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A rare, chronic, photodermatosis disease characterized by intensely pruritic, polymorphic, erythematous, excoriated and/or lichenified papules, macules, plaques and nodules, occurring on sun-exposed areas of the skin (particularly face, nose, lips, and ears), frequently associating cheilitis (especially of the lower lip) and conjuctivitis, which are present year-round or only in the spring/summer (depending on geographic location), observed mainly in Native Americans and Mestizos. Cheilitis may be the sole clinical presentation. Histologically, the presence of lymphoid follicles in mucosa is pathognomonic. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Actinic prurigo	c0406217	6,000	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=330061	2021-01-23T18:45:24	{"mesh": ["C566780"], "omim": ["174770"], "umls": ["C0406217"], "icd-10": ["L56.4"], "synonyms": ["Familial polymorphous light eruption of American Indians", "Hereditary polymorphous light eruption of American Indians", "Hutchinson summer prurigo", "Hydroa aestivale"]}
Froyshov Larsen et al. (1978) described a new syndrome in 6 females in 2 sibships with a high degree of consanguinity and a male in another family. The syndrome consisted of total colorblindness from progressive cone dystrophy, degenerative liver disease, and endocrine dysfunction (hypothyroidism, 'maturity-onset diabetes of the young', repeated abortions or infertility). The fundi showed attenuated retinal vessels, disc pallor, and a generalized atrophic appearance without pigmentation. Photopic function was lost; scotopic function was well preserved (Hansen et al., 1978). Creatine phosphokinase was elevated in the blood of all patients (Berg et al., 1978). Eyes \- Total colorblindness \- Progressive cone dystrophy \- Attenuated retinal vessels \- Disc pallor \- Atrophic retinal appearance \- No retinal pigmentation \- Photopic function lost \- Scotopic function well preserved Inheritance \- Autosomal recessive Endocrine \- Hypothyroidism \- Maturity-onset diabetes of the young (MODY) Misc \- Repeated abortions GU \- Infertility Lab \- Elevated blood creatine phosphokinase GI \- Degenerative liver disease ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	RETINOHEPATOENDOCRINOLOGIC SYNDROME	c1849399	6,001	omim	https://www.omim.org/entry/268040	2019-09-22T16:22:41	{"mesh": ["C564839"], "omim": ["268040"], "orphanet": ["3087"], "synonyms": ["Alternative titles", "RHE SYNDROME"]}
"In-toe" redirects here. For the process of pulling something, see Towing. For the surfing technique, see Tow-in surfing. For the automotive term, see Toe (automotive). Pigeon toe Other namesMetatarsuhnvarus, metatarsus adductus, in-toe gait, intoeing, false clubfoot SpecialtyPediatrics, orthopedics Pigeon toe, also known as in-toeing, is a condition which causes the toes to point inward when walking. It is most common in infants and children under two years of age[1] and, when not the result of simple muscle weakness,[2] normally arises from underlying conditions, such as a twisted shin bone or an excessive anteversion (femoral head is more than 15° from the angle of torsion) resulting in the twisting of the thigh bone when the front part of a person's foot is turned in. ## Contents * 1 Causes * 1.1 Metatarsus adductus * 1.2 Tibial torsion * 1.3 Femoral anteversion * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Causes[edit] The cause of in-toeing can be differentiated based on the location of the disalignment. The variants are:[3][4] * Curved foot (metatarsus adductus) * Twisted shin (tibial torsion) * Twisted thighbone (femoral anteversion) ### Metatarsus adductus[edit] The most common form of being pigeon toed, when the feet bend inward from the middle part of the foot to the toes. ### Tibial torsion[edit] The tibia or lower leg slightly or severely twists inward when walking or standing. ### Femoral anteversion[edit] The femur or thigh bone turns inward when walking. ## Diagnosis[edit] A Sgarlato's angle of more than 15° indicates pigeon toe.[5] Pigeon toe can be diagnosed by physical examination alone.[6] This can classify the deformity into "flexible", when the foot can be straightened by hand, or otherwise "nonflexible".[6] Still, X-rays are often done in the case of nonflexible pigeon toe.[6] On X-ray, the severity of the condition can be measured with a "metatarsus adductus angle", which is the angle between the directions of the metatarsal bones, as compared to the lesser tarsus (the cuneiforms, the cuboid and the navicular bone).[7] Many variants of this measurement exist, but Sgarlato's angle has been found to at least have favorable correlation with other measurements.[8] Sgarlato's angle is defined as the angle between:[5][9] * A line through the longitudinal axis of the second metatarsal bone. * The longitudinal axis of the lesser tarsal bones. For this purpose, one line is drawn between the lateral limits of the fourth tarsometatarsal joint and the calcaneocuboid joint, and another line is drawn between the medial limits of the talonavicular joint and the 1st tarsometatarsal joint. The transverse axis is defined as going through the middle of those lines, and hence the longitudinal axis is perpendicular to this axis. This angle is normally up to 15°, and an increased angle indicates pigeon toe.[5] Yet, it becomes more difficult to infer the locations of the joints in younger children due to incomplete ossification of the bones, especially when younger than 3–4 years. ## Treatment[edit] In those less than eight years old with simple in-toeing and minor symptoms, no specific treatment is needed.[10] ## See also[edit] * Bow-leggedness ## References[edit] 1. ^ "Pigeon toe (in-toeing)". University of Iowa Hospitals and Clinics. 2005. Retrieved 2008-11-27. 2. ^ Glenn Copeland; Stan Solomon; Mark Myerson (2005). The Good Foot Book. New York: Hunter House. pp. 96–97. ISBN 0-89793-448-2. 3. ^ "Intoeing". American Academy of Orthopaedic Surgeons. Retrieved 6 July 2013. "Reviewed by members of the Pediatric Orthopaedic Society of North America" 4. ^ Clifford R. Wheeless III (ed.). "Internal Tibial Torsion". Wheeless' Textbook of Orthopaedics. Retrieved 6 July 2013. 5. ^ a b c Chen L, Wang C, Wang X, Huang J, Zhang C, Zhang Y, Ma X (2014). "A reappraisal of the relationship between metatarsus adductus and hallux valgus". Chin. Med. J. 127 (11): 2067–72. PMID 24890154. 6. ^ a b c "Metatarsus Adductus". Lucile Packard Children's Hospital. Retrieved 2018-02-03. 7. ^ Dawoodi, Aryan I.S.; Perera, Anthony (2012). "Reliability of metatarsus adductus angle and correlation with hallux valgus". Foot and Ankle Surgery. 18 (3): 180–186. doi:10.1016/j.fas.2011.10.001. ISSN 1268-7731. 8. ^ Michael Crawford, Donald Green. "METATARSUS ADDUCTUS: Radiographic and Pathomechanical Analysis" (PDF). The Podiatry Institute. 9. ^ Loh, Bryan; Chen, Jerry Yongqiang; Yew, Andy Khye Soon; Chong, Hwei Chi; Yeo, Malcolm Guan Hin; Tao, Peng; Koo, Kevin; Rikhraj Singh, Inderjeet (2015). "Prevalence of Metatarsus Adductus in Symptomatic Hallux Valgus and Its Influence on Functional Outcome". Foot & Ankle International. 36 (11): 1316–1321. doi:10.1177/1071100715595618. ISSN 1071-1007. 10. ^ "Five Things Physicians and Patients Should Question" (PDF). American Academy of Pediatrics-Section on Orthopaedics and the Pediatric Orthopaedic Society of North America. Retrieved 24 February 2018. ## External links[edit] Classification D * ICD-10: M20.5, Q66.2 * ICD-9-CM: 754.53 * MeSH: D000070592 External resources * MedlinePlus: 001601 * UK information from Oxford Hospitals NHS Trust * Metatarsus Adductus on POSNA—The Pediatric Orthopaedic Society of North America * 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 * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Pigeon toe	c0231791	6,002	wikipedia	https://en.wikipedia.org/wiki/Pigeon_toe	2021-01-18T18:31:24	{"gard": ["3570"], "mesh": ["D000070592"], "umls": ["C0231791", "C4082169"], "icd-9": ["754.53"], "icd-10": ["Q66.2"], "wikidata": ["Q1524166"]}
A number sign (#) is used with this entry because poor metabolism of efavirenz and susceptibility to efavirenz central nervous system (CNS) toxicity are associated with variation in the CYP2B6 gene (123930) on chromosome 19q13.2. Description Highly active antiretroviral therapy (HAART) has reduced mortality associated with acquired immunodeficiency syndrome (AIDS; see 609423) by at least 70%. Efavirenz is a non-nucleoside reverse transcriptase inhibitor that is frequently prescribed with 2 nucleoside reverse transcriptase inhibitors as initial therapy for human immunodeficiency virus (HIV) infection. However, during the first weeks of therapy, up to half of patients who receive efavirenz experience CNS side effects, including dizziness, insomnia, impaired concentration, somnolence, and abnormal dreams. Severe depression, aggressive behavior, and paranoid or manic reactions may also occur, and such side effects may reflect varying efavirenz plasma concentrations. Plasma clearance of efavirenz appears slower in African Americans than in European Americans, and studies have suggested earlier virologic failure on efavirenz for both African Americans and Hispanics compared with European Americans. Efavirenz is metabolized primarily by hepatic CYP2B6, with some involvement of CYP3A (CYP3A4; 124010) (summary by Haas et al., 2004). Mapping Poor metabolism of efavirenz and susceptibility to efavirenz CNS toxicity are associated with variation in the CYPB2B6 gene, which Trask et al. (1993) mapped to chromosome 19q13.2. Molecular Genetics Haas et al. (2004) examined associations between CNS side effects and efavirenz plasma concentration-time profiles and polymorphisms in the CYP2B6, CYP3A4 (124010), CYP3A5 (605325), and MDR1 (ABCB1; 171050) genes in 157 American HIV-infected patients. They found that homozygosity for a nonsynonymous CYP2B6 SNP, 516G-T (rs3745274; 123930.0001), was present in 20% of African Americans compared with only 3% of European Americans and was associated with higher efavirenz exposure in plasma (p less than 0.0001). The median 24-hour area under the curve of efavirenz was about 3-fold higher in 516T homozygotes than in 516G homozygotes, and was intermediate in 516GT heterozygotes, regardless of ethnicity, suggesting a gene dosage effect. Among all patients, CNS side effects at week 1 were associated with 516T (p = 0.036). There were no significant immunologic or virologic differences for polymorphisms in any of the genes studied. Haas et al. (2004) concluded that interindividual differences in drug metabolism may, in part, explain susceptibility to efavirenz CNS side effects. Carr et al. (2010) determined plasma efavirenz concentrations in 219 HIV-positive Chilean patients and identified 11 CYP2B6 SNPs that were significantly associated with drug concentrations. Of these, only 516G-T (p = 5.6 x 10(-20)) was exonic. However, a composite model in which 516G-T was combined with 2 other SNPs was more strongly associated with efavirenz plasma concentrations than 516G-T alone. Elens et al. (2010) studied 50 HIV-infected patients from Belgium and confirmed that minimum trough plasma level concentrations of efavirenz were associated with CYP2B6 allelic status. They also found that cell-associated concentrations of efavirenz were associated with CYP2B6 516G-T. Elens et al. (2010) concluded that knowledge of CYP2B6 genetic status should be taken into account for efavirenz treatment. The Q172H (123930.0001) and K262R (123930.0002) substitutions define the CYP2B66 allele. In a study of 35 Japanese patients taking efavirenz, Tsuchiya et al. (2004) found that 2 patients who were homozygous for the 6 allele had significantly higher plasma efavirenz levels compared to those who were heterozygous for the 6 allele or those without the 6 allele. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	EFAVIRENZ, POOR METABOLISM OF	c3281154	6,003	omim	https://www.omim.org/entry/614546	2019-09-22T15:54:53	{"omim": ["614546"], "orphanet": ["240869"], "synonyms": []}
Najm type X-linked intellectual deficit is a rare cerebellar dysgenesis syndrome characterized by variable clinical manifestations ranging from mild intellectual deficit with or without congenital nystagmus, to severe cognitive impairment associated with cerebellar and pontine hypoplasia/atrophy and abnormalities of cortical development. ## Epidemiology Prevalence of this rare neurological syndrome is unknown. Up to 35 families have been reported to date. ## Clinical description Patients (mostly females) have been reported to have variable clinical manifestations including intellectual deficit, severe developmental delay, seizures, unsteady gait, sensorineural hearing loss and postnatal microcephaly (in most cases). Minor facial anomalies include: low or broad forehead, hypertelorism, long philtrum and micrognathia. Ocular findings are also variable and include congenital nystagmus, strabismus, cataracts, myopia or reduced visual acuity. Males appear to be more severely affected. ## Etiology Point mutations and deletions in the CASK gene (Xp11.4) have been found in patients with this syndrome. ## Diagnostic methods Magnetic resonance imaging (MRI) generally shows pontocerebellar hypoplasia/atrophy and simplified cortical gyri. Molecular genetic testing is needed to confirm diagnosis. ## Genetic counseling Transmission follows an X-linked dominant pattern. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	X-linked intellectual disability, Najm type	c2677903	6,004	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=163937	2021-01-23T17:33:13	{"gard": ["12669"], "mesh": ["C567466"], "omim": ["300749"], "umls": ["C2677903"], "icd-10": ["Q04.3"], "synonyms": ["MICPCH", "X-linked intellectual disability-microcephaly-pontocerebellar hypoplasia syndrome"]}
Dysmorphism-short stature-deafness-disorder of sex development syndrome is characterized by dysmorphism (including facial asymmetry, arched eyebrows, hypertelorism, broad and flat nasal bridge, microtia, small nose with anteverted nostrils, micrognathia), deafness, cleft palate, male pseudohermaphroditism, and growth and psychomotor retardation. It has been described in two siblings. It is transmitted as an autosomal recessive trait. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Dysmorphism-short stature-deafness-disorder of sex development syndrome	None	6,005	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2282	2021-01-23T18:09:34	{"icd-10": ["Q87.8"], "synonyms": ["Dysmorphism-short stature-hearing loss-disorder of sex development syndrome", "Ieshima-Koeda-Inagaki syndrome"]}
Seller et al. (1996) described a sporadic case of lethal chondrodysplasia in a male fetus born of first-cousin Caucasian parents. The fetus manifested an absence of ossification of the skull vault and vertebral bodies in the cervical and thoracic regions, platyspondyly in the lumbar region, and short angulated ulnae, radii, femora, tibiae, and fibulae. The fetus also presented sclerosis of scapulae and iliac bones, and humeri with mixed sclerosis affecting the metaphyses and with lysis affecting predominantly the diaphyses. Seller et al. (1996) suggested that this fetus represents a 'new' autosomal recessive form of lethal chondrodysplasia. INHERITANCE \- Autosomal recessive GROWTH Height \- Short limb dwarfism CHEST Ribs Sternum Clavicles & Scapulae \- Sclerotic scapulae SKELETAL Skull \- Absent ossification of skull vault Spine \- Absent ossification of cervical vertebral bodies \- Absent ossification of thoracic vertebral bodies \- Lumbar platyspondyly Pelvis \- Sclerotic iliac bones Limbs \- Short angulated ulnae \- Short angulated radii \- Short angulated femora \- Short angulated tibiae \- Short angulated fibulae \- Mixed sclerosis of humeral metaphyses \- Humeral diaphyseal lysis MISCELLANEOUS \- Neonatal lethal ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	CHONDRODYSPLASIA, LETHAL, WITH LONG BONE ANGULATION AND MIXED BONE DENSITY	c1832410	6,006	omim	https://www.omim.org/entry/601376	2019-09-22T16:14:56	{"mesh": ["C563330"], "omim": ["601376"]}
Vincent van Gogh, Self-Portrait with Bandaged Ear (1889), Courtauld Institute of Art, London Van Gogh syndrome is a mental condition in which an adult performs self-mutilations. It usually happens on the ground of a specific psychiatric condition.[1][2] The term is derived from the action of Vincent van Gogh in 1888, cutting off his own ear, or a part of it, after a quarrel with fellow artist Paul Gauguin[3][4] during one of his psychotic episodes.[5] Sufferers may burn themselves, attempt to severely damage their genital organs (especially amputate their penis), castrate themselves, extract their own eyes, amputate their own hands, or commit suicide.[5] Self-injury in children may be labeled with different diagnostic terms such as Lesch-Nyhan and Munchausen syndromes.[6] Another medical condition for which the term is used, but only rarely, is when the vision turns yellow for a period of time as, for example, in digoxin toxicity.[7] Van Gogh syndrome is, now, a synonym for Nonsuicidal Self-Injury (NSSI), where participants intentionally and repetitively inflict injuries on their bodies without suicidal intention and not social sanctioned. These injuries are not meant to cause lethal harm and range from biting, scratching, cutting to serious acts like mutilating reproductive parts.[8] Self-injuring occurs quite commonly in children from 9–18 months, and is considered pathological in children beyond 3 years of age.[9] NSSI is most prevalent in adolescents and patients with diagnosed psychological illnesses, however frequent incidents are also recorded among young adults. In the past, NSSI was thought of as symptoms that associated with many psychological conditions, not an entity by itself. With increasing reports of prevalence and causative origins, recently, NSSI has been classified as an independent syndrome that can co-occur with a variety of other mental conditions. The fifth edition of Diagnostic and Statistical Manual of Mental Disorder (DSM-5), published in 2013, has officially recognized NSSI as its own entity and updated diagnostic methods for patients with clinical symptoms for NSSI.[10] NSSI patients usually use self-mutilation as a mean to relieve stress and negative feelings, often harbor thoughts of self-injure, repeat injuries, and experience satisfaction post-action. Although NSSI is often associated with suicidal attempts, there is a clear distinction between the two conditions.[11] People who practice NSSI do not set death as their final goal. Severity of wounds may vary and some may end up needing medical attention, however, the purpose is never to cause lethal harm.[8] Indeed, NSSI serves as several functioning outlets for participants, including negative and positive reinforcements. ## Contents * 1 Diagnostic * 2 Risk factors * 3 Functions * 4 References ## Diagnostic[edit] Because NSSI is associated with a wide range of psychological syndromes, like eating disorders, dissociative disorder, borderline personality, depressive disorders, and suicidal, it used to be regarded as manifesting symptoms of these conditions.[11] Nevertheless, many cases have been reported where patients with NSSI were diagnosed without comorbidity of any other psychological dysfunctions. Thus, it is irrefutable that NSSI is a stand-alone syndrome with distinct symptoms and causes. The DSM-5 outlines 6 criteria that patients must qualify for diagnostic.[12] 1. Criteria A: the person must be involved in at least 5 days of self-mutilation without suicidal intention in the past year. However, this number has been reported to be relatively low when compared to realistic rate for adolescents, which was 11 days in one year.[10] 2. Criteria B: persons must commit self-injure behaviors due to interpersonal problems, whether it is to alleviate unpleasant feelings and stress from such problems, or to seek positive feelings and relief. Studies have shown that females tend to expect relief from negative feelings and stress more than males. 3. Criteria C: persons must be struggling from negative feelings and thoughts prior to NSSI, thoughts of NSSI are premeditated and constantly occupied in their minds. 4. Criteria D: self-injure behaviors must be not socially sanctioned or minor wounds. This means that tattoos, piercings, or scab-picking are not considered as NSSI. 5. Criteria E: NSSI-related emotional issues must be interfering with daily tasks like school/work relationships, or performances. 6. Criteria F: NSSI must not overlap other dysfunctional episodes from other mental conditions, like withdrawal symptoms from drug abuse or eating disorders, psychosis, delirium, or substance intoxication. This criteria serves to rule out any consequential characteristics of self-injury behaviors as result of these episodes. ## Risk factors[edit] Adolescents are the most prevalent age group for NSSI, the average age of onset is around 13–14 years old. Studies showed that adolescents are vulnerable to NSSI due to the sensitive transitional period in life that happens during adolescent years.[8] NSSI is usually induced by stress and feelings of uncontrollable stress and anxiety, while adolescents and young adults face a wide range of challenging life events, different changes, along with limited mental control to protect them from self-harm decisions. Thus, a high percentage of NSSI participants admits to carrying out self-injure behaviors as a mean of coping mechanism. Adolescents also harbor external and internal factors that put them in the at-risk age group.[11] External factors include childhood events, parenting condition, or peers. Children that went through childhood adversities are more prone to cognitive distortion that tend to permit NSSI behaviors. Severity of such adversities also play a major role in increasing risk for adolescents. Those who grew up with child maltreatment like physical/sexual or emotional abuse, household with drug-use problems, negligence, poverty, exposure to parental violence,... are more likely to develop psychopathology in later years.[11] Women with NSSI tendency are shown to have experienced emotion negligence from both parents and insecure paternal bonding, while men with NSSI tendency are predicted to have gone through parental abandonment, mostly from father.[13] Non physically abusive parenting can also place high susceptibility on adolescents. Parental control refers to when parents want to influence their child either by physical or emotional manipulation, while parental support implies behaviors that are encouraging, accepting, and supportive. Households with heavy use of parental control, and lack thereof of parental support, usually lead to high tendency of NSSI. Internal issues stem from emotional dysregulation and psychological distress also push individuals towards NSSI tendency.[11] Inability to digest and process emotional situations can lead to improper or insufficient awareness and understanding of emotional responses. Misjudgment of emotional surroundings also result in outbursts that are beyond acceptable range of emotional response. Individuals that are under psychological distress also fall into the at-risk group due to constant heightened state of anxiety from demanding stressors and unregulated external stimuli. People with other existing psychological conditions like BPD, EDs, or other dissociative disorders may also develop NSSI. NSSI is often seen as a coping mechanism for patients that are suffering with stress and psychopathology.[citation needed] ## Functions[edit] An overwhelming amount of NSSI cases were reported in accordance to stress release intention. Most NSSI patients are associated with sadness, anxiety, depression, feeling of abandoned, and isolated, they often find themselves trapped in high amount of uncontrollable stress and emotional burden that are hard to endure; living quality is also negatively impacted. Inflicting physical wounds is an outlet to relieve unbearable distress, the act of cutting through skin is a mean to physically lesson the pain, and many have reported that feeling of satisfaction and goodness were perceived post-injury.[8] Among other individuals, NSSI behaviors are also considered as a way to self-punish and self-directed anger. Other uses of NSSI include wanting to fit in, gaining attention, and alleviating emotional numbness.[11] NSSI functions are classified into four sub-functions: automatic negative reinforcement, automatic positive reinforcement, social negative reinforcement, and social positive reinforcement. Automatic negative reinforcement aims to eliminate feeling of emotional numbness or negative feelings of emotional disturbances, automatic positive reinforcement seeks to gain any type of feelings, even pain, social negative reinforcement helps individuals get away from feeling peer pressure and being forced to do things against their wills, lastly, social positive reinforcement is done to attain attention, negative or positive.[13] Overall, automatic negative reinforcement and automatic positive reinforcement prevail the other two methods, while automatic negative reinforcement is more common than automatic positive reinforcement. These findings correspond to popular utilization of NSSI as tool to alleviate negative stress. Individuals that participate in automatic positive reinforcement have higher risk for suicidal attempts. The desire to obtain certain feelings from self-mutilation tends to push those individuals towards higher frequency of self-harm repetition, along with desensitization to pain and elimination of fear towards suicidal thoughts.[11] ## References[edit] 1. ^ Abram, Harry S. (1966). "The van Gogh Syndrome: An Unusual Case of Polysurgical Addiction \| American Journal of Psychiatry". American Journal of Psychiatry. 123 (4): 478–481. doi:10.1176/ajp.123.4.478. PMID 5957391. 2. ^ Aryal, S.; Puri, P. R.; Thapa, R.; Roka, Y. B. (2011-11-24). "Van Gogh Syndrome\| Journal of Nepal Health Research Council". Journal of Nepal Health Research Council. Retrieved 2018-09-19. 3. ^ Segen, J. (2010). Concise Dictionary of Modern Medicine. BookBaby. ISBN 9781609840730. Retrieved 2018-09-19. 4. ^ Taylor, R.B. (2016). White Coat Tales: Medicine's Heroes, Heritage, and Misadventures. Springer International Publishing. p. 128. ISBN 9783319290553. Retrieved 2018-09-19. 5. ^ a b "Postgraduate Medical Journal". Blackwell Scientific Publications. 1 July 1998 – via Google Books. 6. ^ "The American Journal of Psychiatry". American Psychiatric Association. 19 September 1967 – via Google Books. 7. ^ "Toronto Notes 2011 - Cardiology_and_Cardiovascular_Surgery - [PDF Document]". vdocuments.site. 8. ^ a b c d Klonsky, E David; Victor, Sarah E; Saffer, Boaz Y (November 2014). "Nonsuicidal Self-Injury: What We Know, and What We Need to Know". Canadian Journal of Psychiatry. 59 (11): 565–568. doi:10.1177/070674371405901101. ISSN 0706-7437. PMC 4244874. PMID 25565471. 9. ^ "Van Gogh syndrome". ResearchGate. Retrieved 2020-04-29. 10. ^ a b Zetterqvist, Maria (2015-12-01). "The DSM-5 diagnosis of nonsuicidal self-injury disorder: A review of the empirical literature". Child and Adolescent Psychiatry and Mental Health. 9: 31. doi:10.1186/s13034-015-0062-7. PMC 4584484. PMID 26417387. 11. ^ a b c d e f g "Nonsuicidal Self-Injury". ResearchGate. Retrieved 2020-04-29. 12. ^ Gratz, Kim L.; Dixon-Gordon, Katherine L.; Chapman, Alexander L.; Tull, Matthew T. (October 2015). "Diagnosis and Characterization of DSM-5 Nonsuicidal Self-Injury Disorder Using the Clinician-Administered Nonsuicidal Self-Injury Disorder Index". Assessment. 22 (5): 527–539. doi:10.1177/1073191114565878. ISSN 1073-1911. PMC 5505727. PMID 25604630. 13. ^ a b Cipriano, Annarosa; Cella, Stefania; Cotrufo, Paolo (2017). "Nonsuicidal Self-injury: A Systematic Review". Frontiers in Psychology. 8: 1946. doi:10.3389/fpsyg.2017.01946. ISSN 1664-1078. PMC 5682335. PMID 29167651. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Van Gogh syndrome	None	6,007	wikipedia	https://en.wikipedia.org/wiki/Van_Gogh_syndrome	2021-01-18T18:50:30	{"wikidata": ["Q4420118"]}
Abortion in New Mexico is legal. 51% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases. The number of abortion clinics in New Mexico has declined over the years, with 26 in 1982, twenty in 1992 and eleven in 2014. There were 4,500 legal abortions in 2014. ## Contents * 1 Terminology * 2 Context * 3 History * 3.1 Legislative history * 3.2 Clinic history * 4 Statistics * 5 Abortion financing * 6 Abortion rights views and activities * 6.1 Protests * 6.2 Views * 7 Anti-abortion views and activities * 8 Footnotes * 9 References ## Terminology[edit] Main article: Abortion See also: Definitions of abortion The abortion debate most commonly relates to the "induced abortion" of an embryo or fetus at some point in a pregnancy, which is also how the term is used in a legal sense.[note 1] Some also use the term "elective abortion", which is used in relation to a claim to an unrestricted right of a woman to an abortion, whether or not she chooses to have one. The term elective abortion or voluntary abortion describes the interruption of pregnancy before viability at the request of the woman, but not for medical reasons.[1] Anti-abortion advocates tend to use terms such as "unborn baby", "unborn child", or "pre-born child",[2][3] and see the medical terms "embryo", "zygote", and "fetus" as dehumanizing.[4][5] Both "pro-choice" and "pro-life" are examples of terms labeled as political framing: they are terms which purposely try to define their philosophies in the best possible light, while by definition attempting to describe their opposition in the worst possible light. "Pro-choice" implies that the alternative viewpoint is "anti-choice", while "pro-life" implies the alternative viewpoint is "pro-death" or "anti-life".[6] The Associated Press encourages journalists to use the terms "abortion rights" and "anti-abortion".[7] ## Context[edit] See also: Abortion in the United States Free birth control correlates to teenage girls having a fewer pregnancies and fewer abortions. A 2014 New England Journal of Medicine study found such a link. At the same time, a 2011 study by Center for Reproductive Rights and Ibis Reproductive Health also found that states with more abortion restrictions have higher rates of maternal death, higher rates of uninsured pregnant women, higher rates of infant and child deaths, higher rates of teen drug and alcohol abuse, and lower rates of cancer screening.[8] According to a 2017 report from the Center for Reproductive Rights and Ibis Reproductive Health, states that tried to pass additional constraints on a women's ability to access legal abortions had fewer policies supporting women's health, maternal health and children's health. These states also tended to resist expanding Medicaid, family leave, medical leave, and sex education in public schools.[9] According to Megan Donovan, a senior policy manager at the Guttmacher Institute, states have legislation seeking to protect a woman's right to access abortion services have the lowest rates of infant mortality in the United States.[9] Poor women in the United States had problems paying for menstrual pads and tampons in 2018 and 2019. Almost two-thirds of American women could not pay for them. These were not available through the federal Women, Infants, and Children Program (WIC).[10] Lack of menstrual supplies has an economic impact on poor women. A study in St. Louis found that 36% had to miss days of work because they lacked adequate menstrual hygiene supplies during their period. This was on top of the fact that many had other menstrual issues including bleeding, cramps and other menstrual induced health issues.[10] This state was one of a majority that taxed essential hygiene products like tampons and menstrual pads as of November 2018.[11][12][13][14] ## History[edit] ### Legislative history[edit] In the late 1960s and early 1970s, Arkansas, Colorado, Georgia, Maryland, New Mexico, North Carolina and Oregon made reforms to their abortion laws, with most of these states providing more detailed medical guidance on when therapeutic abortions could be performed.[15] In 1969, the Legislature passed a law that made it a felony for someone to provide a woman with an abortion unless it was needed to save a woman's life, or because her pregnancy was a result of rape or incest.[16] The U.S. Supreme Court's decision in 1973's Roe v. Wade barred states from regulating abortion in the first trimester;[15] consequently, New Mexico's 1969 abortion law became unenforceable.[16] In March 2019, the Legislature considered a bill that would have repealed the 1969 law. While the New Mexico House of Representatives passed the repeal bill, it was defeated in the State Senate by a vote of 24–18.[16] In 2017, Washington State, New Mexico, Illinois, Alaska, Maryland, Massachusetts, Connecticut, and New Jersey allowed qualified non-physicians to prescribe drugs for medical abortions only.[17] New Mexico had few abortion restrictions in comparison to other states as of May 1, 2018. There are no waiting periods, no required parental consent, and no inability to use state funding for an abortion.[18] ### Clinic history[edit] Number of abortion clinics in New Mexico by year. See also: Abortion clinic Between 1982 and 1992, the number of abortion clinics in the state decreased by six, going from 26 in 1982 to twenty in 1992.[19] In 2014, there were eleven facilities which provided abortions of which nine were abortion clinics.[20][18] In 2014, 91% of the counties in the state did not have an abortion clinic. That year, 48% of women in the state aged 15 – 44 lived in a county without an abortion clinic.[21] In March 2016, there were 6 Planned Parenthood clinics in the state.[22] In 2017, Planned Parenthood closed three clinics in the state. This was done around their plans to try to consolidate reproductive services they offered in the New Mexico.[23] Later that year, there were three total Planned Parenthood clinics in the state. At the time, the population was 456,213 for women aged 15 – 49 of which two offered abortion services.[23] ## Statistics[edit] In the period between 1972 and 1974, there were zero recorded illegal abortion deaths in the state.[24] In 1990, 181,000 women in the state faced the risk of an unintended pregnancy.[19] Between 2011 and 2014, there was a 10% decline in the number of abortions performed in the state.[18] In 2013, among white women aged 15–19, there were abortions 150, 20 abortions for black women aged 15–19, 370 abortions for Hispanic women aged 15–19, and 70 abortions for women of all other races.[25] In 2014, 51% of adults said in a poll by the Pew Research Center that abortion should be legal in all or most cases.[26] In 2017, the state had an infant mortality rate of 5.9 deaths per 1,000 live births.[9] Number of reported abortions, abortion rate and percentage change in rate by geographic region and state in 1992, 1995 and 1996[27] Census division and state Number Rate % change 1992–1996 1992 1995 1996 1992 1995 1996 US Total 1,528,930 1,363,690 1,365,730 25.9 22.9 22.9 –12 Mountain 69,600 63,390 67,020 21 17.9 18.6 –12 Arizona 20,600 18,120 19,310 24.1 19.1 19.8 –18 Colorado 19,880 15,690 18,310 23.6 18 20.9 –12 Idaho 1,710 1,500 1,600 7.2 5.8 6.1 –15 Montana 3,300 3,010 2,900 18.2 16.2 15.6 –14 Nevada 13,300 15,600 15,450 44.2 46.7 44.6 1 New Mexico 6,410 5,450 5,470 17.7 14.4 14.4 –19 Utah 3,940 3,740 3,700 9.3 8.1 7.8 –16 Wyoming 460 280 280 4.3 2.7 2.7 –37 Number, rate, and ratio of reported abortions, by reporting area of residence and occurrence and by percentage of abortions obtained by out-of-state residents, US CDC estimates Location Residence Occurrence % obtained by out-of-state residents Year Ref No. Rate^ Ratio^^ No. Rate^ Ratio^^ New Mexico 3,655 9.2 140 4,500 11.3 173 21 2014 [28] New Mexico 3,502 8.9 142 4,573 11.6 185 27.0 2016 [29] ^number of abortions per 1,000 women aged 15–44; ^^number of abortions per 1,000 live births ## Abortion financing[edit] State Medicaid coverage of medically necessary abortion services. Navy blue: Medicaid covers medically necessary abortion for low-income women through legislation. Royal blue: Medicaid covers medically necessary abortions for low-income women under court order. Gray: Medicaid denies abortion coverage for low-income women except for cases of rape, incest, or life endangerment. Seventeen states including New Mexico used their own funds to cover all or most "medically necessary" abortions sought by low-income women under Medicaid, thirteenof which are required by State court orders to do so.[30] In 2010, the state had 1,270 publicly funded abortions, of which were 0 federally funded and 1,270 were state funded.[31] Public funding was still available in May 2018.[18] ## Abortion rights views and activities[edit] ### Protests[edit] Women from the state participated in marches supporting abortion rights as part of a #StoptheBans movement in May 2019.[32] ### Views[edit] Women in Film Executive Director Kirsten Schaffer said of Georgia and other states similar restrictive abortion bans passed in early 2019, "A woman's right to make choices about her own body is fundamental to her personal and professional well-being. [...] We support people who make the choice not to take their production to Georgia or take a job in Georgia because of the draconian anti-choice law. To that end, we've compiled a list of pro-choice states that offer meaningful tax rebates and production incentives, and encourage everyone to explore these alternatives: California, Colorado, Hawaii, Illinois, Maine, Nevada, New Jersey, New Mexico, New York, Washington."[33] ## Anti-abortion views and activities[edit] On December 6, 2007, Chad Altman and Sergio Baca were arrested for the arson of Dr. Curtis Boyd's clinic in Albuquerque. Baca's girlfriend had scheduled an appointment for an abortion at the clinic.[34][35] ## Footnotes[edit] 1. ^ According to the Supreme Court's decision in Roe v. Wade: > (a) For the stage prior to approximately the end of the first trimester, the abortion decision and its effectuation must be left to the medical judgement of the pregnant woman's attending physician. (b) For the stage subsequent to approximately the end of the first trimester, the State, in promoting its interest in the health of the mother, may, if it chooses, regulate the abortion procedure in ways that are reasonably related to maternal health. (c) For the stage subsequent to viability, the State in promoting its interest in the potentiality of human life may, if it chooses, regulate, and even proscribe, abortion except where it is necessary, in appropriate medical judgement, for the preservation of the life or health of the mother. Likewise, Black's Law Dictionary defines abortion as "knowing destruction" or "intentional expulsion or removal". ## References[edit] 1. ^ Watson, Katie (20 Dec 2019). "Why We Should Stop Using the Term "Elective Abortion"". AMA Journal of Ethics. 