and culture Main article: Societal and cultural aspects of Tourette syndrome Samuel Johnson c. 1772\. Johnson is likely to have had Tourette syndrome. Not everyone with Tourette's wants treatment or a cure, especially if that means they may lose something else in the process.[93][138] The researchers Leckman and Cohen believe that there may be latent advantages associated with an individual's genetic vulnerability to developing Tourette syndrome that may have adaptive value, such as heightened awareness and increased attention to detail and surroundings.[139][140] Accomplished musicians, athletes, public speakers and professionals from all walks of life are found among people with Tourette's.[77][141] The athlete Tim Howard, described by the Chicago Tribune as the "rarest of creatures—an American soccer hero",[142] and by the Tourette Syndrome Association as the "most notable individual with Tourette Syndrome around the world",[143] says that his neurological makeup gave him an enhanced perception and an acute focus that contributed to his success on the field.[110] Samuel Johnson is a historical figure who likely had Tourette syndrome, as evidenced by the writings of his friend James Boswell.[144][145] Johnson wrote A Dictionary of the English Language in 1747, and was a prolific writer, poet, and critic. There is little support[146][147] for speculation that Mozart had Tourette's:[148] the potentially coprolalic aspect of vocal tics is not transferred to writing, so Mozart's scatological writings are not relevant; the composer's available medical history is not thorough; the side effects of other conditions may be misinterpreted; and "the evidence of motor tics in Mozart's life is doubtful".[149] Likely portrayals of TS or tic disorders in fiction predating Gilles de la Tourette's work are "Mr. Pancks" in Charles Dickens's Little Dorrit and "Nikolai Levin" in Leo Tolstoy's Anna Karenina.[150] The entertainment industry has been criticized for depicting those with Tourette syndrome as social misfits whose only tic is coprolalia, which has furthered the public's misunderstanding and stigmatization of those with Tourette's.[151][152][153] The coprolalic symptoms of Tourette's are also fodder for radio and television talk shows in the US[154] and for the British media.[155] High-profile media coverage focuses on treatments that do not have established safety or efficacy, such as deep brain stimulation, and alternative therapies involving unstudied efficacy and side effects are pursued by many parents.[156] ## Research directions Further information: History of Tourette syndrome § Research directions and controversies Research since 1999 has advanced knowledge of Tourette's in the areas of genetics, neuroimaging, neurophysiology, and neuropathology, but questions remain about how best to classify it and how closely it is related to other movement or psychiatric disorders.[3][9][10][11] Modeled after genetic breakthroughs seen with large-scale efforts in other neurodevelopmental disorders, three groups are collaborating in research of the genetics of Tourette's: * The Tourette Syndrome Association International Consortium for Genetics (TSAICG) * Tourette International Collaborative Genetics Study (TIC Genetics) * European Multicentre Tics in Children Studies (EMTICS) Compared to the progress made in gene discovery in certain neurodevelopmental or mental health disorders—autism, schizophrenia and bipolar disorder—the scale of related TS research is lagging in the United States due to funding.[157] ## Notes 1. ^ According to Dale (2017), over time, 15% of people with tics have only TS (85% of people with Tourette's will develop a co-occurring condition).[10] In a 2017 literature review, Sukhodolsky, et al. stated that 37% of individuals in clinical samples had pure TS.[53] Denckla (2006) reported that a review of patient records revealed that about 40% of people with Tourette's have TS-only.[54][55] Dure and DeWolfe (2006) reported that 57% of 656 individuals presenting with tic disorders had tics uncomplicated by other conditions.[17] 2. ^ A prevalence range of 0.1% to 1% yields an estimate of 53,000 to 530,000 school-age children with Tourette's in the United States, using 2000 census data.[47] In the United Kingdom, a prevalence estimate of 1.0% based on the 2001 census meant that about half a million people aged five or older would have Tourette's, although symptoms in older individuals would be almost unrecognizable.[37]Prevalence rates in special education populations are higher.[36] 3. ^ The discrepancy between current and prior prevalence estimates arises from several factors: the ascertainment bias caused by samples that were drawn from clinically referred cases; assessment methods that failed to detect milder cases; and the use of different diagnostic criteria and thresholds.[121] There were few broad-based community studies published before 2000, and most older epidemiological studies were based only on individuals referred to tertiary care or specialty clinics.[122] People with mild symptoms may not have sought treatment and physicians may have avoided an official diagnosis of TS in children due to concerns about stigmatization.[38] Studies are vulnerable to further error because tics vary in intensity and expression, are often intermittent, and are not always recognized by clinicians, individuals with TS, family members, friends or teachers.[32][123] ## References 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 Stern JS (August 2018). "Tourette's syndrome and its borderland" (PDF). Pract Neurol (Historical review). 18 (4): 262–70. doi:10.1136/practneurol-2017-001755. PMID 29636375. 2. ^ a b c "Tourette syndrome fact sheet". National Institute of Neurological Disorders and Stroke. July 6, 2018. Archived from the original on December 1, 2018. Retrieved November 30, 2018. 3. ^ a b c d e f g h i j k l m n o Hollis C, Pennant M, Cuenca J, et al. (January 2016). "Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis". Health Technology Assessment. Southampton (UK): NIHR Journals Library. 20 (4): 1–450. doi:10.3310/hta20040. ISSN 1366-5278. 4. ^ a b c d e f Pringsheim T, Holler-Managan Y, Okun MS, et al. (May 2019). "Comprehensive systematic review summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders". Neurology (Review). 92 (19): 907–15. doi:10.1212/WNL.0000000000007467. PMC 6537130. PMID 31061209. 5. ^ a b c "Tourette's Disorder, 307.23 (F95.2)". Diagnostic and Statistical Manual of Mental Disorders (5th ed.). American Psychiatric Association. 2013. p. 81. 6. ^ Martino D, Hedderly T (February 2019). "Tics and stereotypies: A comparative clinical review". Parkinsonism Relat. Disord. (Review). 59: 117–24. doi:10.1016/j.parkreldis.2019.02.005. PMID 30773283. 7. ^ a b c d e Martino D, Pringsheim TM (February 2018). "Tourette syndrome and other chronic tic disorders: an update on clinical management". Expert Rev Neurother (Review). 18 (2): 125–37. doi:10.1080/14737175.2018.1413938. PMID 29219631. 8. ^ Jankovic J (September 2017). "Tics and Tourette syndrome" (PDF). Practical Neurology: 22–24. Archived from the original (PDF) on March 24, 2019. Retrieved March 24, 2019. 9. ^ a b c d e f g h i j k l m Fernandez TV, State MW, Pittenger C (2018). "Tourette disorder and other tic disorders". Handbook of Clinical Neurology (Review). 147: 343–54. doi:10.1016/B978-0-444-63233-3.00023-3. ISBN 978-0-444-63233-3. PMID 29325623. 10. ^ 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 Dale RC (December 2017). "Tics and Tourette: a clinical, pathophysiological and etiological review". Curr. Opin. Pediatr. (Review). 29 (6): 665–73. doi:10.1097/MOP.0000000000000546. PMID 28915150. 11. ^ a b c d e Sukhodolsky, et al (2017), p. 242. 12. ^ a b c d e f Robertson MM, Eapen V (October 2014). "Tourette's: syndrome, disorder or spectrum? Classificatory challenges and an appraisal of the DSM criteria" (PDF). Asian J Psychiatr (Review). 11: 106–13. doi:10.1016/j.ajp.2014.05.010. PMID 25453712. 13. ^ "Neurodevelopmental disorders". American Psychiatric Association. Archived from the original on May 10, 2011. Retrieved December 29, 2011. 14. ^ "Highlights of changes from DSM-IV-TR to DSM-5" (PDF). American Psychiatric Association. 2013. Archived from the original (PDF) on February 3, 2013. Retrieved June 5, 2013. 15. ^ "International Statistical Classification of Diseases and Related Health Problems 10th Revision: Chapter V: Mental and behavioural disorders". World Health Organization. 2010. Retrieved August 7, 2020. See also ICD version 2007. 16. ^ a b c "Definitions and classification of tic disorders. The Tourette Syndrome Classification Study Group". Arch. Neurol. (Research support). 50 (10): 1013–16. October 1993. doi:10.1001/archneur.1993.00540100012008. PMID 8215958. Archived from the original on April 26, 2006. 17. ^ a b c d Dure LS, DeWolfe J (2006). "Treatment of tics". Adv Neurol (Review). 99: 191–96. PMID 16536366. 18. ^ a b c Hashemiyoon R, Kuhn J, Visser-Vandewalle V (January 2017). "Putting the pieces together in Gilles de la Tourette Syndrome: exploring the link between clinical observations and the biological basis of dysfunction". Brain Topogr (Review). 30 (1): 3–29. doi:10.1007/s10548-016-0525-z. PMC 5219042. PMID 27783238. 19. ^ a b Ludlow AK, Rogers SL (March 2018). "Understanding the impact of diet and nutrition on symptoms of Tourette syndrome: A scoping review". J Child Health Care (Review). 22 (1): 68–83. doi:10.1177/1367493517748373. PMID 29268618. 20. ^ a b c Sukhodolsky, et al (2017), p. 243. 21. ^ Jankovic J (2001). "Differential diagnosis and etiology of tics". Adv Neurol (Review). 85: 15–29. PMID 11530424. 22. ^ a b c Ludolph AG, Roessner V, Münchau A, Müller-Vahl K (November 2012). "Tourette syndrome and other tic disorders in childhood, adolescence and adulthood". Dtsch Arztebl Int (Review). 109 (48): 821–28. doi:10.3238/arztebl.2012.0821. PMC 3523260. PMID 23248712. 23. ^ a b c Muller-Vahl KR (2013) in Martino D, Leckman JF, eds, p. 629. 24. ^ a b c d e Black KJ (March 30, 2007). "Tourette syndrome and other tic disorders". eMedicine. Archived from the original on August 22, 2009. Retrieved August 10, 2009. 25. ^ Miguel EC, do Rosário-Campos MC, Prado HS, et al. (February 2000). "Sensory phenomena in obsessive-compulsive disorder and Tourette's disorder". J Clin Psychiatry. 61 (2): 150–56, quiz 157. doi:10.4088/jcp.v61n0213. PMID 10732667. 26. ^ a b Prado HS, Rosário MC, Lee J, Hounie AG, Shavitt RG, Miguel EC (May 2008). "Sensory phenomena in obsessive-compulsive disorder and tic disorders: a review of the literature". CNS Spectr (Review and meta-anlysis). 13 (5): 425–32. doi:10.1017/s1092852900016606. PMID 18496480. Archived from the original on February 10, 2012. 27. ^ Bliss J (December 1980). "Sensory experiences of Gilles de la Tourette syndrome". Arch. Gen. Psychiatry. 37 (12): 1343–47. doi:10.1001/archpsyc.1980.01780250029002. PMID 6934713. 28. ^ a b Kwak C, Dat Vuong K, Jankovic J (December 2003). "Premonitory sensory phenomenon in Tourette's syndrome". Mov. Disord. 18 (12): 1530–33. doi:10.1002/mds.10618. PMID 14673893. 29. ^ a b c d e f g Swain JE, Scahill L, Lombroso PJ, King RA, Leckman JF (August 2007). "Tourette syndrome and tic disorders: a decade of progress". J Am Acad Child Adolesc Psychiatry (Review). 46 (8): 947–68. doi:10.1097/chi.0b013e318068fbcc. PMID 17667475. 30. ^ a b c d e f g h i j k l m n Singer HS (2011). "Tourette syndrome and other tic disorders". Hyperkinetic Movement Disorders (Historical review). Handbook of Clinical Neurology. 100. pp. 641–57. doi:10.1016/B978-0-444-52014-2.00046-X. ISBN 978-0-444-52014-2. PMID 21496613. Also see Singer HS (March 2005). "Tourette's syndrome: from behaviour to biology". Lancet Neurol (Review). 4 (3): 149–59. doi:10.1016/S1474-4422(05)01012-4. PMID 15721825. 31. ^ a b c d e Leckman JF, Bloch MH, King RA, Scahill L (2006). "Phenomenology of tics and natural history of tic disorders". Adv Neurol (Historical review). 99: 1–16. PMID 16536348. 32. ^ a b c d e f g h i Zinner SH (November 2000). "Tourette disorder". Pediatr Rev (Review). 21 (11): 372–83. doi:10.1542/pir.21-11-372. PMID 11077021. 33. ^ a b c Leckman JF, Zhang H, Vitale A, et al. (July 1998). "Course of tic severity in Tourette syndrome: the first two decades" (PDF). Pediatrics (Research support). 102 (1 Pt 1): 14–19. doi:10.1542/peds.102.1.14. PMID 9651407. Archived from the original (PDF) on January 13, 2012. 34. ^ a b c Fernandez TV, State MW, Pittenger C (2018). "Tourette disorder and other tic disorders". Handbook of Clinical Neurology (Review). 147: 343–54. doi:10.1016/B978-0-444-63233-3.00023-3. ISBN 978-0-444-63233-3. PMID 29325623. Citing Bloch MH (2013) in Martino D, Leckman JF, eds, p. 109: No tics when they reach adulthood, 37%; minimal 18%; mild 26%; moderate 14%; worse 5%. 35. ^ Rapin I (2001). "Autism spectrum disorders: relevance to Tourette syndrome". Adv Neurol (Review). 85: 89–101. PMID 11530449. 36. ^ a b c d e Robertson MM (February 2011). "Gilles de la Tourette syndrome: the complexities of phenotype and treatment". Br J Hosp Med (Lond). 72 (2): 100–07. doi:10.12968/hmed.2011.72.2.100. PMID 21378617. 37. ^ a b Robertson MM (November 2008). "The prevalence and epidemiology of Gilles de la Tourette syndrome. Part 1: the epidemiological and prevalence studies". J Psychosom Res (Review). 65 (5): 461–72. doi:10.1016/j.jpsychores.2008.03.006. PMID 18940377. 38. ^ a b Knight T, Steeves T, Day L, Lowerison M, Jette N, Pringsheim T (August 2012). "Prevalence of tic disorders: a systematic review and meta-analysis". Pediatr. Neurol. (Review). 47 (2): 77–90. doi:10.1016/j.pediatrneurol.2012.05.002. PMID 22759682. 39. ^ Kenney C, Kuo SH, Jimenez-Shahed J (March 2008). "Tourette's syndrome". Am Fam Physician (Review). 77 (5): 651–58. PMID 18350763. 40. ^ Black KJ, Black ER, Greene DJ, Schlaggar BL (2016). "Provisional Tic Disorder: What to tell parents when their child first starts ticcing". F1000Res (Review). 5. doi:10.12688/f1000research.8428.1. PMC 4850871. PMID 27158458. 41. ^ a b c d e f g Robertson MM, Eapen V, Singer HS, et al. (February 2017). "Gilles de la Tourette syndrome" (PDF). Nat Rev Dis Primers (Review). 3: 16097. doi:10.1038/nrdp.2016.97. PMID 28150698. 42. ^ Kammer T (2007). "Mozart in the neurological department – who has the tic?" (PDF). Front Neurol Neurosci (Historical biography). Frontiers of Neurology and Neuroscience. 22: 184–92. doi:10.1159/000102880. ISBN 978-3-8055-8265-0. PMID 17495512. Archived from the original (PDF) on February 7, 2012. 43. ^ Todd O (2005). Malraux: A Life. Knopf. 44. ^ Guidotti TL (May 1985). "André Malraux: a medical interpretation". J R Soc Med (Historical biography). 78 (5): 401–06. doi:10.1177/014107688507800511. PMC 1289723. PMID 3886907. 45. ^ Bloch, State, Pittenger 2011. See also Schapiro 2002 and Coffey BJ, Park KS (May 1997). "Behavioral and emotional aspects of Tourette syndrome". Neurol Clin (Review). 15 (2): 277–89. doi:10.1016/s0733-8619(05)70312-1. PMID 9115461. 46. ^ a b Hirschtritt ME, Lee PC, Pauls DL, et al. (April 2015). "Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in Tourette syndrome". JAMA Psychiatry. 72 (4): 325–33. doi:10.1001/jamapsychiatry.2014.2650. PMC 4446055. PMID 25671412. 47. ^ a b c Scahill L, Williams S, Schwab-Stone M, Applegate J, Leckman JF (2006). "Disruptive behavior problems in a community sample of children with tic disorders". Adv Neurol (Comparative study). 99: 184–90. PMID 16536365. 48. ^ a b c d e f g h i Morand-Beaulieu S, Leclerc JB, Valois P, et al. (August 2017). "A review of the neuropsychological dimensions of Tourette syndrome". Brain Sci (Review). 7 (8): 106. doi:10.3390/brainsci7080106. PMC 5575626. PMID 28820427. 49. ^ a b Sukhodolsky, et al (2017), p. 245. 50. ^ Hounie AG, do Rosario-Campos MC, Diniz JB, et al. (2006). "Obsessive-compulsive disorder in Tourette syndrome". Adv Neurol (Review). 99: 22–38. PMID 16536350. 51. ^ Cravedi E, Deniau E, Giannitelli M, et al. (2017). "Tourette syndrome and other neurodevelopmental disorders: a comprehensive review". Child Adolesc Psychiatry Ment Health (Review). 11: 59. doi:10.1186/s13034-017-0196-x. PMC 5715991. PMID 29225671. 52. ^ Darrow SM, Grados M, Sandor P, et al. (July 2017). "Autism spectrum symptoms in a Tourette's disorder sample". J Am Acad Child Adolesc Psychiatry (Comparative study). 56 (7): 610–17.e1. doi:10.1016/j.jaac.2017.05.002. PMC 5648014. PMID 28647013. 53. ^ a b c d e f Sukhodolsky, et al (2017), p. 244. 54. ^ Denckla MB (August 2006). "Attention-deficit hyperactivity disorder (ADHD) comorbidity: a case for "pure" Tourette syndrome?". J. Child Neurol. (Review). 21 (8): 701–03. doi:10.1177/08830738060210080701. PMID 16970871. 55. ^ a b c d Denckla MB (2006). "Attention deficit hyperactivity disorder: the childhood co-morbidity that most influences the disability burden in Tourette syndrome". Adv Neurol (Review). 99: 17–21. PMID 16536349. 56. ^ a b c Pruitt SK & Packer LE (2013) in Martino D, Leckman JF, eds, pp. 636–37. 57. ^ a b c d e Baldermann JC, Schüller T, Huys D, et al. (2016). "Deep brain stimulation for Tourette syndrome: a systematic review and meta-analysis". Brain Stimul (Review). 9 (2): 296–304. doi:10.1016/j.brs.2015.11.005. PMID 26827109. 58. ^ a b Cavanna AE (November 2018). "The neuropsychiatry of Gilles de la Tourette syndrome: The état de l'art". Rev. Neurol. (Paris) (Review). 174 (9): 621–27. doi:10.1016/j.neurol.2018.06.006. PMID 30098800. 59. ^ a b c d e f g h i j k l Efron D, Dale RC (October 2018). "Tics and Tourette syndrome". J Paediatr Child Health (Review). 54 (10): 1148–53. doi:10.1111/jpc.14165. PMID 30294996. 60. ^ a b c Bloch M, State M, Pittenger C (April 2011). "Recent advances in Tourette syndrome". Curr. Opin. Neurol. (Review). 24 (2): 119–25. doi:10.1097/WCO.0b013e328344648c. PMC 4065550. PMID 21386676. 61. ^ van de Wetering BJ, Heutink P (May 1993). "The genetics of the Gilles de la Tourette syndrome: a review". J. Lab. Clin. Med. (Review). 121 (5): 638–45. PMID 8478592. 62. ^ Paschou P (July 2013). "The genetic basis of Gilles de la Tourette Syndrome". Neurosci Biobehav Rev (Review). 37 (6): 1026–39. doi:10.1016/j.neubiorev.2013.01.016. PMID 23333760. 63. ^ Barnhill J, Bedford J, Crowley J, Soda T (2017). "A search for the common ground between Tic; Obsessive-compulsive and Autism Spectrum Disorders: part I, Tic disorders". AIMS Genet (Review). 4 (1): 32–46. doi:10.3934/genet.2017.1.32. PMC 6690237. PMID 31435502. 64. ^ "PANDAS". National Institutes of Health. Archived from the original on February 12, 2012. Retrieved November 25, 2006. 65. ^ Frick L, Pittenger C (2016). "Microglial dysregulation in OCD, Tourette syndrome, and PANDAS". J Immunol Res (Review). 2016: 8606057. doi:10.1155/2016/8606057. PMC 5174185. PMID 28053994. 66. ^ Hirschtritt ME, Darrow SM, et al. (January 2018). "Genetic and phenotypic overlap of specific obsessive-compulsive and attention-deficit/hyperactive subtypes with Tourette syndrome". Psychol Med. 48 (2): 279–93. doi:10.1017/S0033291717001672. PMID 28651666. 67. ^ Walkup, Mink & Hollenback (2006), p. xv. 68. ^ a b c d Sukhodolsky, et al (2017), p. 246. 69. ^ Cox JH, Seri S, Cavanna AE (May 2018). "Sensory aspects of Tourette syndrome" (PDF). Neurosci Biobehav Rev (Review). 88: 170–76. doi:10.1016/j.neubiorev.2018.03.016. PMID 29559228. 70. ^ Rapanelli M, Pittenger C (July 2016). "Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions". Neuropharmacology (Review). 106: 85–90. doi:10.1016/j.neuropharm.2015.08.019. PMID 26282120. 71. ^ Rapanelli M (February 2017). "The magnificent two: histamine and the H3 receptor as key modulators of striatal circuitry". Prog. Neuropsychopharmacol. Biol. Psychiatry (Review). 73: 36–40. doi:10.1016/j.pnpbp.2016.10.002. PMID 27773554. 72. ^ Bolam JP, Ellender TJ (July 2016). "Histamine and the striatum". Neuropharmacology (Review). 106: 74–84. doi:10.1016/j.neuropharm.2015.08.013. PMC 4917894. PMID 26275849. 73. ^ Sadek B, Saad A, Sadeq A, Jalal F, Stark H (October 2016). "Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases". Behav. Brain Res. (Review). 312: 415–30. doi:10.1016/j.bbr.2016.06.051. PMID 27363923. 74. ^ a b c Walkup JT, Ferrão Y, Leckman JF, Stein DJ, Singer H (June 2010). "Tic disorders: some key issues for DSM-V" (PDF). Depress Anxiety (Review). 27 (6): 600–10. doi:10.1002/da.20711. PMID 20533370. Archived from the original (PDF) on January 20, 2012. 75. ^ a b c "What is Tourette syndrome?" (PDF). Tourette Association of America. Retrieved January 19, 2020. 76. ^ a b Mejia NI, Jankovic J (March 2005). "Secondary tics and tourettism" (PDF). Braz J Psychiatry. 27 (1): 11–17. doi:10.1590/s1516-44462005000100006. PMID 15867978. Archived from the original (PDF) on June 28, 2007. 77. ^ a b c d e Müller-Vahl KR (2013) in Martino D, Leckman JF, eds, p. 625. 78. ^ a b "Summary of Practice: Relevant changes to DSM-IV-TR". American Psychiatric Association. Archived from the original on May 11, 2008. Retrieved December 29, 2011. 79. ^ Martino D, Pringsheim TM, Cavanna AE, et al. (March 2017). "Systematic review of severity scales and screening instruments for tics: Critique and recommendations". Mov. Disord. (Review). 32 (3): 467–73. doi:10.1002/mds.26891. PMC 5482361. PMID 28071825. 80. ^ a b Sukhodolsky, et al (2017), p. 248. 81. ^ a b c d e Scahill L, Erenberg G, Berlin CM, et al. (April 2006). "Contemporary assessment and pharmacotherapy of Tourette syndrome". NeuroRx (Review). 3 (2): 192–206. doi:10.1016/j.nurx.2006.01.009. PMC 3593444. PMID 16554257. 82. ^ a b c Sukhodolsky, et al (2017), p. 247 83. ^ a b c Bagheri MM, Kerbeshian J, Burd L (April 1999). "Recognition and management of Tourette's syndrome and tic disorders". Am Fam Physician (Review). 59 (8): 2263–72, 2274. PMID 10221310. Archived from the original on March 31, 2005. 84. ^ a b c Singer HS (March 2005). "Tourette's syndrome: from behaviour to biology". Lancet Neurol (Review). 4 (3): 149–59. doi:10.1016/S1474-4422(05)01012-4. PMID 15721825. 85. ^ Spencer T, Biederman J, Harding M, et al. (October 1998). "Disentangling the overlap between Tourette's disorder and ADHD". J Child Psychol Psychiatry (Comparative study). 39 (7): 1037–44. doi:10.1111/1469-7610.00406. PMID 9804036. 86. ^ Morand-Beaulieu S, Leclerc JB (January 2020). "[Tourette syndrome: Research challenges to improve clinical practice]". Encephale (in French). doi:10.1016/j.encep.2019.10.002. PMID 32014239. 87. ^ "Tourette syndrome treatments". U.S. Centers for Disease Control and Prevention (CDC). 2019. Retrieved February 26, 2020. 88. ^ a b c d e f Pringsheim T, Okun MS, Müller-Vahl K, et al. (May 2019). "Practice guideline recommendations summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders". Neurology (Review). 92 (19): 896–906. doi:10.1212/WNL.0000000000007466. PMC 6537133. PMID 31061208. 89. ^ a b c Müller-Vahl KR (2013) in Martino D, Leckman JF, eds, p. 628. 90. ^ a b Stern JS, Burza S, Robertson MM (January 2005). "Gilles de la Tourette's syndrome and its impact in the UK". Postgrad Med J (Review). 81 (951): 12–19. doi:10.1136/pgmj.2004.023614. PMC 1743178. PMID 15640424. "Reassurance, explanation, supportive psychotherapy, and psychoeducation are important and ideally the treatment should be multidisciplinary. In mild cases the previous methods may be all that is required, supplemented with contact with the Tourette Syndrome Association where the patient or parents wish." 91. ^ Robertson MM (March 2000). "Tourette syndrome, associated conditions and the complexities of treatment" (PDF). Brain (Review). 123 (Pt 3): 425–62. doi:10.1093/brain/123.3.425. PMID 10686169. Archived from the original (PDF) on June 14, 2007. 92. ^ Peterson BS, Cohen DJ (1998). "The treatment of Tourette's syndrome: multimodal, developmental intervention". J Clin Psychiatry (Review). 59 (Suppl 1): 62–74. PMID 9448671. "Because of the understanding and hope that it provides, education is also the single most important treatment modality that we have in TS." Also see Zinner 2000, PMID 11077021. 93. ^ a b c Müller-Vahl KR (2013) in Martino D, Leckman JF, eds, pp. 623–24. 94. ^ Müller-Vahl KR (2013) in Martino D, Leckman JF, eds, p. 626. "Quite often, the unimpaired child receives medical treatment to reduce tics, when instead the parents should more appropriately receive psychoeducation and social support to better cope with the condition." 95. ^ a b Pruitt SK & Packer LE (2013) in Martino D, Leckman JF, eds, pp. 646–47. 96. ^ a b c d Müller-Vahl KR (2013) in Martino D, Leckman JF, eds, p. 627. 97. ^ Müller-Vahl KR (2013) in Martino D, Leckman JF, eds, p. 633. 98. ^ a b c d Fründt O, Woods D, Ganos C (April 2017). "Behavioral therapy for Tourette syndrome and chronic tic disorders". Neurol Clin Pract (Review). 7 (2): 148–56. doi:10.1212/CPJ.0000000000000348. PMC 5669407. PMID 29185535. 99. ^ Sudhodolsky, et al (2017), p. 250. 100. ^ a b Bloch MH, Leckman JF (December 2009). "Clinical course of Tourette syndrome". J Psychosom Res (Review). 67 (6): 497–501. doi:10.1016/j.jpsychores.2009.09.002. PMC 3974606. PMID 19913654. 101. ^ Woods DW, Himle MB, Conelea CA (2006). "Behavior therapy: other interventions for tic disorders". Adv Neurol (Review). 99: 234–40. PMID 16536371. 102. ^ a b c Sukhodolsky, et al (2017), p. 251. 103. ^ Zinner SH (August 2004). "Tourette syndrome—much more than tics" (PDF). Contemporary Pediatrics. 21 (8): 22–49. Archived from the original (PDF) on September 30, 2007. Retrieved May 20, 2019. 104. ^ Kumar A, Duda L, Mainali G, Asghar S, Byler D (2018). "A comprehensive review of Tourette syndrome and complementary alternative medicine". Curr Dev Disord Rep (Review). 5 (2): 95–100. doi:10.1007/s40474-018-0137-2. PMC 5932093. PMID 29755921. 105. ^ Viswanathan A, Jimenez-Shahed J, Baizabal Carvallo JF, Jankovic J (2012). "Deep brain stimulation for Tourette syndrome: target selection". Stereotact Funct Neurosurg (Review). 90 (4): 213–24. doi:10.1159/000337776. PMID 22699684. 106. ^ a b Rabin ML, Stevens-Haas C, Havrilla E, Devi T, Kurlan R (February 2014). "Movement disorders in women: a review". Mov. Disord. (Review). 29 (2): 177–83. doi:10.1002/mds.25723. PMID 24151214. 107. ^ a b c Kranick SM, Mowry EM, Colcher A, Horn S, Golbe LI (April 2010). "Movement disorders and pregnancy: a review of the literature". Mov. Disord. (Review). 25 (6): 665–71. doi:10.1002/mds.23071. PMID 20437535. 108. ^ Committee on Drugs: American Academy of Pediatrics (April 2000). "Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn". Pediatrics. 105 (4): 880–87. doi:10.1542/peds.105.4.880. PMID 10742343. 109. ^ Baxter K (October 5, 2019). "Column: Tim Howard, whose career is likely to end Sunday, will retire as the best U.S. goalkeeper ever". Los Angeles Times. Retrieved December 28, 2019. 110. ^ a b Howard T (December 6, 2014). "Tim Howard: Growing up with Tourette syndrome and my love of football". The Guardian. Archived from the original on November 15, 2016. Retrieved March 21, 2015. 111. ^ Novotny M, Valis M, Klimova B (2018). "Tourette syndrome: a mini-review". Front Neurol (Review). 9: 139. doi:10.3389/fneur.2018.00139. PMC 5854651. PMID 29593638. 112. ^ Pappert EJ, Goetz CG, Louis ED, Blasucci L, Leurgans S (October 2003). "Objective assessments of longitudinal outcome in Gilles de la Tourette's syndrome". Neurology. 61 (7): 936–40. doi:10.1212/01.wnl.0000086370.10186.7c. PMID 14557563. 113. ^ a b c d e f g Evans J, Seri S, Cavanna AE (September 2016). "The effects of Gilles de la Tourette syndrome and other chronic tic disorders on quality of life across the lifespan: a systematic review". Eur Child Adolesc Psychiatry (Review). 25 (9): 939–48. doi:10.1007/s00787-016-0823-8. PMC 4990617. PMID 26880181. 114. ^ Abi-Jaoude E, Kideckel D, Stephens R, et al. (2009). "Tourette syndrome: a model of integration". In Carlstedt RA (ed.). Handbook of integrative clinical psychology, psychiatry and behavioral medicine: perspectives, practices and research. New York (NY): Springer Publishing. p. 564. 115. ^ Leckman & Cohen (1999), p. 37. "For example, individuals who were misunderstood and punished at home and at school for their tics or who were teased mercilessly by peers and stigmatized by their communities will fare worse than a child whose interpersonal environment was more understanding and supportive." 116. ^ Cohen DJ, Leckman JF, Pauls D (1997). "Neuropsychiatric disorders of childhood: Tourette's syndrome as a model". Acta Paediatr Suppl. Scandinavian University Press. 422: 106–11. doi:10.1111/j.1651-2227.1997.tb18357.x. PMID 9298805. "The individuals with TS who do the best, we believe, are: those who have been able to feel relatively good about themselves and remain close to their families; those who have the capacity for humor and for friendship; those who are less burdened by troubles with attention and behavior, particularly aggression; and those who have not had development derailed by medication." 117. ^ Müller-Vahl KR (2013) in Martino D, Leckman JF, eds, p. 630. 118. ^ Gulati, S (2016). "Tics and Tourette Syndrome – Key Clinical Perspectives: Roger Freeman (ed)". Indian J Pediatr. 83 (11): 1361. doi:10.1007/s12098-016-2176-1. "Tic disorder is a common neurodevelopmental disorder of childhood. It is one of the commonest condition encountered by a pediatrician in office practice, especially in developed countries." 119. ^ Cohen, Jankovic & Goetz (2001), p. xviii. 120. ^ Abuzzahab FE, Anderson FO (June 1973). "Gilles de la Tourette's syndrome; international registry". Minn Med. 56 (6): 492–96. PMID 4514275. 121. ^ a b c Scahill L. "Epidemiology of tic disorders" (PDF). Medical letter: 2004 retrospective summary of TS literature. Tourette Syndrome Association. Archived from the original (PDF) on December 25, 2010. Retrieved June 11, 2007. 122. ^ Bloch, State, Pittenger 2011. See also Zohar AH, Apter A, King RA, et al (1999). "Epidemiological studies" in Leckman & Cohen (1999), pp. 177–92. 123. ^ Hawley JS (June 23, 2008). "Tourette syndrome". eMedicine. Archived from the original on August 4, 2009. Retrieved August 10, 2009. 124. ^ Leckman JF (November 2002). "Tourette's syndrome". Lancet (Review). 360 (9345): 1577–86. doi:10.1016/S0140-6736(02)11526-1. PMID 12443611. 125. ^ Itard J (1825). "Mémoire sur quelques functions involontaires des appareils de la locomotion, de la préhension et de la voix". Arch Gen Med. 8: 385–407. As cited in Newman S (September 2006). "'Study of several involuntary functions of the apparatus of movement, gripping, and voice' by Jean-Marc Gaspard Itard (1825)" (PDF). History of Psychiatry. 17 (67 Pt 3): 333–9. doi:10.1177/0957154X06067668. PMID 17214432. 126. ^ "What is Tourette syndrome?". Tourette Syndrome Association. Archived from the original on January 14, 2012. Retrieved January 14, 2012. 127. ^ Walusinski (2019), pp. xvii–xviii, 23. 128. ^ Rickards H, Cavanna AE (December 2009). "Gilles de la Tourette: the man behind the syndrome". Journal of Psychosomatic Research. 67 (6): 469–74. doi:10.1016/j.jpsychores.2009.07.019. PMID 19913650. 129. ^ Gilles de la Tourette G, Goetz CG, Llawans HL (1982). "Étude sur une affection nerveuse caractérisée par de l'incoordination motrice accompagnée d'echolalie et de coprolalie". Advances in Neurology: Gilles de la Tourette Syndrome. 35: 1–16. As discussed at Black KJ (March 30, 2007). "Tourette syndrome and other tic disorders". eMedicine. Archived from the original on August 22, 2009. Retrieved August 10, 2009. 130. ^ Robertson MM, Reinstein DZ (1991). "Convulsive tic disorder: Georges Gilles de la Tourette, Guinon and Grasset on the phenomenology and psychopathology of Gilles de la Tourette syndrome" (PDF). Behavioural Neurology. 4 (1): 29–56. doi:10.1155/1991/505791. PMID 24487352. 131. ^ Walusinski (2019), pp. xi, 398. "Interne: House physician or house officer. The internes lived at the hospital and had diagnostic and therapeutic responsibilities. Chef de Clinique: Senior house officer or resident. In 1889, when Gilles de la Tourette was Chef de Clinique under Charcot ... " 132. ^ a b Blue T (2002). Tourette syndrome. Essortment, Pagewise Inc. Retrieved on August 10, 2009. 133. ^ Rickards H, Hartley N, Robertson MM (September 1997). "Seignot's paper on the treatment of Tourette's syndrome with haloperidol. Classic Text No. 31". Hist Psychiatry (Historical biography). 8 (31 Pt 3): 433–36. doi:10.1177/0957154X9700803109. PMID 11619589. 134. ^ Gadow KD, Sverd J (2006). "Attention deficit hyperactivity disorder, chronic tic disorder, and methylphenidate". Adv Neurol (Review). 99: 197–207. PMID 16536367. 135. ^ Brody JE (May 29, 1975). "Bizarre outbursts of Tourette's disease victims linked to chemical disorder in brain". The New York Times. Retrieved January 19, 2020. 136. ^ Kushner HI (2000), pp. 142–43, 187, 204, 208–12. 137. ^ Cohen DJ, Leckman JF (January 1994). "Developmental psychopathology and neurobiology of Tourette's syndrome". J Am Acad Child Adolesc Psychiatry (Review). 33 (1): 2–15. doi:10.1097/00004583-199401000-00002. PMID 8138517. "[Pathogenesis of tic disorders involves] interactions among genetic factors, neurobiological substrates, and environmental factors in the production of the clinical phenotypes. The genetic vulnerability factors that underlie Tourette's syndrome and other tic disorders undoubtedly influence the structure and function of the brain, in turn producing clinical symptoms. Available evidence ... also indicates that a range of epigenetic or environmental factors ... are critically involved in the pathogenesis of these disorders." 138. ^ Leckman & Cohen (1999), p. 408. 139. ^ Leckman & Cohen (1999), pp. 18–19, 148–51, 408. 140. ^ Müller-Vahl KR (2013) in Martino D, Leckman JF, eds. p. 624."... a few 'positive' aspects may be closely linked to TS. People with TS, for example, may have positive personality characterisics and talents such as punctuality, correctness, conscientiousness, a sense of justice, quick comprehension, good intelligence, creativity, musicality, and athletic abilities. For that reason, some people with TS even hesitate when asked whether they wish the disorder would disappear completely." 141. ^ Portraits of adults with TS. Tourette Syndrome Association. Retrieved from July 16, 2011 archive.org version on December 21, 2011. 142. ^ Keilman J (January 22, 2015). "Reviews: The Game of Our Lives by David Goldblatt, The Keeper by Tim Howard". Chicago Tribune. Archived from the original on April 2, 2015. Retrieved March 21, 2015. 143. ^ Tim Howard receives first-ever Champion of Hope Award from the National Tourette Syndrome Association. Archived March 30, 2015, at the Wayback Machine Tourette Syndrome Association. October 14, 2014. Retrieved on March 21, 2015. 144. ^ Samuel Johnson. Tourette Syndrome Association. Retrieved from April 7, 2005 archive.org version on December 30, 2011. 145. ^ Pearce JM (July 1994). "Doctor Samuel Johnson: 'the great convulsionary' a victim of Gilles de la Tourette's syndrome". J R Soc Med (Historical biography). 87 (7): 396–99. PMC 1294650. PMID 8046726. 146. ^ Powell H, Kushner HI (2015). "Mozart at play: the limitations of attributing the etiology of genius to tourette syndrome and mental illness". Prog. Brain Res. (Historical biography). 216: 277–91. doi:10.1016/bs.pbr.2014.11.010. PMID 25684294. 147. ^ Bhattacharyya KB, Rai S (2015). "Famous people with Tourette's syndrome: Dr. Samuel Johnson (yes) & Wolfgang Amadeus Mozart (may be): Victims of Tourette's syndrome?". Ann Indian Acad Neurol. 18 (2): 157–61. doi:10.4103/0972-2327.145288. PMC 4445189. PMID 26019411. 148. ^ Simkin B (1992). "Mozart's scatological disorder". BMJ (Historical biography). 305 (6868): 1563–67. doi:10.1136/bmj.305.6868.1563. PMC 1884718. PMID 1286388. Also see: Simkin, Benjamin. Medical and musical byways of Mozartiana. Fithian Press. 2001. ISBN 1-56474-349-7 Review Archived December 7, 2005, at the Wayback Machine, Retrieved on May 14, 2007. 149. ^ Mozart: * Kammer T (2007). "Mozart in the neurological department – who has the tic?" (PDF). Front Neurol Neurosci (Historical biography). Frontiers of Neurology and Neuroscience. 22: 184–92. doi:10.1159/000102880. ISBN 978-3-8055-8265-0. PMID 17495512. Archived from the original (PDF) on February 7, 2012. * Ashoori A, Jankovic J (November 2007). "Mozart's movements and behaviour: a case of Tourette's syndrome?". J. Neurol. Neurosurg. Psychiatry (Historical biography). 78 (11): 1171–75. doi:10.1136/jnnp.2007.114520. PMC 2117611. PMID 17940168. * Sacks O (1992). "Tourette's syndrome and creativity". BMJ (Editorial comment). 305 (6868): 1515–16. doi:10.1136/bmj.305.6868.1515. PMC 1884721. PMID 1286364. 150. ^ Voss H (October 2012). "The representation of movement disorders in fictional literature". J. Neurol. Neurosurg. Psychiatry (Review). 83 (10): 994–99. doi:10.1136/jnnp-2012-302716. PMID 22752692. 151. ^ Calder-Sprackman S, Sutherland S, Doja A (March 2014). "Tourette syndrome in film and television" (PDF). The Canadian Journal of Neurological Sciences. 41 (2): 226–32. doi:10.1017/S0317167100016620. PMID 24534035. 152. ^ Lim Fat MJ, Sell E, Barrowman N, Doja A (2012). "Public perception of Tourette syndrome on YouTube". Journal of Child Neurology. 27 (8): 1011–16. CiteSeerX 10.1.1.997.9069. doi:10.1177/0883073811432294. PMID 22821136. 153. ^ Holtgren B (January 11, 2006). "Truth about Tourette's not what you think". Cincinnati Enquirer. "As medical problems go, Tourette's is, except in the most severe cases, about the most minor imaginable thing to have. ... the freak-show image, unfortunately, still prevails overwhelmingly. The blame for the warped perceptions lies overwhelmingly with the video media—the Internet, movies and TV. If you search for 'Tourette' on Google or YouTube, you'll get a gazillion hits that almost invariably show the most outrageously extreme examples of motor and vocal tics. Television, with notable exceptions such as Oprah, has sensationalized Tourette's so badly, for so long, that it seems beyond hope that most people will ever know the more prosaic truth." 154. ^ US media: * "Oprah and Dr. Laura" (Press release). Tourette Syndrome Association. May 31, 2001. Archived from the original on October 6, 2001. Retrieved December 21, 2011. * "Letter of response to Dr. Phil" (Press release). Tourette Syndrome Association. Archived from the original on August 31, 2008. Retrieved December 21, 2011. * "Letter of response to Garrison Keillor radio show" (Press release). Tourette Syndrome Association. Archived from the original on February 7, 2009. Retrieved December 21, 2011. 155. ^ Guldberg H (May 26, 2006). "Stop celebrating Tourette's". Spiked. Archived from the original on March 14, 2017. Retrieved December 26, 2006. 156. ^ Swerdlow NR (September 2005). "Tourette syndrome: current controversies and the battlefield landscape". Curr Neurol Neurosci Rep. 5 (5): 329–31. doi:10.1007/s11910-005-0054-8. PMID 16131414. 157. ^ Fernandez TV, State MW, Pittenger C (2018). "Tourette disorder and other tic disorders". Handbook of Clinical Neurology (Review). 147: 343–54. doi:10.1016/B978-0-444-63233-3.00023-3. ISBN 978-0-444-63233-3. PMID 29325623. "Regardless of whether the focus is on discovering rare or common sequence or structural genetic variation, it is clear that large collections of biomaterials (likely in the tens of thousands) that are accessible by multiple research groups will be essential for success. Three consortia are now beginning to work toward this goal (TSAICG and TIC Genetics in the United States, and EMTics in the European Union); there is active collaboration among these groups, which will also be essential for success. However, the scale of the funded collection efforts, particularly in the United States, remains quite modest compared to other neuropsychiatric disorders in which there has been success in gene discovery." ### Book sources * Abi-Jaoude E, Kideckel D, Stephens R, et al. (2009). "Tourette syndrome: a model of integration". In Carlstedt RA (ed.). Handbook of Integrative Clinical Psychology, Psychiatry, and Behavioral Medicine: Perspectives, Practices, and Research. New York: Springer Publishing Company. ISBN 978-0-8261-1095-4. * Cohen DJ, Jankovic J, Goetz CG (eds.). Tourette Syndrome. Advances in Neurology. 85. Philadelphia, PA: Lippincott Williams & Wilkins. ISBN 0-7817-2405-8. * Kushner HI (2000). A Cursing Brain?: The Histories of Tourette Syndrome. Harvard University Press. ISBN 0-674-00386-1. * Leckman JF, Cohen DJ (1999). Tourette's Syndrome—Tics, Obsessions, Compulsions: Developmental Psychopathology and Clinical Care. New York: John Wiley & Sons, Inc. ISBN 978-0471160373. * Martino D, Leckman JF, eds. (2013). Tourette syndrome. Oxford University Press. ISBN 978-0199796267. * Bloch MH (2013). "Clinical course and adult outcome in Tourette syndrome". In Martino D, Leckman JF (eds.). Tourette syndrome. Oxford University Press. pp. 107–20. * Müller-Vahl KR (2013). "Information and social support for patients and families". In Martino D, Leckman JF (eds.). Tourette syndrome. Oxford University Press. pp. 623–35. * Pruitt SK, Packer LE (2013). "Tourette syndrome". In Martino D, Leckman JF (eds.). Information and support for educators. Oxford University Press. pp. 636–55. * Sukhodolsky DG, Gladstone TR, Kaushal SA, Piasecka JB, Leckman JF (2017). "Tics and Tourette Syndrome". In Matson JL (ed.). Handbook of Childhood Psychopathology and Developmental Disabilities Treatment. Autism and Child Psychopathology Series. Springer. pp. 241–56. doi:10.1007/978-3-319-71210-9_14. * Walkup JT, Mink JW, Hollenback PJ, eds. (2006). Advances in Neurology, Tourette Syndrome. 99. Philadelphia, PA: Lippincott Williams & Wilkins. ISBN 0-7817-9970-8. * Walusinski O (2019). Georges Gilles de la Tourette: Beyond the Eponym, a Biography. Oxford University Press. ISBN 978-0-19-063603-6. ## Further reading * McGuire JF, Murphy TK, Piacentini J, Storch EA (2018). The Clinician’s Guide to Treatment and Management of Youth with Tourette Syndrome and Tic Disorders. Academic Press. ISBN 978-0128119808. * Olson S (September 2004). "Neurobiology. Making sense of Tourette's". Science. 305 (5689): 1390–92. doi:10.1126/science.305.5689.1390. PMID 15353772. ## External links Wikimedia Commons has media related to Tourette syndrome. Video clips of tics Trailer of documentary produced by HBO and Tourette Syndrome Association * v * t * e * Tourette syndrome at Curlie Classification D * ICD-10: F95.2 * ICD-9-CM: 307.23 * OMIM: 137580 * MeSH: D005879 * DiseasesDB: 5220 * v * t * e Tourette syndrome Main * Causes and origins * History * Societal and cultural aspects * Management Terms * Coprolalia * Copropraxia * Echolalia * Echophenomenon * Echopraxia * Palilalia * Palipraxia * PANDAS * Premonitory urge * Sensory phenomena * Tic * Tic disorder * Tourettism People * Jean-Martin Charcot * Donald J. Cohen * Georges Gilles de la Tourette * Tim Howard * Jean Marc Gaspard Itard * Samuel Johnson * James F. Leckman * Arthur K. Shapiro Organizations * Tourette Association of America * Tourette Canada * Tourettes Action * Yale Child Study Center Media * Front of the Class * Hichki * I Have Tourette's but Tourette's Doesn't Have Me * John's Not Mad * "Le Petit Tourette" * Maze * Motherless Brooklyn * Quit It * The Secret Life of Lele Pons * The Tic Code * Tic Talk: Living with Tourette Syndrome * v * t * e Emotional and behavioral disorders Emotional/behavioral * ADHD * Conduct disorder * Oppositional defiant disorder * Emotional/behavioral disorder (EBD) * Separation anxiety * Social functioning * Selective mutism * RAD * DAD * Tic disorders * Tourette syndrome * Speech disorders * Stuttering * Cluttering * Stereotypic movement disorder * Elimination disorders * Enuresis * Encopresis *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Tourette syndrome

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wikipedia

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

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Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome is a rare, genetic, neurological disorder characterized by mild to severe developmental delay and speech impairment, truncal hypotonia, abnormalities of vision (including cortical visual impairment and abnormal visual-evoked potentials), progressive brain atrophy mainly affecting the cerebellum, and shortened or atrophic corpus callosum. Other clinical findings may include increased muscle tone in the extremities, dystonic posturing, hyporeflexia, scoliosis, postnatal microcephaly and variable facial dysmorphism (e.g. deep-set eyes, gingival hyperplasia, short philtrum and retrognathia). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome

c4225172

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=480898

{"omim": ["616875"]}

A fibrin ring granuloma, also known as doughnut granuloma, is a histopathological finding that is characteristic of Q fever.[1] On hematoxylin-eosin staining, the fibrin ring granuloma consists of a central lipid vacuole (usually washed-out during fixing and staining, leaving only an empty hole) surrounded by a dense red fibrin ring and epithelioid macrophages. Fibrin ring granulomas may also be seen in Hodgkin's disease and infectious mononucleosis.[2][3] ## See also[edit] * Granuloma ## References[edit] 1. ^ Rosen, MD, Yale. "Fibrin Ring Granulomas". Atlas of Granulomatous Diseases. Yale Rosen, MD. Retrieved 2012-09-18. 2. ^ Tjwa M, De Hertogh G, Neuville B, Roskams T, Nevens F, Van Steenbergen W (2001). "Hepatic fibrin-ring granulomas in granulomatous hepatitis: report of four cases and review of the literature". Acta Clin Belg. 56 (6): 341–8. doi:10.1179/acb.2001.051. PMID 11881318. 3. ^ de Bayser L, Roblot P, Ramassamy A, Silvain C, Levillain P, Becq-Giraudon B (July 1993). "Hepatic fibrin-ring granulomas in giant cell arteritis". Gastroenterology. 105 (1): 272–3. PMID 8514044. This article related to pathology 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