20 (12): E1175-1180. doi:10.1001/amajethics.2018.1175. PMID 30585581. 2. ^ Chamberlain, Pam; Hardisty, Jean (2007). "The Importance of the Political 'Framing' of Abortion". The Public Eye Magazine. 14 (1). 3. ^ "The Roberts Court Takes on Abortion". New York Times. November 5, 2006. Retrieved January 18, 2008. 4. ^ Brennan 'Dehumanizing the vulnerable' 2000 5. ^ Getek, Kathryn; Cunningham, Mark (February 1996). "A Sheep in Wolf's Clothing – Language and the Abortion Debate". Princeton Progressive Review. 6. ^ "Example of "anti-life" terminology" (PDF). Archived from the original (PDF) on 2011-07-27. Retrieved 2011-11-16. 7. ^ Goldstein, Norm, ed. The Associated Press Stylebook. Philadelphia: Basic Books, 2007. 8. ^ Castillo, Stephanie (2014-10-03). "States With More Abortion Restrictions Hurt Women's Health, Increase Risk For Maternal Death". Medical Daily. Retrieved 2019-05-27. 9. ^ a b c "States pushing abortion bans have highest infant mortality rates". NBC News. Retrieved 2019-05-25. 10. ^ a b Mundell, E.J. (January 16, 2019). "Two-Thirds of Poor U.S. Women Can't Afford Menstrual Pads, Tampons: Study". US News & World Report. Retrieved May 26, 2019. 11. ^ Larimer, Sarah (January 8, 2016). "The 'tampon tax,' explained". The Washington Post. Archived from the original on December 11, 2016. Retrieved December 10, 2016. 12. ^ Bowerman, Mary (July 25, 2016). "The 'tampon tax' and what it means for you". USA Today. Archived from the original on December 11, 2016. Retrieved December 10, 2016. 13. ^ Hillin, Taryn. "These are the U.S. states that tax women for having periods". Splinter. Retrieved 2017-12-15. 14. ^ "Election Results 2018: Nevada Ballot Questions 1-6". KNTV. Retrieved 2018-11-07. 15. ^ a b Buell, Samuel (1991-01-01). "Criminal Abortion Revisited". New York University Law Review. 66: 1774–1831. 16. ^ a b c "New Mexico Senate upholds dormant ban on abortion". Las Cruces Sun-News. Retrieved 2019-05-28. 17. ^ "Study: Abortions Are Safe When Performed By Nurse Practitioners, Physician Assistants, Certified Nurse Midwives". Retrieved 25 January 2017. 18. ^ a b c d "State Facts About Abortion: New Mexico". Guttmacher Institute. 2016-01-26. Retrieved 2019-05-28. 19. ^ a b Arndorfer, Elizabeth; Michael, Jodi; Moskowitz, Laura; Grant, Juli A.; Siebel, Liza (December 1998). A State-By-State Review of Abortion and Reproductive Rights. Diane Publishing. ISBN 9780788174810. 20. ^ Gould, Rebecca Harrington, Skye. "The number of abortion clinics in the US has plunged in the last decade — here's how many are in each state". Business Insider. Retrieved 2019-05-23. 21. ^ businessinsider (2018-08-04). "This is what could happen if Roe v. Wade fell". Business Insider (in Spanish). Retrieved 2019-05-24. 22. ^ Bohatch, Emily. "27 states with the most Planned Parenthood clinics". thestate. Retrieved 2019-05-24. 23. ^ a b "Here's Where Women Have Less Access to Planned Parenthood". Retrieved 2019-05-23. 24. ^ Cates, Willard; Rochat, Roger (March 1976). "Illegal Abortions in the United States: 1972–1974". Family Planning Perspectives. 8 (2): 86. doi:10.2307/2133995. JSTOR 2133995. PMID 1269687. 25. ^ "No. of abortions among women aged 15–19, by state of residence, 2013 by racial group". Guttmacher Data Center. Retrieved 2019-05-24. 26. ^ "Views about abortion by state - Religion in America: U.S. Religious Data, Demographics and Statistics". Pew Research Center. Retrieved 2019-05-23. 27. ^ "Abortion Incidence and Services in the United States, 1995-1996". Guttmacher Institute. 2005-06-15. Retrieved 2019-06-02. 28. ^ Jatlaoui, Tara C. (2017). "Abortion Surveillance — United States, 2014". MMWR. Surveillance Summaries. 66 (24): 1–48. doi:10.15585/mmwr.ss6624a1. ISSN 1546-0738. PMID 29166366. 29. ^ Jatlaoui, Tara C. (2019). "Abortion Surveillance — United States, 2016". MMWR. Surveillance Summaries. 68. doi:10.15585/mmwr.ss6811a1. ISSN 1546-0738. 30. ^ Francis Roberta W. "Frequently Asked Questions". Equal Rights Amendment. Alice Paul Institute. Archived from the original on 2009-04-17. Retrieved 2009-09-13. 31. ^ "Guttmacher Data Center". data.guttmacher.org. Retrieved 2019-05-24. 32. ^ Bacon, John. "Abortion rights supporters' voices thunder at #StopTheBans rallies across the nation". USA Today. Retrieved 2019-05-25. 33. ^ Low, Matt Donnelly,Gene Maddaus,Elaine; Donnelly, Matt; Maddaus, Gene; Low, Elaine (2019-05-28). "Netflix the Only Hollywood Studio to Speak Out in Attack Against Abortion Rights (Exclusive)". Variety. Retrieved 2019-06-02. 34. ^ "Suspects In Abortion Clinic Fire Plead Not Guilty - Albuquerque News Story - KOAT Albuquerque". 2011-07-13. Archived from the original on 2011-07-13. Retrieved 2019-05-22. 35. ^ "New Mexico: Did You Know? Archived 2011-06-22 at the Wayback Machine". NARAL Pro-Choice America. Archived from the original on June 22, 2011. Retrieved June 21, 2011. Abortion in the United States by state States * Alabama * Alaska * Arizona * Arkansas * California * Colorado * Connecticut * Delaware * Florida * Georgia * Hawaii * Idaho * Illinois * Indiana * Iowa * Kansas * Kentucky * Louisiana * Maine * Maryland * Massachusetts * Michigan * Minnesota * Mississippi * Missouri * Montana * Nebraska * Nevada * New Hampshire * New Jersey * New Mexico * New York * North Carolina * North Dakota * Ohio * Oklahoma * Oregon * Pennsylvania * Rhode Island * South Carolina * South Dakota * Tennessee * Texas * Utah * Vermont * Virginia * Washington * West Virginia * Wisconsin * Wyoming Federal district Washington, D.C. Insular areas * American Samoa * Guam * Northern Mariana Islands * Puerto Rico * U.S. Virgin Islands [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Abortion in New Mexico	None	6,008	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_New_Mexico	2021-01-18T18:58:01	{"wikidata": ["Q64876944"]}
For a discussion of autoimmunity, see 109100. See also vitiligo (606579). Mapping Alkhateeb et al. (2002) estimated that, in 23% of cases, vitiligo is associated with other autoimmune disorders, particularly autoimmune thyroid disease, pernicious anemia (170900), systemic lupus erythematosus (152700), and Addison disease (240200); Spritz et al. (2004) pointed to association with adult-onset insulin-dependent diabetes mellitus (IDDM; 222100). In an extended study with a cohort of 102 multiplex families with vitiligo, Spritz et al. (2004) confirmed the localization of AIS1 (607836) at 73.7 cM on chromosome 1p. In addition, 2 other signals that previously were only suggestive achieved threshold criteria for significant linkage in the larger study. These loci were designated AIS2 at 89.4 cM on chromosome 7 (lod = 3.73), and AIS3 (608392) at 54.2 cM on chromosome 8. The data also provided support for a locus at 4.3 cM on chromosome 17 (lod = 3.07), which was thought to correspond to SLEV1 (606579). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	AUTOIMMUNE DISEASE, SUSCEPTIBILITY TO, 2	c1842113	6,009	omim	https://www.omim.org/entry/608391	2019-09-22T16:07:53	{"omim": ["608391"], "synonyms": ["Alternative titles", "VITILIGO-ASSOCIATED MULTIPLE AUTOIMMUNE DISEASE SUSCEPTIBILITY 3", "AUTOIMMUNE DISEASE SUSCEPTIBILITY LOCUS, CHROMOSOME 7-RELATED"]}
Spondylometaphyseal dysplasia, 'corner fracture' type is a skeletal dysplasia associated with short stature, developmental coxa vara, progressive hip deformity, simulated 'corner fractures' of long tubular bones and vertebral body abnormalities (mostly oval vertebral bodies). ## Epidemiology Less than 30 patients have been reported in the literature. ## Clinical description Tetralogy of Fallot and odontoid hypoplasia have been reported in single patients with this syndrome. ## Etiology Currently, there are no human genes associated with the disease. ## Genetic counseling Autosomal dominant inheritance has been suggested. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Spondylometaphyseal dysplasia, 'corner fracture' type	c0432221	6,010	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93315	2021-01-23T16:58:11	{"gard": ["4991"], "mesh": ["C535793"], "omim": ["184255"], "umls": ["C0432221"], "icd-10": ["Q77.8"], "synonyms": ["Spondylometaphyseal dysplasia, Sutcliffe type"]}
Frontotemporal dementias (FTDs) are a group of neurodegenerative disorders associated with shrinking of the frontal and temporal anterior lobes of the brain. Symptoms include marked changes in social behavior and personality, and/or problems with language. People with behavior changes may have disinhibition (with socially inappropriate behavior), apathy and loss of empathy, hyperorality (eating excessive amounts of food or attempting to consume inedible things), agitation, compulsive behavior, and various other changes. Examples of problems with language include difficulty speaking or understanding speech. Some people with FTD also develop a motor syndrome such as parkinsonism or motor neuron disease (which may be associated with various additional symptoms). There is a strong genetic component to FTDs. It sometimes follows an autosomal dominant inheritance pattern, or sometimes there is a general family history of dementia or psychiatric disorders. The three main genes responsible for familial FTD are MAPT, GRN, and C9orf72. However, the genetic cause of familial FTD cannot always be identified. While there are currently no treatments to slow or stop the progression of the disease, some of the symptoms can be managed. Treatment of symptoms may involve behavior modification, or medications for symptoms such as aggressiveness, agitation, or dangerous behaviors. Anti-depressants have been shown to improve some symptoms. Involving a team of specialists can help ensure that the challenges of the disease are properly addressed. Unfortunately, the outlook for people with FTD is poor, as the disease often progresses rapidly. However, the outlook does vary, with the disease course ranging from less than 2 years in some people, to more than 10 years in others. Although the name and classification of FTD has been a topic of discussion for over a century, the current classification considers Pick’s disease, primary progressive aphasia, and semantic dementia as sub-types of FTD. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Frontotemporal dementia	c0338451	6,011	gard	https://rarediseases.info.nih.gov/diseases/8436/frontotemporal-dementia	2021-01-18T18:00:24	{"mesh": ["D057180"], "omim": ["600274"], "orphanet": ["282"], "synonyms": ["Dementia, frontotemporal, with parkinsonism", "Frontotemporal dementia with parkinsonism", "Frontotemporal lobe dementia (FLDEM)", "MSTD", "Multiple system tauopathy with presenile dementia", "FTD"]}
A number sign (#) is used with this entry because of evidence that early-onset epileptic encephalopathy-25 (EIEE25) is caused by homozygous or compound heterozygous mutation in the SLC13A5 gene (608305) on chromosome 17p13. The disorder shows phenotypic similarities to Kohlschutter-Tonz syndrome (KTZS; 226750), which is caused by mutation in the mutation in the ROGDI gene (614574) on chromosome 16p13. For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see 308350. Clinical Features Thevenon et al. (2014) reported 8 patients from 3 unrelated families with early infantile epileptic encephalopathy. One of the families was consanguineous and of Algerian origin. The patients had onset of seizures between the first hours and first 7 days of life. Seizures were manifest as chewing, cyanosis, clonic movements, abnormal ocular movements, and status epilepticus. EEG studies performed in several patients showed multiple abnormalities, such as rhythmic theta/delta focal discharges from both hemispheres that often involved the temporal or occipital lobes, or multifocal status epilepticus. All patients had profound or severe delayed development with lack of speech, and most patients did not acquire the ability to sit. Eye contact and head control were achieved in most, but not all, patients. Additional variable features included axial hypotonia, peripheral hypertonia, and abnormal involuntary movements such as dystonia and choreoathetosis. The frequency and severity of seizures tended to improve with age, although neurologic outcome remained severe. Hardies et al. (2015) reported 8 patients from 4 unrelated families of European descent with EIEE25. All patients developed focal clonic seizures on the first day of life, followed by ongoing multiple seizure types, including hemiconvulsions and generalized tonic-clonic seizures. Seven patients had status epilepticus, including 1 who died from it, and 6 showed fever sensitivity. Two patients became seizure-free between 3 and 7 years of age. Interictal EEG showed focal abnormalities in all but 1 patient. Three patients responded well to a ketogenic diet. Neurologic outcome varied from mild to severe intellectual disability, plus variable combinations of ataxia, choreoathetosis, spasticity, and microcephaly. All also had tooth hypoplasia or hypodontia, which was also noted in 3 of the patients reported by Thevenon et al. (2014). Schossig et al. (2017) reported 10 patients from 5 unrelated families with EIEE25 with amelogenesis imperfecta. Nine patients presented with a clinical diagnosis of KTZS, but did not carry pathogenic mutations in the ROGDI gene. The patients developed refractory seizures in the first days or months of life and thereafter showed global developmental delay with moderate to severe intellectual disability and delayed walking or difficulty walking. They had EEG abnormalities, such as focal slowing, multiepileptiform potentials, generalized spike-wave activity, and sometimes hypsarrhythmia. Additional features included axial hypotonia, limb spasticity causing gait impairment, cerebellar ataxia, coordination defects, dystonia, and pyramidal signs. Communication skills were very poor. Brain imaging was normal. Two sibs (family C) had previously been reported by De Souza et al. (2014) and 3 other German sibs (family D) had previously been reported by Hardies et al. (2015). All patients had dental abnormalities, including delayed eruption, hypodontia, tooth hypoplasia, yellow discoloration, thin enamel, and enamel chipping. Permanent teeth were small and cylindrical with discoloration and secondary molars and premolars were extremely worn. Weeke et al. (2017) reported 8 patients from 5 families with EIEE25 confirmed by genetic analysis. All patients presented with refractory neonatal seizures on the first day of life after an uncomplicated pregnancy. Six of 7 infants with a neonatal MRI had a characteristic MRI pattern with punctate white matter lesions (PWML), which were no longer visible at the age of 6 months but resulted in gliotic scarring visible on MRI at the age of 18 months. The same pattern of gliotic scarring was seen on the MRIs of the infant without a neonatal scan. The findings indicated that some patients with EIEE25 may have subtle or transient brain imaging abnormalities. Inheritance The transmission pattern of EIEE25 in the families reported by Thevenon et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In 7 patients from 3 unrelated families with early infantile epileptic encephalopathy, Thevenon et al. (2014) identified homozygous or compound heterozygous missense mutations in the SLC13A5 gene (608305.0001-608305.0003). The mutations in the first 2 families were found by whole-exome sequencing. The mutations occurred at highly conserved residues in the sodium-binding domains, which are important for citrate transport, but functional studies were not performed. In 8 patients from 4 unrelated families with EIEE25, Hardies et al. (2015) identified 7 different biallelic mutations in the SLC13A5 gene (608305.0001-608305.0002; 608305.0004-608305.0008). Mutations in the first 3 families were found by whole-exome or whole-genome sequencing and segregated with the disorder in the families. Five mutations were missense mutations and 2 were truncating mutations; 2 mutations had previously been reported by Thevenon et al. (2014). In vitro functional expression studies in HEK293T cells showed that all mutant proteins lost citrate transport activity, even though some missense mutations were correctly expressed at the plasma membrane. Hardies et al. (2015) noted that neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates and thus rely on the uptake of intermediates, such as citrate, to maintain energy status and neurotransmitter production. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly Teeth \- Hypodontia \- Delayed eruption \- Worn molars \- Amelogenesis imperfecta, hypoplastic \- Hypoplastic enamel \- Enamel chipping \- Yellow surface \- Pits on teeth MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Delayed psychomotor development, severe to profound \- Lack of speech acquisition \- Status epilepticus \- Tonic seizures \- Multifocal seizures \- Axial hypotonia \- Peripheral hypertonia \- Ataxia \- Spasticity \- Abnormal involuntary movements \- Multifocal discharges seen on EEG \- White matter abnormalities \- Gliotic changes \- Delayed myelination MISCELLANEOUS \- Onset in the first hours or days of life \- Seizures are poorly responsive to treatment \- Ketogenic diet may be effective \- Seizure severity and frequency tend to improve with age MOLECULAR BASIS \- Caused by mutation in the solute carrier family 13 (sodium-dependent citrate transporter), member 5 gene (SLC13A5, 608305.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 25, WITH AMELOGENESIS IMPERFECTA	c4014621	6,012	omim	https://www.omim.org/entry/615905	2019-09-22T15:50:44	{"doid": ["0080453"], "omim": ["615905"], "orphanet": ["442835"], "synonyms": ["Undetermined EOEE"]}
Cervical dystonia is a neurological condition characterized by excessive pulling of the muscles of the neck and shoulder resulting in abnormal movements of the head (dystonia). Most commonly, the head turns to one side or the other. Tilting sideways, or to the back or front may also occur. The turning or tilting movements may be accompanied by shaking movement (tremor) and/or soreness of the muscles of the neck and shoulders. Cervical dystonia can occur at any age, but most cases occur in middle age. It often begins slowly and usually reaches a plateau over a few months or years. The cause of cervical dystonia is often unknown. In some cases there is a family history. Several genes have been associated with cervical dystonia, including GNAL, THAP1, CIZ1, and ANO3. Other cases may be linked to an underlying disease (e.g. Parkinson disease), neck trauma, or certain medications. Treatment may include local injections of botulinum toxin, pain medications, benzodiazepines (anti-anxiety medications), anticholinergics, physical therapy, or surgery. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Cervical dystonia	c0949445	6,013	gard	https://rarediseases.info.nih.gov/diseases/10668/cervical-dystonia	2021-01-18T18:01:32	{"mesh": ["D014103"], "umls": ["C0949445"], "synonyms": ["Spasmodic torticollis"]}
A number sign (#) is used with this entry because some cases of idiopathic pulmonary fibrosis (IPF) are caused by heterozygous mutation in the SFTPA2 gene (178642), encoding pulmonary surfactant protein A2, on chromosome 10q22. Evidence suggests that susceptibility to the disease may also be conferred by a polymorphism in the SFTPA1 gene (178630) on chromosome 10q22 or a promoter mutation in the MUC5B gene (600770) on chromosome 11p15. Description Idiopathic pulmonary fibrosis is one of a family of idiopathic pneumonias sharing clinical features of shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees in inflammation, fibrosis, or both on lung biopsy. In some cases, the disorder can be rapidly progressive and characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Although older studies included several forms of interstitial pneumonia under the term 'idiopathic pulmonary fibrosis,' the clinical label of 'idiopathic pulmonary fibrosis' should be reserved for patients with a specific form of fibrosing interstitial pneumonia referred to as usual interstitial pneumonia (Gross and Hunninghake, 2001). It is estimated that 0.5 to 2.2% of cases of idiopathic pulmonary fibrosis are familial (Marshall et al., 2000). Pulmonary fibrosis can also be a feature in patients with mutations in the TERT (187270) or the TERC (602322) gene; see PFBMFT1 (614742) and PFBMFT2 (614743). Some patients with surfactant protein C deficiency (610913) who survive to adulthood manifest features of pulmonary fibrosis. Clinical Features McKusick and Fisher (1958) described 3 cases. Donohue et al. (1959) reported a Canadian family with 8 cases in 4 generations, and Rezek and Talbert (1962) reported father and daughter. Jacox et al. (1964) described a family in which idiopathic pulmonary fibrosis had been observed in 8 definite and 3 probable instances in a dominant pedigree pattern. Apparent male-to-male transmission had occurred in 1 instance. Increase of a gamma-globulin fraction was thought to be a possible integral part of the syndrome. Hughes (1964) described the disorder in a mother and 2 daughters. Davies and Potts (1964) observed affected brothers in whom clubbing of the fingers was present for many years before the development of respiratory symptoms. Koch (1965) observed a family with 3 definite and 5 probable cases. The definite cases included an instance of father-to-son transmission; one patient developed bronchial carcinoma. Swaye et al. (1969) described 8 cases in 3 generations. In 1 case, the diagnosis was made at age 3.5 years by lung biopsy. Two brothers had coexistent pulmonary fibrosis and bronchogenic cancer. Wagley (1972) described a family in which 3 brothers and a sister had well-documented pulmonary fibrosis and their mother, 2 of their sibs, and the son of 1 brother probably had pulmonary fibrosis. Gadek et al. (1979) found high concentrations of collagenase in the lower respiratory tract of patients with idiopathic pulmonary fibrosis. Beaumont et al. (1981) reported the occurrence of interstitial pulmonary fibrosis and alveolar cell carcinoma (ACC) in a family. At the time of report, 5 members had pulmonary fibrosis, of whom 3 had ACC. A sixth member had ACC without proven pulmonary fibrosis. Ten Kate (1981) stated that 1 of the 2 with pulmonary fibrosis without ACC had developed ACC. ACC with familial pulmonary fibrosis was reported by McKusick and Fisher (1958). In familial idiopathic pulmonary fibrosis, there is a characteristic pattern of alveolar inflammation that features neutrophil accumulation and macrophage activation. Bitterman et al. (1986) found that, despite being clinically normal in every respect, about half the first-degree relatives of patients with familial idiopathic fibrosis (they studied 3 families) had a similar pattern of alveolar inflammation. From studies of 5 patients with idiopathic pulmonary fibrosis, Antoniades et al. (1990) suggested that overproduction of platelet-derived growth factor-beta (190040) may play an important role in pathogenesis. Farrell et al. (1986) described a family in which 3 members had a parenchymal pulmonary disorder beginning in infancy. At age 4 months, the proposita had several upper respiratory infections and thereafter insidiously developed progressive respiratory failure. The authors reported proliferation and desquamation of type II pneumonocytes filling the alveolar spaces. Electron microscopy showed that the pneumocytes contained abundant lamellar bodies in the cytoplasm. The paternal uncle and aunt of the proposita died at 8 and 7 months, respectively. In the last month of life, each had lung biopsy which showed proliferation of alveolar cells, diffuse pulmonary fibrosis, and cystic changes suggestive of idiopathic pulmonary fibrosis. Steroids were not effective in the proposita, but chloroquine was dramatically beneficial. After 4 months of treatment, repeat lung biopsy showed great improvement and at the time of report the child, aged 4 years, had shown satisfactory growth and development. ### Hamman-Rich Disease Hamman and Rich (1944) described 4 adults who presented with cough and shortness of breath rapidly progressing to fatal right-sided heart failure. Postmortem pathologic examination reported 'acute diffuse interstitial fibrosis of the lung.' After reviewing histologic material from 3 of the 4 original cases described by Hamman and Rich (1944) as well as 29 cases of their own, Olson et al. (1990) concluded that Hamman-Rich disease is an acute disorder rather than a chronic interstitial pneumonia. The patients present with the adult respiratory distress syndrome (ARDS). Of their 29 patients, 12 survived, some after long and complicated hospitalization. Population Genetics Hunninghake et al. (2013) examined chest CT scans of 2,633 individuals enrolled in the Framingham Heart Study and found that 177 of them (7%) had interstitial lung abnormalities, and that 47 (27%) of those could be classified as fibrosis. Inheritance Male-to-male transmission in several reported families with pulmonary fibrosis (e.g., Jacox et al., 1964; Koch, 1965; Solliday et al., 1973) suggested autosomal dominant inheritance. Pathogenesis Marshall et al. (2000) asked adult pulmonary physicians in the U.K. to identify all families under their care in which 2 or more individuals had been diagnosed with fibrosing alveolitis of unknown cause. Each proband was sent a questionnaire designed to delineate possible environmental/occupational exposures and to obtain pedigree data. They identified 25 families comprising 67 cases. Suitable data for analysis were available for 21 families (57 cases). The male:female ratio was 1.75:1 (p less than 0.05). A high resolution computed tomography scan was performed in 93% and the diagnosis of cryptogenic fibrosing alveolitis was confirmed on biopsy specimens in 32%. The mean age at diagnosis was 55.5 years. Fifty percent of cases were 'ever smokers' and 18% had been diagnosed as asthmatic. Exposure to known fibrogenic agents was recorded by 36% of patients. In no families did all affected members report the same exposure. A wide range of agents was implicated, including coal dust, wood dust, metal dust, and adhesives; the exposure was occupational in only 2 cases and in most the exposure was in the home. In 1 case there was exposure to asbestos but open lung biopsy showed typical features of cryptogenic fibrosing alveolitis and no asbestos bodies. In 1 case there was exposure to wood dust, which Hubbard et al. (1996) suggested may be a fibrogenic agent. The study demonstrated a prevalence of 1.34 cases per million in the U.K. population. Mode of inheritance was not clear. They showed 3 pedigrees in which a father and one or more children were affected. Familial cases occurred in persons younger at diagnosis but were otherwise indistinguishable from nonfamilial cases. Gross and Hunninghake (2001) reviewed idiopathic pulmonary fibrosis, emphasizing definition, pathogenesis, diagnosis, natural history, and therapy. Antoniou et al. (2004) provided a 'top ten list' of references pertaining to etiopathogenesis, prognosis, diagnosis, therapy, and other aspects of idiopathic pulmonary fibrosis. Using microarray, immunohistochemical, RT-PCR, and immunoblot analyses, Wang et al. (2006) found that expression of CAV1 (601047) was significantly reduced in lung tissue and in KRT19 (148020)-positive epithelial cells, but not in CD31 (PECAM1; 173445)-positive endothelial cells, of IPF patients compared with controls. Transfer of Cav1 into mice suppressed bleomycin-induced IPF. Treatment of human pulmonary fibroblasts with TGFB (190180) decreased CAV1 mRNA and protein expression. CAV1 suppressed TGFB-induced extracellular matrix (ECM) production via the JNK (MAPK8; 601158) pathway, and it modulated SMAD (e.g., SMAD3; 603109) signaling by fibroblasts. Wang et al. (2006) concluded that CAV1 inhibits production of ECM molecules by fibroblasts and suggested that it may be a therapeutic target for IPF patients. Alder et al. (2008) studied telomere length in 62 patients with idiopathic interstitial pneumonia (IIP), 50 (81%) of whom had been diagnosed with idiopathic pulmonary fibrosis. They found that IIP patients had shorter leukocyte telomeres compared to age-matched controls (p less than 0.0001). Screening the TERT and TERC genes in 100 consecutive patients, including the 62 individuals in whom telomere length had been measured, revealed a mutation in TERC in only 1 patient (602322.0010). The authors noted that a subset of patients (10%) with no family history and no detectable mutations in telomerase had telomere lengths in the range of known mutation carriers. The presence of individuals with very short telomeres suggested the presence of other genetic mechanisms that can lead to telomere shortening. From a total of 150 IIP patients, Alder et al. (2008) detected a cluster of 4 (3%) IPF patients who also had cryptogenic liver cirrhosis, suggesting that the observed telomere shortening has consequences and can contribute to what appears clinically as 'idiopathic' progressive organ failure in the lung and the liver. In a bleomycin-induced mouse model of pulmonary fibrosis, Oga et al. (2009) demonstrated that loss of prostaglandin F receptor (PTGFR; 600563) selectively attenuated pulmonary fibrosis while maintaining levels of alveolar inflammation and TGFB stimulation similar to those of wildtype mice, and that PTGFR deficiency and inhibition of TGFB signaling additively decreased fibrosis. PGF(2-alpha) was found to be abundant in bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis; in addition, PGF(2-alpha) stimulated proliferation and collagen production of lung fibroblasts via PTGFR independently of TGFB. Oga et al. (2009) concluded that PTGFR signaling facilitates pulmonary fibrosis independently of TGFB. Mapping Wang et al. (2009) performed whole-genome linkage analysis in 29 members of a 4-generation family segregating autosomal dominant idiopathic pulmonary fibrosis with or without lung cancer (see 211980) and obtained a model-free lod score of 3.22 on chromosome 10. All affected family members shared an identical-by-descent region on chromosome 10 between markers rs877783 and rs4869, a 15.7-Mb interval containing 118 annotated genes. Molecular Genetics ### Mutation in the SFTPA2 Gene In a 4-generation family segregating autosomal dominant IPF with or without lung cancer mapping to chromosome 10, Wang et al. (2009) sequenced the candidate genes SFTPA1 (178630) and SFTPA2 (178642) and identified heterozygosity for a missense mutation in SFTPA2 (178642.0001) that segregated with disease. SFTPA1 and SFTPA2 were then sequenced in 58 additional IPF probands, and a heterozygous missense mutation in SFTPA2 (178642.0002) was identified in a 45-year-old man with IPF and lung cancer. The patient reported multiple family members over 3 generations with undefined lung disease, pulmonary fibrosis, and/or lung cancer, but they were not available for study. Neither mutation was found in 3,557 population-based controls, and transfection studies showed that the mutant proteins are retained in the endoplasmic reticulum and are not secreted. ### Association with MUC5B Using a genomewide linkage scan, Seibold et al. (2011) detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. They found association of the minor allele (T) of a single-nucleotide polymorphism (SNP) in the promoter of the MUC5B gene, rs35705950 (600770.0001), with idiopathic pulmonary fibrosis (allelic association, p = 2.5 x 10(-37)) and with familial interstitial pneumonia (allelic association p = 1.2 x 10(-15)). MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P less than 0.001). The variant allele of rs35705950 was associated with upregulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wildtype allele, P less than 0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. In a study of 341 cases with idiopathic pulmonary fibrosis from the University of Pittsburgh and the University of Chicago and 802 controls from the same 2 centers, Zhang et al. (2011) confirmed the findings of Seibold et al. (2011), finding strong association of the minor allele at rs35705950 with pulmonary fibrosis (P = 7.6 x 10(-40)). ### Association with the Major Histocompatibility Complex Falfan-Valencia et al. (2005) evaluated polymorphisms of the major histocompatibility complex (MHC; see 142800) on chromosome 6q21 in a cohort of 75 IPF patients and 95 controls. In addition, they examined the effect of bronchoalveolar lavage (BAL) from IPF patients with different MHC haplotypes. They reported findings suggesting that some MHC polymorphisms confer susceptibility to IPF and suggested that this susceptibility might be related to the induction of epithelial cell apoptosis, a critical process in the development of the disease. Aquino-Galvez et al. (2009) analyzed the MICA gene (600169) in 80 sporadic IPF patients and 201 controls and found a significant increase of MICA001 in the IPF cohort (odds ratio, 2.91; corrected p = 0.03). In addition, the MICA 001/00201 genotype was significantly increased in patients with IPF compared with healthy controls (odds ratio, 4.72; corrected p = 0.01). Strong immunoreactive MICA staining was localized in alveolar epithelial cells and fibroblasts from IPF lungs, whereas control lungs were negative. Soluble MICA was detected in 35% of IPF patients compared to 12% of control subjects (p = 0.0007). The expression of the MICA receptor NKG2D (KLRK1; 611817) was significantly decreased in gamma/delta T cells and natural killer cells obtained from IPF lungs. Aquino-Galvez et al. (2009) concluded that MICA polymorphisms and abnormal expression of NKG2D might contribute to IPF susceptibility. ### Associations Pending Confirmation Selman et al. (2003) studied 84 unrelated patients with idiopathic pulmonary fibrosis. All patients presented with progressive dyspnea and cough, predominantly basal inspiratory crackles, radiographic bilateral interstitial opacities, high resolution computed tomography scan patterns with varying degrees of reticular infiltrates, subpleural and basal honeycombing, and sparse ground-glass opacification. All patients showed significant reduction in lung volumes and hypoxemia at rest that worsened with exercise. Among 54 nonsmokers, they found an association between an allele of the SPA1 gene, designated 6A(4) (178630.0001), and pulmonary fibrosis. This polymorphism was associated with idiopathic pulmonary fibrosis in nonsmokers but not in smokers. Hodgson et al. (2006) performed a genomewide scan in 6 multiplex families with familial idiopathic pulmonary fibrosis who originated from southeastern Finland. Most Finnish multiplex families were clustered in that geographic region, and the population history suggested that the clustering might be explained by an ancestor shared among the patients. The genomewide scan identified 5 loci of interest. A shared haplotype on 4q31 was significantly more frequent among the patients than in population-based controls. The shared haplotype harbored 2 functionally uncharacterized genes, ELMOD2 (610196) and LOC152586 (610310), of which only ELMOD2 was expressed in lung and showed significantly decreased mRNA expression in lung from idiopathic pulmonary fibrosis when compared with that of healthy lung. The results suggested that ELMOD2 may be a candidate gene for susceptibility to familial IPF. Animal Model To examine the possibility that the fibroblasts involved in pulmonary fibrosis are of extrapulmonary origin and derived from bone marrow progenitor cells, Hashimoto et al. (2004) produced adult mice durably engrafted with bone marrow isolated from transgenic mice expressing enhanced GFP. Induction of pulmonary fibrosis in these chimeric mice by endotracheal bleomycin (BLM) injection caused large numbers of GFP+ cells to appear in active fibrotic lesions, whereas only a few GFP+ cells could be identified in control lungs. Flow cytometric analysis of lung cells confirmed the increase and revealed significant increase in GFP+ cells that also expressed type I collagen (see 120150). Fibrocytes present in the peripheral circulation were first identified by Bucala et al. (1994). These cells comprised a minor component of the circulating pool of leukocytes (less than 1%) and expressed a characteristic pattern of markers, including collagen I and CD45 (151460). When cultured in vitro, these cells became adherent and developed a spindle-shaped morphology. Subsequent studies showed that these circulating fibrocytes express chemokine receptors such as CXCR4 (162643) and CCR7 (600242). Pulmonary fibrosis was originally thought to be mediated solely by resident lung fibroblasts. Phillips et al. (2004) showed that a population of human circulating fibrocytes positive for CD45, type I collagen, and CXCR4 migrates in response to CXCL12 (600835) and traffics to the lungs in a murine model of bleomycin-induced pulmonary fibrosis. They demonstrated that murine fibrocytes of this type also traffic to the lungs in response to a bleomycin challenge. Maximal intrapulmonary recruitment of these fibrocytes directly correlated with increased collagen deposition in the lungs. Treatment of bleomycin-exposed animals with specific neutralizing anti-CXCL12 antibodies inhibited intrapulmonary recruitment of circulating fibrocytes of this type and attenuated lung fibrosis. Thus, Phillips et al. (2004) demonstrated that circulating fibrocytes contribute to the pathogenesis of pulmonary fibrosis. Imai et al. (2005) reported that ACE2 (300335) and the angiotensin II type 2 receptor (300034) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE (106180), angiotensin II (see 106150), and the angiotensin II type 1a receptor (106165), promote disease pathogenesis, induce lung edemas, and impair lung function. Imai et al. (2005) showed that mice deficient for ACE show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Imai et al. (2005) concluded that their data identified a critical function for ACE2 in acute lung injury. Tager et al. (2008) found elevated levels of the lysolipid mediator lysophosphatidic acid (LPA) in bronchoalveolar lavage (BAL) fluid from mice following lung injury in the bleomycin model of pulmonary fibrosis. In mice lacking the LPA receptor Edg2 (602282), both accumulation of fibroblasts and vascular leak induced by bleomycin challenge were markedly attenuated compared to wildtype mice, whereas leukocyte recruitment was preserved during the first week after injury. In BAL fluid from patients with idiopathic pulmonary fibrosis, LPA levels were also increased, and inhibition of EDG2 markedly reduced fibroblast responses to the chemotactic activity of BAL fluid. Tager et al. (2008) concluded that the LPA-EDG2 pathway mediates both excessive accumulation of fibroblasts and persistent vascular leak that have been implicated in pulmonary fibrosis. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Pulmonary hypertension, severe (in end-stage disease) RESPIRATORY Airways \- Bronchogenic carcinoma (some) Lung \- Exertional dyspnea \- Cough, nonproductive \- Pulmonary fibrosis with fibroblast foci on histology \- Honeycomb fibrosis, varying in age and location \- Pneumonia, usual interstitial \- Alveolar cell carcinoma (some) \- Adenocarcinoma (some) ABDOMEN Liver \- Cirrhosis, cryptogenic SKELETAL Hands \- Finger clubbing (seen in up to 50% of patients) NEOPLASIA \- Alveolar cell carcinoma (some) \- Bronchogenic carcinoma (some) \- Adenocarcinoma of lung (some) MOLECULAR BASIS \- Caused by mutation in the pulmonary-associated surfactant protein A2 gene (SFTPA2, 178642.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA [kDa]: kilodalton	PULMONARY FIBROSIS, IDIOPATHIC	c0085786	6,014	omim	https://www.omim.org/entry/178500	2019-09-22T16:35:24	{"doid": ["0050156"], "mesh": ["D011658"], "omim": ["178500"], "icd-9": ["516.31"], "icd-10": ["J84.112"], "orphanet": ["2032", "79126"], "synonyms": ["Alternative titles", "IDIOPATHIC PULMONARY FIBROSIS, FAMILIAL", "FIBROSING ALVEOLITIS, CRYPTOGENIC", "FIBROCYSTIC PULMONARY DYSPLASIA", "INTERSTITIAL PNEUMONITIS, USUAL"], "genereviews": ["NBK1230"]}