Fibrin ring granuloma

c1443897

wikipedia

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

{"umls": ["C1443897"], "wikidata": ["Q5446442"]}

Seborrhoeic dermatitis Other namesSeborrhoea, sebopsoriasis, seborrhoeic eczema, pityriasis capitis[1] An example of seborrhoeic dermatitis between the nose and mouth SpecialtyDermatology SymptomsItchy, flaking, greasy, red, and inflamed skin[2][3] DurationLong term[4] CausesMultiple factors[4] Risk factorsStress, winter, poor immune function, Parkinson disease[4] Diagnostic methodBased on symptoms[4] Differential diagnosisPsoriasis, atopic dermatitis, tinea capitis, rosacea, systemic lupus erythematosus[4] MedicationAntifungal cream, anti-inflammatory agents, coal tar, phototherapy[3] Frequency~5% (adults),[4] ~10% (babies)[5] Seborrhoeic dermatitis, also known as seborrhoea, is a long-term skin disorder.[4] Symptoms include red, scaly, greasy, itchy, and inflamed skin.[2][3] Areas of the skin rich in oil-producing glands are often affected including the scalp, face, and chest.[4] It can result in social or self-esteem problems.[4] In babies, when the scalp is primarily involved, it is called cradle cap.[2] Dandruff is a milder form of the condition without inflammation.[6] The cause is unclear but believed to involve a number of genetic and environmental factors.[2][4] Risk factors include poor immune function, Parkinson disease, and alcoholic pancreatitis.[4][6] The condition may worsen with stress or during the winter.[4] The Malassezia yeast is believed to play a role.[6] It is not a result of poor hygiene.[7] Diagnosis is typically based on the symptoms.[4] The typical treatment is antifungal cream and anti-inflammatory agents.[3] Specifically, ketoconazole or ciclopirox are effective.[8] It is unclear if other antifungals, such as miconazole, are equally effective as they have been poorly studied.[8] Other options may include salicylic acid, coal tar, benzoyl peroxide, and phototherapy.[3] The condition is most common in infants within the 3 first months or in adults aged 30 to 70 years.[2] In adults between 1% and 10% of people are affected.[4] Males are more often affected than females.[4] Up to 70% of babies may be affected at some point in time.[5] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Management * 3.1 Medications * 3.1.1 Antifungals * 3.1.2 Anti-inflammatory treatments * 3.1.3 Antiandrogens * 3.1.4 Antihistamines * 3.1.5 Other treatments * 3.2 Phototherapy * 4 Epidemiology * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Seborrhoeic dermatitis on scalp Acute form of seborrhoeic dermatitis on scalp Seborrhoeic dermatitis' symptoms appear gradually, and usually the first signs are flaky skin and scalp.[9] Symptoms occur most commonly anywhere on the skin of the scalp, behind the ears, on the face, and in areas where the skin folds. Flakes may be yellow, white or grayish.[10] Redness and flaking may also occur on the skin near the eyelashes, on the forehead, around the sides of the nose, on the chest, and on the upper back. In more severe cases, yellowish to reddish scaly pimples appear along the hairline, behind the ears, in the ear canal, on the eyebrows, on the bridge of the nose, around the nose, on the chest, and on the upper back.[11] Commonly, patients experience mild redness, scaly skin lesions and in some cases hair loss.[12] Other symptoms include patchy scaling or thick crusts on the scalp, red, greasy skin covered with flaky white or yellow scales, itching, soreness and yellow or white scales that may attach to the hair shaft.[13] Seborrhoeic dermatitis can occur in infants younger than three months and it causes a thick, oily, yellowish crust around the hairline and on the scalp. Itching is not common among infants. Frequently, a stubborn diaper rash accompanies the scalp rash.[11] ## Causes[edit] The cause of seborrhoeic dermatitis has not been fully clarified.[1][14] The condition is thought to be due to a local inflammatory response to over-colonization by Malassezia fungi species in sebum-producing skin areas including the scalp, face, chest, back, underarms, and groin.[3][14] This is based on observations of high counts of Malassezia species in skin affected by seborrhoeic dermatitis and on the effectiveness of antifungals in treating the condition.[14] Such species of Malassezia include M. furfur (formerly P. ovale), M. globosa, M. restricta, M. sympodialis, and M. slooffiae.[3] Although Malassezia appears to be the central predisposing factor in seborrhoeic dermatitis, it is thought that other factors are necessary for the presence of Malassezia to result in the pathology characteristic of the condition.[14] This is based on the fact that summer growth of Malassezia in the skin alone do not result in seborrhoeic dermatitis.[14] Besides antifungals, the effectiveness of anti-inflammatory drugs, which reduce inflammation, and antiandrogens, which reduce sebum production, provide further insights into the pathophysiology of seborrhoeic dermatitis.[3][15][16] Eunuchs, owing to their low androgen levels and small sebaceous glands, do not develop seborrheic dermatitis.[17] In addition to the presence of Malassezia, genetic, environmental, hormonal, and immune-system factors are necessary for and/or modulate the expression of seborrhoeic dermatitis.[18][19] The condition may be aggravated by illness, psychological stress, fatigue, sleep deprivation, change of season, and reduced general health.[20] In children and babies, excessive vitamin A intake[21] or issues with Δ6-desaturase enzymes[20] have been correlated with increased risk. Seborrhoeic dermatitis-like eruptions are also associated with vitamin B6 deficiency.[22] Those with immunodeficiency (especially infection with HIV) and with neurological disorders such as Parkinson's disease (for which the condition is an autonomic sign) and stroke are particularly prone to it.[23] ## Management[edit] ### Medications[edit] A variety of different types of medications are able to reduce symptoms of seborrhoeic dermatitis.[3] These include certain antifungals, anti-inflammatory agents like corticosteroids and nonsteroidal anti-inflammatory drugs, antiandrogens, and antihistamines, among others.[3][1] #### Antifungals[edit] Regular use of an over-the-counter or prescription antifungal shampoo or cream may help those with recurrent episodes. The topical antifungal medications ketoconazole and ciclopirox have the best evidence.[8] It is unclear if other antifungals are equally effective as this has not been sufficiently studied.[8] Antifungals that have been studied and found to be effective in the treatment of seborrhoeic dermatitis include ketoconazole, fluconazole, miconazole, bifonazole, sertaconazole, clotrimazole, flutrimazole, ciclopirox, terbinafine, butenafine, selenium sulfide, and lithium salts such as lithium gluconate and lithium succinate.[8][3] Topical climbazole appears to have little effectiveness in the treatment of seborrhoeic dermatitis.[8] Systemic therapy with oral antifungals including itraconazole, fluconazole, ketoconazole, and terbinafine is effective.[3] #### Anti-inflammatory treatments[edit] Topical corticosteroids have been shown to be effective in short-term treatment of serborrhoeic dermatitis, and are as effective or more effective than antifungal treatment with azoles. There is also evidence for the effectiveness of calcineurin inhibitors like tacrolimus and pimecrolimus as well as lithium salt therapy.[24] Oral immunosuppressive treatment, such as with prednisone, has been used in short courses as a last resort in seborrhoeic dermatitis due to its potential side effects.[25] #### Antiandrogens[edit] Seborrhoea is recognized as an androgen-sensitive condition – that is, it is caused or aggravated by androgen sex hormones such as testosterone and dihydrotestosterone – and is a common symptom of hyperandrogenism (e.g., that seen in polycystic ovary syndrome).[26][27] In addition, seborrhoea, as well as acne, are commonly associated with puberty due to the steep increase of androgen levels at that time.[28] In accordance with the involvement of androgens in seborrhoea, antiandrogens, such as cyproterone acetate,[29] spironolactone,[30] flutamide,[31][32] and nilutamide,[33][34] are highly effective in alleviating the condition.[26][35] As such, they are used in the treatment of seborrhoea,[26][35] particularly severe cases.[36] While beneficial in seborrhoea, effectiveness may vary with different antiandrogens; for instance, spironolactone (which is regarded as a relatively weak antiandrogen) has been found to produce a 50% improvement after three months of treatment, whereas flutamide has been found to result in an 80% improvement within three months.[26][32] Cyproterone acetate is similarly more potent and effective than spironolactone, and results in considerable improvement or disappearance of acne and seborrhoea in 90% of patients within three months.[37] Systemic antiandrogen therapy are generally used to treat seborrhoea only in women, and not in men, as these medications can result in feminization (e.g., gynecomastia), sexual dysfunction, and infertility in males.[38][39] In addition, antiandrogens theoretically have the potential to feminize male fetuses in pregnant women, and for this reason, are usually combined with effective birth control in sexually active women who can or may become pregnant.[37] #### Antihistamines[edit] Antihistamines are used primarily to reduce itching, if present. However, research studies suggest that some antihistamines have anti-inflammatory properties.[40] #### Other treatments[edit] * Coal tar can be effective,[citation needed] but, although no significant increased risk of cancer in human treatment with coal tar shampoos has been found,[41] caution is advised since coal tar is carcinogenic in animals, and heavy human occupational exposures do increase cancer risks. * Isotretinoin, a sebosuppressive agent, may be used to reduce sebaceous gland activity as a last resort in refractory disease. However, isotretinoin has potentially serious side effects and few patients with seborrhoea are appropriate candidates for therapy.[25] * Keratolytics like topical urea[42] * Metronidazole[8] * Topical 4% nicotinamide[3] ### Phototherapy[edit] See also: Photodynamic therapy Another potential option is natural and artificial UV radiation since it can curb the growth of Malassezia yeast [43] Some recommend photodynamic therapy using UV-A and UV-B laser or red and blue LED light to inhibit the growth of Malassezia fungus and reduce seborrhoeic inflammation.[44][45][46] ## Epidemiology[edit] Seborrhoea affects 1 to 5% of the general population.[1][47][48] It is slightly more common in men, but affected women tend to have more severe symptoms.[48] The condition usually recurs throughout a person's lifetime.[49] Seborrhoea can occur in any age group[49] but usually starts at puberty and peaks in incidence at around 40 years of age.[50] It can reportedly affect as many as 31% of older people.[48] Severity is worse in dry climates.[49] ## See also[edit] * Seborrheic keratosis ## References[edit] 1. ^ a b c d Dessinioti, C; Katsambas, A (Jul–Aug 2013). "Seborrheic dermatitis: etiology, risk factors, and treatments: facts and controversies". Clinics in Dermatology. 31 (4): 343–51. doi:10.1016/j.clindermatol.2013.01.001. PMID 23806151. 2. ^ a b c d e "Seborrheic Dermatitis - Dermatologic Disorders". Merck Manuals Professional Edition. Retrieved 22 November 2019. 3. ^ a b c d e f g h i j k l m Borda, LJ; Perper, M; Keri, JE (March 2019). "Treatment of seborrheic dermatitis: a comprehensive review". The Journal of Dermatological Treatment. 30 (2): 158–169. doi:10.1080/09546634.2018.1473554. PMID 29737895. 4. ^ a b c d e f g h i j k l m n o Ijaz, N; Fitzgerald, D (2 June 2017). "Seborrhoeic dermatitis". British Journal of Hospital Medicine. 78 (6): C88–C91. doi:10.12968/hmed.2017.78.6.C88. PMID 28614013. 5. ^ a b Nobles, T; Krishnamurthy, K (January 2019). "Cradle Cap". PMID 30285358. Cite journal requires `|journal=` (help) 6. ^ a b c Naldi, L; Diphoorn, J (27 May 2015). "Seborrhoeic dermatitis of the scalp". BMJ Clinical Evidence. 2015. PMC 4445675. PMID 26016669. 7. ^ "Seborrheic dermatitis". American Academy of Dermatology. Archived from the original on 21 October 2017. Retrieved 20 October 2017. 8. ^ a b c d e f g Okokon, EO; Verbeek, JH; Ruotsalainen, JH; Ojo, OA; Bakhoya, VN (28 April 2015). "Topical antifungals for seborrhoeic dermatitis". The Cochrane Database of Systematic Reviews. 4 (5): CD008138. doi:10.1002/14651858.CD008138.pub3. PMC 4448221. PMID 25933684. 9. ^ "Dermatitis Seborrheic Treatment". Archived from the original on 2010-06-02. Retrieved June 11, 2010. 10. ^ "Seborrheic Dermatitis". Archived from the original on June 15, 2010. Retrieved June 11, 2010. 11. ^ a b "Dermatitis". Archived from the original on September 25, 2011. Retrieved June 11, 2010. 12. ^ "What is Seborrheic Dermatitis?". Archived from the original on April 20, 2010. Retrieved June 11, 2010. 13. ^ "Symptoms". Archived from the original on May 26, 2010. Retrieved June 11, 2010. 14. ^ a b c d e Wikramanayake TC, Borda LJ, Miteva M, Paus R (September 2019). "Seborrheic dermatitis-Looking beyond Malassezia". Exp. Dermatol. 28 (9): 991–1001. doi:10.1111/exd.14006. PMID 31310695. 15. ^ Trivedi, M.K.; Shinkai, K.; Murase, J.E. (2017). "A Review of hormone-based therapies to treat adult acne vulgaris in women". International Journal of Women's Dermatology. 3 (1): 44–52. doi:10.1016/j.ijwd.2017.02.018. ISSN 2352-6475. PMC 5419026. PMID 28492054. 16. ^ Paradisi, Roberto; Fabbri, Raffaella; Porcu, Eleonora; Battaglia, Cesare; Seracchioli, Renato; Venturoli, Stefano (2010). "Retrospective, observational study on the effects and tolerability of flutamide in a large population of patients with acne and seborrhea over a 15-year period". Gynecological Endocrinology. 27 (10): 823–829. doi:10.3109/09513590.2010.526664. ISSN 0951-3590. PMID 21117864. 17. ^ Orfanos, C. E.; Frost, Ph. (1990). "Seborrhoeic Dermatitis, Scalp Psoriasis and Hair". Hair and Hair Diseases. pp. 641–661. doi:10.1007/978-3-642-74612-3_25. ISBN 978-3-642-74614-7. 18. ^ Johnson, Betty Anne; Nunley, Julia R. (May 2000). "Treatment of seborrheic dermatitis". American Family Physician. 61 (9): 2703–10, 2713–4. PMID 10821151. Archived from the original on 2010-07-06. 19. ^ Janniger CK, Schwartz RA (July 1995). "Seborrheic dermatitis". American Family Physician. 52 (1): 149–55, 159–60. PMID 7604759. 20. ^ a b Schwartz, Robert A.; Janusz, Christopher A.; Janniger, Camila K. (July 2006). "Seborrheic dermatitis: an overview". American Family Physician. 74 (1): 125–30. PMID 16848386. 21. ^ MedlinePlus Encyclopedia: Hypervitaminosis A 22. ^ Alamgir, A.N.M. (2018). Therapeutic Use of Medicinal Plants and their Extracts: Volume 2: Phytochemistry and Bioactive Compounds. Springer. p. 435. ISBN 978-3319923871. 23. ^ "Seborrhoeic dermatitis and dandruff (seborrheic eczema). DermNet NZ". . DermNet NZ. 2012-03-20. Archived from the original on 2012-06-15. Retrieved 2012-06-10. 24. ^ Kastarinen, Helena; Oksanen, Tuija; Okokon, Enembe O; Kiviniemi, Vesa V; Airola, Kristiina; Jyrkkä, Johanna; Oravilahti, Tuomas; Rannanheimo, Piia K; Verbeek, Jos H (2014-05-19). "Topical anti-inflammatory agents for seborrhoeic dermatitis of the face or scalp". Cochrane Database of Systematic Reviews (5): CD009446. doi:10.1002/14651858.CD009446.pub2. ISSN 1465-1858. PMC 6483543. PMID 24838779. 25. ^ a b Gupta, AK; Richardson, M; Paquet, M (January 2014). "Systematic review of oral treatments for seborrheic dermatitis". Journal of the European Academy of Dermatology and Venereology : JEADV. 28 (1): 16–26. doi:10.1111/jdv.12197. PMID 23802806. 26. ^ a b c d Singh, Shankar; Gauthier, Sylvain; Labrie, Fernand (2000). "Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships". Current Medicinal Chemistry. 7 (2): 211–247. doi:10.2174/0929867003375371. ISSN 0929-8673. PMID 10637363. 27. ^ Zouboulis, Christos C.; Degitz, Klaus (2004). "Androgen action on human skin – from basic research to clinical significance". Experimental Dermatology. 13 (s4): 5–10. doi:10.1111/j.1600-0625.2004.00255.x. ISSN 0906-6705. PMID 15507105. 28. ^ De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, Koch C, McLachlan R, New M, Rebar R, Singer F, Vinik A, Weickert MO, Handelsman DJ (2000). "Androgen Physiology, Pharmacology and Abuse". PMID 25905231. Cite journal requires `|journal=` (help) 29. ^ Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1004–. ISBN 978-0-7817-1750-2. Archived from the original on 2013-06-02. 30. ^ G. Plewig; A.M. Kligman (6 December 2012). ACNE and ROSACEA. Springer Science & Business Media. pp. 66, 685, 687. ISBN 978-3-642-59715-2. Archived from the original on 19 March 2017. 31. ^ NADIR R. FARID; Evanthia Diamanti-Kandarakis (27 February 2009). Diagnosis and Management of Polycystic Ovary Syndrome. Springer Science & Business Media. pp. 240–. ISBN 978-0-387-09718-3. Archived from the original on 19 March 2017. 32. ^ a b Bentham Science Publishers (September 1999). Current Pharmaceutical Design. Bentham Science Publishers. pp. 717–. 33. ^ Couzinet B, Thomas G, Thalabard JC, Brailly S, Schaison G (1989). "Effects of a pure antiandrogen on gonadotropin secretion in normal women and in polycystic ovarian disease". Fertil. Steril. 52 (1): 42–50. doi:10.1016/s0015-0282(16)60786-0. PMID 2744186. 34. ^ Namer M (1988). "Clinical applications of antiandrogens". J. Steroid Biochem. 31 (4B): 719–29. doi:10.1016/0022-4731(88)90023-4. PMID 2462132. 35. ^ a b Mutschler; Hartmut Derendorf (1995). Drug Actions: Basic Principles and Theraputic Aspects. CRC Press. pp. 304–. ISBN 978-0-8493-7774-7. Archived from the original on 2017-11-05. 36. ^ Joseph T. DiPiro; Robert L. Talbert; Gary C. Yee; Gary R. Matzke; Barbara G. Wells; L. Michael Posey (6 July 2008). Pharmacotherapy: A Pathophysiologic Approach. McGraw Hill Professional. p. 1598. ISBN 978-0-07-164325-2. Archived from the original on 19 March 2017. 37. ^ a b A. Hughes; S. H. Hasan; G. W. Oertel; H. E. Voss; F. Bahner; F. Neumann; H. Steinbeck; K.-J. Gräf; J. Brotherton; H. J. Horn; R. K. Wagner (27 November 2013). Androgens II and Antiandrogens / Androgene II und Antiandrogene. Springer Science & Business Media. pp. 351, 516. ISBN 978-3-642-80859-3. Archived from the original on 19 March 2017. 38. ^ Larry E. Millikan (19 April 2016). Drug Therapy in Dermatology. CRC Press. pp. 295–. ISBN 978-0-203-90831-0. Archived from the original on 29 July 2017. 39. ^ Sara Brenner (13 December 2013). The Clinical Nanomedicine Handbook. CRC Press. pp. 97–. ISBN 978-1-4398-3478-7. Archived from the original on 5 November 2017. 40. ^ Grob, JJ; Castelain, M.; Richard, MA; Bonniol, JP; Beraud, V.; Adhoute, H.; Guillou, N.; Bonerandi, JJ (1998). "Antiinflammatory properties of cetirizine in a human contact dermatitis model. Clinical evaluation of patch tests is not hampered by antihistamines". Acta Dermato-Venereologica. 78 (3): 194–7. doi:10.1080/000155598441512. PMID 9602225. 41. ^ Roelofzen JH, Aben KK, Oldenhof UT, et al. (April 2010). "No increased risk of cancer after coal tar treatment in patients with psoriasis or eczema" (PDF). J. Invest. Dermatol. 130 (4): 953–61. doi:10.1038/jid.2009.389. PMID 20016499. 42. ^ Piquero-Casals J, Hexsel D, Mir-Bonafé JF, Rozas-Muñoz E (September 2019). "Topical Non-Pharmacological Treatment for Facial Seborrheic Dermatitis". Dermatol Ther (Heidelb). 9 (3): 469–477. doi:10.1007/s13555-019-00319-0. PMC 6704200. PMID 31396944. 43. ^ Wikler, JR.; Janssen N.; Bruynzeel DP.; Nieboer C. (1990). "The effect of UV-light on pityrosporum yeasts: ultrastructural changes and inhibition of growth". Acta Dermato-venereologica. Stockholm. 70 (1): 69–71. PMID 1967880. 44. ^ Wikler JR, Janssen N, Bruynzeel DP, Nieboer C (1990). "The effect of UV-light on pityrosporum yeasts: ultrastructural changes and inhibition of growth". Acta Dermato-venereologica. 70 (1): 69–71. PMID 1967880. 45. ^ Calzavara-Pinton PG, Venturini M, Sala R (2005). "A comprehensive overview of photodynamic therapy in the treatment of superficial fungal infections of the skin". Photochem Photobiol. 78 (1): 1–6. doi:10.1016/j.jphotobiol.2004.06.006. PMID 15629243. 46. ^ Abels, Christoph; Jori, Giulio; Szeimies, Rolf-Markus; Maisch, Tim (2004-10-11). "Antibacterial photodynamic therapy in dermatology – Photochemical & Photobiological Sciences (RSC Publishing)". Photochemical & Photobiological Sciences. rsc.org. 3 (10): 907–917. doi:10.1039/B407622B. PMID 15480480. 47. ^ Mark A. Goldstein; Myrna Chandler Goldstein; Larry P. Credit (17 March 2009). Your Best Medicine: From Conventional and Complementary Medicine--Expert-Endorsed Therapeutic Solutions to Relieve Symptoms and Speed Healing. Rodale. pp. 462–. ISBN 978-1-60529-656-2. Archived from the original on 5 November 2017. 48. ^ a b c Miranda A. Farage; Kenneth W. Miller; Howard I. Maibach (2 December 2009). Textbook of Aging Skin. Springer Science & Business Media. pp. 534–. ISBN 978-3-540-89655-5. Archived from the original on 5 November 2017. 49. ^ a b c Jeanette Jacknin (2001). Smart Medicine for Your Skin: A Comprehensive Guide to Understanding Conventional and Alternative Therapies to Heal Common Skin Problems. Penguin. pp. 271–. ISBN 978-1-58333-098-2. Archived from the original on 2017-11-05. 50. ^ Ooi ET, Tidman MJ (2014). "Improving the management of seborrhoeic dermatitis". Practitioner. 258 (1768): 23–6, 3. PMID 24689165. ## External links[edit] Classification D * ICD-10: L21 * ICD-9-CM: 690.1 * MeSH: D012628 * DiseasesDB: 11911 External resources * MedlinePlus: 000963 * eMedicine: derm/396 Wikimedia Commons has media related to Seborrhoeic dermatitis. * American Academy of Dermatology: Seborrheic dermatitis * 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 Dermatitis and eczema Atopic dermatitis * Besnier's prurigo Seborrheic dermatitis * Pityriasis simplex capillitii * Cradle cap Contact dermatitis (allergic, irritant) * plants: Urushiol-induced contact dermatitis * African blackwood dermatitis * Tulip fingers * other: Abietic acid dermatitis * Diaper rash * Airbag dermatitis * Baboon syndrome * Contact stomatitis * Protein contact dermatitis Eczema * Autoimmune estrogen dermatitis * Autoimmune progesterone dermatitis * Breast eczema * Ear eczema * Eyelid dermatitis * Topical steroid addiction * Hand eczema * Chronic vesiculobullous hand eczema * Hyperkeratotic hand dermatitis * Autosensitization dermatitis/Id reaction * Candidid * Dermatophytid * Molluscum dermatitis * Circumostomy eczema * Dyshidrosis * Juvenile plantar dermatosis * Nummular eczema * Nutritional deficiency eczema * Sulzberger–Garbe syndrome * Xerotic eczema Pruritus/Itch/ Prurigo * Lichen simplex chronicus/Prurigo nodularis * by location: Pruritus ani * Pruritus scroti * Pruritus vulvae * Scalp pruritus * Drug-induced pruritus * Hydroxyethyl starch-induced pruritus * Senile pruritus * Aquagenic pruritus * Aquadynia * Adult blaschkitis * due to liver disease * Biliary pruritus * Cholestatic pruritus * Prion pruritus * Prurigo pigmentosa * Prurigo simplex * Puncta pruritica * Uremic pruritus Other * substances taken internally: Bromoderma * Fixed drug reaction * Nummular dermatitis * Pityriasis alba * Papuloerythroderma of Ofuji * v * t * e Other dermatological preparations (D11) Anti-seborrheics * Antiandrogens * Bicalutamide * Cyproterone acetate * Flutamide * Spironolactone * Antifungals * Bifonazole * Cetrimonium bromide (cetrimide) * Ciclopirox olamine (ciclopirox) * Climbazole * Clotrimazole * Ketoconazole * Miconazole * Piroctone olamine * Selenium disulfide (selenium sulfide) * Xenysalate * Zinc pyrithione (pyrithione zinc) * Antihistamines * Calcineurin inhibitors * Cyclosporin * Pimecrolimus * Tacrolimus * Isotretinoin * Keratolytics * Coal tar * Resorcinol * Salicylic acid * Sulfur * Urea (urea-containing cream) * Lithium salts * Lithium gluconate * Lithium succinate * Topical corticosteroids (e.g., hydrocortisone) Skin lightening * Hydroquinone * Mequinol * Monobenzone Skin darkening * Afamelanotide * Melanotan II Anti-inflammatories * Oxaceprol * Gamolenic acid * Pimecrolimus * Tacrolimus * Alitretinoin * Topical corticosteroids (e.g., hydrocortisone) Alopecia treatments * 5α-Reductase inhibitors * Alfatradiol * Dutasteride * Finasteride * Saw palmetto extract * Antiandrogens * Bicalutamide * Cyproterone acetate * Flutamide * Spironolactone * Topilutamide (fluridil) * Potassium channel openers * Minoxidil * Others * Nepidermin Hair growth inhibitors * 5α-Reductase inhibitors * Dutasteride * Finasteride * Antiandrogens * Bicalutamide * Cyproterone acetate * Flutamide * Spironolactone * Eflornithine Others * Androgens (e.g., testosterone) * Brimonidine * Calcium gluconate * Estrogens (e.g., estradiol) * Hyaluronic acid * Magnesium sulfate * Pregnenolone acetate * Progestogens (e.g., progesterone) * Povidone-iodine * Tiratricol * Medicine portal *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Seborrhoeic dermatitis

c0036508

wikipedia

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

{"mesh": ["D012628"], "umls": ["C0036508", "C3806554"], "icd-10": ["L21"], "wikidata": ["Q448310"]}

Mucosal lentigines Other namesLabial, penile, and vulvar melanosis, and Melanotic macules SpecialtyDermatology Mucosal lentigines is a cutaneous condition characterized by light brown macules on mucosal surfaces.[1]:686 ## See also[edit] * Lentigo * Skin lesion ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 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

Mucosal lentigines

None

wikipedia

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

{"wikidata": ["Q6931263"]}

Coloboma is an eye abnormality that occurs before birth. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in one of several parts of the eye, including the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision. Colobomas affecting the iris, which result in a "keyhole" appearance of the pupil, generally do not lead to vision loss. Colobomas involving the retina result in vision loss in specific parts of the visual field. Large retinal colobomas or those affecting the optic nerve can cause low vision, which means vision loss that cannot be completely corrected with glasses or contact lenses. Some people with coloboma also have a condition called microphthalmia. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss. People with coloboma may also have other eye abnormalities, including clouding of the lens of the eye (cataract), increased pressure inside the eye (glaucoma) that can damage the optic nerve, vision problems such as nearsightedness (myopia), involuntary back-and-forth eye movements (nystagmus), or separation of the retina from the back of the eye (retinal detachment). Some individuals have coloboma as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When coloboma occurs by itself, it is described as nonsyndromic or isolated. Colobomas involving the eyeball should be distinguished from gaps that occur in the eyelids. While these eyelid gaps are also called colobomas, they arise from abnormalities in different structures during early development. ## Frequency Coloboma occurs in approximately 1 in 10,000 people. Because coloboma does not always affect vision or the outward appearance of the eye, some people with this condition are likely undiagnosed. ## Causes Coloboma arises from abnormal development of the eye. During the second month of development before birth, a seam called the optic fissure (also known as the choroidal fissure or embryonic fissure) closes to form the structures of the eye. When the optic fissure does not close completely, the result is a coloboma. Because the optic fissure forms at the bottom of the eyeball during development, colobomas occur in the lower half of the eye. The particular structure within the eye affected by the coloboma depends on the part of the optic fissure that failed to close. Coloboma may be caused by changes in many genes involved in the early development of the eye, most of which have not been identified. The condition may also result from a chromosomal abnormality affecting one or more genes. Most genetic changes associated with coloboma have been identified only in very small numbers of affected individuals. The risk of coloboma may also be increased by environmental factors that affect early development, such as exposure to alcohol during pregnancy. In these cases, affected individuals usually have other health problems in addition to coloboma. ### Learn more about the genes associated with Coloboma * ACTB * ACTG1 * BCOR * CHD7 * DPYD * FOXL2 * FRAS1 * FREM1 * FREM2 * GDF3 * GDF6 * GJA1 * GRIP1 * HCCS * KAT6B * KMT2D * LRP2 * OTX2 * PAX2 * PAX6 * POLR1C * POLR1D * PORCN * PQBP1 * PTCH1 * RAB3GAP1 * RAB3GAP2 * SALL1 * SALL4 * SHH * SIX3 * SMOC1 * SOX2 * TBC1D20 * TCOF1 * TFAP2A * ZEB2 * ZIC2 Additional Information from NCBI Gene: * ABCB6 * ALDH1A3 * ATOH7 * BMP4 * BMP7 * C12orf57 * CC2D2A * CLDN19 * CRIM1 * CRYAA * CRYBA4 * CRYBB2 * DHX38 * ERCC1 * ERCC5 * FADD * FAM111A * FNBP4 * FZD5 * HMGB3 * HMX1 * IGBP1 * MAB21L2 * MAF * MFRP * NAA10 * PDE6D * PIGL * PRSS56 * RARB * RAX * RBP4 * RPGRIP1L * SALL2 * SCLT1 * SEMA3E * SIX6 * SRD5A3 * STRA6 * TBC1D32 * TBX22 * TENM3 * TMEM67 * TMEM98 * TMX3 * VAX1 * VSX2 * YAP1 ## Inheritance Pattern Most often, isolated coloboma is not inherited, and there is only one affected individual in a family. However, the affected individual is still at risk of passing the coloboma on to his or her own children. In cases when it is passed down in families, coloboma can have different inheritance patterns. Isolated coloboma is sometimes inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. Isolated coloboma can also be inherited in an autosomal recessive pattern, which means both copies of a gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of a mutated gene, but they typically do not show signs and symptoms of the condition. Less commonly, isolated coloboma may have X-linked dominant or X-linked recessive patterns of inheritance. X-linked means that a gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. X-linked dominant means that in females (who have two X chromosomes), a mutation in one of the two copies of a gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of a gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females. X-linked recessive means that in females, a mutation would have to occur in both copies of a gene to cause the disorder. In males, one altered copy of a gene in each cell is sufficient to cause the condition. Because it is unlikely that females will have two altered copies of a particular gene, males are affected by X-linked recessive disorders much more frequently than females. When coloboma occurs as a feature of a genetic syndrome or chromosomal abnormality, it may cluster in families according to the inheritance pattern for that condition, which may be autosomal dominant, autosomal recessive, or X-linked. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Coloboma

c0009363

medlineplus

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

{"gard": ["1434", "8502", "1432"], "mesh": ["D003103"], "omim": ["120200", "216820"], "synonyms": []}

Ménétrier disease is a gastrointestinal condition characterized by overgrowth of the mucous cells (foveola) in the mucous membrane lining the stomach, causing enlarged gastric folds. This leads to excessive mucus production, causing protein loss from the stomach and low or absent levels of stomach acid. Symptoms may include pain in the upper middle region of the stomach, nausea, vomiting, and diarrhea. The cause of Ménétrier disease is largely not known, although some cases are associated with infection, particularly pediatric cases, which can be caused by CMV infections. Treatment may include medications such as cetuximab and gastrectomy in severe cases. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Menetrier disease

c0017155

gard

https://rarediseases.info.nih.gov/diseases/2436/menetrier-disease

{"mesh": ["D005758"], "omim": ["137280"], "orphanet": ["2494"], "synonyms": ["Giant hypertrophic gastritis", "Giant hypertrophic gastropathy", "Gastroenteropathy, protein losing", "Giant hypertrophy of the gastric mucosa", "Hypertrophic gastropathy"]}

A number sign (#) is used with this entry because this form of Zellweger syndrome (PBD12A) is caused by homozygous mutation in the PEX19 gene (600279) on chromosome 1q23. Description Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 14 (CG14, equivalent to CGJ) have mutations in the PEX19 gene. For information on the history of PBD complementation groups, see 214100. Clinical Features Mohamed et al. (2010) studied a female infant, born of consanguineous Saudi parents, with Zellweger syndrome, The patient had neonatal hypotonia, poor growth, and subtle dysmorphic features, including cranial asymmetry, triangular face, low hairline, open fontanels, and broad nasal bridge. Laboratory studies showed elevated liver enzymes, hyperbilirubinemia, and a very long chain fatty acid (VLCFA) profile consistent with a PBD. Brain imaging showed cerebral atrophy, cortical changes, and diffuse demyelination. There was a complete absence of peroxisomes in patient fibroblasts. The patient had a severe clinical course, complicated by global developmental delay, refractory seizures, renal tubular defect, multiple gallstones, and recurrent hospitalizations. She died of sepsis at age 16 months. Molecular Genetics Kinoshita et al. (1998) identified complementation group J (CGJ) from patients with Zellweger syndrome. Two Chinese hamster ovary cell mutants were also found to belong to this group. In no CGJ mutant cell were peroxisomal ghosts found. Matsuzono et al. (1999) identified a homozygous 1-bp insertion in the PEX19 gene (600279.0001) in a patient with Zellweger syndrome of complementation group J. Mohamed et al. (2010) identified a homozygous frameshift mutation in the PEX19 gene (600279.0002) in a female infant with Zellweger syndrome. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (3rd centile) Weight \- Low weight (3rd centile) HEAD & NECK Head \- Small head (3rd centile) \- Hydrocephalus \- Scaphocephaly Face \- Triangular face \- Prominent premaxilla \- Small receding chin Ears \- Asymmetric abnormal ears Eyes \- Epicanthal folds \- Periorbital puffiness Nose \- Prominent nose \- Broad nasal bridge CARDIOVASCULAR Heart \- Systolic murmur \- Patent ductus arteriosus \- Atrial septal defect \- Double outlet right ventricle (DORV) ABDOMEN Liver \- Hyperbilirubinemia \- Liver failure Biliary Tract \- Gallstones GENITOURINARY External Genitalia (Male) \- Abnormal male genitals Kidneys \- Renal tubular defect SKELETAL \- Dense bones Skull \- Cranial asymmetry \- Wide anterior fontanel \- Wide posterior fontanel \- Open sagittal metopic sutures MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Absent Moro reflex \- Absent palmar grasp \- Brisk tendon reflexes \- Epilepsy (resistant to conventional anticonvulsant drugs) \- Global developmental delay \- Cerebral atrophy seen on MRI \- Diffuse demyelination seen on MRI HEMATOLOGY \- Disseminated coagulopathy PRENATAL MANIFESTATIONS Movement \- Reduced fetal movement Amniotic Fluid \- Diminished amniotic fluid LABORATORY ABNORMALITIES \- Elevated plasma very long chain fatty acids (VLCFA) \- Complete absence of peroxisomes in fibroblasts \- Deficiency of dihydroxyacetonephosphate acyltransferase (DHAPAT) \- Decreased pristanic acid beta-oxidation \- Decreased phytanic acid alpha-oxidation MISCELLANEOUS \- Recurrent severe sepsis \- Death by 16 months of age \- Three patients have been reported (last curated January 2017) MOLECULAR BASIS \- Caused by mutation in the peroxisome biogenesis factor 19 gene (PEX19, 600279.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

PEROXISOME BIOGENESIS DISORDER 12A (ZELLWEGER)

c0043459

omim

https://www.omim.org/entry/614886

{"doid": ["0080486"], "mesh": ["D015211"], "omim": ["614886"], "orphanet": ["912"]}

Oesophageal atresia (OA) encompasses a group of congenital anomalies with an interruption in the continuity of the oesophagus, with or without persistent communication with the trachea. ## Epidemiology OA occurs in 1 in 2500 live births. ## Clinical description Infants with OA are unable to swallow saliva and are noted to have excessive salivation requiring repeated suctioning. Associated anomalies occur in 50% of cases, the majority involving one or more of the VACTERL association anomalies (vertebral, anorectal, cardiac, tracheooesophageal, renal and limb defects). In 86% of cases there is a distal tracheooesophageal fistula, in 7% of cases there is no fistulous connection, while in 4% of cases there is a tracheooesophageal fistula without atresia. The remaining cases are made up of patients with OA with proximal, or both proximal and distal, tracheooesophageal fistula. ## Etiology The aetiology is largely unknown and is likely to be multifactorial, however, various clues have been uncovered in animal models, particularly defects in the expression of the Sonic hedgehog (Shh) gene. ## Diagnostic methods The diagnosis may be suspected prenatally by a small or absent stomach bubble on ultrasound scan at around 18 weeks of gestation. The likelihood of an atresia is increased by the presence of polyhydramnios. Inserting a nasogastric tube at birth allows the diagnosis to be confirmed or excluded and should be performed in all infants born to a mother with polyhydramnios, as well as in infants who produce excessive mucus soon after delivery. In OA, the tube will not progress beyond 10 cm from the mouth. Further confirmation is obtained by plain X-ray of the chest and abdomen. ## Genetic counseling The vast majority of cases are sporadic and the recurrence risk for siblings is 1%. ## Management and treatment Definitive management involves disconnection of the tracheooesophageal fistula, closure of the tracheal defect and primary anastomosis of the oesophagus. Delayed primary repair should be attempted when there is a 'long gap' between the ends of the oesophagus. Only very rarely willoesophageal replacement be required. ## Prognosis Survival is directly related to birth weight and to the presence of a major cardiac defect. Infants weighing over 1500 g and having no major cardiac problems have a near 100% survival rate, but the survival rate decreases in the presence of additional risk factors. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Esophageal atresia

c0014850

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1199

{"gard": ["6381"], "mesh": ["D004933"], "omim": ["189960"], "umls": ["C0014850"], "icd-10": ["Q39.0", "Q39.1"]}

Striate palmoplantar keratoderma is an isolated, focal, hereditary palmoplantar keratoderma characterized by linear hyperkeratosis along the flexor aspect of the fingers and on palms, as well as focal hyperkeratosis of the plantar skin. Patients present with painful thickening of the skin on palms and soles, with occasional fissuring, blistering and hyperhidrosis. Rarely, hyperkeratosis on other areas may be seen (knees, dorsal aspects of the digits). Histopatologically, widened intercellular spaces between keratinocytes are observed. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Striate palmoplantar keratoderma

c2931122

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=50942

{"mesh": ["C536162"], "omim": ["148700", "607654", "612908"], "icd-10": ["Q82.8"], "synonyms": ["Keratosis palmoplantaris striata", "Keratosis palmoplantaris striata et areata", "Keratosis palmoplantaris varians of Wachters"]}

Blount disease is a growth disorder of the shin bone (tibia) characterized by inward turning of the lower leg (bowing) that slowly worsens over time. While it is not uncommon for young children to have bowed legs, typically the bowing improves with age. There are two types of Blount disease (early-onset and late-onset), based on whether symptoms begin before or after four years of age. Blount disease may occur in one or both legs and can lead to shortening of the affected leg and other changes within bones of the legs. The cause of Blount disease is not well understood; however, a variety of hereditary and genetic factors are likely involved. The condition is more common among certain populations and is associated with obesity and early walking. Treatment may involve bracing and/or surgery. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Blount disease

c0175756

gard

https://rarediseases.info.nih.gov/diseases/916/blount-disease

{"mesh": ["C536237"], "omim": ["188700"], "orphanet": ["2768"], "synonyms": ["Tibia vara", "Osteochondrosis deformans tibiae", "Blount's disease", "Blount-Barber syndrome", "Erlacher-Blount syndrome", "Osteochondrosis deformans tibiae, familial infantile type"]}

## Clinical Features Gottron (1940) reported a brother and sister, aged 16 and 19 years, whose hands and feet had appeared old since infancy because of thin skin. General physical and mental development were normal. Less severe skin atrophy was present elsewhere. Huttova et al. (1967) also described affected sibs. The disorder is often misdiagnosed as the Ehlers-Danlos syndrome (EDS). Indeed, this may be Ehlers-Danlos syndrome type IV (130050). Some of the features are seen in mandibuloacral dysplasia (248370). De Groot et al. (1980) defended the existence of acrogeria as an entity distinct from EDS IV. They observed affected mother and son, the first instance of 2 generations being affected and only the second instance of familiality, Gottron's being the first. The mother was the seventh of 10 children in a nonconsanguineous family. Vessels were conspicuous over the trunk. The mother showed elastosis perforans as did the female reported by Gottron and 2 previously reported patients. Small stature and micrognathia were present in several reported patients. Unlike EDS IV, cigarette-paper scars and intestinal catastrophes were not features. De Groot et al. (1980) found reports of 19 cases. Gilkes et al. (1974) introduced the term metageria for the premature aging syndrome that he reported. Greally et al. (1992) suggested the term acrometageria. They reported the case of a boy with aged facies, scoliosis, wrinkled skin of the feet and hands, joint hypermobility, and mental retardation. No abnormality of type III collagen (COL3A1; 120180) was demonstrated. Blaszczyk et al. (2000) described a 46-year-old mother and her 20-year-old son with presumed acrogeria of the Gottron type. Abnormality of type III collagen was excluded. The appearance of the hands was strikingly that for which acrogeria is an appropriate description. Skin atrophy of the distal limbs had been noted since age 7 in the mother and age 3 in the son. The son had brownish discoloration of the skin of the anterior aspects of the legs with bruising and ulcerations. The striking features illustrated by photographs were beaked nose and conspicuous mandible. Another son, aged 24, was said not to have acrogeria. Jablonska (2001) stated that the beaked nose and jutting chin were not present in the unaffected son. Rezai-Delui et al. (1999) described a highly consanguineous family from a small village in Iran in which 4 members (3 males and 1 female) in the sixth generation had acrogeria. All 4 patients showed growth deficiency, which began in the first year of life, and bore a striking resemblance to each other, with proportionate short stature, beaked nose, protruding eyes, receding chins, slender extremities, prominent joints, and cutaneous atrophy. All had dystrophic nails and sparse hair, marked delay in onset and completion of the primary dentition, and displaced and missing permanent dentition. Two patients had mildly hypermobile joints in infancy, and 2 patients, aged 5 and 7 years, had various degrees of limitation of movement of the knees, wrists, and elbows. Two of the patients died suddenly at age 30 months and age 3 years. Radiologic features included micrognathia, wide sutures and fontanels, wormian bones, delayed ossification of carpal bones, coxa valga, and avascular necrosis of the femoral head. None of the parents were affected. Maroofian et al. (2018) reported that the 2 other affected patients in this family also died suddenly of unknown cause. Inheritance The transmission pattern of Gottron-type acrogeria has suggested autosomal dominant inheritance in some families (e.g., Jansen et al., 2000 and Hadj-Rabia et al., 2014) and autosomal recessive inheritance in others (Rezai-Delui et al., 1999). Molecular Genetics In a 43-year-old man with a diagnosis of Gottron-type acrogeria, Jansen et al. (2000) identified a heterozygous mutation in the COL3A1 gene: a G-C transversion in exon 48, resulting in a gly1006-to-arg substitution. However, the article made no mention of vascular imaging in the patient. In a 36-year-old man with a diagnosis of Gottron-type acrogeria, Hadj-Rabia et al. (2014) excluded mutation in the COL3A1 gene. By screening for mutation in the LMNA gene (150330), they identified a heterozygous transition (c.1771T-A) in exon 11, resulting in a cys591-to-ser substitution. The patient reported that his father was affected, but his DNA was not available for study. Maroofian et al. (2018) studied the consanguineous Iranian family in which 4 members were described by Rezai-Delui et al. (1999) as having an autosomal recessive form of Gottron-type acrogeria. Because no biologic samples from the 4 deceased patients were available, they directly sequenced the LMNA and ZMPSTE24 (606480) genes in the parents and 1 healthy sib of 2 affected sibs. No mutations were found in the LMNA gene, but the parents and the proband's unaffected brother were heterozygous for a 3-bp deletion (c.1052_1054delTTA) in exon 8 of the ZMPSTE24 gene, predicted to result in deletion of an isoleucine (Ile351del) in the highly conserved transmembrane helix VI region. The variant was not found in the 1000 Genomes Project, dbSNP, Exome Variant Server, or the Greater Middle East Variome Project databases or in an in-house ethnically matched database. It was found in 1 of 246,128 alleles in the gnomAD database. The authors noted that in the absence of DNA or cells derived from any of the patients, the link between this novel mutation, in its homozygous state, and the Gottron acrogeria phenotype cannot be established confidently in this family. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

ACROGERIA, GOTTRON TYPE

c0238590

omim

https://www.omim.org/entry/201200

{"omim": ["201200"], "orphanet": ["2500"], "synonyms": ["Alternative titles", "METAGERIA", "ACROMETAGERIA"]}

Distal 7q11.23 microduplication syndrome is a rare chromosomal anomaly characterized by a predominantly neuropsychiatric phenotype with a few dysmorphic characteristics. Speech delay, learning difficulties, attention deficit hyperactivity disorder, bipolar disorder and aggressiveness have been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Distal 7q11.23 microduplication syndrome

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=261102

{"icd-10": ["Q92.3"], "synonyms": ["Distal dup(7)(q11.23)", "Distal trisomy 7q11.23", "Dup7q11.23D"]}

A number sign (#) is used with this entry because of evidence that familial British dementia (FBD) is caused by heterozygous mutation in the ITM2B gene (603904) on chromosome 13q14. Familial Danish dementia (FDD; 117300) is also caused by mutation in the ITM2B gene. Clinical Features Worster-Drought et al. (1933) described 9 affected persons in 3 generations. Onset occurred between 40 and 60 years of age with early onset of spasticity with increased deep tendon reflexes and tone. Muscular rigidity was present only late in the illness, with legs maintained rigidly in extension with pronounced resistance to passive movement in any direction. There was truncal ataxia and Romberg sign, but no impairment of the optic nerves. No tremors, spontaneous movements, or sensory changes were observed. Mental deterioration was progressive, with survival as long as 13 years after onset. It began with apathy and impaired memory for recent events, and progressed to complete disorientation, with monosyllabic speech and paucity of spontaneous movement. Paresis of pyramidal and extrapyramidal type is rare in Pick disease and occurs late. No male-to-male transmission was noted by Worster-Drought et al. (1940), although 12 persons in 3 generations were affected. Pathologic examination of 1 patient by Worster-Drought et al. (1940) demonstrated widespread demyelination of the brain, especially around small hyalinized blood vessels which were surrounded by distinctive densely woven tangles of fibers and microglia that were easily distinguishable from the senile plaques seen in Alzheimer disease (AD; 104300). The perivascular formations distinguished the disorder from Binswanger disease. There was little neuronal loss, except of some cerebellar Purkinje cells, and hippocampal neurofibrillary tangles were considerably less abundant than in Alzheimer disease. The corpus callosum was severely affected, but there was sparing of U-fibers. Hyalinization of small vessels in the white matter and pia distinguished the disorder from Creutzfeldt-Jakob disease (123400), in which the blood vessels are normal. There was no abnormality of the adrenal glands. There was mild elevation of CSF protein but no serologic evidence of syphilis. Plant et al. (1990) noted that the affected sibs described by Griffiths et al. (1982) shared a common ancestor with the family described by Worster-Drought et al. (1940). They provided clinical and pathologic information on an additional family member. An MRI scan taken 3 years after the onset of symptoms at age 58 demonstrated extensive alteration of signal intensity in periventricular white matter, with sparing of U fibers, as well as abnormal signal intensity in brainstem and cerebellar white matter. Postmortem examination demonstrated small cystic infarctions in the deep periventricular white matter as well as more diffuse abnormality of the white matter, particularly in the parietal and occipital lobes. Histologic findings were similar to those reported by Worster-Drought et al. (1940), with congophilia and faint PAS-positivity noted in perivascular plaques. Molecular Genetics Studying amyloid fibrils from a patient described by Plant et al. (1990), who was a member of the pedigree reported by Worster-Drought et al. (1933), Vidal et al. (1999) identified a unique 4-kD protein subunit, which they called ABRI. This highly insoluble peptide is a fragment of a putative type II single-spanning transmembrane precursor that is encoded by the BRI gene, located on chromosome 13. A single base substitution at the stop codon of ITM2B (X267R; 603904.0001) generates a longer open reading frame, resulting in a larger, 277-residue precursor. Release of the 34 C-terminal amino acids from the mutated precursor generates the ABRI subunit. Antibodies against the amyloid or homologous synthetic peptides recognize both parenchymal and vascular lesions in FBD patients. The point mutation at the stop codon of ITM2B results in the generation of the ABRI peptide, which is deposited as amyloid fibrils causing neuronal dysfunction and dementia. The X267R mutation was present in heterozygosity in 7 affected family members, but was not found in 7 unaffected members of the pedigree, in 42 individuals with unrelated neurologic disorders, or in 71 ethnically matched control individuals. Pathogenesis Like Alzheimer disease, FBD and FDD are associated with amyloid deposition and neurodegeneration in the central nervous system. In addition, proteins of the complement system and their proinflammatory activation products, which are among the inflammatory markers associated with lesions characteristic of AD, are also associated with FBD and FDD. Rostagno et al. (2002) showed that parenchymal plaques and cerebrovascular amyloid deposits in FBD and FDD brain sections contained complement activation products of the classical and alternative pathways, including iC3b, C4d, Bb, and C5b-9. Hemolytic studies of amyloid peptides from FBD (ABri) and FDD (ADan) showed specific binding to C1q and activation of both the classical (70-75% of activation) and alternative pathways (25-30% of activation), at levels comparable to those generated by beta-amyloid 1-42 in AD. Rostagno et al. (2002) suggested that the chronic inflammatory response generated by amyloid peptides may be a contributing factor to the pathogenesis of FBD, FDD, and AD. Misc \- Onset between age 40 and 60 Neuro \- Progressive mental deterioration \- Spasticity \- Increased DTR \- Increased muscle tone \- Muscular rigidity \- No tremors, spontaneous movements or sensory changes Inheritance \- Autosomal dominant ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

CEREBRAL AMYLOID ANGIOPATHY, ITM2B-RELATED, 1

c1867773

omim

https://www.omim.org/entry/176500

{"doid": ["0070029"], "omim": ["176500"], "orphanet": ["439254", "97345"], "synonyms": ["ITM2B-related amyloidosis", "ITM2B-related cerebral amyloid angiopathy", "CEREBRAL AMYLOID ANGIOPATHY, BRITISH TYPE", "PRESENILE DEMENTIA WITH SPASTIC ATAXIA", "Alternative titles", "Familial cerebral amyloid angiopathy", "DEMENTIA, FAMILIAL BRITISH"]}