This designation may be appropriate for the malformation syndrome described by Sakati et al. (1971) in a single male. The calvaria was large and the face disproportionately small. All cranial sutures were fused. The ears were dysplastic and low-set. Maxillary hypoplasia, dental crowding, prognathism and short neck with low hairline were features. A sixth digit had been removed from the right hand. The feet were adducted and showed polysyndactyly with 7 toes on the right and 6 toes on the left. The tibias were hypoplastic and the fibulas were deformed and displaced. The chromosomes were normal. Advanced parental age supported new dominant mutation as the cause. No other cases have, it seems, been reported. Eyes \- Shallow orbits \- Hypertelorism Facies \- Flat facies \- Small facies \- Prognathism \- Maxillary hypoplasia Skull \- Craniosynostosis \- Acrocephaly Teeth \- Dental crowding Neck \- Short neck with low hairline Inheritance \- Autosomal dominant Limbs \- Preaxial polydactyly \- Syndactyly \- Broad thumbs and broad great toes \- Hypoplastic legs Ears \- Dysplastic ears \- Low-set ears ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	ACROCEPHALOPOLYSYNDACTYLY TYPE III	c1275079	6,015	omim	https://www.omim.org/entry/101120	2019-09-22T16:45:29	{"doid": ["0060359"], "mesh": ["C537227"], "omim": ["101120"], "synonyms": ["Alternative titles", "ACPS III", "ACPS WITH LEG HYPOPLASIA", "SAKATI-NYHAN SYNDROME"]}
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Find sources: "Achlorhydria" – news · newspapers · books · scholar · JSTOR (February 2013) (Learn how and when to remove this template message) Achlorhydria Other namesHypochlorhydria Hydrogen chloride (major component of gastric acid) Pronunciation * /eɪklɔːrˈhaɪdriə/ SpecialtyInternal medicine Achlorhydria and hypochlorhydria refer to states where the production of hydrochloric acid in gastric secretions of the stomach and other digestive organs is absent or low, respectively.[1] It is associated with various other medical problems. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Risk Factors * 3.1 Other * 4 Diagnosis * 5 Treatment * 6 Prognosis * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Irrespective of the cause, achlorhydria can result as known complications of bacterial overgrowth and intestinal metaplasia and symptoms are often consistent with those diseases: * gastroesophageal reflux disease[2] * abdominal discomfort * early satiety * weight loss * diarrhea * constipation * abdominal bloating * anemia * stomach infection * malabsorption of food * carcinoma of stomach Since acidic pH facilitates the absorption of iron, achlorhydric patients often develop iron deficiency anemia. Acidic environment of stomach helps conversion of pepsinogen into pepsin, which is highly important in digesting the protein into smaller components, such as a complex protein into simple peptides and amino acids inside the stomach, which are later absorbed by the gastrointestinal tract. Bacterial overgrowth and B12 deficiency (pernicious anemia) can cause micronutrient deficiencies that result in various clinical neurological manifestations, including visual changes, paresthesias, ataxia, limb weakness, gait disturbance, memory defects, hallucinations and personality and mood changes. Risk of particular infections, such as Vibrio vulnificus (commonly from seafood) is increased. Even without bacterial overgrowth, low stomach acid (high pH) can lead to nutritional deficiencies through decreased absorption of basic electrolytes (magnesium, zinc, etc.) and vitamins (including vitamin C, vitamin K, and the B complex of vitamins). Such deficiencies may be involved in the development of a wide range of pathologies, from fairly benign neuromuscular issues to life-threatening diseases. ## Causes[edit] * The slowing of the body's basal metabolic rate associated with hypothyroidism * Pernicious anemia where there is antibody production against parietal cells which normally produce gastric acid.[3] * The use of antacids or drugs that decrease gastric acid production (such as H2-receptor antagonists) or transport (such as proton pump inhibitors). * A symptom of rare diseases such as mucolipidosis (type IV). * A symptom of Helicobacter pylori infection which neutralizes and decreases secretion of gastric acid to aid its survival in the stomach.[4] * A symptom of atrophic gastritis or of stomach cancer. * Radiation therapy involving the stomach. * Gastric bypass procedures such as a duodenal switch and RNY, where the largest acid producing parts of the stomach are either removed, or blinded. * VIPomas (vasoactive intestinal peptides) and somatostatinomas are both islet cell tumors of the pancreas. * Pellagra, caused by niacin deficiency. * Chloride, sodium, potassium, zinc and/or iodine deficiency, as these elements are needed to produce adequate levels of stomach acid (HCl). * Sjögren's syndrome, an autoimmune disorder that destroys many of the body's moisture-producing enzymes * Ménétrier's disease, characterized by hyperplasia of mucous cells in the stomach also causing excess protein loss, leading to hypoalbuminemia. Presents with abdominal pain and edema ## Risk Factors[edit] Age It was found that the incidence of achlorhydria in patients under the age of 60 was around 2.3%, whereas it was 5% in patients over the age of 60.[5] In a persons 30s, the prevalence is about 2.5%, and increases to 12% in a persons 80s. An absence of hydrochloric acid increases with advancing age. A lack of hydrochloric acid produced by the stomach is one of the most common age-related caused of a harmed digestive system.[6] Among men and women, 27% suffer from a varying degree of achlorhydria. US researchers found that over 30% of women and men over the age of 60 suffer from having little to no acid secretion in the stomach. Additionally, 40% of postmenopausal women have shown to have no basal gastric acid secretion in the stomach, with 39.8% occurring in females 80 to 89 years old [6] Autoimmune Disorders Autoimmune disorders are also linked to advancing age, specifically autoimmune gastritis, which is when the body produces unwelcomed antibodies and causes inflammation of the stomach.[5] Autoimmune disorders are also a cause for small bacterial growth in the bowel and a deficiency of Vitamin B-12. These have also proved to be factors of acid secretion in the stomach.[7] Hypothyroidism: Thyroid hormones are a factor in the decreasing of hydrochloric acid in the stomach, thus hypothyroidism is associated with a greater risk of developing achlorhydria.[5] Autoimmune conditions are often managed using various treatments, however these treatments have no known effect on achlorhydria.[5] ### Other[edit] Other risk factors include, over the counter acid-blocking medications and antibiotics that may be used to block stomach acid. These medications are often taken by individuals for a longer than recommended period, even for years, despite causing adverse effects on stomach acid secretion.[7] Stress has also been proven to be linked to symptoms associated with achlorhydria including constant belching, constipation, and abdominal pain.[7] ## Diagnosis[edit] For practical purposes, gastric pH and endoscopy should be done in someone with suspected achlorhydria. Older testing methods using fluid aspiration through a nasogastric tube can be done, but these procedures can cause significant discomfort and are less efficient ways to obtain a diagnosis. A complete 24-hour profile of gastric acid secretion is best obtained during an esophageal pH monitoring study. Achlorhydria may also be documented by measurements of extremely low levels of pepsinogen A (PgA) (< 17 µg/L) in blood serum. The diagnosis may be supported by high serum gastrin levels (> 500–1000 pg/mL).[8] The "Heidelberg test" is an alternative way to measure stomach acid and diagnose hypochlorhydria/achlorhydria. A check can exclude deficiencies in iron, calcium, prothrombin time, vitamin B-12, vitamin D, and thiamine. Complete blood count with indices and peripheral smears can be examined to exclude anemia. Elevation of serum folate is suggestive of small bowel bacterial overgrowth. Bacterial folate can be absorbed into the circulation. Once achlorhydria is confirmed, a hydrogen breath test can check for bacterial overgrowth. ## Treatment[edit] Treatment focuses on addressing the underlying cause of symptoms. Treatment of gastritis that leads to pernicious anemia consists of parenteral vitamin B-12 injection. Associated immune-mediated conditions (e.g., insulin-dependent diabetes mellitus, autoimmune thyroiditis) should also be treated. However, treatment of these disorders has no known effect in the treatment of achlorhydria. Achlorhydria associated with Helicobacter pylori infection may respond to H. pylori eradication therapy, although resumption of gastric acid secretion may only be partial and it may not always reverse the condition completely.[9] Antimicrobial agents, including metronidazole, amoxicillin/clavulanate potassium, ciprofloxacin, and rifaximin, can be used to treat bacterial overgrowth. Achlorhydria resulting from long-term proton-pump inhibitor (PPI) use may be treated by dose reduction or withdrawal of the PPI. ## Prognosis[edit] Little is known on the prognosis of achlorhydria, although there have been reports of an increased risk of gastric cancer.[10] A 2007 review article noted that non-Helicobacter bacterial species can be cultured from achlorhydric (pH > 4.0) stomachs, whereas normal stomach pH only permits the growth of Helicobacter species. Bacterial overgrowth may cause false-positive H. pylori test results due to the change in pH from urease activity.[11] Small bowel bacterial overgrowth is a chronic condition. Retreatment may be necessary once every 1–6 months.[12] Prudent use of antibacterials now calls for an antibacterial stewardship policy to manage antibiotic resistance.[13] ## See also[edit] * Atrophic gastritis * Fundic gland polyposis * Hyperchlorhydria * Isopropamide ## References[edit] 1. ^ Kohli, Divyanshoo R., Jennifer Lee, and Timothy R. Koch. "Achlorhydria." Medscape. Ed. B S. Anand. N.p., 29 Apr. 2015. Web. 25 May 2015. 2. ^ Kines, Kasia, and Tina Krupczak. "Nutritional Interventions for Gastroesophageal Reflux, Irritable Bowel Syndrome, and Hypochlorhydria: A Case Report." Integr Med. 2016 Aug 15; 15(4): 49-53. 3. ^ "Achlorhydria". Medscape. Jul 15, 2016. Retrieved 11 October 2018. 4. ^ El-Omar EM, Oien K, El-Nujumi A, et al. (1997). "Helicobacter pylori infection and chronic gastric acid hyposecretion". Gastroenterology. 113 (1): 15–24. doi:10.1016/S0016-5085(97)70075-1. PMID 9207257. 5. ^ a b c d Team 2, Health Jade (2019-09-02). "Achlorhydria definition, causes, symptoms, diagnosis, treatment & prognosis". Health Jade. Retrieved 2019-11-15. 6. ^ a b English, James (2018-11-25). "Gastric Balance: Heartburn Not Always Caused by Excess Acid". Nutrition Review. Retrieved 2019-11-15. 7. ^ a b c Kines, Kasia; Krupczak, Tina (August 2016). "Nutritional Interventions for Gastroesophageal Reflux, Irritable Bowel Syndrome, and Hypochlorhydria: A Case Report". Integrative Medicine: A Clinician's Journal. 15 (4): 49–53. ISSN 1546-993X. PMC 4991651. PMID 27574495. 8. ^ Divyanshoo Rai Kohli. "Achlorhydria Workup". Medscape. Retrieved 13 September 2014. 9. ^ Iijima, K.; Sekine, H.; Koike, T.; Imatani, A.; Ohara, S.; Shimosegawa, T. (2004). "Long-term effect of Helicobacter pylori eradication on the reversibility of acid secretion in profound hypochlorhydria". Alimentary Pharmacology and Therapeutics. 19 (11): 1181–1188. doi:10.1111/j.1365-2036.2004.01948.x. PMID 15153171. 10. ^ Svendsen JH, Dahl C, Svendsen LB, Christiansen PM (1986). "Gastric cancer risk in achlorhydric patients. A long-term follow-up study". Scand. J. Gastroenterol. 21 (1): 16–20. doi:10.3109/00365528609034615. PMID 3952447. 11. ^ Brandi G (Aug 2006). "Urease-positive bacteria other than Helicobacter pylori in human gastric juice and mucosa". Am J Gastroenterol. 101 (8): 1756–61. PMID 16780553. 12. ^ Divyanshoo Rai Kohli. "Achlorhydria Follow-up". Medscape. Retrieved 13 September 2014. 13. ^ Lee CR, Cho IH, Jeong BC, Lee SH (Sep 12, 2013). "Strategies to minimize antibiotic resistance". Int J Environ Res Public Health. 10 (9): 4274–305. doi:10.3390/ijerph10094274. PMC 3799537. PMID 24036486. ## External links[edit] Classification D * ICD-10: K31.8 * ICD-10-CM: K31.83 * ICD-9-CM: 536.0 * MeSH: D000126 * DiseasesDB: 29513 External resources * eMedicine: med/18 * 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]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Achlorhydria	c0001075	6,016	wikipedia	https://en.wikipedia.org/wiki/Achlorhydria	2021-01-18T18:41:13	{"mesh": ["D000126"], "umls": ["C0001075"], "icd-9": ["536.0"], "icd-10": ["K31.8"], "wikidata": ["Q340548"]}
A goldfish with fish dropsy Dropsy is a disease in fish caused by the buildup of fluid inside the body cavity or tissues. As a symptom rather than a disease, it can indicate a number of underlying diseases, including bacterial infections, parasitic infections, or liver dysfunction.[1] ## Treatment[edit] Because dropsy is a symptom of an illness, its cause may or may not be contagious. However, it is standard practice to quarantine sick fish to prevent spreading the underlying cause to the other fish in the tank community.[1] ## Prognosis[edit] By the time a disorder reaches the point of causing dropsy, it can often be fatal and at the very least the fish is very ill and requires immediate quarantine and treatment.[1] ## References[edit] 1. ^ a b c David Alderton (2003). Freshwater Aquariums: Basic Aquarium Setup and Maintenance. p. 129. ISBN 1-931993-11-4. * v * t * e Aquariums and fishkeeping Aquarium types * Freshwater * Marine * Reef * Brackish-water * Community * Biotope Aquarium décor and equipment * Airstone * Algae scrubber * Berlin Method * Bog-wood / Driftwood * Calcium reactor * Deep sand bed * Filter * Fishcam * Fish feeder * Heater * Lighting * Live rock / Live sand * Powerhead * Protein skimmer * Refugium * Substrate * Sump Fish terms / types * Algae eater * Bottom feeder * Coldwater * Dither * Hardy * Painted * Tropical Fish food * Brine shrimp * Daphnia * Feeder fish * Feeder shrimp * Infusoria * Shrimp mix * Tubifex tubifex Other concepts * Aquarium fishery * Aquascaping * Artificial seawater * Bath treatment * Clean-up crew * Disease in ornamental fish * Macquarium * Project Piaba * Reef safe * Spawning trigger * Water conditioner People * Takashi Amano * Herbert R. Axelrod * Leonhard Baldner * Pierre Carbonnier * Edward Edwards * Philip Henry Gosse * Sven O. Kullander * William Alford Lloyd * Paul Matte * Julian Sprung * Anna Thynne * Charles Haskins Townsend * Jeanne Villepreux-Power * Robert Warington Magazines * Aquarium Fish International * Koi * Practical Fishkeeping * Tropical Fish Hobbyist Companies * Dennerle * Drs. Foster & Smith * Eheim * Hikari * Hagen * Sera * Tetra * Wardley Lists * Aquarium diseases * Aquarium fish by scientific name * Freshwater aquarium fish / amphibians / invertebrates / plants * Marine aquarium fish / invertebrates / plants * Brackish aquarium fish / invertebrates / plants [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Dropsy (fish disease)	None	6,017	wikipedia	https://en.wikipedia.org/wiki/Dropsy_(fish_disease)	2021-01-18T19:01:20	{"wikidata": ["Q8563411"]}
A number sign (#) is used with this entry because VKCFD2 is caused by homozygous mutation in the VKORC1 gene (608547), which encodes vitamin K epoxide reductase, on chromosome 16p11. For a general phenotypic description and a discussion of genetic heterogeneity of combined deficiency of vitamin K-dependent clotting factors, see VKCFD1 (277450). Description Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome (Fregin et al., 2002). Clinical Features Oldenburg et al. (2000) described 2 pedigrees showing an autosomal recessive transmission of familial multiple coagulation factor deficiency. The first pedigree was a consanguineous kindred of Lebanese origin with 8 children alive. There were 2 further children who died, one on day 3 after birth from intracranial hemorrhage, and the other during the first year of life. Four sibs had experienced severe bleeding previously. The second family, of German origin, was apparently nonconsanguineous; however, distant consanguinity could not be ruled out, since both maternal and paternal grandparents originated from neighboring villages. Internal hydrocephalus caused by intracranial bleeding had been diagnosed in 1 child. Oldenburg et al. (2000) excluded mutations in the GGCX gene in these families. Mapping Fregin et al. (2002) excluded mutations in the genes encoding microsomal epoxide hydrolase (EPHX1; 132810) and DT-diaphorase (NQO1; 125860) in the families with multiple coagulation factor deficiency reported by Oldenburg et al. (2000). They performed a genomewide linkage analysis in these 2 pedigrees and found a total maximum 2-point lod score of 3.4 at theta of 0.0 in the interval between markers D16S3131 on chromosome 16p12 and D16S419 on chromosome 16q21. In both families, patients were autozygous for 26 and 28 markers, respectively, in an interval of 3 cM. Thus, Fregin et al. (2002) assigned a second locus for combined multiple coagulation factor deficiency, VKCFD2, to chromosome 16p12-q21. They suggested that the warfarin resistance phenotype in mice and rats (see 122700) and familial combined deficiency of vitamin K-dependent clotting factors in humans may be allelic mutations, and, assuming a single gene for both phenotypes, mouse-human homology maps would restrict the candidate gene region to the short arm of chromosome 16. Molecular Genetics In 2 unrelated index patients with VKCFD2 and their affected sibs, Rost et al. (2004) identified an arg98-to-trp mutation in vitamin K epoxide reductase (608547.0001). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	VITAMIN K-DEPENDENT CLOTTING FACTORS, COMBINED DEFICIENCY OF, 2	c1848534	6,018	omim	https://www.omim.org/entry/607473	2019-09-22T16:09:16	{"mesh": ["C564741"], "omim": ["607473"], "orphanet": ["98434"]}
A number sign (#) is used with this entry because of evidence that dosage-sensitive sex reversal is due to duplication of the DAX1 gene (NR0B1; 300473) on chromosome Xp21.3-p21.2. For a discussion of genetic heterogeneity of 46,XY sex reversal, see SRXY1 (400044). Clinical Features The existence of an X-specific gene involved in human sex determination was first postulated by German et al. (1978), on the basis of a family with an apparent X-linked mode of inheritance of 46,XY gonadal dysgenesis. A number of families with X-linked recessive (or sex-limited autosomal dominant) transmission of the disorder were reported thereafter (reviewed by Fechner et al., 1993). Bardoni et al. (1994) studied 4 patients with 46,XY sex reversal, who were raised as girls due to their having either ambiguous or female external genitalia. Histologic examination of the internal genitalia was performed in 3 of the patients and confirmed partial gonadal dysgenesis. The authors noted that the patients exhibited a complex phenotype, including mental retardation and multiple minor malformation, but clinical details were not provided in that report. Smyk et al. (2007) reported a 21-year-old 46,XY female who presented with primary amenorrhea, a small immature uterus, and gonadal dysgenesis without adrenal insufficiency, in whom they identified a submicroscopic 257-kb deletion with a distal breakpoint 11.3 kb upstream of the NR0B1 gene. The deletion was also present in the patient's mother, who had a history of ovarian cysts, but was not found in 1,184 controls. The authors suggested that loss of regulatory sequences may have resulted in position effect upregulation of NR0B1 expression. Molecular Genetics Bardoni et al. (1994) studied 8 patients with duplications at chromosome Xp21, including 4 who had 46,XY sex reversal and 4 who were 46,XY phenotypic males. Breakpoint analysis identified an approximately 20-Mb region on Xp21.2-p22.1 that was duplicated only in the 46,XY females. Further analysis involving 1 additional 46,XY sex-reversed patient with a submicroscopic duplication on Xp defined a 160-kb critical region adjacent to the congenital adrenal hypoplasia locus (AHC; 300200) that was exclusively duplicated in the patients with male-to-female sex reversal; the authors designated the locus DSS for 'dosage sensitive sex reversal' (see 300473.0014). Identification of males deleted for DSS suggested that the locus is not required for testis differentiation. Bardoni et al. (1994) proposed that DSS has a role in ovarian development and/or functions as a link between ovary and testis formation. Animal Model Swain et al. (1998) created a transgenic mouse model for studying events in mammalian sex differentiation. The data showed that Dax1 functions as an anti-testis gene by acting antagonistically to Sry. This suggested that dosage-sensitive sex reversal can be caused by duplication of the DAX1 gene in humans. GU \- Male-to-female sex reversal Lab \- Normal 46,XY karyotype Inheritance \- X-linked ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	46,XY SEX REVERSAL 2	c2936694	6,019	omim	https://www.omim.org/entry/300018	2019-09-22T16:20:58	{"doid": ["14448"], "mesh": ["D006061"], "omim": ["300018"], "orphanet": ["242", "251510"], "synonyms": ["Alternative titles", "46,XY SEX REVERSAL, DAX1-RELATED", "DOSAGE-SENSITIVE SEX REVERSAL"]}
A number sign (#) is used with this entry because of evidence that holoprosencephaly-2 (HPE2) is caused by heterozygous mutation in the homeobox-containing SIX3 gene (603714) on chromosome 2p21. For phenotypic information and a general discussion of genetic heterogeneity in holoprosencephaly, see HPE1 (236100). Clinical Features Martin et al. (1977) described a kindred with 7 persons affected with a syndrome manifested by cleft lip and anterior cleft palate, hypotelorism, microcephaly, mental retardation, scoliosis, and chronic constipation. The disorder bore similarities to familial holoprosencephaly. Three of 4 affected males survived past 20 years of age. All 3 affected females died early in infancy. Although no affected male begot an affected son, 2 presumed carrier males had an affected son. Jaramillo et al. (1988) described a family in which several persons had variable combinations of craniofacial defects. The most severely affected relatives had holoprosencephaly, whereas others had only mild facial dysmorphism and decreased bitemporal diameters. One member of the family had a single central maxillary incisor. Male-to-male transmission occurred. Hennekam et al. (1991) described a family in which 1 sib had holoprosencephaly and microcephaly, a second sib had microcephaly alone, and the mother had microcephaly with single central maxillary incisor, submucous cleft palate, absence of the nasal septal cartilage, and hypotelorism. Solomon et al. (2009) reported a large kindred in which at least 15 individuals spanning 5 generations had a variable severity of holoprosencephaly. The proband was ascertained at birth because of alobar HPE, macrocephaly, severe hypotelorism, short nose with upturned nares, hypoplastic philtrum, and low-set ears. In a family review, 2 deceased individuals had full HPE as observed in the proposita, 5 had died in early infancy from unknown causes, and at least 9 had a subtle facial microform with short angular nose with hypotelorism or narrow nasal bridge. Genetic analysis identified a heterozygous mutation (W113C; 603714.0007) in the SIX3 gene in 6 affected individuals. Solomon et al. (2009) commented that the studies of this family spanned 15 years, and that the analysis was complicated by reduced penetrance, variable expressivity, and phenocopies. By detailed ophthalmologic examination of 3 patients with genetically confirmed HPE2, Pineda-Alvarez et al. (2011) found several subtle abnormalities, including refractory errors, small corneal diameter, astigmatism, cataracts, fine nystagmus, strabismus, and dysplastic optic nerve. The patients were part of a larger cohort of 10 patients with genetically confirmed HPE. All had at least 2 ophthalmologic anomalies, including refractive errors, microcornea, microphthalmia, blepharoptosis, exotropia, and coloboma. The findings contributed to the understanding of the phenotypic variability of the HPE spectrum and showed that subtle intraocular abnormalities can occur in HPE. Inheritance Cantu et al. (1978) described holoprosencephaly in 2 successive generations and suggested autosomal dominant inheritance. Some heterozygotes had mild abnormalities of midface development. Benke and Cohen (1983) described a kindred ascertained through a holoprosencephalic child and containing 6 other affected members in 3 generations. Dominant inheritance with reduced penetrance was suggested. Odent et al. (1998) reviewed 258 holoprosencephaly records involving at least 1 affected child and found 97 cases in 79 families with nonsyndromic, nonchromosomal holoprosencephaly. A high degree of familial aggregation was found in 29% of families. By segregation analysis, Odent et al. (1998) concluded that autosomal dominant inheritance with incomplete penetrance (82% for major and 88% for major and minor) was the most likely mode of inheritance. Sporadic cases accounted for 68%, and the recurrence risk after an isolated case was predicted to be 13 to 14%. Cytogenetics On the basis of 3 patients with holoprosencephaly and various interstitial deletions of chromosome 2q, Munke et al. (1989) hypothesized that the gene involved in early embryonic brain development is located in band 2p21, the smallest of the 3 overlapping deletions. Grundy et al. (1989) reported a case of synophthalmic cyclopia and alobar holoprosencephaly associated with an interstitial deletion del(2)(p21p23). Cytogenetic abnormalities observed in several reported cases point to the location of a causative gene on 2p, specifically 2p21 (Hecht et al., 1991). Schell et al. (1996) reported the molecular genetic characterization of 9 HPE patients with cytogenetic deletions or translocations involving 2p21. They determined the parental origin of the deleted chromosomes and defined the HPE2 critical region between D2S119 and D2S88/D2S391. As a first step toward cloning the HPE2 gene which is clearly crucial for normal brain development, they constructed a YAC contig that spans the smallest region of deletion overlap. Several of the YACs spanned 3 different 2p21 breakpoints in HPE patients. These YACs narrowed the HPE2 critical region to less than 1 Mb. Molecular Genetics Wallis et al. (1999) demonstrated mutations in the SIX3 gene (603714.0001-603714.0003) in patients with holoprosencephaly. In 6 Brazilian patients with HPE2, Ribeiro et al. (2006) identified 5 missense mutations and 2 frameshift mutations in the SIX3 gene. Comparison of patients with missense versus frameshift mutations showed essentially no difference. Experience with these patients suggested that SIX3 mutations result in a more severe phenotype than other gene mutations for holoprosencephaly. One patient had a double heterozygosity for SIX3 mutation (603714.0005 and 603714.0006). Three mutations were paternally transmitted, 2 were maternal, and 1 was a de novo event. The 5 parental mutation carriers appeared normal. Among 94 fetuses with HPE and a normal karyotype, Bendavid et al. (2006) used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to screen for microdeletions in the 4 major HPE genes, SHH (600725), SIX3, ZIC2 (603073), and TGIF (602630). Microdeletions were identified in 8 (8.5%) fetuses: 2 in SHH, 2 in SIX3, 3 in ZIC2, and 1 in TGIF. Further analysis showed that the entire gene was missing in each case. Point mutations in 1 of the 4 genes were identified in 13 of the fetuses. Combining the instances of point mutations and microdeletions for the 94 cases yielded the following percentages: SHH (6.3%), ZIC2 (8.5%), SIX3 (5.3%), and TGIF (2%). Bendavid et al. (2006) reported the use of 2 complementary assays for HPE-associated submicroscopic deletions: a multicolor fluorescence in situ hybridization (FISH) assay using probes for the 4 major HPE genes and 2 candidate genes (DISP1, 607502 and FOXA2, 600288) followed by quantitative PCR to selected samples. Microdeletions for SHH, ZIC2, SIX3, or TGIF were found in 16 of 339 severe HPE cases (i.e., with CNF findings; 4.7%). In contrast, no deletions were found in 85 patients at the mildest end of the HPE spectrum. Based on their data, Bendavid et al. (2006) suggested that microdeletion testing should be considered as part of an evaluation of holoprosencephaly, especially in severe HPE cases. Genotype/Phenotype Correlations Among 34 patients with holoprosencephaly, Dubourg et al. (2004) observed that mutation in the SIX3 gene was associated with atelencephaly. Lacbawan et al. (2009) identified SIX3 mutations in 4.7% of 800 probands and relatives with HPE. In total, 138 cases of HPE were identified, 59 of whom had not previously been reported. Mutations in SIX3 resulted in more severe HPE than in other cases of nonchromosomal, nonsyndromic HPE. An overrepresentation of severe HPE was found in patients whose mutations conferred greater loss of protein function, as measured by an in vitro assay. The gender ratio in this combined set of patients was 1.5:1 (F:M), and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occurred de novo. There was a wide intrafamilial clinical range of features, and penetrance was estimated to be at least 62% from diagnosis on clinical grounds alone. The data suggested that SIX3 mutations result in relatively severe HPE, but also indicated that variability may be due to a multi-hit mechanism. Mercier et al. (2011) reported the clinical and molecular features of a large European series of 645 HPE probands (51% fetuses) and 699 relatives in order to examine genotype/phenotype correlations. The facial features were assigned to 4 categories: categories 1 and 2 had severe facial defects, whereas microforms were listed as 3 and 4. SIX3 mutations were found in 5.1% of probands, and most (57%) had severe HPE, including atelencephaly/aprosencephaly, as well as severe facial and ophthalmologic defects. About 24% had extracraniofacial defects, mostly visceral, skeletal, and of the extremities. The sex ratio favored females, suggesting that SIX3 mutations may be embryonically lethal in males. SIX3 mutations were highly heritable (88%), but only 3 of 17 parents had a microform. Statistical analysis showed a positive correlation between the severity of the brain malformation and facial features for SIX3 mutations, and those with SIX3 mutations had a more severe HPE type compared to those with other mutations. Based on these results, Mercier et al. (2011) proposed an algorithm for molecular analysis in HPE. Population Genetics In a targeted screening study of 4 genes in 186 Dutch patients with holoprosencephaly, Paulussen et al. (2010) found that 21 (24%) had heterozygous mutations in 1 of 3 of the genes. Three (3.5%) had mutations in the SHH gene (600725), 9 (10.5%) had mutations in the ZIC2 gene (603073), and 9 (10.5%) had mutations in the SIX3 gene. None had mutations in the TGIF gene (602630). Two deletions were detected, 1 encompassing the ZIC2 gene and another encompassing the SIX3 gene. About half of the mutations were de novo; 1 was germline mosaic. There was marked clinical variability, but those with ZIC2 mutations tended to have less severe facial malformations. Five of 7 parental carriers were asymptomatic, and 2 had minor HPE signs. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Microcephaly Face \- Premaxillary agenesis \- Midface hypoplasia Eyes \- Cyclopia \- Ocular hypotelorism \- Colobomata \- Microphthalmia \- Varying degrees of doubling of intrinsic ocular structures Nose \- Arrhinia \- Blind-ending proboscis \- Agenesis of nasal bones Mouth \- Median cleft lip/palate Teeth \- Central incisor NEUROLOGIC Central Nervous System \- Holoprosencephaly (HPE) \- Atelencephaly \- Mental retardation \- Developmental delay \- Seizures \- Hypotonia \- Agenesis of the corpus callosum \- Cerebellar hypoplasia \- Alobar HPE shows absence of interhemispheric cleavage and single ventricle \- Semilobar HPE shows posterior interhemispheric fissure with rudimentary cerebral hemispheres and single ventricle \- Lobar HPE shows clear interhemispheric fissure and 2 lateral ventricles ENDOCRINE FEATURES \- Endocrine dysgenesis \- Pituitary agenesis \- Hypophyseal agenesis \- Hypothalamic dysfunction \- Hypoplastic adrenal glands \- Diabetes insipidus MISCELLANEOUS \- Genetic heterogeneity \- Variable severity \- Spectrum of malformations resulting from impaired midline cleavage of the embryonic forebrain \- Incomplete penetrance MOLECULAR BASIS \- Caused by mutation in the SIX homeobox 3 gene (SIX3, 603714.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	HOLOPROSENCEPHALY 2	c0751617	6,020	omim	https://www.omim.org/entry/157170	2019-09-22T16:38:10	{"doid": ["0110872"], "mesh": ["D016142"], "omim": ["157170"], "orphanet": ["93926", "280195", "220386", "93925", "280200", "93924", "2162"], "synonyms": ["MIH type HPE", "Middle interhemispheric fusion variant", "MIH", "Syntelencephaly", "Middle interhemispheric variant of holoprosencephaly", "MIHF", "Septopreoptic HPE", "MIHV"], "genereviews": ["NBK1530"]}