A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-2 (LCA2) is caused by homozygous or compound heterozygous mutation in the RPE65 gene (180069) on chromosome 1p31. Mutations in this gene also cause retinitis pigmentosa (RP20; 613794). Description Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). For a general description and a discussion of genetic heterogeneity of LCA, see 204000. Clinical Features Waardenburg and Schappert-Kimmijser (1963) published a pedigree that showed all normal children from 2 affected parents with Leber congenital amaurosis (LCA). The mother had 2 affected sisters and the father was the product of a first-cousin marriage. Keratoconus (or keratoglobus), a frequent feature of this condition, was not present in either parent but was found in one of the mother's affected sisters. This condition is, of course, not to be confused with Leber optic atrophy. Chung and Traboulsi (2009) noted that LCA2 is distinguished by moderate visual impairment at infancy that progresses to total blindness by mid to late adulthood. One of the unique qualities of LCA2 is that, even with profound early visual impairment, retinal cells are relatively preserved. Morimura et al. (1998) summarized the clinical criteria distinguishing retinitis pigmentosa (RP) from LCA. RP is the diagnosis given to patients with photoreceptor degeneration who have good central vision within the first decade of life. The diagnosis of LCA is given to patients who are born blind or who lose vision within a few months after birth. Both diagnostic entities feature attenuated retinal vessels and a variable amount of retinal pigmentation in older patients and a reduced or nondetectable electroretinogram (ERG) at all ages. Morimura et al. (1998) noted that there was no universally accepted diagnostic term for those patients with retinal degeneration who lose useful (ambulatory) vision during the first few years of life, with ophthalmologists considering such cases as either LCA or severe RP. Yzer et al. (2003) studied 14 patients with early-onset retinal dystrophy from 10 related Dutch families from a genetically isolated population living on a former island in the Netherlands, previously reported by Schappert-Kimmijser et al. (1959), as having a high incidence of LCA. None of the 14 newborns followed objects or made eye contact, leading their parents to suspect visual impairment within the first 3 months of life. All had night blindness, and none had photophobia, and all but 2 children showed early-onset nystagmus or developed nystagmus before 6 years of age. A wide range of visual acuities was observed at first examination, and at follow-up visual acuity had remained relatively stable in 9 patients, whereas in 4 it had deteriorated. In the 7 patients in whom color vision testing could be performed, color vision was severely disturbed and tended to the tritan axis (see 190900). Visual field defects were slightly progressive, but peripheral fields remained relatively stable in 10 patients. ERGs were performed by 3 years of age in 12 patients, of whom 7 had no responses detected (5 within the first year of life); in 4 patients, severely reduced photopic responses were measured with absent scotopic responses, and in only 1 patient were both scotopic and photopic responses measured. Yzer et al. (2003) noted that the age of onset of the retinal dystrophy in these patients suggested LCA, but that several characteristics, including visual acuity, visual fields, and night blindness, led them to classify the phenotype as an early-onset severe retinal dystrophy. Al-Khayer et al. (2004) reported a 35-year-old patient with LCA due to compound heterozygosity for mutations in the RPE65 gene. She had severe visual deficits and had presented in infancy with night blindness, nystagmus, and absent rod and cone electroretinograms. Although in early childhood her visual acuity was 20/60 in both eyes and color recognition was normal, at age 35 years her acuity had declined to 2/200 in the right eye and 1/200 in the left eye. Mapping Yzer et al. (2003) performed linkage analysis in 10 related Dutch families with early-onset severe retinal dystrophy and identified homozygosity for the 'b' allele of marker D1S2803 in all but 1 affected individual from 8 informative families. Analysis of marker D1S2895, located 3 cM proximal to the RPE65 gene (180069), also revealed homozygosity of 1 allele in 5 of 8 informative families. Molecular Genetics The existence of at least 2 genetically distinct forms of Leber congenital amaurosis was established by the demonstration of Marlhens et al. (1997) that the disorder can be caused not only by mutations in the gene for retinal guanylate cyclase (600179), but also by mutations in the RPE65 gene. In 2 sibs with LCA2, they identified compound heterozygosity for mutations in the RPE65 gene: a 1-bp deletion (180069.0001) and a nonsense mutation (180069.0002) inherited from the mother and father, respectively. In 13 patients with early-onset severe retinal dystrophy from 9 related Dutch families from a genetically isolated population living on a former island, Yzer et al. (2003) analyzed the RPE65 gene and identified homozygosity for a missense mutation (Y368H; 180069.0009). A patient from another related family was found to be compound heterozygous for Y368H and a splice site mutation (180069.0010). Among 25 unaffected sibs tested, 17 were heterozygous for the Y368H mutation, and 8 did not carry the mutation. The Y368H mutation was found in 3 (3.1%) of 96 unrelated controls from the same isolated Dutch population. Yzer et al. (2003) noted that in a study of the same genetically isolated Dutch population, Schappert-Kimmijser et al. (1959) ascertained 13 LCA patients in 8 families; Yzer et al. (2003) predicted that most if not all of those patients carried the Y368H founder mutation. The Y368H founder mutation was not detected in 86 LCA patients from a different white population or in 94 controls from the Netherlands, but analysis of 75 Dutch patients with autosomal recessive or isolated retinitis pigmentosa revealed the presence of the mutation in heterozygosity in 1 Dutch patient with RP and early-onset vision loss. Al-Khayer et al. (2004) identified compound heterozygosity for mutations in the RPE65 gene (180069.0011 and 180069.0012) in a 35-year-old woman with LCA2. Clinical Management ### Gene Therapy Hauswirth et al. (2008) reported results at 90 days after RPE65 gene therapy in 3 young adults with LCA2, 2 of whom were homozygous and 1 compound heterozygous for mutations that had been previously reported to be associated with LCA and for which little or no RPE65 isomerase activity had been demonstrated by in vitro studies. The eye with worse visual function received vector administration in each case. Post-treatment visual acuity was not significantly different from baseline. All patients reported increased visual sensitivity in the study eye, especially noticeable under reduced ambient light conditions; dark-adapted full-field sensitivity testing showed significant increases compared to the control eye (p less than 0.001). Hauswirth et al. (2008) reviewed the results of 2 concurrent RPE65 gene therapy trials (Bainbridge et al., 2008; Maguire et al., 2008), but noted that outcomes were difficult to compare due to differences in technique among the 3 studies, including vector titer, area of RPE exposed to vector, and regulatory elements used to control expression of the human RPE65 cDNA, as well as large differences in visual function at baseline in each trial. Cideciyan et al. (2008) analyzed rod and cone kinetics in the 3 LCA2 patients reported by Hauswirth et al. (2008) who had undergone RPE65 gene therapy. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas, with increases up to 50-fold for cones and up to 63,000-fold for rods. Noting that visual loss in LCA2 is due to a combination of biochemical blockade of the retinoid cycle and degeneration of retinal photoreceptors, Cideciyan et al. (2008) related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area, and found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. The reconstituted retinoid cycle was not completely normal, however: although cone-sensitivity recovery time was rapid, resensitization kinetics of the newly treated rods were remarkably slow and required 8 hours or more to reach full sensitivity, compared with less than 1 hour in normal eyes. Cideciyan et al. (2009) provided follow-up on 1 of the patients previously studied by Hauswirth et al. (2008) who, 12 months after RPE65 gene therapy for LCA2, reported perception of the lowest luminance target for the first time, which was found to be accompanied by a distinct shift in fixation into the treated superotemporal retina. Further examination revealed that foveal sensitivities in her 2 eyes were similar, but the superotemporal region of the treated eye was remarkably different from the cone blindness in the comparable region of the untreated eye. Cideciyan et al. (2009) concluded that the change in fixation was driven by treatment-created extrafoveal cone vision with better sensitivity and greater expanse than the untreated foveal region, suggesting the slow development of a 'pseudo-fovea' and an underlying experience-dependent plasticity of the adult visual system. Maguire et al. (2009) assessed the retinal and visual function in 12 patients aged 8 to 44 years with RPE65-associated Leber congenital amaurosis who had received 1 subretinal injection of adeno-associated virus (AAV) containing the RPE65 gene in the worse eye at low (1.5 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years. Patients had at least 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. Gene therapy was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision. Animal Model Aguirre et al. (1998) described a 4-bp deletion in the RPE65 gene in a form of retinal dystrophy in dogs of the Swedish Briard breed. The disorder was initially described by Narfstrom et al. (1989) as a stationary disorder analogous to human congenital stationary night blindness (CSNB). The disorder was later described as having a progressive component and was termed hereditary retinal dystrophy (Wrigstad et al., 1994). Aguirre et al. (1998) studied 10 Briard dogs affected with what has been called CSNB in the U.S. The dogs originated from stock in the U.S., Canada, and France. Identification of the same mutation in all of these dogs suggested a founder effect. Brain \- Hypoplastic cerebellar vermis Neuro \- Mental retardation Eye \- Pigmentary retinopathy \- Blindness \- Central visual loss \- Fundus atrophy \- Cataract \- Keratoconus \- Photophobia \- Eye poking \- Reduced electroretinogram (ERG) Inheritance \- Autosomal recessive with at least 6 different loci ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

LEBER CONGENITAL AMAUROSIS 2

c0339527

omim

https://www.omim.org/entry/204100

{"doid": ["0110016"], "mesh": ["D057130"], "omim": ["204100"], "orphanet": ["65"], "synonyms": ["Alternative titles", "AMAUROSIS CONGENITA OF LEBER II"], "genereviews": ["NBK531510"]}

A rare intestinal condition characterized by an abnormal communication between the lower rectum and the perianal skin, which usually develops after an acute perianal abscess. A fistulous traject may be established on either side of the anus (never in the midline) and mucous or fecal discharge can appear. The skin around the external orifice can be irritated. Males are more often affected than females. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Anal fistula

c0205929

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228113

{"mesh": ["D012003"], "umls": ["C0205929"], "icd-10": ["K60.3"]}

A number sign (#) is used with this entry because infantile epileptic encephalopathy-13 (EIEE13) is caused by heterozygous mutation in the SCN8A gene (600702) on chromosome 12q13. For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350). Clinical Features Veeramah et al. (2012) reported a girl with early-onset epileptic encephalopathy. She developed refractory generalized seizures at age 6 months. At age 4 years, the seizure phenotype changed to epileptic spasms, followed by regression of speech and language skills. She also had developmental delay, intellectual disability, hypotonia, and difficulties with coordination and balance. The language and communication problems, in combination with regression in social interaction and the development of obsessive-compulsive and repetitive behaviors, led to the classification of autism at age 5 years. Initial electroencephalogram (EEG) showed bifrontal spikes and brief bursts of generalized spike-wave activity. Later EEG showed diffuse slowing, multifocal spikes, and frontally predominant generalized spikes. Brain MRI was normal. The patient died suddenly at age 15 years. There was no family history of a similar disorder. Carvill et al. (2013) identified a heterozygous mutation in the SCN8A gene (L1290V; 600702.0003) in a boy with EIEE13. The mutation was inherited from his father, who was found to be somatic mosaic for the mutation. No further clinical information was provided. The patient was part of a cohort of 500 cases of epileptic encephalopathy who underwent sequencing of candidate genes; he was the only patient found to carry an SCN8A mutation. Ohba et al. (2014) reported 7 unrelated children with EIEE13 ranging between 1 and 13 years of age. Five patients were Japanese and 2 were Israeli. Two patients had onset of intractable seizures in the first days of life, and 5 had onset between 3 and 7 months of age. Seizure type was variable and included tonic-clonic, absence, and atonic. All patients had developed delayed psychomotor development with severe to profound intellectual disability; 3 were bedridden at the time of the report. Brain imaging showed mild cerebral atrophy in all but 1 patient. Initial EEG was normal in 4 patients, but most eventually showed some abnormalities. Over time, 1 patient became seizure-free with medication and 3 were controlled with medication. De Kovel et al. (2014) reported a 3-year-old girl with EIEE13 who had onset of intractable seizures at age 6 months. She had slightly delayed development in early infancy, but showed development regression, progressive microcephaly, and severe psychomotor retardation after seizure onset. EEG showed hypsarrhythmia, and seizures continued despite multiple medications. Brain imaging was initially normal but showed diffuse brain atrophy, mild cerebellar atrophy, and interrupted myelination at age 9 months. At age 3 years, she was unable to sit without support and had no speech. Molecular Genetics In a girl with infantile epileptic encephalopathy-13, Veeramah et al. (2012) identified a de novo heterozygous mutation in the SCN8A gene (N1768D; 600702.0002). The mutation was identified by whole-genome sequencing. In vitro functional expression studies showed that the mutation caused a dominant gain-of-function effect, with neuronal hyperexcitability, persistent sodium currents, incomplete channel inactivation, increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency. Whole-genome sequencing also identified putative recessive variants in the NRP2 (602070) and UNC13C (614568) genes in the proband, which may have contributed to the phenotype. In 7 unrelated patients with early-onset epileptic encephalopathy, Ohba et al. (2014) identified 7 different de novo heterozygous missense mutations in the SCN8A gene (see, e.g., 600702.0004-600702.0006). Whole-exome or targeted capture sequencing detected mutations in 6 (10%) of 60 patients with EIEE and in 1 (16.7%) of 6 patients diagnosed clinically with malignant migrating partial seizures of infancy (MMPSI). Functional studies of the variants were not performed, but all occurred at highly conserved residues scattered throughout the gene with variable predicted effects. There were no apparent genotype-phenotype correlations. In a 3-year-old girl with EIEE13, de Kovel et al. (2014) identified a de novo heterozygous missense mutation in the SCN8A gene (R223G; 600702.0007). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro cellular functional expression studies showed that the mutant protein had significantly reduced stability (about 20% of wildtype) and that the mutant channel had reduced peak current amplitude (20% of wildtype) at 37 degrees C. There was a 3-fold increase in the ramp current at 30 degrees C, but this was still a significant reduction in terms of absolute current levels. The findings were consistent with a loss-of-function effect. De Kovel et al. (2014) noted that SCN8A is expressed in inhibitory neurons, where a loss of function may yield an epileptic phenotype. Genotype/Phenotype Correlations In 2 unrelated patients with EIEE13, Blanchard et al. (2015) identified 2 different de novo heterozygous missense mutations in the SCN8A gene (N984K, 600702.0008 and G1451S, 600702.0009). The patients were ascertained from a cohort of 500 patients with intellectual disability and 100 patients with a movement disorder who underwent exome sequencing. In vitro functional expression studies showed that the N984K mutation resulted in increased channel opening and increased neuronal excitability, consistent with a gain of function, whereas the G1451S mutation resulted in decreased current density, consistent with a loss of function. The patient with the N984K mutation had onset of intractable seizures at age 6 weeks and severe developmental delay with no speech and inability to sit independently at age 7 years; the patient with the G1451S mutation had a slightly less severe phenotype, with onset of seizures at age 18 months, moderate to severe developmental delay, spastic tetraplegia, ataxia, and nystagmus with cerebellar atrophy at age 33 years. Blanchard et al. (2015) concluded that SCN8A mutations resulting in a gain of function may result in a more severe phenotype, but noted that the G1451S mutation may also have some gain-of-function effects that were not detected in the cellular assay. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly, progressive (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Seizures, refractory \- Epileptic encephalopathy \- Epileptic spasms \- Delayed psychomotor development \- Psychomotor regression \- Intellectual disability \- Impaired coordination \- Impaired balance \- Speech and language regression \- Generalized spike-wave activity seen on EEG \- Diffuse slowing \- Multifocal spikes \- Slow spike-wave discharges \- Cerebral atrophy (in some patients) Behavioral Psychiatric Manifestations \- Autism MISCELLANEOUS \- Onset of seizures before age 2 years MOLECULAR BASIS \- Caused by mutation in the voltage-gated sodium channel, type VIII, alpha subunit gene (SCN8A, 600702.0002 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 13

c3281191

omim

https://www.omim.org/entry/614558

{"doid": ["0080445"], "omim": ["614558"], "orphanet": ["442835"], "synonyms": ["Undetermined EOEE"], "genereviews": ["NBK379665"]}

Congenital heart disease characterized by underdevelopment of the structures on the right side of the heart commonly associated with atrial septal defect Hypoplastic right heart syndrome SpecialtyCardiology Hypoplastic right heart syndrome is a congenital heart defect in which the right atrium and right ventricle are underdeveloped. This defect causes inadequate blood flow to the lungs and thus, a blue or cyanotic infant.[1] ## Contents * 1 Symptoms * 2 Causes * 3 Pathogenesis * 3.1 Anatomy * 4 Diagnosis * 5 Treatment * 5.1 Follow-up care * 6 Prevalence * 7 References * 8 External links ## Symptoms[edit] Common symptoms include a grayish-blue (cyanosis) coloration to the skin, lips, fingernails and other parts of the body.[2] Other pronounced symptoms can be rapid/difficulty breathing, poor feeding, cold hands or feet, or being inactive and drowsy. "In a baby with hypoplastic left heart syndrome, if the natural connections between the heart's left and right sides (foramen oval and ductus arteriosus) are allowed to close, he or she may go into shock." Signs of shock can include cool or clammy skin, a weak or rapid pulse, and dilated pupils.[3] ## Causes[edit] The Notch-signaling pathway is involved in multiple processes during heart development, along with Wnt signaling. Cardiomyocyte differentiation, patterning of the different cardiac regions, valve development, ventricular trabeculation, and outflow tract development have all been shown to depend on the activity of specific Notch-signaling elements. The importance of Notch signaling in human disease is evident from the discovery that many mutations in components of this pathway are inherited in several genetic and acquired disorders, though one cannot acquire hypoplastic right heart syndrome. Some of the mutations are thought to be on chromosome 2. Other deletions are thought to be chromosomal arms 9q34 and 20p12, which contain NOTCH1 and JAG1 and deletion of band q22 or q24. Wnt signaling also plays a role along with Notch 1,2 and JAG in the formation of cardiac tissues and heart development. When there are mutations in the Notch and Wnt pathways, Notch and Wnt are either not signaled or inhibited. These pathways have to signal proteins and other pathways, like Tbx2, 3 and 20, Bmp2, 10, and Hey1 and 2 which play a major role in different parts of the heart developing. When these proteins and other pathways are not signaled or are inhibited abnormalities form. ## Pathogenesis[edit] When the right side of the heart is more underdeveloped than the left side, this is known as hypoplastic right heart syndrome. HRHS is known for the pulmonary atresia valves, the tricuspid valve, and the hypoplastic pulmonary artery fail to form properly. HRHS also causes the right ventricle to be a fair amount smaller than the left side.[2] In people with hypoplastic right heart syndrome, the heart is not able to adequately pump blood to the lungs. The result of this is an inadequate supply of oxygenated blood to be circulated to the body. The severity of underdevelopment varies for each individual. A special team of pediatric cardiologists is required to develop a treatment plan. ### Anatomy[edit] A healthy heart has four valves, separated by flaps that open and close to control blood flow between the chambers. When the heart beats, oxygen-poor blood enters the right atrium. The blood then flows into the right ventricle, where it enters the pulmonary artery to travel to the lungs for oxygen. Oxygen-rich blood returns to the left atrium, where it then travels into the left ventricle. The left ventricle pushes the oxygenated blood into the aorta to be circulated to the rest of the body.[4] The heart is a mesoderm-derived organ; Mesoderm is the middle germ layer of an embryo, whose formation is regulated by various genes. Initially, the most important is expression of Nkx2.5, CR1, pitx2, anf and mhc2a, is responsible for differentiation of the types of cardiomyocytes to determine which part of the heart they go to. In a later in differentiation, activation of hand1, hand2 and other genes was revealed to help in development. Expression of these genes expression is regulated by various processes, including transcription and growth factors, as well as proteins like fibrillin, Wnt, BMP2, BMP 4, BMP5, BMP7, which aid in different heart development features like the valves and septum, and other substances, such as retinoid and folic acid. Crucial steps in heart formation are development of the ventricles and atrium formation, as well as septation and valve formation. Any disturbances of such processes may lead to various congenital heart diseases and defects that could be initiated by various genetic, epigenetic or environmental factors. The most common heart malformations from genetic or epigenetic problems are: stenosis of the aorta and pulmonary trunk, which is a narrowing of the vessels, atrial and/or ventricular septal defect, tricuspid atresia, hypoplastic left and right heart. When you have hypoplastic right or left heart more than one of these problems occur together. ## Diagnosis[edit] If a cardiac anomaly is suspected in a routine ultrasound during pregnancy, often a perinatologist (maternal-fetal specialist) will perform a fetal echocardiogram (noninvasive ultrasound of the fetus heart), which may be able to confirm a diagnosis of HRHS. This can help with possible options for treatment.[5][6] ## Treatment[edit] There is no cure for hypoplastic right heart syndrome. A three-stage surgical procedure is commonly used to treat the condition. The surgeries rearrange the blood flow within the heart and allow the left ventricles to do the work for the underdeveloped right side of the heart. The three surgeries are spread out over the patients first few years of life. The first procedure, usually either the Norwood procedure or BT shunt, is typically done within the first few days or weeks of life. The second procedure, called the Glenn procedure, is usually performed between four and twelve months of age. The last surgery, known as the Fontan procedure, is typically performed around the age of 18 months and older. These surgeries change the blood flow to the lungs so that there is always oxygenated blood. In a stage 1 Norwood procedure for hypoplastic right heart, the main pulmonary artery is separated from the left and right portions of the pulmonary artery and joined with the upper portion of the aorta. The proximal pulmonary artery is connected to the aortic arch, while the narrowed segment of the pulmonary trunk is repaired. An aortopulmonary shunt is created to connect the aorta to the main pulmonary artery to provide pulmonary blood flow to the lungs. The Glenn procedure disconnects the superior vena cava from the heart and connects it to the right pulmonary artery so deoxygenated blood from the upper body goes directly to the lungs. The Fontan procedure, done usually after the patient is two years old, disconnects the inferior vena cava from the heart and connects it directly with the other pulmonary artery so that deoxygenated blood from the lower body then is sent directly to the lungs. ### Follow-up care[edit] With a series of operations or even a heart transplant, a newborn can be treated but not be cured. Young individuals who have undergone reconstructive surgery must refer to a cardiologist who is experienced in congenital heart diseases,[7] "Children with HLHS are at an increased level for developing endocarditis." Kids that have been diagnosed with HRHS must limit the physical activity they participate in to their own endurance level.[8] ## Prevalence[edit] Hypoplastic right heart syndrome is less common than hypoplastic left heart syndrome within the United States alone it occurs in 1 in 60,000 births as opposed to the latter that occurs in 1 in 4,300 births.[2][5][9] This rare anomaly requires prenatal diagnosis since it needs immediate and emergency treatment. Pregnant women whose pregnancy is complicated with this anomaly should be referred to a level 3 hospital with pediatric cardiology and pediatric cardiothoracic surgical team. It can be associated with aortic stenosis.[10] ## References[edit] 1. ^ "Hypoplastic right heart syndrome". Genetic and Rare Diseases Information Center (GARD). Retrieved 17 April 2018. 2. ^ a b c CHD-UK, Hypoplastic Right heart Syndrome (HRHS), 2007-2015. 25 April 2015. 3. ^ Mayo Foundation for Medical Education and Research, Hypoplastic Left Heart Syndrome, 1998-2015. 12 April 2015. 4. ^ Heart Contraction and Blood Flow Archived 2014-10-07 at the Wayback Machine. National Institutes of Health. 5. ^ a b "Hypoplastic Right Heart Syndrome (HRHS): Diagnosis & Treatment | SSM Health". 6. ^ Barrett, Heidi (January 11, 2016). "Hypoplasia of the Right Ventricle". 7. ^ Reviewed by David J. Goldberg, MD, About Hypoplastic Left Heart Syndrome (HLHS), 2013-2015. Web. 12 April 2015 8. ^ American Heart Association, Single Ventricle Defects, 2015. 12 April 2015. 9. ^ Paulick J, Tennstedt C, Schwabe M, Körner H, Bommer C, Chaoui R (May 2004). "Prenatal diagnosis of an isochromosome 5p in a fetus with increased nuchal translucency thickness and pulmonary atresia with hypoplastic right heart at 14 weeks". Prenat. Diagn. 24 (5): 371–4. doi:10.1002/pd.877. PMID 15164412. 10. ^ Sharma J, Friedman D, Schiller M, Flynn P, Alonso ML (December 1997). "Aortic stenosis in hypoplastic right heart syndrome, associated with interstitial deletion of chromosome 2". Int. J. Cardiol. 62 (3): 199–202. doi:10.1016/S0167-5273(97)00255-6. PMID 9476678. ## External links[edit] Classification D * ICD-10: Q22.6 * ICD-9-CM: 746.8 (CDC/BPA 746.882) * v * t * e Congenital heart defects Heart septal defect Aortopulmonary septal defect * Double outlet right ventricle * Taussig–Bing syndrome * Transposition of the great vessels * dextro * levo * Persistent truncus arteriosus * Aortopulmonary window Atrial septal defect * Sinus venosus atrial septal defect * Lutembacher's syndrome Ventricular septal defect * Tetralogy of Fallot Atrioventricular septal defect * Ostium primum Consequences * Cardiac shunt * Cyanotic heart disease * Eisenmenger syndrome Valvular heart disease Right * pulmonary valves * stenosis * insufficiency * absence * tricuspid valves * stenosis * atresia * Ebstein's anomaly Left * aortic valves * stenosis * insufficiency * bicuspid * mitral valves * stenosis * regurgitation Other * Underdeveloped heart chambers * right * left * Uhl anomaly * Dextrocardia * Levocardia * Cor triatriatum * Crisscross heart * Brugada syndrome * Coronary artery anomaly * Anomalous aortic origin of a coronary artery * Ventricular inversion *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Hypoplastic right heart syndrome

c0344963

wikipedia

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

{"gard": ["2922"], "umls": ["C0265856", "C0344963"], "orphanet": ["98723"], "wikidata": ["Q17091221"]}

A rare, lethal skeletal dysplasia characterized by short limbed dwarfism, osteogenesis imperfecta, and punctate calcification within cartilage. It has been described in less than ten cases. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Astley-Kendall dysplasia

c1300228

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85175

{"mesh": ["C535392"], "umls": ["C1300228"], "icd-10": ["Q77.3"]}

Not to be confused with Dental cyst. Relative incidence of odontogenic cysts.[1] Paradental cyst is labeled at right. Paradental cysts constitute a family of inflammatory odontogenic cyst, that typically appear in relation to crown or root of partially erupted molar tooth. When the cyst is developed in the distal region of partially erupted third molar or in other locations in the dentition, it called simply paradental cyst, but the unique cyst that developed in the buccal bifurcation region of the mandibular first molars in the second half of the first decade of life is called buccal bifurcation cyst and has unique clinical features and management considerations in comparison to the other paradental cysts.[2] ## See also[edit] * Cyst * Odontogenic cyst ## References[edit] 1. ^ Leandro Bezerra Borges; Francisco Vagnaldo Fechine; Mário Rogério Lima Mota; Fabrício Bitu Sousa; Ana Paula Negreiros Nunes Alves (2012). "Odontogenic lesions of the jaw: a clinical-pathological study of 461 cases". Revista Gaúcha de Odontologia. 60 (1). 2. ^ Zadik Y, Yitschaky O, Neuman T, Nitzan DW (May 2011). "On the Self-Resolution Nature of the Buccal Bifurcation Cyst". J Oral Maxillofac Surg. 69 (7): e282–4. doi:10.1016/j.joms.2011.02.124. PMID 21571416.[dead link] This article related to pathology 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

Paradental cyst

c0031087

wikipedia

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

{"mesh": ["D010509"], "wikidata": ["Q11546777"]}

Distal 17p13.3 microdeletion syndrome is a rare partial monosomy of the short arm of chromosome 17 with a variable phenotype characterized by prenatal and postnatal growth retardation, developmental delay, mild intellectual disability, macrocephaly, mild facial dysmorphisms including prominent forehead, hypertelorism, thick upper and/or lower lip vermillion, and structural abnormalities of the brain variably including white matter abnormalities, prominent Virchow-Robin spaces, Chiari I malformation, corpus callosum hypoplasia, but no lissencephaly. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Distal 17p13.3 microdeletion syndrome

c4707092

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=261257

{"icd-10": ["Q93.5"], "synonyms": ["Distal del(17)(p13.3 )", "Distal monosomy 17p13.3"]}

Stark (1940) observed congenital weakness of cranial nerves III, IV and VII in 2 sisters and a brother from a consanguineous mating. Thomas (1898) described congenital facial paralysis in 2 brothers who also had malformed external ears. Cadwalader (1922) reported affected sibs from a first-cousin marriage. Inheritance \- Autosomal recessive Neuro \- Cranial nerve paresis \- Facial palsy \- Cranial nerve III, IV and VII weakness Ears \- Malformed external ears ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

CRANIAL NERVES, CONGENITAL PARESIS OF

c1857531

omim

https://www.omim.org/entry/218100

{"mesh": ["C565673"], "omim": ["218100"]}

In 2 male offspring of Kuwaiti first-cousins, Reardon et al. (1990) described congenital heart malformation and skeletal dysplasia, including coronal clefting of the vertebral bodies and short limbs. They found no report of an entirely similar case. Cardiac \- Congenital heart defect Skel \- Dysplasia \- Vertebral body coronal clefting Limbs \- Short Inheritance \- Autosomal recessive ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

CARDIOSKELETAL SYNDROME, KUWAITI TYPE

c1859327

omim

https://www.omim.org/entry/212135

{"mesh": ["C535850"], "omim": ["212135"], "orphanet": ["1354"]}

Psychological defense mechanism articulated by Alfred Adler Superiority complex is a term coined by Alfred Adler in the early 1900s, as part of his school of individual psychology. A superiority complex is a defense mechanism that develops over time to help a person cope with painful feelings of inferiority.[1][2] Individuals with this complex typically come across as supercilious, haughty, and disdainful toward others. They may treat others in an imperious, overbearing, and even aggressive manner.[3][4] In everyday usage, the term "superiority complex" is used to refer to an overly high opinion of oneself. ## Contents * 1 Alfred Adler * 2 Other interpretations * 3 Cultural examples * 4 See also * 5 References ## Alfred Adler[edit] Alfred Adler was the first to use the term superiority complex. He claimed that a superiority complex essentially came from the need to overcome underlying feelings of inferiority: an inferiority complex.[5] Throughout his works Adler intertwines the occurrence of an inferiority complex and a superiority complex as cause and effect.[6] Among his writings touching on the topic were Understanding Human Nature (1927),[7] and Superiority and Social Interest: A Collection of Later Writings, a collection of twenty-one papers written by Adler and published posthumously in 1964.[8] Adler distinguished a normal striving to achieve from superiority complexes,[9] the latter being attempts in order to overcompensate a feeling of inferiority.[5] He states that those with an inferiority complex develop a superiority complex to overcome the difficulties presented by the former, primarily by inflating their sense of self-importance in some way.[10] Dreams of heroism, and a false assumption of success,[11] revealed for Adler the reactive nature of such strivings.[12] While Adler considered what he refers to in his writing as striving for superiority was a universal of human nature,[5] he thought sound-minded individuals do not strive for personal superiority over others, rather for personal ambition and success through work. By contrast, those with an actual superiority complex were riddled with conceited fantasies, and with dreams of immutable supremacy.[13] ## Other interpretations[edit] * In contrast, an edition of the DSM-IV-TR that was published about twenty years after Alfred Adler's works disagreed that superiority complex (under the formal name of grandiose delusion in the DSM IV) came solely from the effects of an inferiority complex.[14] The DSM IV states that a second cause to this delusional disorder could stem from an exaggerated emotional state. * Ada Kahn has argued that the superiority and inferiority complexes cannot both be found in the same individual, since an individual with a superiority complex truly believes that they are superior to others.[15] She claimed that - whereas an inferiority complex may manifest with the behaviors that are intended to show others that one is superior, such as expensive material possessions, or an obsession with vanity and appearances to conceal feelings of inadequacy - superiority complex sufferers do not always care about image or vanity, since they have innate feelings of superiority, and thus do not usually concern themselves with proving their superiority to others. * Vera Hoorens say that those exhibiting the superiority complex have a self-image of supremacy.[16] Whereas individuals with an inferiority complex tend to present themselves in the best light possible, those with a superiority complex may not even attempt to make themselves look good, or to express their superiority to others. They may speak as if they are all-knowing and better than others, but ultimately do not care if others think so or not, much like with the cognitive bias known as illusory superiority.[16] Accordingly, they may be viewed in a negative light by those around them, since they are not concerned with the opinions of others about themselves. Other people may not distinguish between those with low self-opinion who care deeply about the opinion of others, and those with the actual complex, who feel superior and with high self-esteem, and do not care at all about the opinion of others. ## Cultural examples[edit] * Driven to achieve in order to overcompensate his humble origins, and small stature,[17] Picasso was described by his ex, Fernande Olivier, as possessing a superiority complex: "He said he could only be touched by things to which he felt superior".[18] * Beethoven's nobility pretence was the result of a superiority complex;[19] but it was the same complex that fuelled his extraordinary musical achievements. As Ernst Bloch said of the young musician's boastful claims, "This piece of presumption was needed to enable him to become Beethoven".[20] ## See also[edit] * Psychology portal * Society portal * Complex * Dunning–Kruger effect * Egotism * God complex * Hubris * Impostor syndrome * Inferiority complex * Megalomania * Narcissism * Narcissistic personality disorder * Self-righteousness * Superior (hierarchy) * Supremacy ## References[edit] 1. ^ Alfred Adler, The Neurotic Constitution: Outlines of a Comparative Individualistic Psychology and Psychotherapy, trans. Bernard Glueck and John E. Lind (New York: Moffat, Yard & Co., 1917), xvii ("... so the traits of character, especially the neurotic ones, serve as a psychic means and form of expression for the purpose of entering into an account with life, for the purpose of assuming an attitude, of gaining a fixed point in the vicissitudes of life, for the purpose of reaching that security-giving goal, the feeling of superiority."). 2. ^ "American Heritage Dictionary of the English Language". ahdictionary.com (5th ed.). 2018. Retrieved 5 October 2020. 3. ^ Alfred Adler, The Neurotic Constitution: Outlines of a Comparative Individualistic Psychology and Psychotherapy, trans. Bernard Glueck and John E. Lind (New York: Moffat, Yard & Co., 1917), 327 ("Usually one sees deviations and circuitous paths in following which the sadistic trait seems wholly or in part lost. In this way the neurotic succeeds in gaining superiority over the weak, or he operates on this new line so skillfully as to manage to set up an aggression which enables him to dominate and torture others."). 4. ^ "superiority complex". Medical Dictionary for the Health Professions and Nursing. Retrieved 5 October 2020. "...a constellation of behaviors–eg, aggressiveness, assertiveness, self-aggrandization, etc, which may represent overcompensation for a deep-rooted sense of inadequacy." 5. ^ a b c Adler, Alfred, 1870-1937 (1964-12-30). The Individual Psychology of Alfred Adler : a Systematic Presentation in Selections from His Writings (First ed.). New York. ISBN 9780061311543. OCLC 5692434.CS1 maint: multiple names: authors list (link) 6. ^ H Mosak, Primer of Adlerian Psychology (2013) p 83 7. ^ "PsycNET". psycnet.apa.org. Retrieved 2019-11-07. 8. ^ "PsycNET". psycnet.apa.org. Retrieved 2019-11-07. 9. ^ R Sharf, Theories of Psychotherapy and Counselling (2011) p. 130 10. ^ R Scharf, Theories of Psychotherapy and Counselling (2011) p. 130 11. ^ A Adler, Collected Clinical Works of Alfred Adler (2002) p. 78 12. ^ H Mosak, Primer of Adlerian Psychology (2013) p 83 13. ^ R Gregory ed., The Oxford Companion to the Mind (1987) p. 368 and p. 6 14. ^ Diagnostic and statistical manual of mental disorders : DSM-IV. American Psychiatric Association., American Psychiatric Association. Task Force on DSM-IV. (4th ed.). Washington, DC: American Psychiatric Association. 1994. ISBN 0890420610. OCLC 29953039.CS1 maint: others (link) 15. ^ Kahn, Ada P. (2000). Facing fears : the sourcebook for phobias, fears, and anxieties. Doctor, Ronald M. (Ronald Manual). New York: Checkmark Books. ISBN 0816039925. OCLC 42603180. 16. ^ a b Hoorens, Vera (December 1995). "Self-Favoring Biases, Self-Presentation, and the Self-Other Asymmetry in Social Comparison". Journal of Personality. 63 (4): 793–817. doi:10.1111/j.1467-6494.1995.tb00317.x. ISSN 0022-3506. 17. ^ J Richardson A Life of Picasso Vol I (London 1992) p. 48-9 18. ^ Quoted in J Richardson A Life of Picasso Vol II (London 1996) p. 189 19. ^ Max Graf, From Beethoven to Shostakovich (2013) 20. ^ Quoted in M Solomon, Beethoven Essays (London 1988) p. 55 * v * t * e Narcissism Types * Collective * Egomania * Flying monkeys * Healthy * Malignant * Narcissistic personality disorder * Spiritual * Workplace Characteristics * Betrayal * Boasting * Egocentrism * Egotism * Empathy (lack of) * Envy * Entitlement (exaggerated sense of) * Fantasy * Grandiosity * Hubris * Magical thinking * Manipulative * Narcissistic abuse * Narcissistic elation * Narcissistic rage and narcissistic injury * Narcissistic mortification * Narcissistic supply * Narcissistic withdrawal * Perfectionism * Self-esteem * Self-righteousness * Shamelessness * Superficial charm * Superiority complex * True self and false self * Vanity Defences * Denial * Idealization and devaluation * Distortion * Projection * Splitting Cultural phenomena * Control freak * Don Juanism * Dorian Gray syndrome * My way or the highway * Selfie Related articles * Codependency * Counterdependency * Dark triad * Ego ideal * "Egomania" (film) * Egotheism * Empire-building * God complex * History of narcissism * Messiah complex * Micromanagement * Narcissism of small differences * Narcissistic leadership * Narcissistic parent * Narcissistic Personality Inventory * Narcissus (mythology) * On Narcissism * Sam Vaknin * Self-love * Self-serving bias * Spoiled child * The Culture of Narcissism * Workplace bullying *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Superiority complex

None

wikipedia

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

{"wikidata": ["Q3269302"]}

A number sign (#) is used with this entry because of evidence that susceptibility to idiopathic generalized epilepsy-15 (EIG15) is caused by heterozygous mutation in the RORB gene (601972) on chromosome 9q22. Description Susceptibility to idiopathic generalized epilepsy-15 (EIG15) is an autosomal dominant seizure disorder characterized by onset of variable types of seizures in the first decade. Absence seizures are the most common manifestation, but most patients also develop other types, including clonic or generalized tonic-clonic seizures. EEG tends to show 3-Hz spike-wave discharges, whereas brain imaging is normal. The majority of patients also have developmental delay associated with impaired intellectual development apparent from infancy or early childhood (summary by Rudolf et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy, see EIG (600669). Clinical Features Rudolf et al. (2016) reported a 4-generation French family in which 4 individuals (patients 4, 13, 14, and 20) had onset of absence seizures and rare generalized tonic-clonic seizures between 3 and 11 years of age. EEG showed generalized polyspikes followed by typical 3-Hz spike-and-wave absence seizures with loss of consciousness, ocular elevation, eyelid myoclonia, and neck and shoulder myoclonia of limited amplitude, mostly triggered by intermittent photic stimulation (IPS) at eye closure. The epilepsy was controlled by medication. Three patients were noted to have mild intellectual disability (IQ range from 62 to 73). There was evidence of possible incomplete penetrance and/or phenocopies within the family: the RORB variant was also found in patient 10, who had isolated photoparoxysmal response (PPR) during IPS, but whose seizure state could not be confirmed, and in patient 23, who reportedly had 1 absence seizure at age 9 years, but refused EEG investigations. In addition, there were 3 family members (11, 15, and 21) who had isolated PPR during IPS, but they did not carry the variant; these 3 patients did not have seizures. Rudolf et al. (2016) subsequently identified 4 unrelated patients with early-onset seizures and impaired intellectual development. Patient AG1 was an 18-year-old woman who developed febrile seizures at age 3 years that progressed to febrile and nonfebrile generalized tonic-clonic seizures. Initially refractory, the seizures eventually were controlled with medication, and she became seizure-free off medication during her teenage years. She had developmental delay since age 15 months, abnormal behaviors such as stereotypies, compulsive behaviors, and aggression, autism spectrum disorder, significant sleep disturbances, and moderate to severe cognitive deficits (IQ of 40). Patient RO1 was a 4-year-old boy who developed clonic seizures at age 4 months, followed by clonic-atonic and atypical absence seizures. The seizures were refractory to medication, and EEG showed background slowing and frequent multifocal spikes. He had developmental delay beginning around 10 months of age, and later showed severe intellectual impairment with a developmental quotient of 50%. The remaining 2 patients had onset of absence and/or generalized seizures between 2 and 4 years of age. A 10-year-old girl (patient GE0705) had refractory seizures, eyelid myoclonia triggered by IPS, and global developmental delay with learning difficulties, speech impairment, and IQ less than 50. She also had strabismus and hypermetropia. A 28-year-old man (patient EC-CAE300) had variable seizure types that were partially responsive to treatment, learning difficulties, dyslexia, and behavioral problems with aggressive features. Brain imaging was normal in all 4 patients. Inheritance The transmission pattern of EIG15 in the family reported by Rudolf et al. (2016) was consistent with autosomal dominant inheritance with possible incomplete penetrance. Molecular Genetics In 4 affected members of a 4-generation French family with EIG15, Rudolf et al. (2016) identified a heterozygous nonsense mutation in the RORB gene (R66X; 601972.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed that the mutant transcript escaped nonsense-mediated mRNA decay, but no mutant protein was detected in the nucleoplasm of transfected COS7 cells, consistent with a loss of function. There was evidence of possible incomplete penetrance and/or phenocopies within the family. Three additional unrelated patients with a similar phenotype were found to have de novo heterozygous point mutations or intragenic deletions in the RORB gene (601972.0002-601972.0004). Molecular modeling suggested that some of these mutations would interfere with DNA binding or be pathogenic; additional functional studies of the variants and studies of patients cells were not performed. Three additional patients with a similar phenotype who had larger or more complex deletions or translocations involving the RORB gene were also identified, suggesting that RORB plays a role in neurodevelopment and possibly neuronal hyperexcitability. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Eyelid myoclonus \- Abnormal cortical paroxysmal response to intermittent photic stimulation \- Photosensitivity NEUROLOGIC Central Nervous System \- Seizures, variable types, early-onset \- Absence seizures \- Tonic seizures \- Tonic-atonic seizures \- Generalized tonic-clonic seizures \- Myoclonus \- Developmental delay \- Impaired intellectual development, mild to severe \- Learning disabilities \- Speech delay \- Generalized polyspikes seen on EEG \- 3-Hz spike-wave discharges \- Background slowing (in some patients) Behavioral Psychiatric Manifestations \- Behavioral problems, variable (in some patients) \- Aggression \- Autistic features MISCELLANEOUS \- Onset in first decade \- Variable phenotype \- Seizures may initially be refractory to medication \- Incomplete penetrance \- De novo mutation (in some patients) MOLECULAR BASIS \- Caused by mutation in the RAR-related orphan receptor B gene (RORB, 601972.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