Cerebral contusion CT scan showing cerebral contusions, hemorrhage within the hemispheres, subdural hematoma on the left, and skull fractures[1] SpecialtyEmergency medicine Cerebral contusion, Latin contusio cerebri, a form of traumatic brain injury, is a bruise of the brain tissue.[2] Like bruises in other tissues, cerebral contusion can be associated with multiple microhemorrhages, small blood vessel leaks into brain tissue. Contusion occurs in 20–30% of severe head injuries.[3] A cerebral laceration is a similar injury except that, according to their respective definitions, the pia-arachnoid membranes are torn over the site of injury in laceration and are not torn in contusion.[4][5] The injury can cause a decline in mental function in the long term and in the emergency setting may result in brain herniation, a life-threatening condition in which parts of the brain are squeezed past parts of the skull.[3] Thus treatment aims to prevent dangerous rises in intracranial pressure, the pressure within the skull. Contusions are likely to heal on their own without medical intervention.[6] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Features * 3.1 Multiple petechial hemorrhages * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] The symptoms of a cerebral contusion depend on the severity of the injury, ranging from minor to severe. Individuals may experience a headache, confusion, sleepiness, dizziness, loss of consciousness, nausea and vomiting, seizures, difficulty with coordination and movement, lightheadedness, tinnitus, and spinning sensations. They may also have difficulty with memory, vision, speech, hearing, managing emotions, and thinking.[7] Signs also depend on the contusion's location in the brain.[7] ## Causes[edit] The interior of the skull has sharp ridges by which a moving brain can be injured. Often caused by a blow to the head, contusions commonly occur in coup or contre-coup injuries. In coup injuries, the brain is injured directly under the area of impact, while in contrecoup injuries it is injured on the side opposite the impact. Contusions occur primarily in the cortical tissue, especially under the site of impact or in areas of the brain located near sharp ridges on the inside of the skull. The brain may be contused when it collides with bony protuberances on the inside surface of the skull.[8] The protuberances are located on the inside of the skull under the frontal and temporal lobes and on the roof of the ocular orbit.[9] Thus, the tips of the frontal and temporal lobes located near the bony ridges in the skull are areas where contusions frequently occur and are most severe.[10] For this reason, attention, emotional and memory problems, which are associated with damage to frontal and temporal lobes, are much more common in head trauma survivors than are syndromes associated with damage to other areas of the brain.[11] ## Features[edit] Contusions, which are frequently associated with edema, are especially likely to cause increases in intracranial pressure (ICP) and concomitant crushing of delicate brain tissue. They typically form in a wedge-shape with the widest part in the outermost part of the brain.[12] The distinction between contusion and intracerebral hemorrhage is blurry because both involve bleeding within the brain tissue; however, an arbitrary cutoff exists that the injury is a contusion if two thirds or less of the tissue involved is blood and a hemorrhage otherwise.[3] The contusion may cause swelling of the surrounding brain tissue, which may be irritated by toxins released in the contusion.[3] The swelling is worst at around four to six days after the injury.[3] Extensive contusion associated with subdural hematoma is called burst lobe.[5] Cases of a burst frontal or temporal lobe are associated with high mortality and morbidity.[5] Old or remote contusions are associated with resorption of the injured tissue, resulting in various degrees of cavitation, in addition to the presence of a golden-yellow discoloration due to residual hemosiderin. These remote contusions are often referred to as plaque jaune or yellow plaque.[13] ### Multiple petechial hemorrhages[edit] Numerous small contusions from broken capillaries that occur in grey matter under the cortex are called multiple petechial hemorrhages or multifocal hemorrhagic contusion.[14] Caused by shearing injuries at the time of impact, these contusions occur especially at the junction between grey and white matter and in the upper brain stem, basal ganglia, thalamus and areas near the third ventricle.[14] The hemorrhages can occur as the result of brain herniation, which can cause arteries to tear and bleed.[14] A type of diffuse brain injury, multiple petechial hemorrhages are not always visible using current imaging techniques like CT and MRI scans. This may be the case even if the injury is quite severe, though these may show up days after the injury.[15] Hemorrhages may be larger than in normal contusions if the injury is quite severe. This type of injury has a poor prognosis if the patient is comatose, even with no apparent causes for the coma.[15] ## Treatment[edit] MRI showing damage due to herniation in a patient who had had contusions in the frontal lobes.[1] Since cerebral swelling presents a danger to the patient, treatment of cerebral contusion aims to prevent swelling. Measures to avoid swelling include prevention of hypotension (low blood pressure), hyponatremia (insufficient sodium), and hypercapnia (increased carbon dioxide in the blood).[3] Due to the danger of increased intracranial pressure, surgery may be necessary to reduce it.[3] People with cerebral contusion may require intensive care and close monitoring.[3] ## References[edit] 1. ^ a b Rehman T, Ali R, Tawil I, Yonas H (2008). "Rapid progression of traumatic bifrontal contusions to transtentorial herniation: A case report". Cases Journal. 1 (1): 203. doi:10.1186/1757-1626-1-203. PMC 2566562. PMID 18831756. 2. ^ Hardman JM, Manoukian A (2002). "Pathology of Head Trauma". Neuroimaging Clinics of North America. 12 (2): 175–187, vii. doi:10.1016/S1052-5149(02)00009-6. PMID 12391630. 3. ^ a b c d e f g h Khoshyomn S, Tranmer BI (May 2004). "Diagnosis and management of pediatric closed head injury". Seminars in Pediatric Surgery. 13 (2): 80–86. doi:10.1053/j.sempedsurg.2004.01.003. PMID 15362277. 4. ^ Granacher RP (2007). Traumatic Brain Injury: Methods for Clinical & Forensic Neuropsychiatric Assessment (Second ed.). Boca Raton: CRC. p. 26. ISBN 978-0-8493-8138-6. Retrieved 2008-07-06. 5. ^ a b c Gennarelli GA, Graham DI (2005). "Neuropathology". In Silver JM, McAllister TW, Yudofsky SC (eds.). Textbook Of Traumatic Brain Injury. Washington, DC: American Psychiatric Association. p. 29. ISBN 1-58562-105-6. Retrieved 2008-06-10. 6. ^ Sanders MJ and McKenna K. 2001. Mosby’s Paramedic Textbook, 2nd revised Ed. Chapter 22, "Head and Facial Trauma." Mosby. 7. ^ a b Kushner D (1998). "Mild Traumatic Brain Injury: Toward Understanding Manifestations and Treatment". Archives of Internal Medicine. 158 (15): 1617–1624. doi:10.1001/archinte.158.15.1617. PMID 9701095. 8. ^ Rao V, Lyketsos C (2000). "Neuropsychiatric Sequelae of Traumatic Brain Injury". Psychosomatics. 41 (2): 95–103. doi:10.1176/appi.psy.41.2.95. PMID 10749946. 9. ^ Shepherd S. 2004. "Head Trauma." Emedicine.com. Retrieved on 2008-01-10. 10. ^ Graham DI and Gennareli TA. Chapter 5, "Pathology of Brain Damage After Head Injury" Cooper P and Golfinos G. 2000. Head Injury, 4th Ed. Morgan Hill, New York. 11. ^ Bigler, ED. 2000. The Lesion(s) in Traumatic Brain Injury: Implications for Clinical Neuropsychology. Accessed through web archive. Retrieved on 2008-01-17. 12. ^ Vinas FC and Pilitsis J. 2006. "Penetrating Head Trauma." Emedicine.com. Retrieved on 2008-01-10. 13. ^ "Archived copy". Archived from the original on 2010-11-09. Retrieved 2009-01-07.CS1 maint: archived copy as title (link) 14. ^ a b c "Brain Injury, Traumatic". Medcyclopaedia. GE. Archived from the original on 2011-05-26. 15. ^ a b Downie A. 2001. "Tutorial: CT in Head Trauma" Archived 2005-11-06 at the Wayback Machine. Retrieved May 8, 2008 ## External links[edit] Classification D * ICD-10: S06.2, S06.3 * ICD-9-CM: 851 * MeSH: D000070624 * v * t * e Nonmusculoskeletal injuries of head (head injury) and neck Intracranial * see neurotrauma Extracranial/ facial trauma eye: * Black eye * Eye injury * Corneal abrasion ear: * Perforated eardrum Either/both * Penetrating head injury * v * t * e Neurotrauma Traumatic brain injury * Intracranial hemorrhage * Intra-axial * Intraparenchymal hemorrhage * Intraventricular hemorrhage * Extra-axial * Subdural hematoma * Epidural hematoma * Subarachnoid hemorrhage * Brain herniation * Cerebral contusion * Cerebral laceration * Concussion * Post-concussion syndrome * Second-impact syndrome * Dementia pugilistica * Chronic traumatic encephalopathy * Diffuse axonal injury * Abusive head trauma * Penetrating head injury Spinal cord injury * Anterior spinal artery syndrome * Brown-Séquard syndrome * Cauda equina syndrome * Central cord syndrome * Paraplegia * Posterior cord syndrome * Spinal cord injury without radiographic abnormality * Tetraplegia (Quadriplegia) Peripheral nerves * Nerve injury * Peripheral nerve injury * classification * Wallerian degeneration * Injury of accessory nerve * Brachial plexus injury * Traumatic neuroma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Cerebral contusion	c0149844	6,021	wikipedia	https://en.wikipedia.org/wiki/Cerebral_contusion	2021-01-18T18:46:01	{"mesh": ["D000070624"], "umls": ["C0149844"], "icd-9": ["851"], "icd-10": ["S06.3", "S06.2"], "wikidata": ["Q591639"]}
A form of limb-girdle muscular dystrophy characterized by proximal weakness (manifesting as slowness in running) presenting in infancy, along with calf hypertrophy, mild lordosis, scapular winging and normal intelligence (or mild intellectual disability). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	POMT2-related limb-girdle muscular dystrophy R14	c3150418	6,022	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=206559	2021-01-23T17:53:27	{"gard": ["12539"], "omim": ["613158"], "icd-10": ["G71.0"], "synonyms": ["Autosomal recessive limb-girdle muscular dystrophy type 2N", "LGMD type 2N", "LGMD2N", "Limb-girdle muscular dystrophy type 2N", "POMT2-related LGMD R14"]}
A rare hepatic disease characterized by the features of classic autoimmune hepatitis (i. e. clinical presentation as acute or chronic cryptogenic hepatitis, interface hepatitis on histological examination, elevated serum aspartate aminotransferase and alanine aminotransferase levels, therapeutic response to corticosteroids) in the absence of specific serum autoantibodies. Clinical manifestations include fatigue, malaise, arthralgia, jaundice, at later stages also signs of advanced chronic liver disease, such as spider nevi, caput medusae, splenomegaly, ascites, and palmar erythema. Presence of concurrent autoimmune diseases is frequently observed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Seronegative autoimmune hepatitis	None	6,023	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=563589	2021-01-23T17:12:40	{"synonyms": ["Autoantibody-negative autoimmune hepatitis", "Seronegative AIH"]}
Coccidioidomycosis is a fungal infection caused by Coccidioides immitis and C. posadasii, which is endemic to the Southwestern United States, Central America, South America and Mexico, and is acquired by inhalation of the infective arthroconidia, often found in soil. In most cases it is a benign, self-limiting febrile illness, but in a minority of cases it can become a potentially lethal infection of the lungs and, extremely rarely, spread to other organs (through hematogenous dissemination) with manifestations including meningitis, osteomyelitis, and skin and soft-tissue involvement. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Coccidioidomycosis	c0009186	6,024	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=228123	2021-01-23T19:00:53	{"gard": ["9525"], "mesh": ["D003047"], "umls": ["C0009186", "C0153257", "C0851907"], "icd-10": ["B38.0", "B38.1", "B38.2", "B38.3", "B38.4", "B38.7", "B38.8", "B38.9"], "synonyms": ["California disease", "Coccidioides infection", "Desert fever", "Desert rheumatism", "San Joaquin valley fever", "Valley fever"]}
## Summary ### Clinical characteristics. Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. ### Diagnosis/testing. Clinical diagnostic criteria are available for Williams syndrome; however, the diagnosis requires detection of a recurrent 7q11.23 contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene (ELN). This contiguous gene deletion can be detected using fluorescent in situ hybridization (FISH) and/or deletion/duplication testing. ### Management. Treatment of manifestations: Early intervention programs, special education programs, and vocational training address developmental disabilities; programs include speech/language, physical, occupational, feeding, and sensory integration therapies. Psychological and psychiatric evaluation and treatment provide individualized behavioral counseling and medications, especially for attention deficit disorder and anxiety. Surgery may be required for supravalvar aortic or pulmonary artery stenosis, mitral valve insufficiency, and/or renal artery stenosis. Treatment of hypercalcemia may include diet modification, oral corticosteroids, and/or intravenous pamidronate. Refer to a nephrologist for management of nephrocalcinosis, persistent hypercalcemia, and/or hypercalciuria. Treatment of hypertension, hyperopia, and recurrent otitis media does not differ from that in the general population. Orthodontic referral should be considered for malocclusion. Infants with feeding problems may benefit from feeding therapy. Constipation should be aggressively managed at all ages. Early puberty may be treated with a gonadotropin-releasing hormone agonist. Prevention of secondary complications: Range of motion exercises to prevent or ameliorate joint contractures; anesthesia consultation and electrocardiogram prior to sedation and surgical procedures. Surveillance: Annual medical evaluation, vision screening, hearing evaluation, measurement of blood pressure in both arms, calcium/creatinine ratio in spot urine, and urinalysis. Children younger than age two years should have serum calcium studies every four to six months. Thyroid function should be checked yearly until age three years and every two years thereafter. Additional periodic evaluations for all individuals include: measurement of serum concentration of calcium every two years; cardiology evaluation for elastin arteriopathy at least annually for the first five years and every two to three years thereafter for life; and renal and bladder ultrasound examination every ten years. Additional periodic evaluations during adulthood include: oral glucose tolerance; cardiac evaluation for mitral valve prolapse, aortic insufficiency, hypertension, long QT interval, and arterial stenoses; and ophthalmologic evaluation for cataracts. Agents/circumstances to avoid: Multivitamins for children because all pediatric multivitamin preparations contain vitamin D. ### Genetic counseling. Williams syndrome is transmitted in an autosomal dominant manner. Most cases are de novo occurrences, but occasionally, parent-to-child transmission is observed. Prenatal testing is possible but is rarely used because most cases occur in a single family member only, and no prenatal indicators exist for low-risk pregnancies. ## Diagnosis Clinical diagnostic criteria are available for Williams syndrome (WS) [Preus 1984, Committee on Genetics 2001, Committee on Genetics 2002]. The WS phenotype is variable, and no single clinical feature is required to establish the diagnosis. ### Suggestive Findings Williams syndrome (WS) should be suspected in individuals with the following findings: * Cardiovascular disease (elastin arteriopathy). Any artery may be narrowed. Supravalvar aortic stenosis (SVAS) is the most clinically significant and most common cardiovascular finding, occurring in 75% of affected individuals. Peripheral pulmonic stenosis (PPS) is common in infancy. * Distinctive facies. Broad forehead, bitemporal narrowing, periorbital fullness, a stellate/lacy iris pattern (Figure 1), strabismus, short nose, broad nasal tip, malar flattening, long philtrum, thick vermilion of the upper and lower lips, wide mouth, malocclusion, small jaw, and large ear lobes are observed at all ages (Figure 2). Young children have epicanthal folds, full cheeks, and small, widely spaced teeth (Figure 3), while adults typically have a long face and neck, accentuated by sloping shoulders, resulting in a more gaunt appearance (Figure 4). * Connective tissue abnormalities. Hoarse voice, inguinal/umbilical hernia, bowel/bladder diverticulae, rectal prolapse, joint limitation or laxity, and soft, lax skin are observed. * Intellectual disability. Most individuals have some degree of intellectual disability, which can range from severe to mild. Some have average intelligence. * Specific cognitive profile. Strengths in verbal short-term memory and language and extreme weakness in visuospatial construction are typical. The Williams syndrome cognitive profile is independent of IQ. * Unique personality. Overfriendliness, empathy, generalized anxiety, specific phobias, and attention deficit disorder are commonly observed. * Growth abnormalities. The growth pattern is characterized by: prenatal growth deficiency, failure to thrive in infancy (70%), poor weight gain and linear growth in the first four years; a rate of linear growth that is 75% of normal in childhood; and a brief pubertal growth spurt. The mean adult height is below the third centile. * Endocrine abnormalities. Findings include idiopathic hypercalcemia, hypercalciuria, hypothyroidism, subclinical hypothyroidism, and early puberty. An increased frequency of abnormal oral glucose tolerance tests, obesity, and diabetes mellitus is observed, especially in adults. #### Figure 1. Note the stellate iris pattern in an individual with Williams syndrome. #### Figure 2. A broad forehead, bitemporal narrowing, periorbital fullness, strabismus, short nose, broad nasal tip, malar flattening, long philtrum, thick vermilion of the upper and lower lips, wide mouth, malocclusion, small jaw, and large earlobes are observed at (more...) #### Figure 3. Young children with Williams syndrome typically have epicanthal folds, full cheeks, and small, widely spaced teeth as seen in these children at the following ages: A. Newborn #### Figure 4. Adults typically have a long face and neck, accentuated by sloping shoulders, resulting in a gaunt appearance, as seen in this affected individual, age 43 years. Note: See the National Human Genome Research Institute (NHGRI) Atlas of Human Malformation Syndromes (scroll to ATLAS IMAGES) for photographs of individuals with Williams syndrome from diverse ethnic backgrounds. ### Establishing the Diagnosis The diagnosis of Williams syndrome (WS) is established by detection of the 1.5-1.8-Mb heterozygous microdeletion at chromosome 7q11.23. For this GeneReview, WS is defined as the presence of this recurrent 1.5-1.8-Mb deletion at the approximate position of chr7:72,744,454-74,142,513 in the reference genome (NCBI Build GRCh37/hg19). Note: The phenotype of significantly larger or smaller deletions within this region may be clinically distinct from WS (see Genetically Related Disorders). Although several genes of interest (e.g., ELN) are within the 1.5-1.8-Mb recurrent microdeletion, no single gene in which pathogenic variants are causative of WS has been identified (see Molecular Genetics for genes of interest in the deleted region). Genomic testing methods that determine the copy number of sequences can include chromosomal microarray (CMA) or targeted deletion analysis by fluorescence in situ hybridization (FISH). Note: WS cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques. * Chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays can detect the recurrent deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 7q11.23 region. Note: (1) Most individuals with WS are identified by CMA performed in the context of developmental delay, intellectual disability, or autism spectrum disorders. (2) The recurrent deletion was detected by early arrays (e.g., BAC arrays). * Targeted deletion analysis. A FISH probe targeted to the 7q11.23 region can be reliably used for diagnosis in situations where CMA is not available. FISH analysis may be used to test at-risk relatives of a proband known to have WS. Note: (1) Targeted deletion testing by FISH is not appropriate for the relative of an individual suspected of having WS in whom a deletion was not detected by FISH or by CMA designed to target 7q11.23. BY definition, such individuals do not have WS. (2) It is not possible to size the microdeletion routinely by use of FISH. ### Table 1. Genomic Testing Used in Williams Syndrome View in own window Deletion 1ISCA ID 2Region Location 3, 4MethodSensitivity ProbandAt-risk family members 1.5-1.8-Mb heterozygous deletion at 7q11.23ISCA-37392GRCh37/hg19 chr7: 72,744,454-74,142,513CMA 5100%100% FISH100%100% 6 1\. See Molecular Genetics for details of the deletion. 2\. Standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (ClinGen) project (formerly the International Standards for Cytogenomic Arrays (ISCA) Consortium) 3\. Genomic coordinates represent the minimum deletion size associated with the 7q11.23 recurrent microdeletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the microdeletion as calculated from these genomic positions may differ from the expected microdeletion size due to the presence of segmental duplications near breakpoints. The phenotype of significantly larger or smaller microdeletions within this region may be clinically distinct from the recurrent 7q11.23 microdeletion (see Genetically Related Disorders). 4\. See Molecular Genetics for genes of interest included in this region. 5\. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP genotyping arrays. CMA designs in current clinical use target the 7q11.23 region. 6\. FISH is not appropriate as a diagnostic method for the relative of an affected individual in whom Williams syndrome was not detected by FISH or by CMA designed to target this region. Evaluating at-risk relatives. FISH can be used to identify Williams syndrome in at-risk relatives of the proband. Testing of parental samples is indicated only if the relative has signs or symptoms of Williams syndrome (see Genetic Counseling). ## Clinical Characteristics ### Clinical Description Infancy. The infant with Williams syndrome (WS) is often born post-term and is small for the family background. Feeding difficulties leading to failure to gain weight are common, including gastroesophageal (G-E) reflux, disordered suck and swallow, textural aversion, and vomiting. Prolonged colic (>4 months) may be related to G-E reflux, chronic constipation, and/or idiopathic hypercalcemia. Other medical problems that often occur in the first year include strabismus, chronic otitis media, rectal prolapse, umbilical and/or inguinal hernia, and cardiovascular disease [Morris et al 1988]. Infants with WS are hypotonic and typically have hyperextensible joints, resulting in delayed attainment of motor milestones. Walking usually occurs by age 24 months. Speech is also delayed but later becomes a relative strength. Fine motor difficulties are present at all ages. Cognitive abilities. Intellectual disability, usually mild, occurs in 75% of individuals with WS. The cognitive profile is distinctive, consisting of strengths in verbal short-term memory and language but extreme weakness in visuospatial constructive cognition [Mervis et al 2000]. As a result, children with WS usually score higher on verbal subtests than on tests measuring visuospatial construction [Greer et al 1997, Mervis et al 1998]. No gender difference in IQ is reported and the IQ is stable over time in children [Mervis et al 2012b]. Academically, individuals with WS perform relatively well in reading, and adults may read at the high school level, though the range of achievement is wide. Reading skills correlate with cognitive ability rather than language-related skills [Levy et al 2003]. Difficulty with writing, drawing, and mathematics is significant, although many adults with WS are able to perform simple addition. Adaptive behavior is less than expected for IQ in both children and adults [Davies et al 1997, Howlin & Udwin 2006, Mervis & Pitts 2015], and adversely affects the ability of adults with WS to function independently. Unique personality/behavior. The characteristic personality profile of WS includes overfriendliness, social disinhibition, excessive empathy, attention problems, and non-social anxiety [Einfeld et al 2001, Doyle et al 2004, Morris 2010, Muñoz et al 2010]. Other common behavior problems include difficulty with sensory modulation/sensory processing, difficulty with emotional regulation, perseveration, and specific phobias (80%) [Dykens 2003, Laws & Bishop 2004, John & Mervis 2010, Pitts et al 2016]. Some have overlapping symptoms with autism spectrum disorder, such as restricted interests and repetitive behavior [Klein-Tasman et al 2009]. Compared to other children with disabilities, children with WS rate high on measures of the following: empathy, gregariousness, people-orientation, tenseness, sensitivity, and "visibility" (easily noticed) [Klein-Tasman & Mervis 2003]. In children, attention deficit disorder occurs in 65% and anxiety disorder in 57% (usually specific phobias) [Leyfer et al 2006]. Anxiety is common across the life span; longitudinal studies of anxiety indicate a prevalence of 80% [Woodruff-Borden et al 2010]. Sleep. Sleep problems are reported in 65% and include increased sleep latency and decreased sleep efficiency [Goldman et al 2009, Mason et al 2011]. Abnormal or absent nocturnal melatonin peak has been documented in recent studies [Sniecinska-Cooper et al 2015, Santoro et al 2016]. Cardiovascular disease. Elastin arteriopathy is present in 75%-80% of affected individuals and may affect any artery [Morris et al 1988, Pober et al 2008, Del Pasqua et al 2009, Collins et al 2010b]. Peripheral pulmonic stenosis (PPS) is common in infancy but usually improves over time. The most common arteriopathy is supravalvar aortic stenosis (SVAS), which may worsen over time, especially in the first five years of life [Collins et al 2010b]. The greatest morbidity results from this aortic narrowing, which can be either a discrete hourglass stenosis or diffuse aortic stenosis. If untreated, the resultant increase in arterial resistance leads to elevated left heart pressure, cardiac hypertrophy, and cardiac failure. Middle aortic syndrome, including diffuse narrowing of the thoracic and abdominal aorta, occurs rarely but can be difficult to treat and may require reintervention [Radford & Pohlner 2000]. Individuals with combined SVAS and PPS (biventricular outflow tract obstruction) may develop biventricular hypertrophy and hypertension, increasing the risk for myocardial ischemia, dysrhythmias, and sudden death [Pham et al 2009]. Coronary artery stenosis has been implicated in some cases of sudden death in WS [Bird et al 1996]. The incidence of sudden death in one cohort of 293 individuals with WS was 1/1000 patient years, which is 25 to 100 times higher than the age-matched population [Wessel et al 2004]. Corrected QT prolongation has been reported in 13.6% of individuals with WS; screening for repolarization abnormalities is recommended [Collins et al 2010a]. Anesthesia and sedation is associated with an increased risk for adverse events including cardiac arrest in individuals with WS [Burch et al 2008, Olsen et al 2014]. Sedation and anesthesia risk assessment and management guidelines have been developed [Burch et al 2008, Matisoff et al 2015, Latham et al 2016]. The prevalence of hypertension in individuals with WS is 40%-50%. Hypertension may present at any age [Broder et al 1999, Giordano et al 2001, Eronen et al 2002, Bouchireb et al 2010] and may be secondary to renal artery stenosis in some cases [Deal et al 1992]. Increased vascular stiffness has been documented in WS and responds to antihypertensive medication [Kozel et al 2014]. Mitral valve prolapse and aortic insufficiency have been reported in adults [Morris et al 1990, Kececioglu et al 1993, Collins et al 2010a]. Stenosis of the mesenteric arteries may contribute to abdominal pain. Neurovascular abnormalities are rarely reported but may result in stroke [Ardinger et al 1994, Soper et al 1995, Cherniske et al 2004]. Eye, ear, nose, and throat. Lacrimal duct obstruction, hyperopia (67%), and strabismus (~50%) are common in individuals with WS [Kapp et al 1995, Weber et al 2014]. Cataracts have been reported in adults [Cherniske et al 2004]. Chronic otitis media is seen in 50% of affected individuals. Increased sensitivity to sound is common (90%), and individuals with WS report discomfort at 20 decibels (db) lower than controls [Gothelf et al 2006]. Many report specific phobias for certain sounds [Levitin et al 2005]. Progressive sensorineural hearing loss has been observed; mild to moderate hearing loss is detected in 63% of children and 92% of adults [Gothelf et al 2006, Marler et al 2010]. Mild to moderate high-frequency sensorineural hearing loss is common in adults, as is excessive build-up of ear wax [Cherniske et al 2004]. Most individuals have a hoarse or low-pitched voice; vocal cord abnormalities secondary to elastin deficiency are likely causative [Vaux et al 2003]. Dental problems include microdontia, enamel hypoplasia, and malocclusion [Hertzberg et al 1994]. One or more permanent teeth are missing in 40% of individuals with WS [Axelsson et al 2003]. Gastrointestinal difficulties. Individuals with WS have sensory defensiveness, both auditory [Van Borsel et al 1997] and tactile. The difficulty with food textures leads to problems in transitioning from breast milk or formula to solid foods in infancy. Chronic abdominal pain is a common complaint of children and adults with WS; possible causes include G-E reflux, hiatal hernia, peptic ulcer disease, cholelithiasis, diverticulitis, ischemic bowel disease, chronic constipation, and somatization of anxiety. The prevalence of diverticulitis is increased in adolescents [Stagi et al 2010] and adults with WS [Partsch et al 2005]. Complications of constipation may include rectal prolapse, hemorrhoids, or intestinal perforation. Hypercalcemia may contribute to irritability, vomiting, constipation, and muscle cramps; it is more common in infancy but may recur in adults [Morris et al 1990, Pober et al 1993]. Urinary tract abnormalities. Urinary frequency and enuresis (50%) are common in children with WS. Renal artery stenosis is found in 50% of individuals with WS, structural abnormalities of the urinary tract in 10%, bladder diverticulae in 50%, and nephrocalcinosis in fewer than 5% [Pober et al 1993, Pankau et al 1996, Sforzini et al 2002, Sammour et al 2006, Sammour et al, 2014]. Bladder capacity is reduced, and detrusor overactivity is observed in 60% [Sammour et al 2006]. Average daytime urinary continence is at age four years, nocturnal continence occurs in 50% by age ten years. Nocturnal enuresis occurs in an estimated 3% of adults [von Gontard et al 2016]. Musculoskeletal/neurologic problems. The hypotonia and lax joints of the young child lead to abnormal compensatory postures to achieve stability. Older children and adults with WS typically have hypertonia and hyperactive deep-tendon reflexes. Gradual tightening of the heel cords and hamstrings occurs, resulting in a stiff and awkward gait, kyphosis, and lordosis by adolescence [Morris et al 1988, Kaplan et al 1989]. Scoliosis is present in 18% [Morris et al 2010]. Ten percent have radioulnar synostosis [Morris & Carey 1990]. Fine motor function is impaired, leading to difficulty with tool use and handwriting at all ages. Cerebellar signs in adults include ataxia, dysmetria, and tremor [Pober & Morris 2007]. Neuroimaging. Reduced brain size, reduced gray matter volume especially in the parietal and occipital regions, and increased gyral complexity are seen on brain MRI [Jackowski et al 2009, Eisenberg et al 2010]. Reduced posterior fossa size coupled with preserved cerebellar size may contribute to Chiari 1 malformation found in some affected individuals [Pober & Filiano 1995, Mercuri et al 1997]. Growth. Individuals with WS are short for their family background. Specific growth curves for WS are available [Morris et al 1988, Saul et al 1988, Martin et al 2007]. Poor weight gain is observed in 70% of infants. The growth pattern is characterized by prenatal growth deficiency, poor weight gain, and poor linear growth in the first four years, a rate of linear growth that is 75% of normal in childhood, and a brief pubertal growth spurt. The mean adult height is below the third centile. Obesity is a common problem in older children and adults [Cherniske et al 2004]. Puberty may occur early, and central precocious puberty is present in 18% [Partsch et al 2002]. Hormonal suppression with gonadotropin-releasing hormone is well tolerated by girls with either early or precocious puberty, and treated girls are taller than WS controls [Spielmann et al 2015]. Hypercalcemia. Idiopathic hypercalcemia occurs in 15%-50%, and is most often symptomatic (irritability, vomiting, constipation) in the first two years [Martin et al 1984, Morris et al 1988, Kim et al 2016]. Hypercalcemia is associated with dehydration, hypercalciuria, and nephrocalcinosis; compared to controls, higher median serum calcium levels are found in all age groups [Sindhar et al 2016]. The etiology of hypercalcemia in WS is unknown [Stagi et al 2016]. Endocrine problems. Endocrine abnormalities include hypothyroidism (10%), and early (though not precocious) puberty (50%) [Kim et al 2016]. Subclinical hypothyroidism (TSH elevation with normal T3/T4 levels) occurs in 31%, and occurs more frequently in children than in adults [Palacios-Verdú et al 2015]. Prevalence of impaired glucose tolerance is 26% in adolescents [Stagi et al 2014] and 63% in young adults [Masserini et al 2013]. An increased frequency of abnormal oral glucose tolerance tests and diabetes mellitus is observed in adults with WS [Cherniske et al 2004]. Other * The hair grays prematurely [Morris et al 1988]. * Soft, lax skin is typical. * Distinctive facial features are present and evolve with age (see Suggestive Findings). ### Genotype-Phenotype Correlations The 7q11.23 recurrent deletions of the WBSCR comprise either 1.55 megabases (Mb) (90%-95% of individuals with WS) or 1.84 Mb (5%-10% of individuals with WS) [Bayés et al 2003, Palacios-Verdú et al 2015]. * Hypertension is less prevalent in those individuals with WS who are hemizygous for NCF1, located in one of the blocks of low copy repeats that flank the WBSCR [Del Campo et al 2006]. * A more severe phenotype with lower cognitive ability is observed in individuals with very large deletions (>2-4 Mb) that include the WBSCR than in individuals with a typical 1.5-1.8-Mb WBSCR deletion [Stock et al 2003, Marshall et al 2008]. Shorter deletions within the WBSCR have a variable phenotype depending on the extent of the deletion. * Individuals with partial WBSCR deletions that include the usual telomeric breakpoint (including GTF2I) have classic WS features, including intellectual disability [Botta et al 1999, Heller et al 2003]. * Those with partial WBSCR deletions that do not include deletion of GTF2I – including some individuals with de novo short deletions and families with "SVAS plus" – do not have intellectual disability but often demonstrate the WS cognitive profile [Morris et al 2003]. In two families, deletion of ELN and an additional gene, LIMK1, was associated with the WS cognitive profile but not with intellectual disability or other characteristics of WS [Frangiskakis et al 1996]. Another family with a similar deletion did not have the WS cognitive profile [Tassabehji et al 1998]. Deletions within the WBSCR may be of maternal or paternal origin [Ewart et al 1993a, Dutly & Schinzel 1996, Urbán et al 1996]. No phenotypic differences have been related to the parent of origin in some series [Wu et al 1998], while microcephaly has been correlated with maternal origin of the WBSCR deletion in others [Del Campo et al 2006]. ### Penetrance Penetrance is 100%; expression of the phenotypic features is variable. ### Nomenclature The first descriptions of WS were incomplete in that they reflected the chief complaint of the individual or the medical specialty of the observer. Thus, nephrologists and endocrinologists described "idiopathic infantile hypercalcemia" (IHC), and cardiologists reported "supravalvular aortic stenosis syndrome" (SASS). Early reports also noted dysmorphic facial features that were thought to resemble elves of legend: for a time, the term “Williams elfin facies syndrome” was used. After the reports of Williams et al [1961] and Beuren et al [1962], the condition was called Williams syndrome in the US and Williams-Beuren syndrome in Europe. ### Prevalence A study of WS in Norway reported a prevalence of 1:7500 [Strømme et al 2002]. ## Differential Diagnosis Williams syndrome (WS) should be distinguished from other syndromes characterized by developmental delay, attention deficit hyperactivity disorder, short stature, distinctive facies, and/or congenital heart disease. These include: Noonan syndrome, deletion 22q11.2 (DiGeorge syndrome), Smith-Magenis syndrome, Kabuki syndrome, and fetal alcohol syndrome. Individuals with supravalvular aortic stenosis (SVAS) should be evaluated to determine if WS or autosomal dominant SVAS (OMIM 185500) is the appropriate diagnosis. ### Table 2. Disorders to Consider in the Differential Diagnosis of Williams Syndrome View in own window DisorderGene(s)MOIClinical Features of the Disorder Most Common Congenital Heart DiseaseDistinguishing Facial FeaturesAdditional Features Williams syndromeSee footnote 1ADSupravalvar aortic stenosis * Stellate/lacy iris * Periorbital fullness * Wide mouth * Loss of cupid’s bow of the upper lip * Full lower lip * Large earlobes * Hypercalcemia * Hoarse voice * Overly friendly personality Noonan syndromePTPN11 SOS1 RAF1 RIT1 KRAS NRAS BRAF MAP2K1ADPulmonary valve stenosis * Wide-set eyes * Full upper eyelid / ptosis * Deeply grooved philtrum * Defined peaks of the upper lip vermillion * Low-set posteriorly rotated ears * Broad/webbed neck * Pectus deformity * Wide-set nipples * Lymphatic dysplasia 22q11.2 deletion syndromeSee footnote 2ADConotruncal heart defects * Hooded eyelids * Hypoplastic ala nasi * High nasal root * Small ears * Hypocalcemia * Immunodeficiency * Palate abnormalities Smith-Magenis syndromeRAI1 3See footnote 3Septal defects * Deep-set eyes * Iris dysplasia * Upslanting palpebral fissures * Short philtrum * Downturned upper lip * Self-injurious behavior * Hoarse voice Kabuki syndromeKMT2DAD 4Coarctation of the aorta * Long palpebral fissures * Everted lower eyelids * Large ears * Cleft lip/palate * Vertebral anomalies KDM6AXL 5 Fetal alcohol syndromeNA 6Septal defects * Short palpebral fissures * Flat philtrum * Thin upper lip vermillion * Small ears * Disinhibited behavior AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NA = not applicable; XL = X-linked 1\. Williams syndrome is caused by a contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene (ELN). 2\. 22q11.2 deletion syndrome is caused by deletion of genes within the DiGeorge chromosome region (DGCR). About 93% of probands have a de novo deletion of 22q11.2 and 7% have inherited the 22q11.2 deletion from a parent. 3\. Smith-Magenis syndrome is caused by deletion or mutation of RAI1 on chromosome 17p11.2. Virtually all occurrences are de novo. 4\. KMT2D-related Kabuki syndrome is inherited in an autosomal dominant manner. 5\. To date, only six individuals with Kabuki syndrome caused by pathogenic variants or deletions of KDM6A have been reported; all have had a proven or apparent de novo variant. While X-linked inheritance is theoretically possible, no familial cases of Kabuki syndrome resulting from pathogenic variants in KDM6A have been reported. 6\. Fetal alcohol syndrome is caused by prenatal exposure to alcohol. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Williams syndrome (WS), and to guide medical management, the following evaluations are recommended [Committee on Genetics 2001, Committee on Genetics 2002]: * Complete physical and neurologic examination * Plotting of growth parameters on Williams syndrome growth charts * Cardiology evaluation * Full clinical evaluation by a cardiologist with experience in treating WS * Measurement of blood pressure in all four limbs * Echocardiogram, including Doppler flow studies * Electrocardiogram * Additional cardiovascular imaging studies (computed tomography, magnetic resonance angiography, or cardiac catheterization) may be required in individuals with diminished pulses, bruits, or signs of diffuse thoracic aortic stenosis. * Urinary system evaluation * Ultrasound examination of the bladder and kidneys * Serum concentration of BUN and creatinine * Urinalysis * Calcium determinations * Serum concentration of calcium or ionized calcium * Calcium/creatinine determination on a spot urine sample (See Sargent et al [1993] for normal values.) * Thyroid function tests * Ophthalmologic evaluation * Baseline audiologic evaluation * Multidisciplinary developmental evaluation, including assessment of motor, speech, language, personal-social, general cognitive, and vocational skills * Assessment of behavior including attention, anxiety, and adaptive skills * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Cognitive/behavioral. Developmental disabilities should be addressed by early intervention programs, special education programs, and vocational training. Recommended therapies include speech/language, physical, and occupational therapy. Consider hippotherapy (use of equine movement during speech, physical, and/or occupational therapy). * Verbal strengths can be used to assist in learning spatial tasks. * Phonics methods are recommended to teach reading [John & Mervis 2010]. * Mastery of daily living skills contributes to adult well-being and should be encouraged. Psychological evaluation, polysomnography, and psychiatric evaluation should guide therapy for the individual. * Behavior in young children may be addressed using techniques based on applied behavior analysis [Mervis & John 2010]. * Behavioral counseling and psychotropic medication are often used to manage behavior problems, especially attention deficit disorder and anxiety, which require pharmacologic treatment in approximately 50% [Cherniske et al 2004]. * Self-calming techniques can help manage anxiety. Cardiovascular. Surgical correction of SVAS is performed in 20%-30% [Kececioglu et al 1993, Bruno et al 2003, Collins et al 2010b]. Surgical treatment of mitral valve insufficiency or renal artery stenosis may be required. Hypertension is usually treated medically. In one series, calcium channel blockers were used successfully [Bouchireb et al 2010]. Antihypertensive therapy also results in improvement in vascular stiffness [Kozel et al 2014]. Lifelong monitoring of the cardiovascular system by a cardiologist familiar with treating WS is recommended. Hypercalcemia. Management of hypercalcemia involves the following: * Hydration status should be assessed; increase water intake as indicated. * The diet should be adjusted with the help of a nutritionist so that the calcium intake is not higher than 100% of the recommended daily intake (RDI) [Ross et al 2011]. If the serum concentration of calcium remains elevated, dietary calcium should be reduced; but the serum concentration of calcium must be monitored. Parents should be counseled not to restrict dietary intake of calcium without medical supervision. * Vitamin supplements containing vitamin D should be avoided. If vitamin D deficiency is suspected, it is important to check vitamin D levels prior to initiating therapy, and calcium levels must be monitored during treatment. Absorption of calcium from the gut is increased in Williams syndrome (cause unknown) and vitamin D promotes calcium absorption. * Refractory hypercalcemia may be treated with oral steroids. * Intravenous pamidronate has been used successfully to treat infants with severe symptomatic hypercalcemia [Cagle et al 2004, Oliveri et al 2004]. * Referral to an endocrinologist and/or nephrologist is recommended for treatment of persistent hypercalcemia, hypercalciuria, and/or nephrocalcinosis. Eye, ear, nose, and throat. Hyperopia is treated with corrective lenses; strabismus is treated with patching of one eye or surgery; dacrostenosis is treated as in the general population. Recurrent otitis media may be treated with tympanotomy tubes. Hypersensitivity to sounds may be treated with ear protection when increased noise levels can be predicted. Dental care may require assistance with daily brushing and flossing. Dental cleaning frequency should be increased to every four months in adolescents and adults. Orthodontic referral should be considered for treatment of malocclusion. Gastrointestinal.The treatment of feeding problems in infancy and abdominal pain in children and adults depends on the cause (e.g., G-E reflux, hypercalcemia, hiatal hernia, and/or diverticulitis). Infants often benefit from feeding therapy. Constipation must be aggressively managed at all ages due to the increased risk for early onset diverticulosis/diverticulitis. Treatment usually includes dietary increase in water and fiber followed by osmotic laxative treatment. Severe abdominal pain may indicate diverticulitis and/or intestinal perforation, which may occur at a young age in WS. Urinary tract abnormalities. Individuals with febrile urinary tract infections will likely require investigation of the lower urinary tract such as voiding cystourethrogram to direct treatment. Endocrine. Early puberty may be treated with a gonadotropin-releasing hormone agonist [Partsch et al 2002, Pober 2010]. Hypothyroidism is treated with oral thyroxine therapy; subclinical hypothyroidism typically is monitored but does not require treatment. ### Prevention of Secondary Complications The following are indicated: * Exercise and a balanced diet to avoid insulin resistance/diabetes mellitus * Range of motion exercises to prevent or ameliorate joint contractures * Because of the increased risk for myocardial insufficiency in individuals with biventricular outflow tract obstruction, especially during induction of anesthesia [Horowitz et al 2002] and because there is an increased risk for adverse events with sedation or anesthesia in WS, anesthesia consultation for surgical procedures. Guidelines for sedation and anesthesia risk assessment and anesthetic management for WS have been published [Burch et al 2008, Matisoff et al 2015, Latham et al 2016]. Electrocardiogram prior to surgery. * Awareness of the risk for myocardial insufficiency and cardiac arrest; for surgical procedures, use of a center equipped for cardiopulmonary resuscitation ### Surveillance ### Table 3. Surveillance for Williams Syndrome View in own window Interval / AgeTest/Measurement In infants – toddlers * Serum calcium determination every 4-6 months until age 2 years * Thyroid function test yearly until age 3 years Annual / all ages 1 * Medical evaluation * Vision screening to monitor for refractive errors and strabismus * Hearing evaluation * Monitoring of blood pressure in both arms * Measurement of calcium/creatinine ratio in a random spot urine and urinalysis * Cardiology evaluation at least yearly for the first 5 years, every 2-3 years thereafter for life Every 2 years * Serum concentration of calcium * Thyroid function and TSH level Every 10 years * Renal and bladder ultrasound In adults * Oral glucose tolerance test (OGTT) starting at age 20 years to evaluate for diabetes mellitus 2 * Evaluation for mitral valve prolapse, aortic insufficiency, hypertension, long QT interval, and arterial stenoses * Evaluation for cataracts 1\. Except as noted 2\. If normal, OGTT should be repeated every five years. ### Agents/Circumstances to Avoid Children with WS should not be given multivitamins because all pediatric multivitamin preparations contain vitamin D. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Pregnancies in women with WS are high risk. They should be monitored for the development of pregnancy-induced hypertension, arrhythmias, and heart failure. Regular urinalyses should be performed in late gestation due to the increased risk for urinary tract infection. Ultrasound monitoring of the fetus is suggested [Lin et al 2008]. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Williams Syndrome	c0175702	6,025	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1249/	2021-01-18T20:49:33	{"mesh": ["D018980"], "synonyms": ["Williams-Beuren Syndrome"]}
Not to be confused with Carney complex or Carney-Stratakis syndrome. Carney triad (CT) is characterized by the coexistence of three types of neoplasms, mainly in young women,[1] including gastric gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal paraganglioma.[2] The underlying genetic defect remains elusive. CT is distinct from Carney complex, and the Carney-Stratakis syndrome. ## Contents * 1 Background * 2 Taxonomy * 2.1 Carney complex * 2.2 Carney–Stratakis syndrome * 3 References ## Background[edit] Carney triad (CT), named for J Aidan Carney, is considered to be a specific type of multiple endocrine neoplasia (MEN). The three classically associated tumors are a subset of gastric epithelioid leiomyosarcoma (it is now known that this subset is actually gastrointestinal stromal tumor arising from the interstitial cells of Cajal), pulmonary chondroma, and extra-adrenal paraganglioma.[2] The condition manifests more commonly in females. Multiple tumors in multiple organs in young patients, with occasional sibling involvement, suggested an inherited disorder, but the underlying genetic basis has not been identified.[1] In addition to these three classical tumors, there is an increased incidence of pheochromocytoma, esophageal leiomyoma and adrenocortical adenoma.[3] The original description employed the then-prevailing terminology of gastric epithelioid leiomyosarcoma. Subsequent advances in molecular biology have led to the current terminology of gastrointestinal stromal tumors (GISTs).[4] However, there is limited evidence to suggest that the gastrointestinal stromal tumors (GIST) in Carney triad lack CD117 (c-kit) mutations (i.e., they are wild-type), and hence these GISTs may prove unresponsive to Imatinib.[5] ## Taxonomy[edit] Carney triad is distinct from two other multiple neoplasia syndromes, also described by J. Aiden Carney. ### Carney complex[edit] The Carney complex is a distinct entity,[6] characterized by myxomatous neoplasms (cardiac, endocrine, cutaneous and neural), and a host of pigmented lesions of the skin and mucosae, including the rarely occurring epitheloid blue nevus.[7][8] ### Carney–Stratakis syndrome[edit] A third condition, the Carney–Stratakis syndrome (CSS), describes the dyad of hereditary gastrointestinal stromal tumor (GIST) and paraganglioma, that is caused by germline mutations in the mitochondrial tumor suppressor gene pathway involving the succinate dehydrogenase subunits SDHD, SDHC and SDHB.[3] ## References[edit] 1. ^ a b OMIM - Online Mendelian Inheritance in Man. Carney Triad (OMIM 604287) [1] 2. ^ a b Carney JA. "The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paraganglioma: a five-year review." Medicine (Baltimore). 1983;62(3): 159-169. 3. ^ a b Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med. 2009;266(1):43. PMID 19522824 4. ^ Boccon-Gibod L, Boman F, Boudjemaa S, Fabre M, Leverger G, Carney AJ. "Separate occurrence of extra-adrenal paraganglioma and gastrointestinal stromal tumor in monozygotic twins: probable familial Carney syndrome." Pediatr Dev Pathol. 2004;7(4):380-4. 5. ^ Diment J, Tamborini E, Casali P, Gronchi A, Carney JA, Colecchia M. "Carney triad: case report and molecular analysis of gastric tumor." Hum Pathol. 2005;36(1):112-6. 6. ^ Gaissmaier et al. (letter and response) Carney Complex. Circulation 1999;100 (25); e150 http://circ.ahajournals.org/cgi/reprint/100/25/e150 7. ^ Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore). 1985;64(4):270-83. 8. ^ Iglesias C, Torrelo A, Colmenero I, Mediero IG, Zambrano A, Requenca L. Isolated multiple congential epithelioid blue naevus. British Journal of Dermatology 2005;152:391-393. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Carney's triad	c1858592	6,026	wikipedia	https://en.wikipedia.org/wiki/Carney%27s_triad	2021-01-18T18:51:33	{"gard": ["10924"], "mesh": ["C565803"], "umls": ["C1858592"], "orphanet": ["139411"], "wikidata": ["Q5044023"]}
8p23.1 duplication syndrome is a rare chromosomal anomaly syndrome, resulting from the partial duplication of the short arm of chromosome 8, with a highly variable phenotype, principally characterized by mild to moderate developmental delay, intellectual disability, mild facial dysmorphism (incl. prominent forehead, arched eyebrows, broad nasal bridge, upturned nares, cleft lip and/or palate) and congenital cardiac anomalies (e.g., atrioventricular septal defect). Other reported features include macrocephaly, behavioral abnormalities (e.g., attention deficit disorder), seizures, hypotonia and ocular and digital anomalies (poly/syndactyly). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	8p23.1 duplication syndrome	c4707330	6,027	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251076	2021-01-23T19:06:34	{"gard": ["10304"], "icd-10": ["Q92.3"], "synonyms": ["Dup(8)(p23.1p23.1)", "Trisomy 8p23.1"]}
Abortion in the Czech Republic is legally allowed up to 12 weeks of pregnancy, with medical indications up to 24 weeks of pregnancy, in case of grave problems with the fetus at any time. Those performed for medical indications are covered by public health insurance, but, otherwise abortion is relatively affordable in the Czech Republic. In Czech, induced abortion is referred to as interrupce or umělé přerušení těhotenství, often colloquially potrat ("miscarriage"). ## Contents * 1 History * 2 Statistics * 3 Public opinion * 4 See also * 5 References * 6 External links ## History[edit] The number of induced abortions in the Czech Republic between 1958 and 2005. In 1957 abortions were legalized in Czechoslovakia, although with restrictions that depended on the current policy of the government. In 1986 the restrictions were lifted resulting in growth of the number of abortions. Since 1993, abortions for non-medical reasons have not been paid for by the public health system. The absolute peak of the number of abortions was reached in 1990 at over 100,000 per year, but has declined steadily down since then, reaching less than 1/3 of the peak level in 2004. Reasons for this decrease have included the wider availability of contraception and better sex education. Medical abortion (with mifepristone) was registered in 2013.[1] ## Statistics[edit] Total number of abortions in 2009 was 40 528 [2][3] of which 14 629 (i.e. 3.1%) were spontaneous abortions, 24 636 (60,79%) induced abortions (historically the lowest number ever) of which 77% were "mini-interruptions" (within 8 weeks of pregnancy). 1,300 ectopic pregnancies were aborted. Total abortions per woman is 0.53, induced abortions is 0.34. As of 2010[update], the abortion rate was 10.7 abortions per 1,000 women aged 15–44 years.[4] Regionally, the highest abortion ratio is in northern and north-western Bohemia due to the structure of the population (in 2002 in Tachov District 31.3% of abortions were induced). The lowest ratios are in rural districts of southern Moravia and Bohemian-Moravian Highlands (in 2002 in Žďár nad Sázavou District 15.5% of abortions were induced).[5][6] Abortion ratios in large industrial cities are generally higher compared to small towns and the countryside. Married women form the largest segment but their ratio is decreasing in favour of unmarried young women. Women with tertiary level of education have about 6% of induced abortions. In 2009 7.5% of the women are foreigners living in the Czech Republic. Official statistics about abortion tourism (mainly from neighbouring Poland where legal induced abortion is strictly limited) do not exist but the numbers are estimated to be low. ## Public opinion[edit] Main article: Societal attitudes towards abortion The public in the Czech Republic generally supports the legality of abortion. This has been confirmed by a number of opinion polls. * An April 2003 CDC/ORC Macro report examined opinions on abortion among women aged 15 to 44, asking, "Do you think that a woman always has the right to decide about her pregnancy, including whether to have an abortion?" In 2003, 85% of Czechs surveyed thought a woman always had the right to an abortion and 15% did not. Of those 15%, 91% believed abortion was acceptable in cases of life endangerment, 74% in cases of fetal defects, 72% in cases of risk to health, 71% in cases of rape, 16% if the family could not financially support a child, and 8% if the woman was unmarried.[7] * A May 2005 Euro RSCG/TNS Sofres poll examined attitudes toward abortion in 10 European countries, asking polltakers whether they agreed with the statement, "If a woman doesn't want children, she should be allowed to have an abortion". 66% of Czechs replied "very much", 15% replied "a little", 8% replied "not really", and replied 10% "not at all". Support for the availability of abortion in the Czech Republic, at 81%, was the highest out of all the nations featured in the poll.[8] * A May 2007 CVVM poll found that 72% of Czechs believe that abortion should be allowed "at the request of the woman", 19% that it should be allowed for "societal reasons", 5% that it should be allowed only if "a woman’s health is at risk", 1% that it should be "banned".[9] * In a Pew Research survey from 2013, when asked about morality of abortion, 49% of respondents in the Czech Republic said that abortion is morally acceptable and 18% said it was unacceptable, and 18% that it was not a moral issue.[10] ## See also[edit] * Czech Republic portal * Abortion law * Abortion debate * Religion and abortion ## References[edit] 1. ^ https://www.womenonwaves.org/en/page/3226/czech-republic 2. ^ "Potraty v roce 2009" (PDF) (in Czech). Ústav zdravotnických informací a statistiky (Office of Medical Information and Statistics). Retrieved 2010-05-06.[dead link] 3. ^ "Potraty 2009 v číslech". [Vitalia.cz] (in Czech). [IInfo.cz]. 2010-05-05. Archived from the original on 7 May 2010. Retrieved 2010-05-06. 4. ^ "World Abortion Policies 2013". United Nations. 2013. Retrieved 3 March 2014. 5. ^ "Regional ratios of induced abortions in 2002" (PDF). 6. ^ "Regional ratios of induced abortions in 2006". 7. ^ Centers for Disease Control and Prevention and ORC Macro. (2003). Reproductive, Maternal and Child Health in Eastern Europe and Eurasia: A Comparative Report. Retrieved February 12, 2007. 8. ^ TNS Sofres. (May 2005). European Values Archived 2007-06-19 at the Wayback Machine. Retrieved January 11, 2007. 9. ^ "Most in Czech Republic Support Abortion Rights[permanent dead link]." (June 10, 2007). Angus Reid Global Monitor. Retrieved June 20, 2007. 10. ^ "Global Views on Morality \| Pew Research Center". Pewglobal.org. 2014-04-15. Archived from the original on 2016-04-20. Retrieved 2016-04-09. ## External links[edit] (all texts in Czech language) * Legal details * Abortion statistics: overview, detailed. * Text of current abortion law (PDF) * v * t * e Abortion in Europe Sovereign states * Albania * Andorra * Armenia * Austria * Azerbaijan * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Cyprus * Czech Republic * Denmark * Estonia * Finland * France * Georgia * Germany * Greece * Hungary * Iceland * Ireland * * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Turkey * Ukraine * United Kingdom * England * Northern Ireland * Scotland * Wales * Vatican City States with limited recognition * Abkhazia * Artsakh * Kosovo * Northern Cyprus * South Ossetia * Transnistria * v * t * e Abortion Main topics * Definitions * History * 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Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * 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Judaism * Scientology * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Abortion in the Czech Republic	None	6,028	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_the_Czech_Republic	2021-01-18T18:50:00	{"wikidata": ["Q2811855"]}
Signs and symptoms due to benzodiazepines discontinuation in physically dependent persons Benzodiazepine withdrawal syndrome Other namesBenzo withdrawal Diazepam is sometimes used in the treatment of benzodiazepine withdrawal.[1] SpecialtyPsychiatry Benzodiazepines The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties. * Pronunciation: /ˌbɛnzoʊdaɪˈæzəpiːn/ * Benzodiazepine * List of benzodiazepines * Benzodiazepine overdose * Benzodiazepine dependence * Benzodiazepine misuse * Benzodiazepine withdrawal syndrome * Effects of long-term benzodiazepine use * v * t * e Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal or BZD withdrawal —is the cluster of signs and symptoms that emerge when a person who has been taking benzodiazepines, either medically or recreationally, and has developed a physical dependence, undergoes dosage reduction or discontinuation. Development of physical dependence and the resulting withdrawal symptoms, some of which may last for years, may result from taking the medication as prescribed. Benzodiazepine withdrawal is characterized by sleep disturbance, irritability, increased tension and anxiety, panic attacks, hand tremor, shaking, sweating, difficulty with concentration, confusion and cognitive difficulty, memory problems, dry retching and nausea, weight loss, palpitations, headache, muscular pain and stiffness, a host of perceptual changes, hallucinations, seizures, psychosis,[2] and increased risk of suicide[3][4] (see "signs and symptoms" section below for full list). Further, these symptoms are notable for the manner in which they wax and wane and vary in severity from day to day or week by week instead of steadily decreasing in a straightforward monotonic manner.[5] This phenomenon is often referred to as "waves" and "windows". It is a potentially serious condition, and is complex and often protracted in its course.[6][7] Long-term benzodiazepine use, defined as daily use for at least three months,[8] is not desirable because of the associated increased risk of dependence,[9] dose escalation, loss of efficacy, increased risk of accidents and falls, particularly for the elderly,[10] as well as cognitive,[11] neurological, and intellectual impairments.[12] Use of short-acting hypnotics, while being effective at initiating sleep, worsen the second half of sleep due to withdrawal effects.[13] Benzodiazepine withdrawal can be severe and can provoke life-threatening withdrawal symptoms, such as seizures,[14] particularly with abrupt or overly rapid dosage reduction from high doses or long time users.[6] A severe withdrawal response can nevertheless occur despite gradual dose reduction, or from relatively low doses in short time users,[15] even after a single large dose in animal models.[16][17] A minority of individuals will experience a protracted withdrawal syndrome whose symptoms may persist at a sub-acute level for months, or years after cessation of benzodiazepines. The likelihood of developing a protracted withdrawal syndrome can be minimized by a slow, gradual reduction in dosage.[18] Chronic exposure to benzodiazepines causes neural adaptations that counteract the drug's effects, leading to tolerance and dependence.[19] Despite taking a constant therapeutic dose, long-term use of benzodiazepines may lead to the emergence of withdrawal-like symptoms, particularly between doses.[20] When the drug is discontinued or the dosage reduced, withdrawal symptoms may appear and remain until the body reverses the physiological adaptations.[21] These rebound symptoms may be identical to the symptoms for which the drug was initially taken, or may be part of discontinuation symptoms.[22] In severe cases, the withdrawal reaction may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, and, especially at high doses, seizure disorders.[23] Failure to recognize discontinuation symptoms can lead to false evidence for the need to take benzodiazepines, which in turn leads to withdrawal failure and reinstatement of benzodiazepines, often to higher doses.[23] Awareness of the withdrawal reactions, individualized taper strategies according to withdrawal severity, the addition of alternative strategies such as reassurance and referral to benzodiazepine withdrawal support groups, all increase the success rate of withdrawal.[24][25] ## Contents * 1 Signs and symptoms * 2 Mechanism * 3 Diagnosis * 4 Prevention * 5 Management * 5.1 Medications * 5.2 Inpatient treatment * 6 Prognosis * 6.1 Withdrawal process * 6.2 Duration * 6.3 Protracted withdrawal syndrome * 7 Epidemiology * 8 Special populations * 8.1 Pediatrics * 8.2 Pregnancy * 8.3 Elderly * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] Withdrawal effects caused by sedative-hypnotics discontinuation, such as benzodiazepines, barbiturates, or alcohol, can cause serious medical complications. They are cited to be more hazardous to withdraw from than opioids.[26] Users typically receive little advice and support for discontinuation.[27] Some withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed,[22] and can be acute or protracted in duration. Onset of symptoms from long half-life benzodiazepines might be delayed for up to three weeks, although withdrawal symptoms from short-acting ones often present early, usually within 24–48 hours.[28] There may be no fundamental differences in symptoms from either high or low dose discontinuation, but symptoms tend to be more severe from higher doses.[29] Daytime reemergence and rebound withdrawal symptoms, sometimes confused with interdose withdrawal, may occur once dependence has set in. 'Reemergence' is the return of symptoms for which the drug was initially prescribed, in contrast, 'rebound' symptoms are a return of the symptoms for which the benzodiazepine was initially taken, but at a more intense level than before; whereas 'interdose withdrawal' is when a prior dosage of drug wears off and beginnings of an entirely new cycle of withdrawal sets in, the symptoms of which dissipate upon taking the next dosage but after which yet another entirely new cycle of withdrawal begins when that dosage wears off, a new onset of withdrawal between each dosage thus called 'interdose withdrawal' and if not properly treated can recur indefinitely in a vicious circle (for which a benzo with a long half life, e.g. diazepam, can be substituted so the drug does not wear off between doses).[30] Withdrawal symptoms may appear for the first time during dose reduction, and include insomnia, anxiety, distress, weight loss, dizziness, night sweats, shakes, muscle twitches, aphasia, panic attacks, depression, derealization, paranoia, indigestion, diarrhea, photo phobia etc., and are more commonly associated with short-acting benzodiazepines discontinuation, like triazolam.[23][31] Daytime symptoms can occur after a few days to a few weeks of administration of nightly benzodiazepine use[32][33] or z-drugs such as zopiclone;[34] withdrawal-related insomnia rebounds worse than baseline,[35][36] and for rapidly eliminated benzodiazepines, including triazolam and temazepam, this may occur even when used briefly and intermittently, according to a small 1991 study (n=18).[37] The following symptoms may emerge during gradual or abrupt dosage reduction: * Akathisia * Agitation and anxiety,[1] possible terror and panic attacks[2][38] * Blurred vision[38] * Chest pain[38] * Depersonalization[39] and derealisation (feelings of unreality)[40] * Depression (can be severe),[41] possible suicidal ideation * Dilated pupils[23] * Dizziness[38] * Dry mouth[38] * Dysphoria[42][43] * Elevation in blood pressure[44] * Fatigue and weakness[38] * Gastrointestinal disturbance (including nausea, diarrhea, vomiting)[45][46][47] * Hearing disturbance[38] * Headache[2] * Hot and cold spells[38] * Hyperosmia[48] * Hypertension[49] * Hypnagogic hallucinations[18] * Hypochondriasis[38] * Increased sensitivity to touch[40] * Increased urinary frequency[38] * Insomnia[45] * Impaired memory and concentration[2][38] * Loss of appetite and weight loss[50] * Mild to moderate aphasia[48] * Mood swings[38] * Muscular spasms, cramps, discomfort or fasciculations[51] * Nightmares[45] * Obsessive compulsive disorder[52][53] * Paraesthesia[38][40][48][6][54] * Paranoia[48] * Perspiration[2] * Photophobia[48] * Postural hypotension[45] * REM sleep rebound[55] * Restless legs syndrome[25] * Stiffness[38] * Taste and smell disturbances[38] * Tachycardia[56] * Tinnitus[57] * Tremor[58][59] * Visual disturbances[40] Rapid discontinuation may result in a more serious syndrome * Catatonia, which may result in death[60][61][62] * Confusion[1] * Convulsions,[1] which may result in death[63][64] * Coma[65] (rare) * Delirium tremens[66][67] * Hyperthermia[45] * Mania[68][69] * Neuroleptic malignant syndrome-like event[70][71] (rare) * Organic brain syndrome[72] * Post-traumatic stress disorder[25] * Psychosis[73][74] * Suicidal ideation[75] or suicide[3][4] * Violence and aggression[38][76] As withdrawal progresses, patients often find their physical and mental health improves with improved mood and improved cognition. ## Mechanism[edit] Main article: Benzodiazepine dependence § Mechanism See also: Alcohol withdrawal syndrome § Kindling, and Kindling (sedative–hypnotic withdrawal) The neuroadaptive processes involved in tolerance, dependence, and withdrawal mechanisms implicate both the GABAergic and the glutamatergic systems.[19] Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system; roughly one-quarter to one-third of synapses use GABA.[77] GABA mediates the influx of chloride ions through ligand-gated chloride channels called GABAA receptors. When chloride enters the nerve cell, the cell membrane potential hyperpolarizes thereby inhibiting depolarization, or reduction in the firing rate of the post-synaptic nerve cell.[78] Benzodiazepines potentiate the action of GABA,[79] by binding a site between the α and γ subunits of the 5-subunit receptor[80] thereby increasing the frequency of the GABA-gated chloride channel opening in the presence of GABA.[81] When potentiation is sustained by long-term use, neuroadaptations occur which result in decreased GABAergic response. What is certain is that surface GABAA receptor protein levels are altered in response to benzodiazepine exposure, as is receptor turnover rate.[82] The exact reason for the reduced responsiveness has not been elucidated but down-regulation of the number of receptors has only been observed at some receptor locations including in the pars reticulata of the substantia nigra; down-regulation of the number of receptors or internalization does not appear to be the main mechanism at other locations.[83] Evidence exists for other hypotheses including changes in the receptor conformation, changes in turnover, recycling, or production rates, degree of phosphorylation and receptor gene expression, subunit composition, decreased coupling mechanisms between the GABA and benzodiazepine site, decrease in GABA production, and compensatory increased glutamatergic activity.[19][82] A unified model hypothesis involves a combination of internalization of the receptor, followed by preferential degradation of certain receptor sub-units, which provides the nuclear activation for changes in receptor gene transcription.[82] It has been postulated that when benzodiazepines are cleared from the brain, these neuroadaptations are "unmasked", leading to unopposed excitability of the neuron.[84] Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system.[85] Increased glutamate excitatory activity during withdrawal may lead to sensitization or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse.[86][87][88] Those who have a prior history of withdrawing from benzodiazepines are found to be less likely to succeed the next time around.[89] ## Diagnosis[edit] In severe cases, the withdrawal reaction or protracted withdrawal may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, agitated depression, panic disorder, generalised anxiety disorder, and complex partial seizures and, especially at high doses, seizure disorders.[23] Failure to recognize discontinuation symptoms can lead to false evidence for the need to take benzodiazepines, which in turn leads to withdrawal failure and reinstatement of benzodiazepines, often to higher doses. Pre-existing disorder or other causes typically do not improve, whereas symptoms of protracted withdrawal gradually improve over the ensuing months.[23] Symptoms may lack a psychological cause and can fluctuate in intensity with periods of good and bad days until eventual recovery.[90][91] ## Prevention[edit] According to the British National Formulary, it is better to withdraw too slowly rather than too quickly from benzodiazepines.[28] The rate of dosage reduction is best carried out so as to minimize the symptoms' intensity and severity. Anecdotally, a slow rate of reduction may reduce the risk of developing a severe protracted syndrome. Long half-life benzodiazepines like diazepam[1] or chlordiazepoxide are preferred to minimize rebound effects and are available in low dose forms. Some people may not fully stabilize between dose reductions, even when the rate of reduction is slowed. Such people sometimes simply need to persist as they may not feel better until they have been fully withdrawn from them for a period of time.[92] ## Management[edit] Chlordiazepoxide, 5 mg capsules, are sometimes used as an alternative to diazepam for benzodiazepine withdrawal. Like diazepam, it has a long elimination half-life and long-acting active metabolites.[6][93] Management of benzodiazepine dependence involves considering the person's age, comorbidity and the pharmacological pathways of benzodiazepines.[94] Psychological interventions may provide a small but significant additional benefit over gradual dose reduction alone at post-cessation and at follow-up.[95] The psychological interventions studied were relaxation training, cognitive-behavioral treatment of insomnia, and self-monitoring of consumption and symptoms, goal-setting, management of withdrawal and coping with anxiety.[95] There is no standard approach to managing benzodiazepine withdrawal.[96] With sufficient motivation and the proper approach, almost anyone can successfully withdraw from benzodiazepines. However, a prolonged and severe syndrome can lead to collapsed marriages, business failures, bankruptcy, hospitalization, and the most serious adverse effect, suicide.[3] As such, long-term users should not be forced to discontinue against their will.[6] Over-rapid withdrawal, lack of explanation, and failure to reassure individuals that they are experiencing temporary withdrawal symptoms led some people to experience increased panic and fears they are going mad, with some people developing a condition similar to post-traumatic stress disorder as a result. A slow withdrawal regimen, coupled with reassurance from family, friends, and peers improves the outcome.[6][18] According to a 2015 Cochrane review, cognitive behavior therapy plus taper was effective in achieving discontinuation in the short-term but the effect was not certain after six months.[97] ### Medications[edit] While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use.[95] Some studies found that the abrupt substitution of substitutive pharmacotherapy was actually less effective than gradual dose reduction alone, and only three studies found benefits of adding melatonin,[98] paroxetine,[99] trazodone,[100] or valproate[100] in conjunction with a gradual dose reduction.[95] * Antipsychotics are generally ineffective for benzodiazepine withdrawal-related psychosis.[54][101] Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions.[28][102][103][104] Some antipsychotic agents may be riskier than others during withdrawal, especially clozapine, olanzapine or low potency phenothiazines (e.g., chlorpromazine), as they lower the seizure threshold and can worsen withdrawal effects; if used, extreme caution is required.[105] * Barbiturates are cross tolerant to benzodiazepines and should generally be avoided; however phenobarbital can be used, as it is relatively safe,[106] see below. * Benzodiazepines or cross tolerant drugs should be avoided after discontinuation, even occasionally. These include the nonbenzodiazepines Z-drugs, which have a similar mechanism of action. This is because tolerance to benzodiazepines has been demonstrated to be still present at four months to two years after withdrawal depending on personal biochemistry. Re-exposures to benzodiazepines typically resulted in a reactivation of the tolerance and benzodiazepine withdrawal syndrome.[107][108] * Bupropion, which is used primarily as an antidepressant and smoking cessation aid, is contraindicated in persons experiencing abrupt withdrawal from benzodiazepines or other sedative-hypnotics (e.g. alcohol), due to an increased risk of seizures.[109] * Buspirone augmentation was not found to increase the discontinuation success rate.[8] * Caffeine may worsen withdrawal symptoms because of its stimulatory properties.[6] At least one animal study has shown some modulation of the benzodiazepine site by caffeine, which produces a lowering of seizure threshold.[110] * Carbamazepine, an anticonvulsant, appears to have some beneficial effects in the treatment and management of benzodiazepine withdrawal; however, research is limited and thus the ability of experts to make recommendations on its use for benzodiazepine withdrawal is not possible at present.[107] * Ethanol, the primary alcohol in alcoholic beverages, even mild to moderate use, has been found to be a significant predictor of withdrawal failure, probably because of its cross tolerance with benzodiazepines.[6][107][111] * Flumazenil has been found to stimulate the reversal of tolerance and the normalization of receptor function. However, further research is needed in the form of randomised trials to demonstrate its role in the treatment of benzodiazepine withdrawal.[112] Flumazenil stimulates the up-regulation and reverses the uncoupling of benzodiazepine receptors to the GABAA receptor, thereby reversing tolerance and reducing withdrawal symptoms and relapse rates.[113][114] Because of limited research and experience compared to the possible risks involved, the flumazenil detoxification method is controversial and can only be done as an inpatient procedure under medical supervision. Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks.[115] This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms. A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles feeling, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo-controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested the most likely explanation is past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but further research is required.[116] A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal.[38] In 2007, Hoffmann–La Roche the makers of flumazenil, acknowledged the existence of protracted benzodiazepine withdrawal syndromes, but did not recommended flumazenil to treat the condition.[117] * Fluoroquinolone antibiotics[118][119][120] have been noted to increase the incidence of a CNS toxicity from 1% in the general population, to 4% in benzodiazepine-dependent population or in those undergoing withdrawal from them. This is probably the result of their GABA antagonistic effects as they have been found to competitively displace benzodiazepines from benzodiazepine receptor sites. This antagonism can precipitate acute withdrawal symptoms, that can persist for weeks or months before subsiding. The symptoms include depression, anxiety, psychosis, paranoia, severe insomnia, parathesia, tinnitus, hypersensitivity to light and sound, tremors, status epilepticus, suicidal thoughts and suicide attempt. Fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal.[6][121][122][123][124] NSAIDs have some mild GABA antagonistic properties and animal research indicate that some may even displace benzodiazepines from their binding site. However, NSAIDs taken in combination with fluoroquinolones cause a very significant increase in GABA antagonism, GABA toxicity, seizures, and other severe adverse effects.[125][126][127] * Imidazenil has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal.[128] * Imipramine was found to statistically increase the discontinuation success rate.[8] * Melatonin augmentation was found to statistically increase the discontinuation success rate for people with insomnia.[8] * Phenobarbital, (a barbiturate), is used at "detox" or other inpatient facilities to prevent seizures during rapid withdrawal or cold turkey. The phenobarbital is followed by a one- to two-week taper, although a slow taper from phenobarbital is preferred.[23] In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.[129][130] * Pregabalin may help reduce the severity of benzodiazepine withdrawal symptoms,[131] and reduce the risk of relapse.[132] * Propranolol was not found to increase the discontinuation success rate.[8] * SSRI antidepressants have been found to have little value in the treatment of benzodiazepine withdrawal.[133] * Trazodone was not found to increase the discontinuation success rate.[8] ### Inpatient treatment[edit] Inpatient drug detox or rehabilitation facilities may be inappropriate for those who have become tolerant or dependent while taking the drug as prescribed, as opposed to recreational use. Such inpatient referrals may be traumatic for non-abusers.[23] ## Prognosis[edit] See also: Protracted withdrawal syndrome A 2006 meta-analysis found evidence for the efficacy of stepped care: minimal intervention (e.g. send an advisory letter, or meet large number of patients to advise discontinuation), followed by systematic tapered discontinuation alone without augmentation if the first try was unsuccessful.[8] Cognitive behavioral therapy improved discontinuation success rates for panic disorder, melatonin for insomnia, and flumazenil or sodium valproate for general long-term benzodiazepine use.[8] A ten-year follow-up found that more than half of those who had successfully withdrawn from long-term use were still abstinent two years later, and that if they were able to maintain this state at two years, they were likely to maintain this state at the ten-year followup.[10] One study found that after one year of abstinence from long-term use of benzodiazepines, cognitive, neurological and intellectual impairments had returned to normal.[134] Those who had a prior psychiatric diagnosis had a similar success rate from a gradual taper at a two-year follow-up.[92][135] Withdrawal from benzodiazepines did not lead to an increased use of antidepressants.[136] ### Withdrawal process[edit] It can be too difficult to withdraw from short- or intermediate-acting benzodiazepines because of the intensity of the rebound symptoms felt between doses.[6][137][138][139] Moreover, short-acting benzodiazepines appear to produce a more intense withdrawal syndrome.[140] For this reason, discontinuation is sometimes carried out by first substituting an equivalent dose of a short-acting benzodiazepine with a longer-acting one like diazepam or chlordiazepoxide. Failure to use the correct equivalent amount can precipitate a severe withdrawal reaction.[141] Benzodiazepines with a half-life of more than 24 hours include chlordiazepoxide, diazepam, clobazam, clonazepam, chlorazepinic acid, ketazolam, medazepam, nordazepam, and prazepam. Benzodiazepines with a half-life of less than 24 hours include alprazolam, bromazepam, brotizolam, flunitrazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, oxazepam, and temazepam.[10] The resultant equivalent dose is then gradually reduced. The consensus is to reduce dosage gradually over several weeks, e.g. 4 or more weeks for diazepam doses over 30 mg/day,[1] with the rate determined by the person's ability to tolerate symptoms.[142] The recommended reduction rates range from 50% of the initial dose every week or so,[143] to 10-25% of the daily dose every 2 weeks.[142] For example, the reduction rate used in the Heather Ashton protocol calls for eliminating 10% of the remaining dose every two to four weeks, depending on the severity and response to reductions with the final dose at 0.5 mg dose of diazepam or 2.5 mg dose of chlordiazepoxide.[6] For most people, discontinuation over 4-6 weeks or 4-8 weeks is suitable.[144] Prolonged period of reduction over many months should be avoided to prevent the withdrawal process from becoming a "morbid focus" for the person.[107] ### Duration[edit] After the last dose has been taken, the acute phase of the withdrawal generally lasts for about two months although withdrawal symptoms, even from low-dose use, can persist for six to twelve months gradually improving over that period,[29][92] however, clinically significant withdrawal symptoms may persist for years, although gradually declining. A clinical trial of patients taking the benzodiazepine alprazolam for as short as eight weeks triggered protracted symptoms of memory deficits which were still present up to eight weeks after cessation of alprazolam.[145] ### Protracted withdrawal syndrome[edit] Protracted withdrawal syndrome refers to symptoms persisting for months or even years. A significant minority of people withdrawing from benzodiazepines, perhaps 10% to 15%, experience a protracted withdrawal syndrome which can sometimes be severe. Symptoms may include tinnitus,[57][146] psychosis, cognitive deficits, gastrointestinal complaints, insomnia, paraesthesia (tingling and numbness), pain (usually in limbs and extremities), muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, dizziness and blepharospasm[18] and may occur even without a pre-existing history of these symptoms. Tinnitus occurring during dose reduction or discontinuation of benzodiazepines is alleviated by recommencement of benzodiazepines. Dizziness is often reported as being the withdrawal symptom that lasts the longest. A study testing neuropsychological factors found psychophysiological markers differing from normals, and concluded that protracted withdrawal syndrome was a genuine iatrogenic condition caused by the long-term use.[147] The causes of persisting symptoms are a combination of pharmacological factors such as persisting drug induced receptor changes, psychological factors both caused by the drug and separate from the drug and possibly in some cases, particularly high dose users, structural brain damage or structural neuronal damage.[18][148] Symptoms continue to improve over time, often to the point where people eventually resume their normal lives, even after years of incapacity.[6] A slow withdrawal rate significantly reduces the risk of a protracted or severe withdrawal state. Protracted withdrawal symptoms can be punctuated by periods of good days and bad days. When symptoms increase periodically during protracted withdrawal, physiological changes may be present, including dilated pupils as well as an increase in blood pressure and heart rate.[23] The change in symptoms has been proposed to be due to changes in receptor sensitivity for GABA during the process of tolerance reversal.[6] A meta-analysis found cognitive impairments in many areas due to benzodiazepine use show improvements after six months of withdrawal, but significant impairments in most areas may be permanent or may require more than six months to reverse.[149] Protracted symptoms continue to fade over a period of many months or several years. There is no known cure for protracted benzodiazepine withdrawal syndrome except time,[18] however, the medication flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks.[115] This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms. ## Epidemiology[edit] The severity and length of the withdrawal syndrome is likely determined by various factors, including rate of tapering, length of use and dosage size, and possible genetic factors.[6][150] Those who have a prior history of withdrawing from benzodiazepines may have a sensitized or kindled central nervous system leading to worsening cognition and symptomatology, and making each subsequent withdrawal period worse.[86][87][88][151] ## Special populations[edit] ### Pediatrics[edit] A neonatal withdrawal syndrome, sometimes severe, can occur when the mother had taken benzodiazepines, especially during the third trimester. Symptoms include hypotonia, apnoeic spells, cyanosis, impaired metabolic responses to cold stress, and seizures. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.[152] A withdrawal syndrome is seen in about 20% of pediatric intensive care unit children after infusions with benzodiazepines or opioids.[153] The likelihood of having the syndrome correlates with total infusion duration and dose, although duration is thought to be more important.[154] Treatment for withdrawal usually involves weaning over a 3- to 21-day period if the infusion lasted for more than a week.[155] Symptoms include tremors, agitation, sleeplessness, inconsolable crying, diarrhea and sweating. In total, over fifty withdrawal symptoms are listed in this review article.[153][156] Environmental measures aimed at easing the symptoms of neonates with severe abstinence syndrome had little impact, but providing a quiet sleep environment helped in mild cases.[153] ### Pregnancy[edit] Discontinuing benzodiazepines or antidepressants abruptly due to concerns of teratogenic effects of the medications has a high risk of causing serious complications, so is not recommended. For example, abrupt withdrawal of benzodiazepines or antidepressants has a high risk of causing extreme withdrawal symptoms, including suicidal ideation and a severe rebound effect of the return of the underlying disorder if present. This can lead to hospitalisation and potentially, suicide. One study reported one-third of mothers who suddenly discontinued or very rapidly tapered their medications became acutely suicidal due to 'unbearable symptoms'. One woman had a medical abortion, as she felt she could no longer cope, and another woman used alcohol in a bid to combat the withdrawal symptoms from benzodiazepines. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines. The study reported physicians generally are not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.[75] ### Elderly[edit] A study of the elderly who were benzodiazepine dependent found withdrawal could be carried out with few complications and could lead to improvements in sleep and cognitive abilities. At 52 weeks after successful withdrawal, a 22% improvement in cognitive status was found, as well as improved social functioning. Those who remained on benzodiazepines experienced a 5% decline in cognitive abilities, which seemed to be faster than that seen in normal aging, suggesting the longer the intake of benzodiazepines, the worse the cognitive effects become. Some worsening of symptoms were seen in the first few months of benzodiazepine abstinence, but at a 24-week followup, elderly subjects were clearly improved compared to those who remained on benzodiazepines. Improvements in sleep were seen at the 24- and 52-week followups. The authors concluded benzodiazepines were not effective in the long term for sleep problems except in suppressing withdrawal-related rebound insomnia. Improvements were seen between 24 and 52 weeks after withdrawal in many factors, including improved sleep and several cognitive and performance abilities. Some cognitive abilities, which are sensitive to benzodiazepines, as well as age, such as episodic memory did not improve. The authors, however, cited a study in younger patients who at a 3.5-year followup showed no memory impairments and speculated that certain memory functions take longer to recover from chronic benzodiazepine use and further improvements in elderly people's cognitive function may occur beyond 52 weeks after withdrawal. The reason it took 24 weeks for improvements to be seen after cessation of benzodiazepine use was due to the time it takes the brain to adapt to the benzodiazepine-free environment.[157] At 24 weeks, significant improvements were found, including accuracy of information processing improved, but a decline was seen in those who remained on benzodiazepines. Further improvements were noted at the 52-week followup, indicating ongoing improvements with benzodiazepine abstinence. Younger people on benzodiazepines also experience cognitive deterioration in visual spatial memory, but are not as vulnerable as the elderly to the cognitive effects.[157] Improved reaction times were noted at 52 weeks in elderly patients free from benzodiazepines. This is an important function in the elderly, especially if they drive a car due to the increased risk of road traffic accidents in benzodiazepine users.[157] At the 24-week followup, 80% of people had successfully withdrawn from benzodiazepines. Part of the success was attributed to the placebo method used for part of the trial which broke the psychological dependence on benzodiazepines when the elderly patients realised they had completed their gradual reduction several weeks previously, and had only been taking placebo tablets. This helped reassure them they could sleep without their pills.[157] The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepine Z drugs.[157] The elimination half-life of diazepam and chlordiazepoxide, as well as other long half-life benzodiazepines, is twice as long in the elderly compared to younger individuals. Many doctors do not adjust benzodiazepine dosage according to age in elderly patients.[158] ## See also[edit] * Psychiatry portal * Alcohol withdrawal syndrome * Benzodiazepine dependence * Benzodiazepine equivalence * Opioid withdrawal syndrome * Physical dependence * Post-acute-withdrawal syndrome * Rebound effect * SSRI discontinuation syndrome * Neuroleptic discontinuation syndrome ## References[edit] 1. ^ a b c d e f Soyka M (2017). "Treatment of Benzodiazepine Dependence". The New England Journal of Medicine. 376 (12): 1147–1157. doi:10.1056/NEJMra1611832. PMID 28328330. 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PMID 14513134. 155. ^ Playfor, Stephen; Jenkins, Ian; Boyles, Carolyne; Choonara, Imti; Davies, Gerald; Haywood, Tim; Hinson, Gillian; Mayer, Anton; Morton, Neil; Ralph, Tanya; Wolf, Andrew; United Kingdom Paediatric Intensive Care Society Sedation; Analgesia Neuromuscular Blockade Working Group (2006). "Consensus guidelines on sedation and analgesia in critically ill children". Intensive Care Medicine. 32 (8): 1125–36. doi:10.1007/s00134-006-0190-x. PMID 16699772. S2CID 8518882. 156. ^ Ista, Erwin; Van Dijk, Monique; Gamel, Claudia; Tibboel, Dick; De Hoog, Matthijs (2007). "Withdrawal symptoms in children after long-term administration of sedatives and/or analgesics: A literature review. 'Assessment remains troublesome'". Intensive Care Medicine. 33 (8): 1396–406. doi:10.1007/s00134-007-0696-x. PMID 17541548. 157. ^ a b c d e Curran, HV; Collins, R; Fletcher, S; Kee, SC; Woods, B; Iliffe, S (2003). "Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life" (PDF). Psychological Medicine. 33 (7): 1223–37. doi:10.1017/S0033291703008213. PMID 14580077. 158. ^ Salzman, Carl (15 May 2004). Clinical geriatric psychopharmacology (4th ed.). USA: Lippincott Williams & Wilkins. pp. 450–3. ISBN 978-0-7817-4380-8. ## External links[edit] Classification D * ICD-10: F13.3 (after persistent use) * Benzodiazepines: How they work and how to withdraw by Professor Heather Ashton * The Minor Tranquilliser Project, For support, Camden, UK * Benzodiazepine withdrawal syndrome at Curlie * v * t * e Psychoactive substance-related disorder General * SID * Substance intoxication / Drug overdose * Substance-induced psychosis * Withdrawal: * Craving * Neonatal withdrawal * Post-acute-withdrawal syndrome (PAWS) * SUD * Substance abuse / Substance-related disorders * Physical dependence / Psychological dependence / Substance dependence Combined substance use * SUD * Polysubstance dependence * SID * Combined drug intoxication (CDI) Alcohol SID Cardiovascular diseases * Alcoholic cardiomyopathy * Alcohol flush reaction (AFR) Gastrointestinal diseases * Alcoholic liver disease (ALD): * Alcoholic hepatitis * Auto-brewery syndrome (ABS) Endocrine diseases * Alcoholic ketoacidosis (AKA) Nervous 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cocaine exposure (PCE) * SUD * Cocaine dependence Hallucinogen * SID * Acute intoxication from hallucinogens (bad trip) * Hallucinogen persisting perception disorder (HPPD) Nicotine * SID * Nicotine poisoning * Nicotine withdrawal * SUD * Nicotine dependence Opioids * SID * Opioid overdose * SUD * Opioid use disorder (OUD) Sedative / hypnotic * SID * Kindling (sedative–hypnotic withdrawal) * benzodiazepine: SID * Benzodiazepine overdose * Benzodiazepine withdrawal * SUD * Benzodiazepine use disorder (BUD) * Benzodiazepine dependence * barbiturate: SID * Barbiturate overdose * SUD * Barbiturate dependence Stimulants * SID * Stimulant psychosis * amphetamine: SUD * Amphetamine dependence Volatile solvent * SID * Sudden sniffing death syndrome (SSDS) * Toluene toxicity * SUD * Inhalant abuse * v * t * e Unnecessary health care Causes * Direct-to-consumer advertising * Overscreening * Overdiagnosis * Fee-for-service * Defensive medicine * Unwarranted variation * Overmedication * Overmedicalization * Prescription cascade * Quaternary prevention * Disease mongering * Political abuse of psychiatry Overused health care * Caesarean delivery on maternal request * Antibiotic misuse * Benzodiazepine use disorder * Effects of long-term benzodiazepine use * Opioid use disorder * Psychoactive drug * Proton-pump inhibitor * Polypharmacy * treatment of incidentaloma Tools and Situations * Deprescribing * Choosing Wisely * Medication discontinuation * Withdrawal syndrome * Antidepressant discontinuation syndrome * Benzodiazepine withdrawal syndrome Works about unnecessary health care * Overtreated * The Treatment Trap * Selling Sickness * Overdosed America [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Benzodiazepine withdrawal syndrome	None	6,029	wikipedia	https://en.wikipedia.org/wiki/Benzodiazepine_withdrawal_syndrome	2021-01-18T18:28:05	{"icd-10": ["F13"], "wikidata": ["Q6119887"]}
Superficial siderosis Other namesSuperficial siderosis of the CNS, Superficial hemosiderosis of the CNS, Superficial hemosiderosis of the central nervous system MRI showing pulsations of CSF (normal individual) Superficial hemosiderosis of the central nervous system is a disease of the brain resulting from chronic iron deposition in neuronal tissues associated with cerebrospinal fluid. This occurs via the deposition of hemosiderin in neuronal tissue, and is associated with neuronal loss, gliosis, and demyelination of neuronal cells. This disease was first discovered in 1908 by R.C. Hamill after performing an autopsy.[1] Detection of this disease was largely post-mortem until the advent of MRI technology, which made diagnosis far easier. Superficial siderosis is largely considered a rare disease, with less than 270 total reported cases in scientific literature as of 2006,[2] and affects people of a wide range of ages with men being approximately three times more frequently affected than women.[3] The number of reported cases of superficial siderosis has increased with advances in MRI technology, but it remains a rare disease. ## Contents * 1 Symptoms * 2 Cause * 3 Pathology * 4 Diagnosis * 5 Treatment * 6 References * 7 External links ## Symptoms[edit] Superficial siderosis is characterized by many symptoms resulting from brain damage:[citation needed] * Sensorineural hearing loss\- This is the most common symptom associated with superficial siderosis and its absence is rare. The highest pitches are often lost first, and over a period of one to twelve years hearing loss progresses to total deafness or loss of all hearing but low pitches. * Ataxia\- The impairment of gait, which is the second most common symptom. * Pyramidal signs\- Various signs that indicate a condition of the pyramidal tracts. * Dementia\- Occurs in approximately one-quarter of those affected by superficial siderosis. * Disturbances of the bladder * Anosmia\- Loss of sense of smell. * Anisocoria\- Unequal size of pupils.[3] ## Cause[edit] The most commonly described underlying cause of superficial siderosis is chronic bleeding into the subarachnoid space of the brain, which releases erythrocytes, or blood cells, into the cerebrospinal fluid. The chronic bleeding can come from many sources such as from an arteriovenous malformation or cavernous malformation, myxopapillary ependymoma of the spinal cord, from chronic subdural hematoma, from a ventricular shunt, or from chronic subarachnoid hemorrhage. Chronic bleeding sources can also be a result of past brain surgery or CNS trauma, which may be the most common cause of superficial siderosis, with superficial siderosis showing up many years later.[4] In up to as many as half of all described cases the source of bleeding was never found.[citation needed] ## Pathology[edit] Blood cells are not native to the cerebrospinal fluid, and their presence there is problematic. Once they eventually break down, they release the heme containing protein hemoglobin. Hemoglobin breaks down and releases iron-containing heme into the cerebrospinal fluid. In response to this upsurge in heme levels, Bergmann glia and microglia produce heme oxygenase 1. Heme oxygenase 1 breaks down free heme into biliverdin, carbon monoxide, and iron. It is this breakdown of heme that is the source of iron deposition that ultimately causes superficial siderosis.[5] The excess free iron is circulated in the cerebrospinal fluid and deposited in neuronal tissues, where it catalyzes the formation of reactive oxygen species which can damage DNA, RNA, proteins, and is otherwise toxic to the cells.[citation needed] Iron deposition is prevalent in siderotic brain tissues, with iron concentrations of 1.79 to 8.26 times normal levels. Ferritin, an iron storage protein, is over-produced in response to excess heme by glial cells in order to sequester iron, with production ranging from 20.1 to 27.4 times normal levels. Excess iron, ferritin, and red blood cells may result in xanthochromia of the cerebrospinal fluid. Amongst neuronal cells types, iron deposition appears to be preferential for oligodendroglial cells, which is supported by the belief that they can act as iron sinks in the central nervous system. Schwann cells are also frequently damaged, contributing to demyelination.[5] Iron deposition is most prevalent in the inferior temporal lobes, the brainstem, the cerebellum, peri-ventricular structures, the spinal cord, and cranial nerve VIII. Iron deposition is also present in cranial nerves I & II, but this damage less frequently presents symptoms when compared to cranial nerve VIII,[3] which can be explained by cranial nerve VIII’s notable segment of glial cells, which are preferentially affected by iron deposition.[6] The presence of ‘foamy’, ‘spheroid’, or ‘cytoid’ bodies in affected neuronal tissues has been noted but what they are and their origin remains somewhat unclear. They are believed to be swollen axonal bodies, but some evidence exists that they may be astrocytic in origin.[7] ## Diagnosis[edit] Early detection of superficial siderosis is usually via MRI. The iron deposition that is characteristic of superficial siderosis shows up as a hypointense band in affected tissues, with a characteristic rim of intensity appearing on the cerebellum; a hyperintense rim is rarely seen.[6] Taking samples of cerebrospinal fluid may also reveal siderosis through xanthochromia, elevated presence of red blood cells, high iron and ferritin concentrations, and elevated levels of the proteins Tau, beta amyloid (Aβ42), neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP), but the CSF is sometimes normal.[8] Detection is complicated by the fact that superficial siderosis is a rare disease and is not well described in neurological texts, so it may go unnoticed until noticeable symptoms appear.[9] ## Treatment[edit] There is no current cure for superficial siderosis, only treatments to help alleviate the current symptoms and to help prevent the development of further symptoms. If a source of bleeding can be identified (sources are frequently not found), then surgical correction of the bleeding source can be performed; this has proved to be effective in halting the development of further symptoms in some cases and has no effect on symptoms that have already presented.[6] Patients with superficial siderosis are often treated with deferiprone (brand name is Ferriprox), a lipid-soluble iron chelator, as this medication has been demonstrated to chelate iron in the central nervous system.[10] While on this drug you will need frequent blood tests (weekly) to keep an eye on the blood levels as this drug is known to lower certain blood levels such as the neutrophils and WBC (white blood count), etc. While it is ok if these levels go low in the average person, if they go low while taking deferiprone (Ferriprox) it can cause life-threatening infections that can result in death.[citation needed] Alleviation of the most common symptom, hearing loss, has been varyingly successful through the use of cochlear implants. Most people do not notice a large improvement after successful implantation, which is most likely due to damage to the vestibulocochlear nerve (cranial nerve VIII) and not the cochlea itself.[11] Some people fare far better, with a return to near normal hearing, but there is little ability to detect how well a person will respond to this treatment at this time.[12] ## References[edit] 1. ^ Hamill, R.C. (1908) Report of a case of melanosis of the brain, cord, and meninges. J. Nerv. Ment. Dis., 35, 594. 2. ^ Scheid, R. et al. (2009) Superficial siderosis of the central nervous system – treatment with steroids? Journal of Clinical Pharmacy and Therapeutics, 34, 603-605. 3. ^ a b c Fearnly, J. M., Stevens, M.J., Rudge, P. (1995) Superficial siderosis of the central nervous system. Brain, 118, 1051-1066. 4. ^ McCarron, M.O. et al. (2003) Superficial siderosis of the central nervous system many years after neurological procedures. Journal of Neurology, Neurosurgery, and Psychiatry, 74, 1326-1328. 5. ^ a b Koeppen, A.H. et al. (2008) The pathology of superficial siderosis of the central nervous system. Acta Neuropathol, 116, 371-382. 6. ^ a b c Kumar, N. (2009) Superficial siderosis: associations and therapeutic implications. Arch Neurol, 64, 491-496. 7. ^ Kellermeir, H., Wang, G., Wiley, C. (2009) Iron localization in superficial siderosis of the nervous system. Neuropathology, 29, 187-195. 8. ^ Kondziella, D., Zetterburg, H. (2008) Hyperphosphorylation of tau protein in superficial CNS siderosis. Journal of the Neurological Sciences, 273, 130-132. 9. ^ Simeoni, S. et al. (2008) Systemic sclerosis and superficial siderosis of the central nervous system: casuality or causality? Rheumatol. Int., 28, 815-818. 10. ^ Levy, Michael. "Observational Study of Deferiprone (Ferriprox®) in the Treatment of Superficial Siderosis". 11. ^ Sydlowski, S.A. et al. (2009) Cochlear implant patients with superficial siderosis. J. Am. Acad. Audiol., 20, 348-352. 12. ^ Hathaway, B. et al. (2006) Successful cochlear implantation in a patient with superficial siderosis. American Journal of Otolarynology-Head and Neck Medicine and Surgery, 27, 255-258. ## External links[edit] Classification D * ICD-10: I69.0 External resources * Orphanet: 247245 * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Superficial siderosis	None	6,030	wikipedia	https://en.wikipedia.org/wiki/Superficial_siderosis	2021-01-18T18:54:18	{"gard": ["9484"], "orphanet": ["247245"], "synonyms": ["Hemosiderosis of the central nervous system", "Superficial hemosiderosis of the CNS", "Superficial hemosiderosis of the central nervous system", "Superficial siderosis of the CNS", "Superficial siderosis of the central nervous system"], "wikidata": ["Q7643329"]}
## Description High density lipoproteins (HDLs) are antiatherogenic lipoproteins that have a major role in transporting cholesterol from peripheral tissues to the liver, where it is removed. Epidemiologic studies show that low levels of high density lipoprotein cholesterol (HDLC; see 604091) are associated with an increased risk of coronary heart disease and an increased mortality rate. HDLC levels are influenced by several genetic and nongenetic factors. Nongenetic factors include smoking, which decreases the HDLC level. Exercise and alcohol increase HDLC levels. Decreased HDLC is often associated with other coronary heart disease risk factors such as obesity, hyperinsulinemia and insulin resistance, hypertriglyceridemia, and hypertension. Mapping Using a multipoint variance components linkage approach, Arya et al. (2002) found strong evidence of linkage of a quantitative trait locus (QTL) for HDLC level to a genetic location between markers D9S925 and D9S741 on chromosome 9p in Mexican Americans (lod score = 3.4). A replication study in an independent set of Mexican American families confirmed the existence of a QTL on 9p. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 1	c1847758	6,031	omim	https://www.omim.org/entry/606613	2019-09-22T16:10:18	{"omim": ["606613"], "synonyms": ["Alternative titles", "HDLC1"]}
Glanzmann thrombasthenia (GT) is a bleeding syndrome characterized by spontaneous mucocutaneous bleeding and an exaggerated response to trauma due to a constitutional thrombocytopenia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Glanzmann thrombasthenia	c0040015	6,032	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=849	2021-01-23T18:39:25	{"gard": ["2478"], "mesh": ["D013915"], "omim": ["273800"], "umls": ["C0040015"], "icd-10": ["D69.1"]}
Granular cell tumor 2-cm tumor presented as an abdominal wall mass in a middle-aged woman SpecialtyOncology Histopathologic image of granular cell tumor of the skin Granular cell tumor is a tumor that can develop on any skin or mucosal surface, but occurs on the tongue 40% of the time. It is also known as Abrikossoff's tumor,[1] Granular cell myoblastoma,[1] Granular cell nerve sheath tumor,[1] and Granular cell schwannoma.[1])Granular cell tumors (GCTs) affect females more often than males.[2] ## Contents * 1 Pathology * 2 Treatment * 3 Epidemiology * 4 See also * 5 References * 6 External links ## Pathology[edit] Granular cell tumors are derived from neural tissue, as can be demonstrated by immunohistochemistry and ultrastructural evidence using electron microscopy. These lesions characteristically consist of polygonal cells with bland nuclei, abundant cytoplasm and fine eosinophilic cytoplasmic granules. The tumor cells stain positively for S-100. Both malignant and benign versions of the tumor exist, where malignant tumors are characterized histologically by features such as spindling, high nuclear to cytoplasmic ratios, pleomorphism, and necrosis. [3] Multiple granular cell tumors may seen in the context of LEOPARD syndrome, due to a mutation in the PTPN11 gene.[4] These tumors on occasion may appear similar to neoplasms of renal (relating to the kidneys) origin or other soft tissue neoplasms. ## Treatment[edit] The primary method for treatment is surgical, not medical. Radiation and chemotherapy are not needed for benign lesions and are not effective for malignant lesions. Benign granular cell tumors have a recurrence rate of 2% to 8% when resection margins are deemed clear of tumor infiltration. When the resection margins of a benign granular cell tumor are positive for tumor infiltration the recurrence rate is increased to 20%. Malignant lesions are aggressive and difficult to eradicate with surgery and have a recurrence rate of 32%. ## Epidemiology[edit] Granular cell tumors can affect all parts of the body; however, the head and neck areas are affected 45% to 65% of the time. Of the head and neck cases 70% of lesions are located intraorally (tongue, oral mucosa, hard palate). The next most common location that lesions are found in the head and neck area is the larynx (10%).[5] Granular cell tumors are also found in the internal organs, particularly in the upper aerodigestive tract. Vaginal granular cell tumor is generally rare.[6] The usual presentation is of slow growing behavior, forming a polygonal accumulation of secondary lysosomes in the cytoplasm. Granular cell tumors are typically solitary and are rarely larger than three centimeters. This type of tumor has been found to be both benign and malignant, although malignancy is rare and constitutes only 2% of all granular cell tumors.[7] ## See also[edit] * List of cutaneous conditions * Glassy cell carcinoma ## References[edit] 1. ^ a b c d Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. pp. 1796, 1804. ISBN 978-1-4160-2999-1. 2. ^ "Granular cell tumor \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". Genetic and rare diseases information center. Retrieved 17 April 2018. 3. ^ Neelon, D.; Lannan, F.; Childs, J. (Jan 2020). "Granular Cell Tumor". StatPearls. PMID 33085297. 4. ^ Schrader, KA.; Nelson, TN.; De Luca, A.; Huntsman, DG.; McGillivray, BC. (Feb 2009). "Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11". Clin Genet. 75 (2): 185–9. doi:10.1111/j.1399-0004.2008.01100.x. PMID 19054014. 5. ^ Kahn, Michael A. Basic Oral and Maxillofacial Pathology. Volume 1. 2001. 6. ^ Danforth's obstetrics and gynecology. Gibbs, Ronald S., 1943-, Danforth, David N. (David Newton), 1912-1990. (10th ed.). Philadelphia: Lippincott Williams & Wilkins. 2008. ISBN 9780781769372. OCLC 187289377.CS1 maint: others (link) 7. ^ Fanburg-Smith JC, Meis-Kindblom JM, et al. Malignant granular cell tumor of soft tissue: diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol. Jul 1998;22(7):779-94. ## External links[edit] Classification D * ICD-10: D36.1 (ILDS D36.170) * ICD-O: M9582/0 * MeSH: D016586 * DiseasesDB: 31674 * SNOMED CT: 12169001 * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Granular cell tumor	c0085167	6,033	wikipedia	https://en.wikipedia.org/wiki/Granular_cell_tumor	2021-01-18T19:05:23	{"gard": ["9618"], "mesh": ["D016586"], "umls": ["C0085167"], "icd-10": ["D36.1"], "wikidata": ["Q940874"]}
This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Digestive system neoplasm" – news · newspapers · books · scholar · JSTOR (December 2020) (Learn how and when to remove this template message) Digestive system neoplasm SpecialtyOncology Digestive system neoplasms are tumors which affect the digestive system. Types include: * esophageal cancer * gastric cancer * small intestinal cancer * colorectal cancer * anal cancer ## References[edit] ## External links[edit] Classification D * ICD-10: C15-C26 D12-D13 * MeSH: D004067 * v * t * e Overview of tumors, cancer and oncology Conditions Benign tumors * Hyperplasia * Cyst * Pseudocyst * Hamartoma Malignant progression * Dysplasia * Carcinoma in situ * Cancer * Metastasis * Primary tumor * Sentinel lymph node Topography * Head and neck (oral, nasopharyngeal) * Digestive system * Respiratory system * Bone * Skin * Blood * Urogenital * Nervous system * Endocrine system Histology * Carcinoma * Sarcoma * Blastoma * Papilloma * Adenoma Other * Precancerous condition * Paraneoplastic syndrome Staging/grading * TNM * Ann Arbor * Prostate cancer staging * Gleason grading system * Dukes classification Carcinogenesis * Cancer cell * Carcinogen * Tumor suppressor genes/oncogenes * Clonally transmissible cancer * Oncovirus * Carcinogenic bacteria Misc. * Research * Index of oncology articles * History * Cancer pain * Cancer and nausea * v * t * e Digestive system neoplasia GI tract Upper Esophagus * Squamous cell carcinoma * Adenocarcinoma Stomach * Gastric carcinoma * Signet ring cell carcinoma * Gastric lymphoma * MALT lymphoma * Linitis plastica Lower Small intestine * Duodenal cancer * Adenocarcinoma Appendix * Carcinoid * Pseudomyxoma peritonei Colon/rectum * Colorectal polyp: adenoma, hyperplastic, juvenile, sessile serrated adenoma, traditional serrated adenoma, Peutz–Jeghers Cronkhite–Canada * Polyposis syndromes: Juvenile * MUTYH-associated * Familial adenomatous/Gardner's * Polymerase proofreading-associated * Serrated polyposis * Neoplasm: Adenocarcinoma * Familial adenomatous polyposis * Hereditary nonpolyposis colorectal cancer Anus * Squamous cell carcinoma Upper and/or lower * Gastrointestinal stromal tumor * Krukenberg tumor (metastatic) Accessory Liver * malignant: Hepatocellular carcinoma * Fibrolamellar * Hepatoblastoma * benign: Hepatocellular adenoma * Cavernous hemangioma * hyperplasia: Focal nodular hyperplasia * Nodular regenerative hyperplasia Biliary tract * bile duct: Cholangiocarcinoma * Klatskin tumor * gallbladder: Gallbladder cancer Pancreas * exocrine pancreas: Adenocarcinoma * Pancreatic ductal carcinoma * cystic neoplasms: Serous microcystic adenoma * Intraductal papillary mucinous neoplasm * Mucinous cystic neoplasm * Solid pseudopapillary neoplasm * Pancreatoblastoma Peritoneum * Primary peritoneal carcinoma * Peritoneal mesothelioma * Desmoplastic small round cell tumor This article about a neoplasm is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Digestive system neoplasm	c0012243	6,034	wikipedia	https://en.wikipedia.org/wiki/Digestive_system_neoplasm	2021-01-18T18:30:20	{"mesh": ["D004067"], "icd-10": ["D13", "C15", "D12", "C26"], "wikidata": ["Q5275615"]}