EPILEPSY, IDIOPATHIC GENERALIZED, SUSCEPTIBILITY TO, 15

None

omim

https://www.omim.org/entry/618357

{"omim": ["618357"]}

This article is about proximal femoral fractures. For fractures of the hip bone, see Pelvic fracture. Hip fracture Other namesProximal femur fracture[1] Intertrochanteric hip fracture in a 17-year-old male SymptomsPain around the hip particularly with movement, shortening of the leg[2] TypesIntracapsular, extracapsular (intertrochanteric, subtrochanteric, greater trochanteric, lesser trochanteric)[1] CausesTrauma such as a fall[1][3] Risk factorsOsteoporosis, taking many medications, alcohol use, metastatic cancer[2][1] Diagnostic methodX-ray, MRI, CT scan, bone scan[3][2] Differential diagnosisOsteoarthritis, avascular necrosis of the hip, hernia, trochanteric bursitis[3] PreventionImproved lighting, removal of loose rugs, exercise, treatment of osteoporosis[1] TreatmentSurgery[1] MedicationOpioids, nerve block[1] Prognosis~20% one year risk of death (older people)[3][1] Frequency~15% of women at some point[1] A hip fracture is a break that occurs in the upper part of the femur (thigh bone).[2] Symptoms may include pain around the hip, particularly with movement, and shortening of the leg.[2] Usually the person cannot walk.[3] They most often occur as a result of a fall.[3] Risk factors include osteoporosis, taking many medications, alcohol use, and metastatic cancer.[2][1] Diagnosis is generally by X-rays.[2] Magnetic resonance imaging, a CT scan, or a bone scan may occasionally be required to make the diagnosis.[3][2] Pain management may involve opioids or a nerve block.[1][4] If the person's health allows, surgery is generally recommended within two days.[2][1] Options for surgery may include a total hip replacement or stabilizing the fracture with screws.[2] Treatment to prevent blood clots following surgery is recommended.[1] About 15% of women break their hip at some point in life;[1] women are more often affected than men.[1] Hip fractures become more common with age.[1] The risk of death in the year following a fracture is about 20% in older people.[3][1] ## Contents * 1 Signs and symptoms * 1.1 Complications * 1.1.1 Medical * 2 Risk factors * 3 Mechanism * 3.1 Functional anatomy * 3.2 Biomechanics * 3.3 Neurological factors * 4 Diagnosis * 4.1 Physical examination * 4.2 Imaging * 4.3 Types * 5 Prevention * 6 Management * 6.1 Intracapsular fractures * 6.2 Trochanteric fracture * 6.3 Subtrochanteric fractures * 6.4 Rehabilitation * 6.5 Nutrition supplementation * 6.6 Surgical complications * 7 Prognosis * 7.1 Post operation * 8 Epidemiology * 8.1 Population * 8.2 Age related * 9 References * 10 External links ## Signs and symptoms[edit] the affected extremity is often shortened and unnaturally, externally rotated compared to the unaffected leg The classic clinical presentation of a hip fracture is an elderly patient who sustained a low-energy fall and now has groin pain and is unable to bear weight.[5] Pain may be referred to the supracondylar knee. On examination, the affected extremity is often shortened and unnaturally, externally rotated compared to the unaffected leg.[6] ### Complications[edit] Nonunion, failure of the fracture to heal, is common in fractures of the neck of the femur, but much more rare with other types of hip fracture. Avascular necrosis of the femoral head occurs frequently (20%) in intracapsular hip fractures, because the blood supply is interrupted.[5] Malunion, healing of the fracture in a distorted position, is very common. The thigh muscles tend to pull on the bone fragments, causing them to overlap and reunite incorrectly. Shortening, varus deformity, valgus deformity, and rotational malunion all occur often because the fracture may be unstable and collapse before it heals. This may not be as much of a concern in patients with limited independence and mobility. Hip fractures rarely result in neurological or vascular injury. #### Medical[edit] Many people are unwell before breaking a hip; it is common for the break to have been caused by a fall due to some illness, especially in the elderly. Nevertheless, the stress of the injury, and a likely surgery, increases the risk of medical illness including heart attack, stroke, and chest infection. Hip fracture patients are at considerable risk for thromboemoblism, blood clots that dislodge and travel in the bloodstream.[5] Deep venous thrombosis (DVT) is when the blood in the leg veins clots and causes pain and swelling. This is very common after hip fracture as the circulation is stagnant and the blood is hypercoagulable as a response to injury. DVT can occur without causing symptoms. A pulmonary embolism (PE) occurs when clotted blood from a DVT comes loose from the leg veins and passes up to the lungs. Circulation to parts of the lungs are cut off which can be very dangerous. Fatal PE may have an incidence of 2% after hip fracture and may contribute to illness and mortality in other cases. Mental confusion is extremely common following a hip fracture. It usually clears completely, but the disorienting experience of pain, immobility, loss of independence, moving to a strange place, surgery, and drugs combine to cause delirium or accentuate pre-existing dementia. Urinary tract infection (UTI) can occur. Patients are immobilized and in bed for many days; they are frequently catheterised, commonly causing infection. Prolonged immobilization and difficulty moving make it hard to avoid pressure sores on the sacrum and heels of patients with hip fractures. Whenever possible, early mobilization is advocated; otherwise, alternating pressure mattresses should be used.[7][8][9] ## Risk factors[edit] Hip fracture following a fall is likely to be a pathological fracture. The most common causes of weakness in bone are:[citation needed] * Osteoporosis. * Other metabolic bone diseases such as Paget's disease, osteomalacia, osteopetrosis and osteogenesis imperfecta. Stress fractures may occur in the hip region with metabolic bone disease. * Elevated levels of homocysteine, a toxic 'natural' amino acid. * Benign or malignant primary bone tumors are rare causes of hip fractures. * Metastatic cancer deposits in the proximal femur may weaken the bone and cause a pathological hip fracture. * Infection in the bone is a rare cause of hip fracture. * Tobacco smoking (associated with osteoporosis). ## Mechanism[edit] X-ray of a normal hip joint. ### Functional anatomy[edit] The hip joint, is a ball-and-socket joint. The femur connects at the acetabulum of the pelvis and projects laterally before angling medially and inferiorly to form the knee. Although this joint has three degrees of freedom, it is still stable due to the interaction of ligaments and cartilage. The labrum lines the circumference of the acetabulum to provide stability and shock absorption. Articular cartilage covers the concave area of acetabulum, providing more stability and shock absorption. Surrounding the entire joint itself is a capsule secured by the tendon of the psoas muscle and three ligaments. The iliofemoral, or Y, ligament is located anteriorly and serves to prevent hip hyperextension. The pubofemoral ligament is located anteriorly just underneath the iliofemoral ligament and serves primarily to resist abduction, extension, and some external rotation. Finally the ischiofemoral ligament on the posterior side of the capsule resists extension, adduction, and internal rotation. When considering the biomechanics of hip fractures, it is important to examine the mechanical loads the hip experiences during low energy falls.[citation needed] ### Biomechanics[edit] The hip joint is unique in that it experiences combined mechanical loads. An axial load along the shaft of the femur results in compressive stress. Bending load at the neck of the femur causes tensile stress along the upper part of the neck and compressive stress along the lower part of the neck. While osteoarthritis and osteoporosis are associated with bone fracture as we age, these diseases are not the cause of the fracture alone. Low energy falls from standing are responsible for the majority of fractures in the elderly, but fall direction is also a key factor.[10][11][12] Elderly tend to fall to the side as instead of forward, and the lateral hip and strikes the ground first.[5] During a sideways fall, the chances of hip fracture see a 15-fold and 12-fold increase in elderly males and females, respectively. ### Neurological factors[edit] Elderly individuals are also predisposed to hip fractures due to many factors that can compromise proprioception and balance, including medications, vertigo, stroke, and peripheral neuropathy.[5][13][14] ## Diagnosis[edit] ### Physical examination[edit] Displaced fractures of the trochanter or femoral neck will classically cause external rotation and shortening of the leg when the patient is laying supine.[5] ### Imaging[edit] Typically, radiographs are taken of the hip from the front (AP view), and side (lateral view). Frog leg views are to be avoided, as they may cause severe pain and further displace the fracture.[5] In situations where a hip fracture is suspected but not obvious on x-ray, an MRI is the next test of choice. If an MRI is not available or the patient can not be placed into the scanner a CT may be used as a substitute. MRI sensitivity for radiographically occult fracture is greater than CT. Bone scan is another useful alternative however substantial drawbacks include decreased sensitivity, early false negative results, and decreased conspicuity of findings due to age related metabolic changes in the elderly.[citation needed] A case demonstrating a possible order of imaging in initially subtle findings: * X-ray showing a suspected compressive subcapital fracture as a radiodense line * CT scan shows the same, atypical for a fracture since the cortex is coherent * T1-weighted, turbo spin echo, MRI confirms a fracture, as the surrounding bone marrow has low signal from edema. As the patients most often require an operation, full pre-operative general investigation is required. This would normally include blood tests, ECG and chest x-ray. ### Types[edit] Hip fracture classification.[15] Subcapital fracture in a 92-year-old woman Fracture (black arrow, pertrochanteric) versus a skin fold (white arrow). X-rays of the affected hip usually make the diagnosis obvious; AP (anteroposterior) and lateral views should be obtained. Capsule Area Classification Intracapsular femoral head AO 31-C1 - 31-C3 Pipkin classification femoral neck Subcapital AO 31-B1 - 31-B3 Garden classification, Pauwel's classification Transcervical Basicervical Extracapsular Trochanteric Intertrochanteric (between the greater and lesser trochanter[16]) AO 31-A1 - 31-A2 Evans' classification (1949), Ramadier's classification (1956), Boyd and Griffin's classification (1949), Decoulx & Lavarde's classification (1969), Ender's classification (1970), Tronzo's classification (1973), Evans-Jensen classification (1975), Deburge's classification (1976), Briot's classification (1980) Pertrochanteric (through the trochanters[16][17]) AO 31-A3 Subtrochanteric AO 32 Seinsheimer classification Trochanteric fractures are subdivided into either intertrochanteric (between the greater and lesser trochanter[16]) or pertrochanteric (through the trochanters[16][17]) by the Müller AO Classification of fractures.[18] Practically, the difference between these types is minor. The terms are often used synonymously.[19][20] An isolated trochanteric fracture involves one of the trochanters without going through the anatomical axis of the femur, and may occur in young individuals due to forceful muscle contraction.[21] Yet, an isolated trochanteric fracture may not be regarded as a true hip fracture because it is not cross-sectional. ## Prevention[edit] The majority of hip fractures are the result of a fall, particularly in the elderly. Therefore, identifying why the fall occurred, and implementing treatments or changes, is key to reducing the occurrence of hip fractures. Multiple contributing factors are often identified.[22] These can include environmental factors and medical factors (such as postural hypotension or co-existing disabilities from disease such as Stroke or Parkinson's Disease which cause visual and/or balance impairments). A recent study has identified a high incidence of undiagnosed cervical spondylotic myelopathy (CSM) amongst patients with a hip fracture.[23] This is relatively unrecognised consequent of CSM.[24] Additionally, there is some evidence to systems designed to offer protection in the case of a fall. Hip protectors, for example appear to decrease the number of hip fractures among the elderly, but they are often not used.[25] ## Management[edit] Most hip fractures are treated surgically by implanting a prosthesis. Surgical treatment outweighs the risks of nonsurgical treatment which requires extensive bedrest.[5] Prolonged immobilization increases risk of thromboembolism, pneumonia, deconditioning, and decubitus ulcers. Regardless, the surgery is a major stress, particularly in the elderly. Pain is also significant, and can also result in immobilization, so patients are encouraged to become mobile as soon as possible, often with the assistance of physical therapy. Skeletal traction pending surgery is not supported by the evidence.[26] Regional nerve blocks are useful for pain management in hip fractures.[27] Surgery can be performed under general anaesthesia or with neuraxial techniques - choice is based on surgical and patient factors, as outcomes such as mortality and post-procedure complications including pneumonia, MI, stroke or confusion, are not affected by anaesthetic technique.[28] Red blood cell transfusion is common for people undergoing hip fracture surgery due to the blood loss sustained during surgery and from the injury. Giving blood when the hemoglobin is less than 10 g/dL versus less than 8 g/dL was of unclear benefit per a 2015 Cochrane review.[29] A review in 2018 however found that waiting until the hemoglobin was less than 8 g/dL or the person had symptoms increased the risk of heart problems.[30] If operative treatment is refused or the risks of surgery are considered to be too high the main emphasis of treatment is on pain relief. Skeletal traction may be considered for long term treatment. Aggressive chest physiotherapy is needed to reduce the risk of pneumonia and skilled rehabilitation and nursing to avoid pressure sores and DVT/pulmonary embolism Most people will be bedbound for several months. Non-operative treatment is now limited to only the most medically unstable or demented patients, or those who are nonambulatory at baseline with minimal pain during transfers.[5] Surgery on the same day or day following the break is estimated to reduce postoperative mortality in people who are medically stable.[31] ### Intracapsular fractures[edit] Fracture treated with cannulated screws For low-grade fractures (Garden types 1 and 2), standard treatment is fixation of the fracture in situ with screws or a sliding screw/plate device. This treatment can also be offered for displaced fractures after the fracture has been reduced. Fractures managed by closed reduction can possibly be treated by percutaneously inserted screws.[32] In elderly patients with displaced or intracapsular fractures many surgeons prefer to undertake a hemiarthroplasty, replacing the broken part of the bone with a metal implant. However, in elderly people who are medically well and still active, a total hip replacement may be indicated. Independently mobile older adults with hip fractures may benefit from a total hip replacement instead of hemiarthroplasty.[33] Traction is contraindicated in femoral neck fractures due to it affecting blood flow to the head of the femur.[34] ### Trochanteric fracture[edit] Fracture supported by dynamic hip screw A trochanteric fracture, below the neck of the femur, has a good chance of healing. Closed reduction may not be satisfactory and open reduction then becomes necessary.[35] The use of open reduction has been reported as 8-13% among pertrochanteric fractures, and 52% among intertrochanteric fractures.[36] Both intertrochanteric and pertrochanteric fractures may be treated by a dynamic hip screw and plate, or an intramedullary rod.[35] The fracture typically takes 3–6 months to heal. As it is only common in elderly, removal of the dynamic hip screw is usually not recommended to avoid unnecessary risk of second operation and the increased risk of re-fracture after implant removal. The most common cause for hip fractures in the elderly is osteoporosis; if this is the case, treatment of the osteoporosis can well reduce the risk of further fracture. Only young patients tend to consider having it removed; the implant may function as a stress riser, increasing the risk of a break if another accident occurs.[citation needed] ### Subtrochanteric fractures[edit] Subtrochanteric fractures may be treated with an intramedullary nail or a screw-plate construction and may require traction pre-operatively, though this practice is uncommon. It is unclear if any specific type of nail results in different outcomes than any other type of nail.[37] A lateral incision over the trochanter is made and a cerclage wire is placed around the fracture for reduction. Once reduction has been achieved a guide canal for the nail is made through the proximal cortex and medullary. The nail is inserted through the canal and is fixated proximally and distally with screws. X-rays are obtained to ensure proper reduction and placement of the nail and screws are achieved. [38] ### Rehabilitation[edit] Rehabilitation has been proven to increase daily functional status. Forty percent of individuals with hip fractures are also diagnosed with dementia or mild cognitive impairment which often results in poorer post-surgical outcomes.[39] In such cases enhanced rehabilitation and care models have been shown to have limited positive effects in reducing delirium and hospital length of stay.[39] It is unclear if the use of anabolic steroids effects recovery.[40] There is not enough evidence to ascertain what are the best strategies to promote walking after hip fracture surgery.[41] ### Nutrition supplementation[edit] Oral supplements with non-protein energy, protein, vitamins and minerals started before or early after surgery may prevent complications during the first year after hip fracture in aged adults; without seemingly effects on mortality.[42] ### Surgical complications[edit] Deep or superficial wound infection has an approximate incidence of 2%. It is a serious problem as superficial infection may lead to deep infection. This may cause infection of the healing bone and contamination of the implants. It is difficult to eliminate infection in the presence of metal foreign bodies such as implants. Bacteria inside the implants are inaccessible to the body's defence system and to antibiotics. The management is to attempt to suppress the infection with drainage and antibiotics until the bone is healed. Then the implant should be removed, following which the infection may clear up. Implant failure may occur; the metal screws and plate can break, back out, or cut out superiorly and enter the joint. This occurs either through inaccurate implant placement or if the fixation does not hold in weak and brittle bone. In the event of failure, the surgery may be redone, or changed to a total hip replacement.Mal-positioning: The fracture can be fixed and subsequently heal in an incorrect position; especially rotation. This may not be a severe problem or may require subsequent osteotomy surgery for correction.[citation needed] ## Prognosis[edit] Hip fractures are very dangerous episodes especially for elderly and frail patients. The risk of dying from the stress of the surgery and the injury in the first thirty days is about 10%. At one year after fracture this may reach 30%.[43] If the condition is untreated the pain and immobility imposed on the patient increase that risk. Problems such as pressure sores and chest infections are all increased by immobility. The prognosis of untreated hip fractures is very poor.[citation needed] ### Post operation[edit] Among those affected over the age of 65, 40% are transferred directly to long-term care facilities, long-term rehabilitation facilities, or nursing homes; most of those affected require some sort of living assistance from family or home-care providers. 50% permanently require walkers, canes, or crutches for mobility; all require some sort of mobility assistance throughout the healing process. Most of the recovery of walking ability and activities of daily living occurs within 6 months of the fracture.[44] After the fracture about half of older people recover their pre-fracture level of mobility and ability to perform instrumental activities of daily living, while 40–70% regain their level of independence for basic activities of daily living.[44] Among those affected over the age of 50, approximately 25% die within the next year due to complications such as blood clots (deep venous thrombosis, pulmonary embolism), infections, and pneumonia.[citation needed] Patients with hip fractures are at high risk for future fractures including hip, wrist, shoulder, and spine. After treatment of the acute fracture, the risk of future fractures should be addressed. Currently, only 1 in 4 patients after a hip fracture receives treatment and work up for osteoporosis, the underlying cause of most of the fractures. Current treatment standards include the starting of a bisphosphonate to reduce future fracture risk by up to 50%.[citation needed] ## Epidemiology[edit] Age-standardised hip fracture rates.[45] Low (<150 / 100,000) Medium (150–250 / 100,000) High (>250 / 100,000) Hip fractures are seen globally and are a serious concern at the individual and population level. By 2050, it is estimated that there will be six million cases of hip fractures worldwide.[46] One study published in 2001 found that in the US alone, 310,000 individuals were hospitalized due to hip fractures, which can account for 30% of Americans who were hospitalized that year.[47] Another study found that in 2011, femur neck fractures were among the most expensive conditions seen in US hospitals, with an aggregated cost of nearly $4.9 billion for 316,000 inpatient hospitalizations.[48] Rates of hip fractures is declining in the United States, possibly due to increased use of bisphosphonates and risk management.[49] Falling, poor vision, weight, and height are all seen as risk factors. Falling is one of the most common risk factors for hip fractures. Approximately 90% of hip fractures are attributed to falls from standing height.[50] Given the high morbidity and mortality associated with hip fractures and the cost to the health system, in England and Wales, the National Hip Fracture Database is a mandatory nationwide audit of care and treatment of all hip fractures.[citation needed] ### Population[edit] All populations experience hip fractures but numbers vary with race, gender, and age. Women suffer three times as many hip fractures as men.[51] In a lifetime, men have an estimated 6% risk whereas postmenopausal women have an estimated 14% risk of suffering a hip fracture.[52] These statistics provide insight over a lifespan, and conclude that women are twice as likely to suffer a hip fracture. The overwhelming majority of hip fractures occur in white individuals, while blacks and Hispanics have a lower rate of them. This may be due to their generally greater bone density and also because whites have longer overall lifespan and higher likelihood of reaching an advanced age where the risk of breaking a hip goes up.[52] Deprivation is also a key factor: in England it has been found that people in the poorest parts of the country are more likely to fracture a hip and less likely to recover well than those in the least deprived areas.[53] ### Age related[edit] Age is the most dominant factor in hip fracture injuries, with most cases occurring in people over 75. The increase of age is related to the increase of the incidence of hip fracture,[46] which is the most frequent cause of hospitalization in centenarians, overcoming congestive heart failure and respiratory infection.[54] Falls are the most common cause of hip fractures; around 30–60% of older adults fall each year. This increases the risk for hip fracture and leads to the increase risk of death in older individuals, the rate of one year mortality is seen from 12–37%.[55] For those remaining patients who do not suffer from mortality, half of them need assistance and cannot live independently. Also, older adults sustain hip fractures because of osteoporosis, which is a degenerative disease due to age and decrease in bone mass. The average age for suffering a hip fracture is 77 years old for women and 72 years old for men.[56] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q Ferri FF (2017). Ferri's Clinical Advisor 2018 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 615. ISBN 9780323529570. Archived from the original on 13 October 2017. 2. ^ a b c d e f g h i j "Hip Fractures". OrthoInfo - AAOS. April 2009. Archived from the original on 29 June 2017. Retrieved 27 September 2017. 3. ^ a b c d e f g h Brunner LC, Eshilian-Oates L, Kuo TY (February 2003). "Hip fractures in adults". American Family Physician. 67 (3): 537–42. PMID 12588076. 4. ^ Guay J, Parker MJ, Griffiths R, Kopp SL (May 2018). "Peripheral Nerve Blocks for Hip Fractures: A Cochrane Review". Anesthesia and Analgesia. 126 (5): 1695–1704. doi:10.1213/ANE.0000000000002489. PMID 28991122. S2CID 37497179. 5. ^ a b c d e f g h i Essentials of musculoskeletal care. Sarwark, John F. Rosemont, Ill.: American Academy of Orthopaedic Surgeons. 2010. ISBN 9780892035793. OCLC 706805938.CS1 maint: others (link) 6. ^ Rabow MW, McPhee SJ, Papadakis MA (2 September 2017). Current medical diagnosis & treatment 2018 (Fifty-seventh ed.). New York. ISBN 9781259861482. OCLC 959649794. 7. ^ "Fractures of the Femoral Neck". Wheeless' Textbook of Orthopaedics. Duke University School of Medicine. Archived from the original on 18 January 2008. Retrieved 27 January 2008. 8. ^ "Intertrochanteric Fractures". Wheeless' Textbook of Orthopaedics. Duke University School of Medicine. Archived from the original on 18 January 2008. Retrieved 27 January 2008. 9. ^ "Damage Control Orthopaedics: Patient Stabilization, Early Mobilization". 74th Annual Meeting of the American Academy of Orthopaedic Surgeons briefing. Medical News Today. 18 February 2007. Archived from the original on 22 November 2008. Retrieved 27 January 2008. 10. ^ Hwang HF, Lee HD, Huang HH, Chen CY, Lin MR (August 2011). "Fall mechanisms, bone strength, and hip fractures in elderly men and women in Taiwan". Osteoporosis International. 22 (8): 2385–93. doi:10.1007/s00198-010-1446-4. PMID 20963399. S2CID 2199032. 11. ^ Rockwood and Green's fractures in adults. Rockwood, Charles A., Jr., 1936-, Green, David P., Bucholz, Robert W. (7th ed.). Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2010. ISBN 9781605476773. OCLC 444336477.CS1 maint: others (link) 12. ^ Nevitt MC, Cummings SR (November 1993). "Type of fall and risk of hip and wrist fractures: the study of osteoporotic fractures. The Study of Osteoporotic Fractures Research Group". Journal of the American Geriatrics Society. 41 (11): 1226–34. doi:10.1111/j.1532-5415.1993.tb07307.x. PMID 8227898. 13. ^ Cumming RG, Le Couteur DG (2003). "Benzodiazepines and risk of hip fractures in older people: a review of the evidence". CNS Drugs. 17 (11): 825–37. doi:10.2165/00023210-200317110-00004. PMID 12921493. S2CID 26038041. 14. ^ Bakken MS, Engeland A, Engesæter LB, Ranhoff AH, Hunskaar S, Ruths S (July 2013). "Increased risk of hip fracture among older people using antidepressant drugs: data from the Norwegian Prescription Database and the Norwegian Hip Fracture Registry". Age and Ageing. 42 (4): 514–20. doi:10.1093/ageing/aft009. PMID 23438446. 15. ^ * "Prevention and Management of Hip Fracture on Older People. Section 7: Surgical management". Scottish Intercollegiate Guidelines Network. Archived from the original on 24 April 2017. Retrieved 23 April 2017. Last modified 15 July 2002 * Area of trochanteric fractures: Ernst Raaymakers, Inger Schipper, Rogier Simmermacher, Chris van der Werken. "Proximal femur". AO Foundation. Archived from the original on 24 April 2017. Retrieved 23 April 2017.CS1 maint: multiple names: authors list (link) * Area of subtrochanteric fractures: Mark A Lee. "Subtrochanteric Hip Fractures". Archived from the original on 26 April 2017. Retrieved 25 April 2017. Updated: 22 Jun 2016 * Area of femoral neck fractures: Page 333 in: Paul Tornetta, III, Sam W. Wiesel (2010). Operative Techniques in Orthopaedic Trauma Surgery. Lippincott Williams & Wilkins. ISBN 9781451102604.CS1 maint: multiple names: authors list (link) 16. ^ a b c d Page 245 in: David J. Dandy, Dennis J. Edwards (2009). Essential Orthopaedics and Trauma, 5th edition. Elsevier Health Sciences. ISBN 9780702042096. 17. ^ a b Schipper IB, Steyerberg EW, Castelein RM, van Vugt AB (February 2001). "Reliability of the AO/ASIF classification for pertrochanteric femoral fractures". Acta Orthopaedica Scandinavica. 72 (1): 36–41. doi:10.1080/000164701753606662. PMID 11327411. S2CID 13405033. 18. ^ Ernst Raaymakers, Inger Schipper, Rogier Simmermacher, Chris van der Werken. "Proximal femur". AO Foundation. Archived from the original on 24 April 2017. Retrieved 23 April 2017.CS1 maint: multiple names: authors list (link) 19. ^ Page 190 in: Richard A. Gosselin, David A. Spiegel, Michelle Foltz (2014). Global Orthopedics: Caring for Musculoskeletal Conditions and Injuries in Austere Settings. Springer Science & Business. ISBN 9781461415787.CS1 maint: multiple names: authors list (link) 20. ^ Page 365 in: Anita K. Simonds (2007). Non-Invasive Respiratory Support, Third edition: A Practical Handbook. CRC Press. ISBN 9780340809846. 21. ^ Page 303 in: Thomas Pope, Hans L. Bloem, Javier Beltran, William B. Morrison, David John Wilson (2014). Musculoskeletal Imaging E-Book (2 ed.). Elsevier Health Sciences. ISBN 9780323278188.CS1 maint: multiple names: authors list (link) 22. ^ Rubenstein LZ (September 2006). "Falls in older people: epidemiology, risk factors and strategies for prevention". Age and Ageing. 35 Suppl 2 (suppl 2): ii37–ii41. doi:10.1093/ageing/afl084. PMID 16926202. Archived from the original on 6 September 2016. 23. ^ Radcliff KE, Curry EP, Trimba R, Walker JB, Purtill JJ, Austin MS, et al. (April 2016). "High Incidence of Undiagnosed Cervical Myelopathy in Patients With Hip Fracture Compared With Controls". Journal of Orthopaedic Trauma. 30 (4): 189–93. doi:10.1097/BOT.0000000000000485. PMID 26562581. S2CID 33628708. 24. ^ "Cervical Spondylotic Myelopathy". Myelopathy.org. Archived from the original on 18 November 2015. Retrieved 9 March 2016. 25. ^ Santesso N, Carrasco-Labra A, Brignardello-Petersen R (March 2014). "Hip protectors for preventing hip fractures in older people". The Cochrane Database of Systematic Reviews. 3 (3): CD001255. doi:10.1002/14651858.CD001255.pub5. PMID 24687239. 26. ^ Handoll HH, Queally JM, Parker MJ (December 2011). "Pre-operative traction for hip fractures in adults". The Cochrane Database of Systematic Reviews (12): CD000168. doi:10.1002/14651858.CD000168.pub3. PMID 22161361. 27. ^ Ritcey B, Pageau P, Woo MY, Perry JJ (January 2016). "Regional Nerve Blocks For Hip and Femoral Neck Fractures in the Emergency Department: A Systematic Review". Canadian Journal of Emergency Medicine. 18 (1): 37–47. doi:10.1017/cem.2015.75. PMID 26330019. 28. ^ Guay J, Parker MJ, Gajendragadkar PR, Kopp S (February 2016). "Anaesthesia for hip fracture surgery in adults". The Cochrane Database of Systematic Reviews. 2: CD000521. doi:10.1002/14651858.CD000521.pub3. PMC 6464323. PMID 26899415. 29. ^ Brunskill SJ, Millette SL, Shokoohi A, Pulford EC, Doree C, Murphy MF, Stanworth S (April 2015). "Red blood cell transfusion for people undergoing hip fracture surgery". The Cochrane Database of Systematic Reviews. 4 (4): CD009699. doi:10.1002/14651858.CD009699.pub2. PMID 25897628. 30. ^ Gu WJ, Gu XP, Wu XD, Chen H, Kwong JS, Zhou LY, et al. (April 2018). "Restrictive Versus Liberal Strategy for Red Blood-Cell Transfusion: A Systematic Review and Meta-Analysis in Orthopaedic Patients". The Journal of Bone and Joint Surgery. American Volume. 100 (8): 686–695. doi:10.2106/JBJS.17.00375. PMID 29664857. S2CID 4940514. 31. ^ Sobolev B, Guy P, Sheehan KJ, Kuramoto L, Sutherland JM, Levy AR, et al. (August 2018). "Mortality effects of timing alternatives for hip fracture surgery". CMAJ. 190 (31): E923–E932. doi:10.1503/cmaj.171512. PMC 6078777. PMID 30087128. 32. ^ Reinhard Hoffmann, Norbert P Haas. "Fractures of the femoral neck (31-B)". OA Foundation. Archived from the original on 27 April 2017., citing: T. P. Rüedi, R. E. Buckley, C.G. Moran (2007). OA Principles of Fracture management. Thieme Medical Publishers. ISBN 9781588905567.CS1 maint: multiple names: authors list (link) 33. ^ Metcalfe D, Judge A, Perry DC, Gabbe B, Zogg CK, Costa ML (May 2019). "Total hip arthroplasty versus hemiarthroplasty for independently mobile older adults with intracapsular hip fractures". BMC Musculoskeletal Disorders. 20 (1): 226. doi:10.1186/s12891-019-2590-4. PMC 6525472. PMID 31101041. 34. ^ Tintinalli, Judith E. (2010). Emergency Medicine: A Comprehensive Study Guide (Emergency Medicine (Tintinalli)). New York: McGraw-Hill Companies. ISBN 978-0-07-148480-0. 35. ^ a b Subtypes of trochanteric fractures: Ernst Raaymakers, Inger Schipper, Rogier Simmermacher, Chris van der Werken. "Proximal femur". OA Foundation. Archived from the original on 24 April 2017. Retrieved 23 April 2017.CS1 maint: multiple names: authors list (link) 36. ^ Boldin C, Seibert FJ, Fankhauser F, Peicha G, Grechenig W, Szyszkowitz R (February 2003). "The proximal femoral nail (PFN)--a minimal invasive treatment of unstable proximal femoral fractures: a prospective study of 55 patients with a follow-up of 15 months". Acta Orthopaedica Scandinavica. 74 (1): 53–8. doi:10.1080/00016470310013662. PMID 12635794. * This study cites the following primary source: Friedl W, Colombo-Benkmann M, Dockter S, et al. (1994). "Gammanagel-osteosynthes per- und subtrochanterer Femurfrakturen". Chirurg. 65. 37. ^ Queally JM, Harris E, Handoll HH, Parker MJ (September 2014). "Intramedullary nails for extracapsular hip fractures in adults". The Cochrane Database of Systematic Reviews. 9 (9): CD004961. doi:10.1002/14651858.CD004961.pub4. PMID 25212485. 38. ^ [1], Weaver M. Closed Cephalomedullary Nailing of Subtrochanteric Hip Fracture. J Med Ins. 2016;2016(100) doi:https://jomi.com/article/100 39. ^ a b Smith TO, Gilbert AW, Sreekanta A, Sahota O, Griffin XL, Cross JL, et al. (February 2020). "Enhanced rehabilitation and care models for adults with dementia following hip fracture surgery". The Cochrane Database of Systematic Reviews. 2: CD010569. doi:10.1002/14651858.CD010569.pub3. PMC 7006792. PMID 32031676. 40. ^ Farooqi V, van den Berg ME, Cameron ID, Crotty M (October 2014). "Anabolic steroids for rehabilitation after hip fracture in older people". The Cochrane Database of Systematic Reviews. 10 (10): CD008887. doi:10.1002/14651858.CD008887.pub2. PMC 6669256. PMID 25284341. 41. ^ Handoll HH, Sherrington C, Mak JC (March 2011). "Interventions for improving mobility after hip fracture surgery in adults". The Cochrane Database of Systematic Reviews. 129 (3): 435. doi:10.1002/14651858.CD001704.pub4. PMID 21412873. 42. ^ Avenell A, Smith TO, Curtain JP, Mak JC, Myint PK (November 2016). "Nutritional supplementation for hip fracture aftercare in older people". The Cochrane Database of Systematic Reviews (published 30 November 2016). 11: CD001880. doi:10.1002/14651858.CD001880.pub6. hdl:2164/9672. PMC 6464805. PMID 27898998. 43. ^ Sedlář M, Kvasnička J, Krška Z, Tománková T, Linhart A (12 February 2015). "Early and subacute inflammatory response and long-term survival after hip trauma and surgery". Archives of Gerontology and Geriatrics. 60 (3): 431–6. doi:10.1016/j.archger.2015.02.002. PMID 25704919. 44. ^ a b Dyer SM, Crotty M, Fairhall N, Magaziner J, Beaupre LA, Cameron ID, Sherrington C (September 2016). "A critical review of the long-term disability outcomes following hip fracture". BMC Geriatrics. 16 (1): 158. doi:10.1186/s12877-016-0332-0. PMC 5010762. PMID 27590604. 45. ^ Kanis JA, Odén A, McCloskey EV, Johansson H, Wahl DA, Cooper C (September 2012). "A systematic review of hip fracture incidence and probability of fracture worldwide". Osteoporosis International. 23 (9): 2239–56. doi:10.1007/s00198-012-1964-3. PMC 3421108. PMID 22419370. 46. ^ a b Kannus P, Parkkari J, Sievanen H, Heinonen A, Vouri I, Jarvinen M (1996). "Epidemiology of hip fractures". Bone. 18 (1 Suppl): 57–63. doi:10.1016/8756-3282(95)00381-9. PMID 8717549. 47. ^ Huddleston JM, Whitford KJ (March 2001). "Medical care of elderly patients with hip fractures". Mayo Clinic Proceedings. 76 (3): 295–8. doi:10.4065/76.3.295. PMID 11243276. 48. ^ Torio CM, Andrews RM. "National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011." HCUP Statistical Brief #160. Agency for Healthcare Research and Quality, Rockville, MD. August 2013. "Statistical Brief #160". Archived from the original on 14 March 2017. Retrieved 1 May 2017. 49. ^ Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB (October 2009). "Incidence and mortality of hip fractures in the United States". JAMA. 302 (14): 1573–9. doi:10.1001/jama.2009.1462. PMC 4410861. PMID 19826027. 50. ^ Cumming RG, Nevitt MC, Cummings SR (1997). "Epidemiology of hip fractures". Epidemiologic Reviews. 19 (2): 244–57. doi:10.1093/oxfordjournals.epirev.a017956. PMID 9494786. 51. ^ "Hip Fractures Among Older Adults". CDC. CDC. Archived from the original on 8 May 2015. Retrieved 13 May 2015. 52. ^ a b Lauritzen JB (1997). "Hip fractures: Epidemiology, risk factors, falls, energy absorption, hip protectors, and prevention". Dan Med Bull. 44 (2): 155–168. PMID 9151010. 53. ^ Bardsley M. "Focus on: Hip fracture". QualityWatch. Nuffield Trust & Health Foundation. Archived from the original on 15 May 2015. Retrieved 13 May 2015. 54. ^ Rodríguez-Molinero A, Yuste A, Banegas JR (February 2010). "High incidence of hip fracture in Spanish centenarians". Journal of the American Geriatrics Society. 58 (2): 403–5. doi:10.1111/j.1532-5415.2009.02706.x. PMID 20370877. 55. ^ Rubenstein LZ, Josephson KR (2002). "The Epidemiology of Falls and Syncope". Clinic in Geriatrics Medicine. 18 (2): 141–150. doi:10.1016/S0749-0690(02)00002-2. PMID 12180240. 56. ^ Baumgaertner MR, Higgins TF. (2002) "Femoral Neck Fractures." Rockwood & Green’s Fractures in Adults. pp. 1579-1586. ## External links[edit] Wikimedia Commons has media related to Hip fractures. * Fractures of the Femoral Neck Wheeless Textbook of Orthopaedics * Intertrochanteric Fractures Wheeless' Textbook of Orthopaedics Classification D * ICD-10: S72.0 * MeSH: D006620 External resources * OrthoInfo: A00392 * 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