For the medical journal, see Experimental Neurology. Central nervous system disease Neurodegeneration Para-sagittal MRI of the head in a patient with benign familial macrocephaly SpecialtyNeurology, Psychiatry Neurodegeneration is the progressive loss of structure or function of neurons, including their death. Many neurodegenerative diseases – including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, and prion diseases – occur as a result of neurodegenerative processes. Such diseases are incurable, resulting in progressive degeneration of neurons.[1] As research progresses, many similarities appear that relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously. There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death.[2][3] Neurodegeneration can be found in many different levels of neuronal circuitry ranging from molecular to systemic. ## Contents * 1 Specific disorders * 1.1 Alzheimer's disease * 1.2 Parkinson's disease * 1.3 Huntington's disease * 1.4 Multiple Sclerosis (MS) * 1.5 Amyotrophic lateral sclerosis (ALS) * 1.6 Batten disease * 2 Risk factor * 3 Mechanisms * 3.1 Genetics * 3.2 Protein misfolding * 3.3 Intracellular mechanisms * 3.3.1 Protein degradation pathways * 3.3.2 Membrane damage * 3.3.3 Mitochondrial dysfunction * 3.3.4 DNA damage * 3.3.5 Axonal transport * 3.4 Programmed cell death * 3.4.1 Apoptosis (type I) * 3.4.2 Autophagic (type II) * 3.4.3 Cytoplasmic (type III) * 3.5 Transglutaminase * 4 Management * 4.1 Animal models in research * 4.2 Other avenues of investigation * 5 See also * 6 References ## Specific disorders[edit] ### Alzheimer's disease[edit] Comparison of brain tissue between healthy individual and Alzheimer's disease patient, demonstrating extent of neuronal death Main article: Alzheimer's disease Alzheimer's disease (AD) is a chronic neurodegenerative disease that results in the loss of neurons and synapses in the cerebral cortex and certain subcortical structures, resulting in gross atrophy of the temporal lobe, parietal lobe, and parts of the frontal cortex and cingulate gyrus.[4] Even with billions of dollars being used to find a treatment for Alzheimer's disease, no effective treatments have been found.[5] However, clinical trials have developed certain compounds that could potentially change the future of Alzheimer's disease treatments.[6] Currently, diagnoses of Alzheimer's is subpar, and better methods need to be utilized for various aspects of clinical diagnoses.[7] Alzheimer's has a 20% misdiagnosis rate.[7] AD pathology is primarily characterized by the presence of senile plaques and neurofibrillary tangles. Plaques are made up of small peptides, typically 39–43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP appears to play roles in normal neuron growth, survival and post-injury repair.[8][9] APP is cleaved into smaller fragments by enzymes such as gamma secretase and beta secretase.[10] One of these fragments gives rise to fibrils of beta-amyloid which can self-assemble into the dense extracellular deposits known as senile plaques or amyloid plaques.[11][12] ### Parkinson's disease[edit] Main article: Parkinson's disease Parkinson's disease (PD) is the second most common neurodegenerative disorder.[13] It typically manifests as bradykinesia, rigidity, resting tremor and posture instability. The crude prevalence rate of PD has been reported to range from 15 per 100,000 to 12,500 per 100,000, and the incidence of PD from 15 per 100,000 to 328 per 100,000, with the disease being less common in Asian countries. PD is primarily characterized by death of dopaminergic neurons in the substantia nigra, a region of the midbrain. The cause of this selective cell death is unknown. Notably, alpha-synuclein-ubiquitin complexes and aggregates are observed to accumulate in Lewy bodies within affected neurons. It is thought that defects in protein transport machinery and regulation, such as RAB1, may play a role in this disease mechanism.[14] Impaired axonal transport of alpha-synuclein may also lead to its accumulation in Lewy bodies. Experiments have revealed reduced transport rates of both wild-type and two familial Parkinson's disease-associated mutant alpha-synucleins through axons of cultured neurons.[15] Membrane damage by alpha-synuclein could be another Parkinson's disease mechanism.[16] The main known risk factor is age. Mutations in genes such as α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA), and tau protein (MAPT) can also cause hereditary PD or increase PD risk.[17] While PD is the second most common neurodegenerative disorder, problems with diagnoses still persist.[18] Problems with the sense of smell is a widespread symptom of Parkinson’s disease (PD), however, some neurologists question its efficacy.[18] This assessment method is a source of controversy among medical professionals.[18] The gut microbiome might play a role in the diagnosis of PD, and research suggests various ways that could revolutionize the future of PD treatment.[19] ### Huntington's disease[edit] Main article: Huntington's disease Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by mutations in the huntingtin gene. HD is characterized by loss of medium spiny neurons and astrogliosis.[20][21][22] The first brain region to be substantially affected is the striatum, followed by degeneration of the frontal and temporal cortices.[23] The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder, notably chorea.[24] Huntington's disease presents itself later in life even though the proteins that cause the disease works towards manifestation from their early stages in the humans affected by the proteins.[25] Along with being a neurodegenerative disorder, HD has links to problems with neurodevelopment.[25] HD is caused by polyglutamine tract expansion in the huntingtin gene, resulting in the mutant huntingtin (mHtt). Aggregates of mhtt form as inclusion bodies in neurons, and may be directly toxic. Additionally, they may damage molecular motors and microtubules to interfere with normal axonal transport, leading to impaired transport of important cargoes such as BDNF.[15] Huntington's disease currently has no effective treatments that would modify the disease.[26] ### Multiple Sclerosis (MS)[edit] Main article: Multiple sclerosis Multiple Sclerosis is a chronic debilitating disease of the central nervous system, caused by an autoimmune attack resulting in the progressive loss of myelin sheath on neuronal axons.[27] The resultant decrease in the speed of signal transduction leads to a loss of functionality that includes both cognitive and motor impairment depending on the location of the lesion.[27] The progression of MS occurs due to episodes of increasing inflammation, which is proposed to be due to the release of antigens such as myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein, causing an autoimmune response.[28] This sets off a cascade of signaling molecules that result in T cells, B cells, and Macrophages to cross the blood-brain barrier and attack myelin on neuronal axons leading to inflammation.[29] Further release of antigens drives subsequent degeneration causing increased inflammation.[30] Multiple sclerosis presents itself as a spectrum based on the degree of inflammation, a majority of patients suffer from early relapsing and remitting episodes of neuronal deterioration following a period of recovery. Some of these individuals may transition to a more linear progression of the disease, while about 15% of others begin with a progressive course on the onset of Multiple sclerosis. The inflammatory response contributes to the loss of the grey matter, and as a result current literature devotes itself to combatting the auto-inflammatory aspect of the disease.[29] While there are several proposed causal links between EBV and the HLA-DRB115:01 allele to the onset of Multiple Sclerosis they may contribute to the degree of autoimmune attack and the resultant inflammation, they do not determine the onset of Multiple Sclerosis.[29] ### Amyotrophic lateral sclerosis (ALS)[edit] Main article: Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is a disease in which motor neurons are selectively targeted for degeneration. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that negatively impacts the upper motor neurons (UMNs) and lower motor neurons (LMNs).[31] In 1993, missense mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) were discovered in a subsets of patients with familial ALS. This discovery led researchers to focus on unlocking the mechanisms for SOD1-mediated diseases. However, the pathogenic mechanism underlying SOD1 mutant toxicity has yet to be resolved. More recently, TDP-43 and FUS protein aggregates have been implicated in some cases of the disease, and a mutation in chromosome 9 (C9orf72) is thought to be the most common known cause of sporadic ALS. It is diagnosed by skeletal muscle weakness that progresses gradually.[31] Early diagnosis of ALS is harder than with other neurodegenerative diseases as there are no highly effective means of determining its early onset.[31] Currently, there is research being done regarding the diagnosis of ALS through upper motor neuron tests.[32] The Penn Upper Motor Neuron Score (PUMNS) consists of 28 criteria with a score range of 0-32.[32] A higher score indicates a higher level of burden present on the upper motor neurons.[32] The PUMNS has proven quite effective in determining the burden that exists on upper motor neurons in affected patients.[32] Independent research provided in vitro evidence that the primary cellular sites where SOD1 mutations act are located on astrocytes.[33][34] Astrocytes then cause the toxic effects on the motor neurons. The specific mechanism of toxicity still needs to be investigated, but the findings are significant because they implicate cells other than neuron cells in neurodegeneration.[35] ### Batten disease[edit] Main article: Batten disease Batten disease is a rare and fatal recessive neurodegenerative disorder that begins in childhood.[36] Batten disease is the common name for a group of lysosomal storage disorders known as neuronal ceroid lipofuscinoses (NCLs) – each caused by a specific gene mutation,[36] of which there are thirteen.[37] Since Batten disease is quite rare, its worldwide prevalence is about 1 in every 100,000 live births.[38] In North America, CLN3 disease (juvenile NCL) typically manifests between the ages of 4 to 7.[39] Batten disease is characterized by motor impairment, epilepsy, dementia, vision loss, and shortened lifespan.[40] A loss of vision is common first sign of Batten disease.[39] Loss of vision is typically proceeded by cognitive and behavioral changes, seizures, and loss of the ability to walk.[39] It is common for people to establish cardiac arrhythmias and difficulties eating food as the disease progresses.[39] Batten disease diagnosis depends on a conflation of many criteria: clinical signs and symptoms, evaluations of the eye, electroencephalograms (EEG), and brain magnetic resonance imaging (MRI) results.[38] The diagnosis provided by these results are corroborated by genetic and biochemical testing.[38] No effective treatments were available to prevent the disease from being widespread before the past few years.[38] In recent years, more models have been created to expedite the research process for methods to treat Batten disease.[38] ## Risk factor[edit] The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations as well as oxidative stress both contribute to aging.[41] Many of these diseases are late-onset, meaning there is some factor that changes as a person ages for each disease.[2] One constant factor is that in each disease, neurons gradually lose function as the disease progresses with age. It has been proposed that DNA damage accumulation provides the underlying causative link between aging and neurodegenerative disease.[42][43] About 20-40% of healthy people between 60 and 78 years old experience discernable decrements in cognitive performance in several domains including working, spatial, and episodic memory, and processing speed.[44] ## Mechanisms[edit] ### Genetics[edit] See also: Trinucleotide repeat disorder and Epigenetics of neurodegenerative diseases Many neurodegenerative diseases are caused by genetic mutations, most of which are located in completely unrelated genes. In many of the different diseases, the mutated gene has a common feature: a repeat of the CAG nucleotide triplet. CAG codes for the amino acid glutamine. A repeat of CAG results in a polyglutamine (polyQ) tract. Diseases associated with such mutations are known as trinucleotide repeat disorders.[45][46] Polyglutamine repeats typically cause dominant pathogenesis. Extra glutamine residues can acquire toxic properties through a variety of ways, including irregular protein folding and degradation pathways, altered subcellular localization, and abnormal interactions with other cellular proteins.[45] PolyQ studies often use a variety of animal models because there is such a clearly defined trigger – repeat expansion. Extensive research has been done using the models of nematode (C. elegans), and fruit fly (Drosophila), mice, and non-human primates.[46][47] Nine inherited neurodegenerative diseases are caused by the expansion of the CAG trinucleotide and polyQ tract, including Huntington's disease and the spinocerebellar ataxias.[48] ### Protein misfolding[edit] Several neurodegenerative diseases are classified as proteopathies as they are associated with the aggregation of misfolded proteins. alpha-synuclein: can aggregate to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Alpha-synuclein is the primary structural component of Lewy body fibrils. In addition, an alpha-synuclein fragment, known as the non-Abeta component (NAC), is found in amyloid plaques in Alzheimer's disease. * tau: hyperphosphorylated tau protein is the main component of neurofibrillary tangles in Alzheimer's disease. * beta amyloid: the major component of senile plaques in Alzheimer's disease. * prion: main component of prion diseases and transmissible spongiform encephalopathy. ### Intracellular mechanisms[edit] #### Protein degradation pathways[edit] Parkinson's disease and Huntington's disease are both late-onset and associated with the accumulation of intracellular toxic proteins. Diseases caused by the aggregation of proteins are known as proteinopathies, and they are primarily caused by aggregates in the following structures:[2] * cytosol, e.g. Parkinson's & Huntington's * nucleus, e.g. Spinocerebellar ataxia type 1 (SCA1) * endoplasmic reticulum (ER), (as seen with neuroserpin mutations that cause familial encephalopathy with neuroserpin inclusion bodies) * extracellularly excreted proteins, amyloid-β in Alzheimer's disease There are two main avenues eukaryotic cells use to remove troublesome proteins or organelles: * ubiquitin–proteasome: protein ubiquitin along with enzymes is key for the degradation of many proteins that cause proteinopathies including polyQ expansions and alpha-synucleins. Research indicates proteasome enzymes may not be able to correctly cleave these irregular proteins, which could possibly result in a more toxic species. This is the primary route cells use to degrade proteins.[2] * Decreased proteasome activity is consistent with models in which intracellular protein aggregates form. It is still unknown whether or not these aggregates are a cause or a result of neurodegeneration.[2] * autophagy–lysosome pathways: a form of programmed cell death (PCD), this becomes the favorable route when a protein is aggregate-prone meaning it is a poor proteasome substrate. This can be split into two forms of autophagy: macroautophagy and chaperone-mediated autophagy (CMA).[2] * macroautophagy is involved with nutrient recycling of macromolecules under conditions of starvation, certain apoptotic pathways, and if absent, leads to the formation of ubiquinated inclusions. Experiments in mice with neuronally confined macroautophagy-gene knockouts develop intraneuronal aggregates leading to neurodegeneration.[2] * chaperone-mediated autophagy defects may also lead to neurodegeneration. Research has shown that mutant proteins bind to the CMA-pathway receptors on lysosomal membrane and in doing so block their own degradation as well as the degradation of other substrates.[2] #### Membrane damage[edit] Damage to the membranes of organelles by monomeric or oligomeric proteins could also contribute to these diseases. Alpha-synuclein can damage membranes by inducing membrane curvature,[16] and cause extensive tubulation and vesiculation when incubated with artificial phospholipid vesicles.[16] The tubes formed from these lipid vesicles consist of both micellar as well as bilayer tubes. Extensive induction of membrane curvature is deleterious to the cell and would eventually lead to cell death.Apart from tubular structures, alpha-synuclein can also form lipoprotein nanoparticles similar to apolipoproteins. #### Mitochondrial dysfunction[edit] The most common form of cell death in neurodegeneration is through the intrinsic mitochondrial apoptotic pathway. This pathway controls the activation of caspase-9 by regulating the release of cytochrome c from the mitochondrial intermembrane space. Reactive oxygen species (ROS) are normal byproducts of mitochondrial respiratory chain activity. ROS concentration is mediated by mitochondrial antioxidants such as manganese superoxide dismutase (SOD2) and glutathione peroxidase. Over production of ROS (oxidative stress) is a central feature of all neurodegenerative disorders. In addition to the generation of ROS, mitochondria are also involved with life-sustaining functions including calcium homeostasis, PCD, mitochondrial fission and fusion, lipid concentration of the mitochondrial membranes, and the mitochondrial permeability transition. Mitochondrial disease leading to neurodegeneration is likely, at least on some level, to involve all of these functions.[49] There is strong evidence that mitochondrial dysfunction and oxidative stress play a causal role in neurodegenerative disease pathogenesis, including in four of the more well known diseases Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis.[41] Neurons are particularly vulnerable to oxidative damage due to their strong metabolic activity associated with high transcription levels, high oxygen consumption, and weak antioxidant defense.[50][51] #### DNA damage[edit] The brain metabolizes as much as a fifth of consumed oxygen, and reactive oxygen species produced by oxidative metabolism are a major source of DNA damage in the brain. Damage to a cell’s DNA is particularly harmful because DNA is the blueprint for protein production and unlike other molecules it cannot simply be replaced by re-synthesis. The vulnerability of post-mitotic neurons to DNA damage (such as oxidative lesions or certain types of DNA strand breaks), coupled with a gradual decline in the activities of repair mechanisms, could lead to accumulation of DNA damage with age and contribute to brain aging and neurodegeneration.[52] DNA single-strand breaks are common and are associated with the neurodegenerative disease ataxia-oculomotor apraxia.[53][51] Increased oxidative DNA damage in the brain is associated with Alzheimer’s disease and Parkinson’s disease.[53] Defective DNA repair has been linked to neurodegenerative disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Cockayne syndrome, Parkinson’s disease and xeroderma pigmentosum.[53][52] #### Axonal transport[edit] Main article: Axonal transport Axonal swelling, and axonal spheroids have been observed in many different neurodegenerative diseases. This suggests that defective axons are not only present in diseased neurons, but also that they may cause certain pathological insult due to accumulation of organelles. Axonal transport can be disrupted by a variety of mechanisms including damage to: kinesin and cytoplasmic dynein, microtubules, cargoes, and mitochondria.[15] When axonal transport is severely disrupted a degenerative pathway known as Wallerian-like degeneration is often triggered.[54] ### Programmed cell death[edit] Programmed cell death (PCD) is death of a cell in any form, mediated by an intracellular program.[55] This process can be activated in neurodegenerative diseases including Parkinson's disease, amytrophic lateral sclerosis, Alzheimer's disease and Huntington's disease.[56] PCD observed in neurodegenerative diseases may be directly pathogenic; alternatively, PCD may occur in response to other injury or disease processes.[3] #### Apoptosis (type I)[edit] Apoptosis is a form of programmed cell death in multicellular organisms. It is one of the main types of programmed cell death (PCD) and involves a series of biochemical events leading to a characteristic cell morphology and death. * Extrinsic apoptotic pathways: Occur when factors outside the cell activate cell surface death receptors (e.g., Fas) that result in the activation of caspases-8 or -10.[3] * Intrinsic apoptotic pathways: Result from mitochondrial release of cytochrome c or endoplasmic reticulum malfunctions, each leading to the activation of caspase-9. The nucleus and Golgi apparatus are other organelles that have damage sensors, which can lead the cells down apoptotic pathways.[3][57] Caspases (cysteine-aspartic acid proteases) cleave at very specific amino acid residues. There are two types of caspases: initiators and effectors. Initiator caspases cleave inactive forms of effector caspases. This activates the effectors that in turn cleave other proteins resulting in apoptotic initiation.[3] #### Autophagic (type II)[edit] Autophagy is a form of intracellular phagocytosis in which a cell actively consumes damaged organelles or misfolded proteins by encapsulating them into an autophagosome, which fuses with a lysosome to destroy the contents of the autophagosome. Because many neurodegenerative diseases show unusual protein aggregates, it is hypothesized that defects in autophagy could be a common mechanism of neurodegeneration.[3] #### Cytoplasmic (type III)[edit] PCD can also occur via non-apoptotic processes, also known as Type III or cytoplasmic cell death. For example, type III PCD might be caused by trophotoxicity, or hyperactivation of trophic factor receptors. Cytotoxins that induce PCD can cause necrosis at low concentrations, or aponecrosis (combination of apoptosis and necrosis) at higher concentrations. It is still unclear exactly what combination of apoptosis, non-apoptosis, and necrosis causes different kinds of aponecrosis.[3] ### Transglutaminase[edit] Transglutaminases are human enzymes ubiquitously present in the human body and in the brain in particular.[58] The main function of transglutaminases is bind proteins and peptides intra- and intermolecularly, by a type of covalent bonds termed isopeptide bonds, in a reaction termed transamidation or crosslinking.[58] Transglutaminase binding of these proteins and peptides make them clump together. The resulting structures are turned extremely resistant to chemical and mechanical disruption.[58] Most relevant human neurodegenerative diseases share the property of having abnormal structures made up of proteins and peptides.[58] Each of these neurodegenerative disesases have one (or several) specific main protein or peptide. In Alzheimer's disease, these are amyloid-beta and tau. In Parkinson’s disease, it is alpha-synuclein. In Huntington’s disease, it is huntingtin.[58] Transglutaminase substrates: Amyloid-beta, tau, alpha-synuclein and huntingtin have been proved to be substrates of transglutaminases in vitro or in vivo, that is, they can be bonded by trasglutaminases by covalent bonds to each other and potentially to any other transglutaminase substrate in the brain.[58] Transglutaminase augmented expression: It has been proved that in these neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease) the expression of the transglutaminase enzyme is increased.[58] Presence of isopeptide bonds in these structures: The presence of isopeptide bonds (the result of the transglutaminase reaction) have been detected in the abnormal structures that are characteristic of these neurodegenerative diseases.[58] Co-localization: Co-localization of transglutaminase mediated isopeptide bonds with these abnormal structures has been detected in the autopsy of brains of patients with these diseases.[58] ## Management[edit] The process of neurodegeneration is not well understood, so the diseases that stem from it have, as yet, no cures. ### Animal models in research[edit] In the search for effective treatments (as opposed to palliative care), investigators employ animal models of disease to test potential therapeutic agents. Model organisms provide an inexpensive and relatively quick means to perform two main functions: target identification and target validation. Together, these help show the value of any specific therapeutic strategies and drugs when attempting to ameliorate disease severity. An example is the drug Dimebon by Medivation, Inc. In 2009 this drug was in phase III clinical trials for use in Alzheimer's disease, and also phase II clinical trials for use in Huntington's disease.[46] In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimer's disease drug Dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease.[59] With CONCERT, the remaining Pfizer and Medivation Phase III trial for Dimebon (latrepirdine) in Alzheimer's disease failed in 2012, effectively ending the development in this indication.[60] In another experiment using a rat model of Alzheimer's disease, it was demonstrated that systemic administration of hypothalamic proline-rich peptide (PRP)-1 offers neuroprotective effects and can prevent neurodegeneration in hippocampus amyloid-beta 25–35. This suggests that there could be therapeutic value to PRP-1.[61] ### Other avenues of investigation[edit] Protein degradation offers therapeutic options both in preventing the synthesis and degradation of irregular proteins. There is also interest in upregulating autophagy to help clear protein aggregates implicated in neurodegeneration. Both of these options involve very complex pathways that we are only beginning to understand.[2] The goal of immunotherapy is to enhance aspects of the immune system. Both active and passive vaccinations have been proposed for Alzheimer's disease and other conditions; however, more research must be done to prove safety and efficacy in humans.[62] A current therapeutic target for the treatment of Alzheimer's disease is the protease β-secretase[63][non-primary source needed], which is involved in the amyloidogenic processing pathway that leads to the pathological accumulation of proteins in the brain. When the gene that encodes for amyloid precursor protein (APP) is spliced by α-secretase[64][non-primary source needed] rather than β-secretase, the toxic protein β amyloid is not produced. Targeted inhibition[65] of β-secretase can potentially prevent the neuronal death that is responsible for the symptoms of Alzheimer's disease. ## See also[edit] * Amyloids * Dementia * JUNQ and IPOD * Nervous system * Prevention of dementia * Proteopathy * Trinucleotide repeat disorders ## References[edit] 1. ^ "What is Neurodegenerative Disease?". JPND Research. JPND Research. Retrieved February 7, 2015. 2. ^ a b c d e f g h i Rubinsztein DC (October 2006). "The roles of intracellular protein-degradation pathways in neurodegeneration". Nature. 443 (7113): 780–6. Bibcode:2006Natur.443..780R. doi:10.1038/nature05291. PMID 17051204. S2CID 4411895. 3. ^ a b c d e f g Bredesen DE, Rao RV, Mehlen P (October 2006). "Cell death in the nervous system". Nature. 443 (7113): 796–802. 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Classification D * ICD-10: G30-G32 * MeSH: D019636 * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Neuroscience * Outline of neuroscience * History of neuroscience Basic science * Behavioral epigenetics * Behavioral genetics * Cellular neuroscience * Computational neuroscience * Connectomics * Imaging genetics * Integrative neuroscience * Molecular neuroscience * Neural engineering * Neuroanatomy * Neurochemistry * Neuroendocrinology * Neurogenetics * Neuroinformatics * Neurometrics * Neuromorphology * Neurophysics * 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[M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Neurodegeneration	c0524851	6,035	wikipedia	https://en.wikipedia.org/wiki/Neurodegeneration	2021-01-18T18:54:54	{"mesh": ["D019636"], "umls": ["C0524851"], "orphanet": ["182070"], "wikidata": ["Q1755122"]}
Ichthyosis follicularis - alopecia - photophobia (IFAP) is a rare genetic disorder characterized by the triad of ichthyosis follicularis, alopecia, and photophobia from birth. ## Epidemiology Prevalence is unknown. Approximately 40 cases have been reported to date. IFAP primarily affects male subjects. Female carriers may develop some clinical features. ## Clinical description All patients present with congenital follicular ichthyosis, alopecia involving the scalp, eyebrows and eyelashes, and photophobia (in the first year of life, infancy or early childhood). Ichthyosis follicularis is characterized by widespread non-inflammatory thorn-like follicular projections. Hyperkeratotic papules are most pronounced over the extensor extremities and scalp and are distributed symmetrically. Non-cicatricial complete body alopecia is also a classical feature. Variable degrees of a collodion membrane may be present in newborns. Psoriasiform plaques, angular cheilitis, periungueal inflammation, dystrophic nails, hypohidrosis and atopic eczema can be present. The palms and soles are generally unaffected. Superficial corneal ulceration and vascularization may lead to progressive corneal scarring. Male patients have relentless progression of corneal vascularization and loss of vision. Atopic keratoconjunctival inflammation, chronic tearing, cataract, horizontal nystagmus, astigmatism and myopia have been reported. In a few cases, mild to severe intellectual disability, short stature, microcephaly, seizures, dysmorphic features (frontal bossing, choanal atresia, large ears), cleft hands, intestinal anomalies (omphalocele, Hirschsprung disease or congenital aganglionic megacolon (see these terms), small intestine stenosis, inguinal hernia), as well as renal, cardiac and vertebral anomalies can be present. Recurrent infections are common. External genitalia are generally normal with a few cases of cryptorchidism and one with hypospadias. Affected or carrier females may have milder symptoms (cutaneous hyperkeratotic lesions that follow the lines of Blaschko, asymmetric distribution of body hair, patchy alopecia). ## Etiology The disorder is caused by mutations in the MBTPS2 gene (Xp22.12-p22.11) leading to impaired cholesterol homeostasis and response to endoplasmic reticulum stress. ## Diagnostic methods Diagnosis is based on the clinical features and on testing of the MBTPS2 gene. ## Differential diagnosis Differential diagnosis includes dermotrichic syndrome, hereditary mucoepithelial dysplasia, keratitis-ichthyosis-deafness (KID syndrome) and keratosis follicularis spinulosa decalvans (see these terms). ## Antenatal diagnosis IFAP cannot be detected prenatally by ultrasound. ## Genetic counseling If the mutation has been identified in a carrier mother, prenatal diagnosis can be proposed. Transmission is X-linked recessive. The mutation might also arise de novo. A few cases of autosomal dominant inheritance have been reported. ## Management and treatment Follicular hyperkeratosis can be treated using topical keratolytics, emollients and urea preparations. A moderate response to acitretin therapy has been found in some patients. Intensive lubrication of the ocular surface is essential. Corneal vascularization does not respond to topical corticosteroids. ## Prognosis Prognosis is variable. Some patients die in the neonatal period while others have normal life expectancy. However, in most patients, progressive loss of vision leads to loss of autonomy. Cardiopulmonary complications are the main cause of death. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Ichthyosis follicularis-alopecia-photophobia syndrome	c1839988	6,036	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2273	2021-01-23T18:25:39	{"gard": ["2952"], "mesh": ["C536085"], "omim": ["308205"], "umls": ["C1839988"], "synonyms": ["IFAP syndrome", "Ichthyosis follicularis-atrichia-photophobia syndrome"]}
A number sign (#) is used with this entry because complete erythrocyte AMP deaminase deficiency is caused by homozygous mutation in the AMPD3 gene (102772) on chromosome 11p15. Description Complete deficiency of erythrocyte AMP deaminase is a clinically benign disorder (Ogasawara et al., 1987; Zydowo et al., 1989). Clinical Features Ogasawara et al. (1987) observed 6 related individuals with complete deficiency of erythrocyte AMP deaminase (isozyme E). All were healthy and had no hematologic disorders. The ATP level was approximately 150% higher in AMP-deficient red cells compared to the level in the control cells. Degradation of adenine nucleotide was slower in the deficient erythrocytes than in the control erythrocytes. Inheritance The erythrocyte AMP deaminase deficiency described by Ogasawara et al. (1987) appeared to be an autosomal recessive trait because both parents had partial deficiency in each case in which this could be studied and all children of completely deficient individuals were partially deficient. Population Genetics Ogasawara et al. (1987) found that the heterozygote frequency of AMPD3 deficiency in Japan, Korea, and Taiwan ranged from 2.7 to 3.6 per 100. In Poland, Zydowo et al. (1989) found a heterozygote frequency of 6.5 per 100. Molecular Genetics In 4 Japanese individuals with erythrocyte AMP deficiency Yamada et al. (1994) identified an R573C mutation in the AMPD3 gene (102772.0001); 2 with complete deficiency, originally reported by Ogasawara et al. (1987), were homozygous for the mutation and 2 with partial deficiency were heterozygous. INHERITANCE \- Autosomal recessive HEMATOLOGY \- Erythrocyte AMP deaminase deficiency MISCELLANEOUS \- Clinically asymptomatic \- Heterozygote frequency estimated at about 1/30 in Japan, Korea, and Taiwan MOLECULAR BASIS \- Caused by mutation in the adenosine monophosphate deaminase-3, isoform E gene (AMPD3, 102772.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	ERYTHROCYTE AMP DEAMINASE DEFICIENCY	c0268123	6,037	omim	https://www.omim.org/entry/612874	2019-09-22T16:00:26	{"omim": ["612874"], "orphanet": ["45"]}