Hip fracture

c0019557

wikipedia

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

{"mesh": ["D006620"], "icd-9": ["820"], "icd-10": ["S72.0"], "wikidata": ["Q240856"]}

Paroxysmal supraventricular tachycardia Other namesSupraventricular tachycardia, paroxysmal atrial tachycardia (PAT)[1] Lead II electrocardiogram strip showing PSVT with a heart rate of about 180. SpecialtyEmergency medicine, cardiology SymptomsPalpitations, feeling lightheaded, sweating, shortness of breath, chest pain[2] Usual onsetStarts and stops suddenly[3] CausesNot known[3] Risk factorsAlcohol, caffeine, nicotine, psychological stress, Wolff-Parkinson-White syndrome[3] Diagnostic methodElectrocardiogram[3] PreventionCatheter ablation[3] TreatmentValsalva maneuver, adenosine, calcium channel blockers, synchronized cardioversion[4] PrognosisGenerally good[3] Frequency2.3 per 1000 people[5] Paroxysmal supraventricular tachycardia (PSVT) is a type of supraventricular tachycardia, named for its intermittent episodes of abrupt onset and termination.[3][6] Often people have no symptoms.[1] Otherwise symptoms may include palpitations, feeling lightheaded, sweating, shortness of breath, and chest pain.[2] The cause is not known.[3] Risk factors include alcohol, caffeine, nicotine, psychological stress, and Wolff-Parkinson-White syndrome which often is inherited from a person's parents.[3] The underlying mechanism typically involves an accessory pathway that results in re-entry.[3] Diagnosis is typically by an electrocardiogram (ECG) which shows narrow QRS complexes and a fast heart rhythm typically between 150 and 240 beats per minute.[3] Vagal maneuvers, such as the Valsalva maneuver, are often used as the initial treatment.[4] If not effective and the person has a normal blood pressure the medication adenosine may be tried.[4] If adenosine is not effective a calcium channel blockers or beta blocker may be used.[4] Otherwise synchronized cardioversion is the treatment.[4] Future episodes can be prevented by catheter ablation.[3] About 2.3 per 1000 people have paroxysmal supraventricular tachycardia.[5] Problems typically begin in those 12 to 45 years old.[3][5] Women are more often affected than men.[3] Outcomes are generally good in those who otherwise have a normal heart.[3] An ultrasound of the heart may be done to rule out underlying heart problems.[1] ## Contents * 1 Signs and symptoms * 2 Types * 3 Treatment * 3.1 Physical maneuvers * 3.2 Medications * 3.3 Cardioversion * 4 References * 5 External links ## Signs and symptoms[edit] Symptoms may include palpitations, feeling faint, sweating, shortness of breath, and chest pain.[2] Episodes start and end suddenly.[3] ## Types[edit] * AV nodal re-entrant tachycardia (AVNRT) makes up 56% of cases[5] * AV reciprocating tachycardia (AVRT) makes up 27% of cases[5] * Wolff-Parkinson-White syndrome[3] * Paroxysmal atrial tachycardia makes up 17% of cases[5] ## Treatment[edit] AV nodal blocking can be achieved in at least three ways: ### Physical maneuvers[edit] A number of physical maneuvers increase the resistance of the AV node to transmit impulses (AV nodal block), principally through activation of the parasympathetic nervous system, conducted to the heart by the vagus nerve. These manipulations are collectively referred to as vagal maneuvers. The Valsalva maneuver should be the first vagal maneuver tried[7] and works by increasing intra-thoracic pressure and affecting baroreceptors (pressure sensors) within the arch of the aorta. It is carried out by asking the patient to hold his/her breath while trying to exhale forcibly as if straining during a bowel movement. Holding the nose and exhaling against the obstruction has a similar effect.[8] There are other vagal maneuvers including: holding one's breath for a few seconds, coughing, plunging the face into cold water,[8] (via the diving reflex[9]), drinking a glass of ice cold water, and standing on one's head. Carotid sinus massage, carried out by firmly pressing the bulb at the top of one of the carotid arteries in the neck, is effective but is often not recommended in the elderly due to the potential risk of stroke in those with atherosclerotic plaque in the carotid arteries. Pressing down gently on the top of closed eyes may also bring heartbeat back to normal rhythm for some people with atrial or supraventricular tachycardia (SVT).[10] This is known as the oculocardiac reflex. ### Medications[edit] Termination of PSVT following adenosine administration Adenosine, an ultra-short-acting AV nodal blocking agent, is indicated if vagal maneuvers are not effective.[11] If unsuccessful or the PSVT recurs diltiazem or verapamil are recommended.[4] Adenosine may be safely used during pregnancy.[12] SVT that does not involve the AV node may respond to other anti-arrhythmic drugs such as sotalol or amiodarone. ### Cardioversion[edit] If the person is hemodynamically unstable or other treatments have not been effective, synchronized electrical cardioversion may be used. In children this is often done with a dose of 0.5 to 1 J/Kg.[13] ## References[edit] 1. ^ a b c Ferri, Fred F. (2012). Ferri's Clinical Advisor 2013,5 Books in 1, Expert Consult - Online and Print,1: Ferri's Clinical Advisor 2013. Elsevier Health Sciences. p. 807. ISBN 978-0323083737. Archived from the original on 2016-10-02. 2. ^ a b c "What Are the Signs and Symptoms of an Arrhythmia?". NHLBI. July 1, 2011. Archived from the original on 19 February 2015. Retrieved 27 September 2016. 3. ^ a b c d e f g h i j k l m n o p q Al-Zaiti, SS; Magdic, KS (September 2016). "Paroxysmal Supraventricular Tachycardia: Pathophysiology, Diagnosis, and Management". Critical Care Nursing Clinics of North America. 28 (3): 309–16. doi:10.1016/j.cnc.2016.04.005. PMID 27484659. 4. ^ a b c d e f Neumar, RW; Shuster, M; Callaway, CW; Gent, LM; Atkins, DL; Bhanji, F; Brooks, SC; de Caen, AR; Donnino, MW; Ferrer, JM; Kleinman, ME; Kronick, SL; Lavonas, EJ; Link, MS; Mancini, ME; Morrison, LJ; O'Connor, RE; Samson, RA; Schexnayder, SM; Singletary, EM; Sinz, EH; Travers, AH; Wyckoff, MH; Hazinski, MF (3 November 2015). "Part 1: Executive Summary: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation. 132 (18 Suppl 2): S315–67. doi:10.1161/cir.0000000000000252. PMID 26472989. 5. ^ a b c d e f Katritsis, Demosthenes G.; Camm, A. John; Gersh, Bernard J. (2016). Clinical Cardiology: Current Practice Guidelines. Oxford University Press. p. 538. ISBN 9780198733324. Archived from the original on 2016-10-02. 6. ^ "Types of Arrhythmia". NHLBI. July 1, 2011. Archived from the original on June 7, 2015. Retrieved September 29, 2016. 7. ^ "BestBets: Comparing Valsalva manoeuvre with carotid sinus massage in adults with supraventricular tachycardia". Archived from the original on 2010-06-16. 8. ^ a b Vibhuti N, Singh; Monika Gugneja (2005-08-22). "Supraventricular Tachycardia". eMedicineHealth.com. Archived from the original on 2008-12-16. Retrieved 2008-11-28. 9. ^ Mathew PK (January 1981). "Diving reflex. Another method of treating paroxysmal supraventricular tachycardia". Arch. Intern. Med. 141 (1): 22–3. doi:10.1001/archinte.141.1.22. PMID 7447580. 10. ^ "Tachycardia | Fast Heart Rate". American Heart Association. Archived from the original on 12 April 2013. Retrieved 19 April 2013. 11. ^ "Adenosine vs Verapamil (calcium channel blocker) in the acute treatment of supraventricular tachycardias". Archived from the original on 2010-06-16. 12. ^ Blomström-Lundqvist ET AL., MANAGEMENT OF PATIENTS WITH Supraventricular Arrhythmias. J Am Coll Cardiol 2003;42:1493–531 "Archived copy". Archived from the original on 2009-03-10. Retrieved 2010-01-17.CS1 maint: archived copy as title (link) 13. ^ de Caen, AR; Berg, MD; Chameides, L; Gooden, CK; Hickey, RW; Scott, HF; Sutton, RM; Tijssen, JA; Topjian, A; van der Jagt, ÉW; Schexnayder, SM; Samson, RA (3 November 2015). "Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation. 132 (18 Suppl 2): S526–42. doi:10.1161/cir.0000000000000266. PMC 6191296. PMID 26473000. ## External links[edit] Classification D * ICD-10: I47.1 * ICD-9-CM: 427.0 * MeSH: D013617 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Paroxysmal supraventricular tachycardia

c0030590

wikipedia

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

{"umls": ["C0030590"], "icd-9": ["427.0"], "wikidata": ["Q28032350"]}

A number sign (#) is used with this entry because pyruvate carboxylase deficiency is caused by homozygous or compound heterozygous mutation in the pyruvate carboxylase gene (PC; 608786) on chromosome 11q13. Clinical Features PC deficiency may be categorized into 3 phenotypic subgroups. Patients from North America ('group A') have lactic acidemia and psychomotor retardation, whereas those from France and the United Kingdom ('group B') have a more complex biochemical phenotype with increased serum lactate, ammonia, citrulline, and lysine, as well as an intracellular redox disturbance in which the cytosolic compartment is more reduced and the mitochondrial compartment is more oxidized. Patients in group B have decreased survival compared to group A, and usually do not survive beyond 3 months of age (Robinson et al., 1987). Group C is relatively benign. ### North American Phenotype ('Group A') Tada et al. (1969) reported a family in which 2 sisters were presumably affected with the same physical and mental retardation. The proband had elevated serum alanine and pyruvate, normal SGPT and liver pyruvate decarboxylase activities, but decreased activity of pyruvate carboxylase. Hyperalaninemia was likely secondary to the increased level of pyruvate. Delvin et al. (1972) noted that 2 forms of pyruvate carboxylase exist in liver, one with a high Km and the other with a low Km for pyruvate. They reported a patient with abnormality of gluconeogenesis and elevated plasma levels of pyruvate, lactate, and alanine in which the low Km enzyme was deficient. Atkin et al. (1979) reported a child with lactic acidosis, severe mental and developmental retardation, and proximal renal acidosis. Laboratory studies showed severe hepatic, renal cortical, and cerebral deficiencies of pyruvate carboxylase activity. Postmortem neuropathologic examination revealed no signs of Leigh syndrome (256000), but developmental and degenerative lesions were observed. Oizumi et al. (1983) reported a patient with PC deficiency associated with renal tubular acidosis and cystinuria. Haworth et al. (1981) reported 2 unrelated Canadian Indian infants with PC deficiency. Both presented in infancy with metabolic acidosis. Laboratory findings included increased plasma lactate, pyruvate, glutamic acid, proline, and alanine, and low PC activity in skin fibroblasts and liver. Both survived until at least 2 years of age with severe mental retardation. Gilbert et al. (1983) reported a case of Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency. Carbone et al. (1998) studied 11 males and 6 females from several Canadian Indian populations. Presentation was at birth in 7, and 1 to 8.5 months in 10. Presenting signs included metabolic acidosis in 10, seizures in 5, respiratory distress in 4, pneumonia in 3, and hypotonia in 3. The clinical course was characterized by frequent lactic acidosis, severe developmental delay, and muscular hypotonia in 17, seizures in 8, hypoglycemia in 4, and other CNS involvement (clonus or athetosis) in 4. Eleven patients died between ages 3 months and 4.75 years; 6 were surviving at ages ranging from 3 months to 19 years. ### 'French form' ('Group B') The second form of PC deficiency, reported particularly from France, presents early with lactic acidosis, but also shows elevated blood levels of ammonia, citrulline, proline, and lysine. In addition, there is an intracellular redox disturbance, with increased lactate/pyruvate and acetoacetate/beta-hydroxybutyrate ratios. Saudubray et al. (1976) reported 2 familial cases of neonatal congenital lactic acidosis with liver PC deficiency. Disease onset was immediately after birth, characterized by major neurologic symptoms, hyperammonemia, and hyperketonemia. Hyperlactic acidemia was associated with an increased lactate/pyruvate ratio and an increased acetoacetate/beta-hydroxybutyrate ratio. The authors suggested that the unusual metabolic pattern resulted from decreased oxaloacetate synthesis resulting from PC deficiency and impaired oxaloacetate-dependent mitochondrial redox shuttles. The disease course was rapidly fatal. Coude et al. (1981) and Bartlett et al. (1984) also reported patients with the group B type of PC deficiency. Robinson et al. (1984) reported 8 patients from 7 families from Canada with pyruvate carboxylase deficiency. Five were of full Amerindian descent, 2 were unrelated Caucasians, and 1 was the offspring of related Egyptian parents. All presented from soon after birth to age 5 months with chronic metabolic acidosis, and 4 had at least 1 episode of hypoglycemia. Six patients died by age 2 years (range 10 days to 2 years), and the 2 living patients were mentally and physically retarded. Using (3)H-biotin labeling and (35)S-streptavidin to detect biotin-containing proteins, and immunodetection with PC antibodies, Robinson et al. (1984) distinguished 2 groups of patients: group 'A' synthesized PC subunits with a normal molecular mass and recognized by antibodies against PC, but showed very little enzymatic activity, (termed CRM(+ve) or type I), whereas group 'B' had no detectable PC subunits and no protein recognized by the antibody (termed CRM(-ve), or type II). The 2 patients with CRM(-ve) results, the Egyptian patient and 1 of the Caucasian patients, had additional biochemical features, including hyperammonemia, citrullinemia, lysinemia, and altered redox states (in 1 patient) similar to the features of patients reported in France. These 2 patients also died early (10 days and 7 weeks) and had hepatomegaly due to excessive fat storage. Robinson et al. (1984) concluded that the 2 subtle types of PC deficiency result from 2 different mutations in the PC gene, 1 that synthesizes an inactive protein and 1 that results in lack of protein expression. In a follow-up study of cultured skin fibroblasts from 16 patients with either French or American PC deficiency, Robinson et al. (1987) confirmed that the North American cases are associated with the presence of a mature biotin-containing protein of the correct molecular weight. Three families with the French presentation had absence of immunoreactive PC protein and PC mRNA; however, another 3 families with the French presentation had evidence of protein production as well as PC mRNA. Robinson et al. (1987) concluded that when a PC enzyme is produced in French cases, it has no activity. Pineda et al. (1995) reported an infant with what they termed the 'French' type of pyruvate carboxylase deficiency, with somewhat less severity. The initial neonatal symptoms were respiratory distress, severe metabolic acidosis, and a tendency to hypoglycemia. At age 6 months, he presented with acute neurologic symptoms, lactic acidosis, and hyperammonemia, and died of pneumonia, cardiac failure, and renal insufficiency. Pyruvate carboxylase deficiency was confirmed by enzymatic studies. Postmortem analysis showed periventricular cysts and diffuse hypomyelination. Brun et al. (1999) reported brother and sister with the severe form of PC deficiency. Both had macrocephaly and severe ischemia-like brain lesions at birth and died in the first week of life with intractable lactic acidemia. In the girl, increased head circumference and periventricular leukomalacia were detected on fetal ultrasonography at 29.4 weeks of gestation. PC activity in cultured skin fibroblasts was less than 2% of control. The lesions were detected at a time of maximal periventricular metabolic demand. Brun et al. (1999) postulated that energy deprivation induced by PC deficiency impairs astrocytic buffering capacity against excitotoxic insult and compromises normal microvascular morphogenesis and autoregulation, both mechanisms leading to cystic degeneration of the periventricular white matter. The authors noted that discovery of cystic periventricular leukomalacia on cerebral ultrasound at birth in a newborn presenting with primary lactic acidemia is highly suggestive of PC deficiency. ### 'Benign' type ('Group C') Van Coster et al. (1991) reported a 7-year-old girl with metabolic and biochemical features of the North American type of PC deficiency who had a benign disease course with preservation of motor and mental abilities. She had several episodes of metabolic acidosis with elevated lactate, pyruvate, alanine, beta-hydroxybutyrate, acetoacetate, lysine, and proline values, which were well-managed by rehydration and bicarbonate therapy. PC activity was 1.8% of normal, and she was CRM(+ve). The authors commented on the unique phenotypic expression in this patient. Schiff et al. (2006) reported a patient with atypical PC deficiency and long survival. He presented at 3 days of age with acute ketoacidosis, tachypnea, and hypotonia. Laboratory studies showed lactacidemia with normal plasma amino acids and ammonia. After successful treatment, he was discharged with an increased lactate-to-pyruvate ratio and avoidance of fasting was advised. During the first 2 years of life, he had mild psychomotor delay and failure to thrive with intermittent acute decompensation. PC activity in cultured skin fibroblasts was severely decreased, leading to the correct diagnosis. Brain MRI at age 18 months showed bilateral high signal intensities in frontoparietal subcortical white matter. At the time of the report, he was 9 years old and showed mild and global psychomotor delay with dysarthria and dysgraphia. Treatment included biotin, L-carnitine, sodium bicarbonate, sodium citrate, and avoidance of fasting. Schiff et al. (2006) noted that relatively long survival into childhood is not a frequent finding for this usually very severe disease. Diagnosis ### Prenatal Diagnosis Tsuchiyama et al. (1983) reported a patient with PC deficiency and PC activity of about 5% of normal. A prenatal diagnosis was performed in the second pregnancy and the PC activities of the cultured amniotic fluid cells obtained by amniocentesis were within normal limits. In a family at risk for PC deficiency, Robinson et al. (1985) confirmed the diagnosis in a fetus by enzyme assay and (3)H-biotin labeling of proteins in cultured fetal skin fibroblasts. Clinical Management Delvin et al. (1971) found responsiveness to thiamine administration in a patient with PC deficiency. As thiamine pyrophosphate is the coenzyme for pyruvate dehydrogenase, a key enzyme for an alternate route of pyruvate metabolism, the authors suggested that thiamine restored pyruvate metabolism by facilitating an alternative mechanism for its oxidation. Maesaka et al. (1976) described 2 sisters with pyruvate carboxylase deficiency, severe mental and motor retardation, and Leigh syndrome. The proband had lactic acidosis, low CSF glucose, hyperalaninemia, and increased urinary lactate, pyruvate, and alanine. Both sibs improved clinically and biochemically after treatment with thiamine and lipoic acid. In a patient with PC deficiency associated with renal tubular acidosis and cystinuria, Oizumi et al. (1983) reported successful treatment with dietary supplement of aspartic acid, asparagine, glutamic acid, and glutamine. Molecular Genetics In 11 Ojibwa and 2 Cree patients with type A pyruvate carboxylase deficiency, Carbone et al. (1998) identified a missense mutation in the PC gene (608786.0001). Two brothers of Micmac origin had a transversion mutation in the PC gene (608786.0002). Carrier frequency was estimated to be as high as 1 in 10 in some groupings. In 2 brothers with type B PC deficiency, Carbone et al. (2002) identified compound heterozygosity for 2 mutations in the PC gene (608786.0005; 608786.0006). Monnot et al. (2009) identified 9 novel mutations in the PC gene (see, e.g., 608786.0007-608786.0009) in 5 unrelated patients with PC deficiency: 3 had the more severe type B PC, and 2 had type A. PC activity in cultured fibroblasts was undetectable in all patients. Three mutations were frameshift, predicted to introduce a premature termination codon, 1 was an in-frame deletion, and 5 were missense substitutions. Although most PC mutations were suggested to interfere with biotin metabolism, none of the patients was biotin-responsive. Genotype/Phenotype Correlations In 5 patients with PC, Monnot et al. (2009) noted that type B was consistently associated with at least 1 truncating mutation, whereas type A always resulted from 2 missense mutations. Population Genetics Carbone et al. (1998) noted that the Canadian Indian population had been strongly represented in their study of CRM(+ve) PC deficiency, there being cases in the Micmac, Cree, and Ojibwa. This common linguistic group was derived from a founder group in southern Ontario approximately 300 B.C. It had been suggested that there could be one or more disease-causing mutations in the PC gene that are unique to the 'Algonkian-speaking peoples' of North America. INHERITANCE \- Autosomal recessive ABDOMEN Liver \- Hepatomegaly GENITOURINARY Kidneys \- Renal tubular acidosis, proximal NEUROLOGIC Central Nervous System \- Psychomotor retardation \- Mental retardation \- Developmental delay \- Hypotonia \- Seizures \- Clonus \- Cystic lesions consistent with Leigh syndrome ( 256000 ) \- Neuronal loss in the cerebral cortex \- Poor myelination \- Periventricular leukomalacia \- Subcortical leukodystrophy METABOLIC FEATURES \- Lactic acidosis LABORATORY ABNORMALITIES \- Decreased pyruvate carboxylase (PC) activity (less than 5%) \- Increased serum lactate \- Increased serum pyruvate \- Increased serum alanine \- Hypoglycemia \- Increased serum ammonia (Group B) \- Increased serum citrulline (Group B) \- Increased serum lysine (Group B) \- Intracellular redox disturbance (reduced cytoplasm and oxidized mitochondria (Group B)) \- Increased lactate: pyruvate ratio (Group B) \- Increased acetoacetate: beta-hydroxybutyrate ratio (Group B) \- Immunoreactive PC protein \- Presence of PC mRNA \- A subset of Group B patients have absence of PC protein and mRNA MISCELLANEOUS \- Onset at birth or in early infancy \- Some patients may respond to thiamine treatment \- Can be categorized into 3 groups \- Group A, found in North American Indians, has lactic acidosis and psychomotor retardation \- Group A patients die in the first years of life \- Group B, found in France and United Kingdom, severe phenotype \- Group B patients die by 3 months of age \- Group C is relatively benign MOLECULAR BASIS \- Caused by mutation in the pyruvate carboxylase gene (PC, 608786.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

PYRUVATE CARBOXYLASE DEFICIENCY

c0034341

omim

https://www.omim.org/entry/266150

{"doid": ["3651"], "mesh": ["D015324"], "omim": ["266150"], "icd-10": ["E74.4"], "orphanet": ["353314", "3008", "353320", "353308"], "synonyms": ["Pyruvate carboxylase deficiency type B", "Alternative titles", "LEIGH NECROTIZING ENCEPHALOPATHY DUE TO PYRUVATE CARBOXYLASE DEFICIENCY", "LEIGH SYNDROME DUE TO PYRUVATE CARBOXYLASE DEFICIENCY", "PC DEFICIENCY", "ATAXIA WITH LACTIC ACIDOSIS II"], "genereviews": ["NBK6852"]}

Cross syndrome Other namesOculocerebral hypopigmentation syndrome, Cross type[1] Cross syndrome is inherited in an autosomal recessive manner SpecialtyEndocrinology Cross–McKusick–Breen syndrome (also known as "Cross syndrome", "hypopigmentation and microphthalmia", and "oculocerebral-hypopigmentation syndrome") is an extremely rare disorder characterized by white skin, blond hair with yellow-gray metallic sheen, small eyes with cloudy corneas, jerky nystagmus, gingival fibromatosis and severe intellectual disability and physical retardation.[2]:867–8 It was characterized in 1967.[3] ## See also[edit] * Oculocerebrocutaneous syndrome * List of cutaneous conditions ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Oculocerebral hypopigmentation syndrome, Cross type". www.orpha.net. Retrieved 19 April 2019. 2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 3. ^ Cross HE, McKusick VA, Breen W (March 1967). "A new oculocerebral syndrome with hypopigmentation". J. Pediatr. 70 (3): 398–406. doi:10.1016/S0022-3476(67)80137-9. PMID 4959856. ## External links[edit] Classification D * ICD-10: E70.3 (ILDS E70.380) * OMIM: 257800 External resources * Orphanet: 2719 * http://www.whonamedit.com/synd.cfm/1387.html * 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 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

Cross syndrome

c2936910

wikipedia

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

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