## Clinical Features Macrocytosis (large erythrocytes) is commonly associated with anemia and megaloblastosis in vitamin B12 or folate deficiency, cytotoxic drug treatment, and genetic disorders such as orotic aciduria (258900), Imerslund-Grasbeck syndrome (261100), and Lesch-Nyhan syndrome (308000). Nonmegaloblastic macrocytosis can be found in liver disease, alcohol abuse, hypothyroidism, and several hematologic disorders. Fauchald (1970) studied 3 brothers with persistent increase in mean cell volume (MCV) and no demonstrable cause for macrocytosis, indicating the existence of a benign form of familial macrocytosis. Three children of the brothers were investigated without similar findings. Sechi et al. (1994) found more marked macrocytosis with MCV ranging from 110 to 125 fL in a 52-year-old woman. The macrocytosis had been demonstrated since age 40. Her 27-year-old daughter had persistent macrocytosis first demonstrated at the age of 25 although of a lesser degree (from 100 to 110 fL), with normal hemoglobin, mean corpuscular hemoglobin concentration (MCHC), peripheral blood morphology, and blood biochemistries, including liver tests, thyroid hormones, serum vitamin B12, and folate levels. Inheritance \- Autosomal dominant Lab \- MCV ranging from 110 to 125 fl Heme \- Benign macrocytosis ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MACROCYTOSIS, FAMILIAL	c1838656	6,038	omim	https://www.omim.org/entry/600084	2019-09-22T16:16:40	{"mesh": ["C564004"], "omim": ["600084"]}
## Summary ### Clinical characteristics. SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS), reported to date in nine children, is characterized by onset of seizures before age six months and either developmental delay or developmental regression with seizure onset. Of these nine children, six had severe developmental delay with no progress of abilities and three made notable neurodevelopmental progress. Eight had postnatal microcephaly and hypotonia. In most children epilepsy begins as focal motor seizures (typically involving head and eye deviation) that become multifocal and intractable to conventional antiepileptic drugs (AEDs). ### Diagnosis/testing. The diagnosis of SLC12A5-EIMFS is established by identification of biallelic SLC12A5 pathogenic variants on molecular genetic testing. ### Management. Treatment of manifestations: There are no specific treatments for seizures in SLC12A5-EIMFS. In general, seizures in EIMFS are resistant to most AEDs. A ketogenic diet and potassium bromide showed attenuation of seizures in three patients each. A multidisciplinary approach to management of hypotonia, feeding difficulties, respiratory problems, and developmental delay is recommended. Surveillance: Routine monitoring of: feeding, nutritional status, swallowing, gastroesophageal reflux, aspiration, and respiratory problems; back for scoliosis and hips for dislocation with spine and hip x-rays; effectiveness of seizure control; development including motor skills, speech/language, and general cognitive and vocational skills. ### Genetic counseling. SLC12A5-EIMFS is inherited in an autosomal recessive manner. The parents of a child with SLC12A5-EIMFS are typically heterozygotes (i.e., carriers of one SLC12A5 pathogenic variant). Heterozygous parents of a child with SLC12A5-EIMFS are not at risk of developing EIMFS. When both parents are heterozygotes (carriers) each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC12A5 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. ## Diagnosis Since 2010 a description of the characteristic symptoms and findings of epilepsy of infancy with migrating focal seizures (EIMFS) has been included in the classification of epilepsy syndromes by the International League Against Epilepsy. The diagnosis of SLC12A5-EIMFS is established by molecular genetic testing. ### Suggestive Findings SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS) should be considered in children with the following epilepsy and electroencephalogram (EEG) findings and family history. Epilepsy features * Seizure onset before age six months * Developmental delay or developmental regression with seizure onset Seizure type * At onset in most children: focal motor seizures that also frequently involve head and eye deviation * Multifocal seizures proving intractable to conventional antiepileptic drugs Epilepsy syndromes. Epilepsy of infancy with migrating focal seizures EEG findings * Interictal multifocal spikes * In a single seizure, ictal-independent, unilateral, and migrating involvement of varying cortical areas with clinical-EEG correlation * Initial EEG may be normal shortly after seizure onset, but epileptiform abnormalities are usually present within one month after first presentation. * Migrating ictal foci may not be seen for several months after presentation. Family history. Consistent with autosomal recessive inheritance, including parental consanguinity or more than one affected child ### Establishing the Diagnosis The diagnosis of SLC12A5-EIMFS is established in a proband with biallelic SLC12A5 pathogenic variants identified by molecular genetic testing (see Table 1). Due to the genetic heterogeneity of early-onset epilepsy, use of either a multigene epilepsy panel or comprehensive genomic testing (exome or genome sequencing) is the preferred initial approach [McTague et al 2016]. Note: Single-gene testing (sequence analysis of SLC12A5, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. #### Testing Options to Consider An epilepsy multigene panel that includes SLC12A5 and other genes of interest (see Differential Diagnosis) typically provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of 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. Of note, given the rarity of SLC12A5-related epilepsy, some epilepsy panels may not include this gene. (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. Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good 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 SLC12A5-EIMFS View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method SLC12A5Sequence analysis 39/9 (100%) 4 Gene-targeted deletion/duplication analysis 5Unknown (no data available) 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. 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\. Stödberg et al [2015], Saitsu et al [2016], Saito et al [2017] 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 SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS) is characterized by severe early-onset epileptic encephalopathy, with a distinct electroclinical phenotype that is common to all EIMFS regardless of cause. To date nine children have been reported with SLC12A5-EIMFS [Stödberg et al 2015, Saitsu et al 2016, Saito et al 2017]. Seizures. In the nine children reported, three clinical stages were evident: * An early stage with emerging focal seizures. Median age of seizure onset was 1.5 months; mean age 1.8 months (range: 1 day - 4 months). * Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation. * Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures. * Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children. * Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common. * A second stage with up to 200 seizures per day at the peak of the seizures, usually at a median age of 16 weeks (range: 1-40 weeks). Either focal status epilepticus or frequent clusters of focal seizures are seen. * A late stage (age >1-2 years) with a reduction of seizure frequency. Of the four children who had seizure-free periods, two relapsed to frequent recurrent seizures. Developmental delay was seen in all nine children. Five children experienced developmental regression (i.e., loss of previously acquired skills) at seizure onset. Severe developmental delay with no progression of skills was seen in six of the nine. In contrast, three of the nine had notable neurodevelopmental progress, either regaining lost skills or acquiring new skills during periods of good seizure control. Two achieved independent ambulation (at ages 2.9 and 4 years) and one spoke single words at age six years. Other * Postnatal (i.e., acquired) microcephaly and hypotonia was noted in eight of the nine children. * Of the four for whom feeding information was available, two had feeding difficulties; none had growth failure. * One had unilateral pyramidal signs. * Hyperkinetic movement disorders, seen in other causes of EIMFS including KCNT1 and SCN2A, have not been reported in SLC12A5-EIMFS [Howell et al 2015, McTague et al 2018]. Outcome. One child with frequent seizures died at age 2.5 years from respiratory infection and cardiac arrest [Stödberg et al 2015]; the others with SLC12A5-EIMFS (ages 3-22 years) are living as of this writing. Electroencephalogram (EEG). Eight children had ictal EEGs consistent with a diagnosis of EIMFS. Early EEGs were not available for one child; thus, a formal diagnosis could not be made despite a clinical history consistent with EIMFS. Interictal EEG features included background slowing and multifocal abnormalities. MRI findings. The following nonspecific MRI features of EIMFS have been observed in SLC12A5-EIMFS: * Delayed myelination * Thin corpus callosum * Cerebral atrophy, either predominantly frontal or global * Increased signal in white matter on diffusion-weighted imaging The following focal abnormalities have been reported in SLC12A5-EIMFS: * Unilateral hippocampal sclerosis noted at age four years (n=1) [Saito et al 2017] * Cerebellar atrophy and bilateral hippocampal atrophy with increased signal on FLAIR imaging at ages ten and 20 years in the oldest individual imaged to date [Saitsu et al 2016]. It is unclear if these findings represent the typical progression of imaging findings in SLC12A5-EIMFS as all other individuals imaged were age four years or younger. Magnetic resonance spectroscopy (MRS) in a child age eight months demonstrated reduction in the relative N-acetyl aspartate peak, consistent with delayed maturation of myelin [Stödberg et al 2015]. ### Genotype-Phenotype Correlations No clear correlation exists between biallelic SLC12A5 variants and phenotype, which may reflect the limited number of affected individuals reported to date. ### Nomenclature EIMFS is a type of early-infantile epileptic encephalopathy (EIEE); OMIM classifies SLC12A5-related epilepsy as EIEE34. Terms previously used for EIMFS include the following: * Migrating partial seizures of infancy (MPSI) * Malignant migrating partial seizures of infancy (MMPSI) * Migrating focal seizures of infancy (MFSI) SLC12A5-related epilepsy includes EIMFS and EIMFS-like severe early-onset epileptic encephalopathy (EIEE with some features of EIMFS but not fulfilling all criteria; e.g., when EEG is not available). ### Prevalence To date, nine probands with SLC12A5-related epilepsy have been reported. The clinical syndrome epilepsy of infancy with migrating focal seizures (EIMFS) of all causes is itself rare. Prevalence of EIMFS was estimated at 0.11 per 100,000 children in the UK (using data that were not from a population-based epidemiologic study) [McTague et al 2013]. ## Differential Diagnosis Since first described by Coppola et al [1995], epilepsy of infancy with migrating focal seizures (EIMFS) has been reported in over 170 individuals. EIMFS is genetically heterogeneous (Table 2). EIMFS can be isolated or have multisystem involvement; both autosomal dominant and recessive inheritance are observed. ### Table 2. Other Disorders to Consider in the Differential Diagnosis of SLC12A5-EIMFS View in own window DisorderGene 1MOIComments Isolated EIMFS EIEE43 (OMIM 617113)GABRB3 2AD1 set of monozygotic twins EIEE14 (OMIM 614959)KCNT1AD 3Causes 30%-50% of EIMFS 4, 5, 6 EIEE12 (OMIM 613722)PLCB1 7AR 81 individual 7 Progressive microcephaly w/seizures & cerebral & cerebellar atrophy (OMIM 615760)QARSAR 82 individuals 9 SMC1A-related EIMFSSMC1A 10XL1 female infant EIEE6SCN1A 11, 12, 13, 14AD 33 individuals 11, 12, 13, 14 EIEE11 (OMIM 613721)SCN2A 15, 16AD 3Severe movement disorder 4; otherwise indistinguishable from other causes of EIMFS EIEE13SCN8A 17AD 31 individual 17 EIEE3 (OMIM 609304)SLC25A22 18AR 82 individuals 18 EIEE16TBC1D24 19, 20AR 83 families 19, 20 EIMFS with multisystem abnormalities ALG3-CDG (CDG-Id) 21ALG 22AR * Abnormalities: gastrointestinal problems, coagulopathy, dysmorphic facial features, spastic quadriparesis * Transferrin isoelectric focusing testing consistent w/CDG type I * On brain MRI: cerebellar atrophy in all; brain stem atrophy in 3/4 * Note: Extensive metabolic investigation in EIMFS is usually unrevealing. ALG1-CDG (CDG-Ik) 21ALG1 22 RFT1-CDG (CDG-In) 21RFT1 22 Adapted from "Supplementary Table 1: Genes Reported in Migrating Partial Seizures of Infancy (MPSI)" [Stödberg et al 2015] AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; EIEE = early-infantile epileptic encephalopathy; EIMFS = epilepsy of infancy with migrating focal seizures; MOI = mode of inheritance; XL = X-linked 1\. Genes are in alphabetic order. 2\. Štěrbová et al [2018] 3\. Typically de novo 4\. Barcia et al [2012] 5\. Møller et al [ 2015] 6\. Lim et al [2016] 7\. Poduri et al [2012], Poduri et al [2013] 8\. Autosomal recessive inheritance of EIMFS is often described in consanguineous families or families with more than one affected individual. 9\. Zhang et al [2014] 10\. Gorman et al [2017] 11\. Carranza Rojo et al [2011] 12\. Howell et al [2015] 13\. Larsen et al [2015] 14\. Freilich et al [2011] 15\. Howell et al [2015] 16\. Wolff et al [2017] 17\. Ohba et al [2014] 18\. Poduri et al [2013] 19\. Milh et al [2013] 20\. See TBC1D24-Related Disorders. 21\. See Congential Disorders of N-Linked Glycosylation and Multiple Pathway Overview. 22\. Barba et al [2016] Other early-infantile epileptic encephalopathies. A large number of genes have been implicated in the broader phenotype of early-onset epilepsy with developmental delay. See Early Infantile Epileptic Encephalopathy, OMIM Phenotypic Series to view genes associated with this phenotype in OMIM. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended. ### Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with SLC12A5-EIMFS View in own window System/ConcernEvaluationComment ConstitutionalAssess for evidence of failure to thrive. EyesOphthalmologic eval incl assessment of vision ENT/MouthAssess hearing. Gastrointestinal/ FeedingAssess swallowing, gastroesophageal reflux, feeding, & nutritional status.Incl assessment by speech & language therapist. RespiratoryAssess respiratory status for evidence of ↑ risk of respiratory infections & aspiration.Preventive measures may be needed (e.g., flu vaccination & prophylactic antibiotics in winter). NeurologicNeurologic evalIncl EEG & brain MRI. MusculoskeletalAssessment of tone by pediatric rehab specialist &/or PT DevelopmentDevelopmental assessmentIncl eval of motor skills, speech/ language, general cognitive, & vocational skills. Miscellaneous/ OtherConsultation w/clinical geneticist &/or genetic counselor PT = physical therapist ### Treatment of Manifestations Seizures. There are no specific treatments for seizures in SLC12A5-EIMFS. Seizures in EIMFS are generally resistant to most antiepileptic drugs. Periods free of seizures or with reduced seizure frequency have been achieved with a ketogenic diet or potassium bromides [Fasulo et al 2012, Ünver et al 2013, Caraballo et al 2014, Caraballo et al 2015] including in children with SLC12A5-EIMFS [Stödberg et al 2015, Saitsu et al 2016, Saito et al 2017]. Seizure reduction has also been reported with: * Levetiracetam, rufinamide, stiripentol, and clonazepam [Coppola et al 1995, Cilio et al 2009, Djuric et al 2011, Vendrame et al 2011, Merdariu et al 2013]; * Cannabinoids [Saade & Joshi 2015]. Epileptic apneas are reported to respond to acetazolamide [Irahara et al 2011]. Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. Hypotonia. Manage postural problems with appropriate seating support. Feeding. Consider gastrostomy insertion and feeding if swallowing is impaired. Respiratory. Children may be susceptible to respiratory infections and aspiration pneumonia if swallowing is impaired. Consider influenza vaccine, prophylactic antibiotics, and chest physiotherapy as appropriate. #### 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. In the US, early intervention is a federally funded program available in all states. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed. Ages 5-21 years * In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. * Discussion of transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a 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. * Consider use of durable medical equipment 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. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist is recommended for affected individuals who have difficulty feeding due to poor oral motor control. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. #### Social/BehavioralConcerns 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 is 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 or destructive behavior can be addressed by a pediatric psychiatrist. ### Surveillance Routine monitoring of: * Feeding, nutritional status, swallowing abilities, gastroesophageal reflux, risk of aspiration pneumonia / respiratory infection * Postural problems (resulting from such complications as scoliosis and hip abnormalities) with regular spine and hip x-rays * Effectiveness of seizure control * Development including motor skills, speech/language, and general cognitive and vocational skills ### 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 [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures	None	6,039	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK537476/	2021-01-18T20:58:45	{"synonyms": ["Early-Infantile Epileptic Encephalopathy 34 (EIEE34)", "SLC12A5-EIMFS"]}
A number sign (#) is used with this entry because familial hypertrophic cardiomyopathy-6 (CMH6) is caused by heterozygous mutation in the gene encoding the gamma-2 regulatory subunit of AMP-activated protein kinase (PRKAG2; 602743) on chromosome 7q36. Mutation in the PRKAG2 gene also causes the Wolff-Parkinson-White preexcitation syndrome (194200) in isolation or in association with cardiac hypertrophy. For a phenotypic general description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600). Description Mutations in the PRKAG2 gene (602743) give rise to a moderate, essentially heart-specific, nonlysosomal glycogenosis with clinical onset typically in late adolescence or in the third decade of life, ventricular pre-excitation predisposing to supraventricular arrhythmias, mild-to-severe cardiac hypertrophy, enhanced risk of sudden cardiac death in midlife, and autosomal dominant inheritance with full penetrance (summary by Burwinkel et al., 2005). Clinical Features Laforet et al. (2006) studied a 38-year-old man who presented after 4 episodes of 'faintness' after swimming and had a 15-year history of lasting muscle stiffness without weakness in the arms and legs after prolonged exercise. He had 2 sibs who were asymptomatic, but a paternal aunt died suddenly at 65 years of age. Electrocardiogram showed sinus bradycardia with high-degree atrioventricular block and left bundle branch block, and a pacemaker was implanted. Echocardiography revealed hypertrophic cardiomyopathy. Limb muscle bulk and strength were normal on clinical examination, but deltoid muscle biopsy revealed sarcolemmal vacuoles in 10% of muscle fibers with intense periodic acid-Schiff staining, and ultrastructural analysis confirmed the presence of nonlysosomal glycogen accumulation. Mapping In a large family with 25 surviving individuals affected by familial hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome (WPW; 194200), or both, MacRae et al. (1995) found close linkage to DNA markers on chromosome 7q3. Four other loci responsible for familial hypertrophic cardiomyopathy had previously been identified (on chromosomes 1, 11, 14, and 15), but no report of individuals with familial hypertrophic cardiomyopathy due to mutation at the previously mapped disease loci were reported to have WPW, although 5 to 10% of hypertrophic cardiomyopathy patients have ventricular preexcitation. An association between WPW and familial hypertrophic cardiomyopathy had been noted in earliest descriptions of the latter condition. Braunwald et al. (1960) proposed that abnormal ventricular activation might result in regional myocardial hypertrophy or that localized hypertrophy might disrupt normal cardiac electrical discontinuity at the atrial ventricular ring. MacRae et al. (1995) performed linkage studies in 2 additional families with typical FHC (without WPW) which did not map to any of the 4 known FHC loci and found that they also did not map to 7q3. Molecular Genetics Sinha et al. (2000) reported a family in which 12 persons had ventricular preexcitation, 6 of whom also had cardiac hypertrophy. Three patients underwent successful ablation of typical accessory atrioventricular bundles, with subsequent loss of preexcitation. Gollob et al. (2001) demonstrated the presence of an R302Q mutation in the PRKAG2 gene (602743.0001) in this kindred. Blair et al. (2001) identified heterozygous mutations in the PRKAG2 gene in 2 families with severe hypertrophic cardiomyopathy associated with conduction and electrocardiographic abnormalities, including WPW ventricular preexcitation syndrome in 3 individuals. Both mutations, 1 missense (H142R; 602743.0002) and 1 in-frame single codon insertion (602743.0003), occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, Blair et al. (2001) proposed that energy compromise may provide a unifying pathogenic mechanism in all forms of CMH. Reports that dominant mutations in PRKAG2, an enzyme that modulates glucose uptake and glycolysis, can cause hypertrophic cardiomyopathy challenged the hypothesis that hypertrophic cardiomyopathy is a disease of the sarcomere. In addition to cardiac hypertrophy, individuals with PRKAG2 mutations frequently manifest electrophysiologic abnormalities, particularly Wolff-Parkinson-White syndrome (Gollob et al., 2001), atrial fibrillation, and progressive development of atrioventricular conduction block. Although atrial fibrillation is common in CMH patients and becomes increasingly prevalent with disease duration, neither accessory pathway nor conduction system diseases are typical features of CMH. To understand the mechanisms by which PRKAG2 defects cause disease, Arad et al. (2002) defined additional, novel mutations, including T400N (602743.0004) in an isolated patient and N488I (602743.0005) in the large family with CMH mapping to 7q3 originally reported by MacRae et al. (1995). A previously unrecognized and unusual histopathology was identified in hearts with PRKAG2 defects, which prompted biochemical analyses of the functional consequences of human PRKAG2 mutations on Snf4, the yeast homolog of the gamma-2 protein kinase subunit. Arad et al. (2002) concluded their data indicated that PRKAG2 defects do not cause CMH, but rather a novel glycogen storage disease of the heart in which hypertrophy, ventricular preexcitation, and conduction system defects coexist. They found that although the cardiac pathology caused by the PRKAG2 mutations R302Q, T400N, and N488I included myocyte enlargement and minimal interstitial fibrosis, these mutations were not associated with myocyte and myofibrillar disarray, the pathognomonic features of hypertrophic cardiomyopathy caused by sarcomere protein mutations. Instead, PRKAG2 mutations caused pronounced vacuole formation within myocytes. Several lines of evidence indicated that these vacuoles are filled with glycogen-associated granules. Analyses of the effects of human PRKAG2 mutations on Snf1/Snf4 kinase function demonstrated constitutive activity, which could foster glycogen accumulation. In 3 sporadic, unrelated patients with lethal congenital glycogen storage disease of the heart (261740), who died of hemodynamic and respiratory failure secondary to hypertrophic nonobstructive cardiomyopathy but also had Wolff-Parkinson-White-like conduction anomalies, Burwinkel et al. (2005) identified heterozygosity for an R531Q mutation in the PRKAG2 gene (602743.0007). They noted that the molecular abnormalities of the R531Q mutant protein are more pronounced than those of other PRKAG2 mutants, which likely accounts for the more severe phenotype. Arad et al. (2005) analyzed the PRKAG2 gene in 35 patients with hypertrophic cardiomyopathy who were negative for mutations in known sarcomere-protein genes, and identified a heterozygous missense mutation (Y487H; 602743.0008) in 1 proband with moderate hypertrophy and an extremely short PR interval. In a child with idiopathic cardiac hypertrophy and presumed sporadic cardiomyopathy, who was negative for mutations in 9 of the known CMH genes, Morita et al. (2008) identified heterozygosity for a missense mutation in the PRKAG2 gene (H530R; 602743.0009). (The parents were not studied.) The mutation was not found in unrelated individuals matched by ancestral origin or in more than 1,000 control chromosomes. In a father, son, and daughter with hypertrophic cardiomyopathy, Kelly et al. (2009) identified heterozygosity for a missense mutation in the PRKAG2 gene (E506Q; 602743.0010). Kelly et al. (2009) stated that 8 affected members of a family reported by Bayrak et al. (2006) with a PRKAG2 mutation at the same codon (E506K) had ventricular preexcitation and mild left ventricular hypertrophy; endomyocardial biopsy of the adult proband showed profound intracellular vacuolization and marked interstitial fibrosis. In the family studied by Kelly et al. (2009), the father had undergone cardiac transplantation for cardiomyopathy at age 29 years. In the 6-year-old daughter, 'prominent forces' were noted on electrocardiography and subsequent 2-D echocardiography revealed left ventricular mass at the 90th percentile for body surface area. The son presented at 6 months of age with a heart murmur and was found to have significant left ventricular hypertrophy on electrocardiogram; 2-D echocardiography showed markedly asymmetric septal hypertrophy and subaortic outflow tract obstruction. Repeat echocardiogram 5 months later showed severely obstructive CMH with hyperdynamic left ventricular systolic function and near-obliteration of the left ventricular cavity, and electrocardiography showed biventricular hypertrophy with a short PR interval (80 ms) and ventricular preexcitation. Examination of endocardial biopsy tissue from the boy showed a normal amount of glycogen present in the myocytes by staining and electron microscopy; a mild increase interstitial connective tissue was thought to represent nonspecific hypertrophic changes in the myocardium. Noting that in the patients reported by Burwinkel et al. (2005), the approximately 4- to 6-fold increase in cardiac mass was associated with only a 3-fold increase in glycogen content and an absence of more organized cellular aggregations of glycogen, Kelly et al. (2009) concluded that CMH due to PRKAG2 mutations may have a degree of cardiac hypertrophy exceeding that expected from observed amounts of glycogen deposition. In a 38-year-old man with hypertrophic cardiomyopathy, severe conduction system abnormalities, and mild skeletal muscle glycogenosis, who was negative for mutation in the LMNA gene (150330), Laforet et al. (2006) identified heterozygosity for mutation in the PRKAG2 gene (602743.0011). Animal Model Arad et al. (2003) constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation (602743.0005). The transgenic mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen, developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiologic testing demonstrated alternative atrioventricular conduction pathways consistent with Wolff-Parkinson-White syndrome. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. Arad et al. (2003) concluded that these data establish that PRKAG2 mutations cause a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiologic findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe (232300), Danon (300257), and other glycogen storage diseases. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Hypertrophic cardiomyopathy \- Wolff-Parkinson-White ventricular preexcitation \- Sinus bradycardia \- Atrioventricular block \- Left bundle branch block \- Atrial fibrillation \- Enlarged myocytes without myofiber disarray \- Glycogen-containing cytosolic vacuoles within cardiomyocytes MUSCLE, SOFT TISSUES \- Glycogenosis of skeletal muscle, mild (in some patients) MISCELLANEOUS \- Genetic heterogeneity (see 192600 ) MOLECULAR BASIS \- Caused by mutation in the protein kinase, AMP-activated, noncatalytic, gamma-2 gene (PRKAG2, 602743.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 6	c1833236	6,040	omim	https://www.omim.org/entry/600858	2019-09-22T16:15:46	{"mesh": ["C563436"], "omim": ["600858"], "genereviews": ["NBK1768"]}
Zimmermann–Laband syndrome Other namesLaband–Zimmermann syndrome,[1] and Laband's syndrome[2] Zimmerman–Laband syndrome has an autosomal dominant pattern of inheritance SpecialtyMedical genetics Zimmermann–Laband syndrome (ZLS),[3] is an extremely rare[4] autosomal dominant[5] congenital disorder. ## Contents * 1 Symptoms and signs * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Symptoms and signs[edit] Symptoms include gingival fibromatosis, associated with hypoplasia of the distal phalanges, nail dysplasia, joint hypermobility, and sometimes hepatosplenomegaly.[6] The nose and pinnae are usually large and poorly developed, which gives the individuals with the syndrome abnormal facial characteristics. Mental retardation may also occur.[7][8] Both males and females are equally affected. Gingival fibromatosis is usually present at birth or appears short after.[2][8] The term Zimmermann–Laband was coined by Carl Jacob Witkop in 1971.[8] ## Genetics[edit] Zimmerman–Laband syndrome is inherited in an autosomal dominant pattern. This means the defective gene is located on an autosome, and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder. The condition is caused by mutations in a potassium channel gene – KCNH1.[9] ## Diagnosis[edit] This section is empty. You can help by adding to it. (May 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (May 2017) ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Bolognia, Jean L; et al. (2007). Dermatology. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ a b Laband Syndrome Archived September 27, 2007, at the Wayback Machine 3. ^ Zimmermann–Laband Syndrome – What does ZLS stand for? Acronyms and abbreviations by the Free Online Dictionary 4. ^ Zimmerman Laband syndrome; Fibromatosis gingival, with abnormal fingers, fingernails, nose and ears, and splenomegaly at NIH's Office of Rare Diseases 5. ^ Holzhausen, M; Gonçalves, D; Corrêa, Fde, O; Spolidorio, Lc; Rodrigues, Vc; Orrico, Sr (August 2003). "A case of Zimmermann–Laband syndrome with supernumerary teeth". Journal of Periodontology. 74 (8): 1225–30. doi:10.1902/jop.2003.74.8.1225. ISSN 0022-3492. PMID 14514238.CS1 maint: multiple names: authors list (link) 6. ^ Atabek ME, Pirgon O, Sert A, Toy H (2005). "Zimmermann–Laband syndrome in an infant with an atypical histologic finding". Pediatr. Dev. Pathol. 8 (6): 654–7. doi:10.1007/s10024-005-0048-1. PMID 16267629. S2CID 41832725. 7. ^ Cat.Inist 8. ^ a b c synd/3783 at Who Named It? 9. ^ Mégarbané A, Al-Ali R, Choucair N, Lek M, Wang E, Ladjimi M, Rose CM, Hobeika R, Macary Y, Temanni R, Jithesh PV, Chouchane A, Sastry KS, Thomas R, Tomei S, Liu W, Marincola FM, MacArthur D, Chouchane L1 (2016) Temple-Baraitser Syndrome and Zimmermann–Laband Syndrome: one clinical entity? BMC Med Genet. 17(1):42. doi: 10.1186/s12881-016-0304-4 ## External links[edit] Classification D * OMIM: 135500 * MeSH: C536725 External resources * Orphanet: 3473 * v * t * e Congenital malformations and deformations of skin appendages Nail disease * Anonychia * Leukonychia * Pachyonychia congenita/Onychauxis * Koilonychia Hair disease * hypotrichosis/abnormalities: keratin disease * Monilethrix * IBIDS syndrome * Sabinas brittle hair syndrome * Pili annulati * Pili torti * Uncombable hair syndrome * Björnstad syndrome * Giant axonal neuropathy with curly hair * hypertrichosis: Zimmermann–Laband syndrome * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Zimmermann–Laband syndrome	c0796013	6,041	wikipedia	https://en.wikipedia.org/wiki/Zimmermann%E2%80%93Laband_syndrome	2021-01-18T18:55:49	{"gard": ["385"], "mesh": ["C536725"], "umls": ["C0796013"], "icd-10": ["Q87.8"], "orphanet": ["3473"], "wikidata": ["Q8072143"]}
Limb-girdle muscular dystrophy due to POMK deficiency is a form of limb-girdle muscular dystrophy presenting in infancy with muscle weakness and delayed motor development (eventually learning to walk at 18 months of age) followed by progressive proximal weakness, pseudohypertrophy of calf muscles, mild facial weakness, and borderline intelligence. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Limb-girdle muscular dystrophy due to POMK deficiency	c4015184	6,042	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=445110	2021-01-23T17:53:11	{"omim": ["616094"], "icd-10": ["G71.0"], "synonyms": ["LGMD due to POMK deficiency"]}
Blum et al. (1993) described a newborn with congenital absence of the insulin-producing beta cells from otherwise normal-appearing pancreatic islets, causing insulin-dependent diabetes mellitus. The infant also had methylmalonic acidemia (251000) and died 16 days after birth. By serotyping of the HLA antigens, DNA typing of HLA-B and HLA class II loci, and study of polymorphic DNA markers of chromosome 6, Abramowicz et al. (1994) demonstrated that the infant had paternal uniparental isodisomy involving at least a 25-cM portion of chromosome 6 that encompasses the MHC. The methylmalonic acidemia was easily explained by duplication of the mutant gene on chromosome 6 inherited from the carrier father. The agenesis of beta cells and consequent insulin-dependent diabetes mellitus suggested the existence of a gene on chromosome 6 involved in beta-cell differentiation. Permanent insulin-dependent diabetes mellitus is very rare in the neonatal period. Abramowicz et al. (1994) stated that 31 well-documented cases had been published (see Dorchy et al., 1974). In most, the pathogenesis is unknown. A very early presentation of autoimmune destruction, which is the most common cause of insulin-dependent diabetes mellitus, had never been irrefutably demonstrated. Rare causes such as aplasia of the pancreas (260370, 600001) and absence of the islets of Langerhans (304790) had been reported. Abramowicz et al. (1994) stated that isolated absence of the beta cells had been shown in one case. Presumably, the disorder is an autosomal recessive. Endocrine \- Neonatal insulin-dependent diabetes mellitus GI \- Congenital absence of pancreatic islet insulin-producing beta cells Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	PANCREATIC BETA CELL AGENESIS WITH NEONATAL DIABETES MELLITUS	c1838655	6,043	omim	https://www.omim.org/entry/600089	2019-09-22T16:16:39	{"mesh": ["C538111"], "omim": ["600089"]}
Excoriation disorder Other namesdermatillomania,[1] skinning disorder, neurotic excoriation, acne excoriee, pathologic skin picking (PSP), compulsive skin picking (CSP), psychogenic excoriation[2][3] Image of person with excoriation disorder with sores as a result of skin picking on arms, shoulders and chest Specialty * Dermatology * Psychiatry Excoriation disorder is an obsessive-compulsive spectrum mental disorder that is characterized by the repeated urge or impulse to pick at one's own skin to the extent that either psychological or physical damage is caused.[4][5] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Neurological * 2.2 Genetic components * 3 Diagnosis * 3.1 Classification * 3.1.1 Similarities with other conditions * 4 Treatment * 4.1 Medication * 4.2 Counseling * 4.3 Developmentally disabled * 4.4 Biofeedback * 5 Prognosis * 6 Epidemiology * 7 History * 8 Society and culture * 9 See also * 10 References * 11 Further reading * 12 External links ## Signs and symptoms[edit] Compulsive picking of the knuckles (via mouth) illustrating potentially temporary disfiguration of the distal and proximal joints of the middle and little fingers. The fingers have been compulsively picked and chewed in someone with excoriation disorder and dermatophagia. Compulsive picking of face using nail pliers and tweezers. Episodes of skin picking are often preceded or accompanied by tension, anxiety, or stress.[6] In some cases, following picking, the affected person may feel depressed.[5] During these moments, there is commonly a compulsive urge to pick, squeeze, or scratch at a surface or region of the body, often at the location of a perceived skin defect. When picking one may feel a sense of relief or satisfaction. The region most commonly picked is the face,[3][6][5] but other frequent locations include the arms, legs, back, gums, neck, shoulders, scalp, abdomen, chest, and extremities such as the fingernails, cuticles, and toenails.[3] Most patients with excoriation disorder report having a primary area of the body that they focus their picking on, but they will often move to other areas of the body to allow their primary picking area to heal.[3] Individuals with excoriation disorder vary in their picking behaviour; some do it briefly multiple times a day while others can do one picking session that can last for hours.[7] The most common way to pick is to use the fingers although a significant minority of people use tools such as tweezers or needles.[8] Skin picking often occurs as a result of some other triggering cause.[5] Some common triggers are feeling or examining irregularities on the skin and feeling anxious or other negative feelings.[8] Complications arising from excoriation disorder include: infection at the site of picking, tissue damage, and sepsis. Damage from picking can be so severe as to require skin grafting. Severe picking can cause epidermal abscesses. Severe cases of excoriation disorder can cause life-threatening injuries. For example, in one reported case a female picked a hole through the bridge of her nose, which required surgery to fix, and a 48-year-old female picked through the skin on her neck exposing the carotid artery. Pain in the neck or back can arise due to prolonged bent-over positions while engaging in the behavior. Besides physical injuries, excoriation disorder can cause severe physical scarring and disfigurement.[3] Excoriation disorder can cause feelings of intense helplessness, guilt, shame, and embarrassment in individuals, and this greatly increases the risk of self-harm.[3] Studies have shown that excoriation disorder presented suicidal ideation in 12% of individuals with this condition, suicide attempts in 11.5% of individuals with this condition, and psychiatric hospitalizations in 15% of individuals with this condition.[3] ## Causes[edit] There have been many different theories regarding the causes of excoriation disorder including biological and environmental factors.[9] A common hypothesis is that excoriation disorder is often a coping mechanism to deal with elevated levels of turmoil, arousal or stress within the individual, and that the individual has an impaired stress response.[3][7] A review of behavioral studies found support in this hypothesis in that skin-picking appears to be maintained by automatic reinforcement within the individual.[7] In contrast to neurological theories, there are some psychologists who believe that picking behavior can be a result of repressed rage felt toward authoritarian parents.[3] A similar theory holds that overbearing parents can cause the behavior to develop in their children.[3] Clinical studies have posited that there is a strong link between traumatic childhood events and excoriation disorder. Those with self-injurious disorders of the skin are found to also frequently report childhood sexual abuse. While attempting to produce diagnostic criteria for excoriation disorder, researchers conversed with 10 patients with the disorder and found that a majority reported personal problems before the picking began, and 4 reported on abuse they suffered in childhood or adolescence.[10] ### Neurological[edit] There is limited knowledge regarding the neurobiology that drives excoriation disorder, and there have been few neuroimaging studies of those with excoriation disorder.[11] Those individuals that have excoriation disorder along with other diagnosed conditions report differing motivations for their picking. Those with both OCD and excoriation disorder report that they will pick their skin due to a perceived contamination of the skin, while those with both body dysmorphic disorder (BDD) and excoriation disorder reportedly pick to fix perceived imperfections in the skin.[3] Studies have shown a linkage between dopamine and the urge to pick. Drugs such as cocaine and methamphetamine, which increase the pharmacological effects of dopamine, have been shown to cause uncontrollable picking in users. These drugs can create the sensation of formication, which feels like something is crawling on or under the skin.[3] Thus, excoriation disorder could result from a dysfunction in the dopamine reward functions.[3] There may be another neurological explanation for excoriation disorder: individuals with the condition have less motor-inhibitory control, but show no sign of difference in cognitive flexibility, when compared to individuals without the condition. Motor-inhibitory control is a function of the right lateralized frontostriatal circuit, which includes the right inferior frontal and bilateral anterior cingulate cortices. The impairment of motor-inhibitory control is similar to the neurological conditions of those who have problems suppressing inappropriate behaviors, such as abusing methamphetamine.[3] ### Genetic components[edit] There is no significant evidence to suggest that skin picking disorders are due to inherited traits or genes, though there have been multiple small studies with similar conclusions in regards to the SAPAP3 gene. Excessive grooming by mice has been observed by researchers after deletion of the SAPAP3 gene.[12] This observation led researchers to study the effects of the SAPAP3 gene on patients with trichotillomania—a disorder marked by the same behaviors directed at one′s own head and body hair. This study revealed a significant link between a single nucleotide polymorphism (SNP) within the SAPAP3 gene and trichotillomania.[12] ## Diagnosis[edit] There has been controversy over the creation of a separate category in the DSM-5 for excoriation (skin picking) disorder.[13] Two of the main reasons for objecting to the inclusion of excoriation disorder in the DSM-5 are: that excoriation disorder may just be a symptom of a different underlying disorder, e.g. OCD or BDD, and excoriation disorder is merely a bad habit and that by allowing this disorder to obtain its own separate category it would force the DSM to include a wide array of bad habits as separate syndromes, e.g., nail biting and nose-picking.[8] Stein has argued that excoriation disorder does qualify as a separate syndrome and should be classified as its own category because: * Excoriation disorder occurs as the primary disorder and not as a subset of a larger disorder. * Excoriation disorder has well-defined clinical features. * There is gathering data on the clinical features and diagnostic criteria for this condition. * There is sufficient data to create this as a separate category for excoriation disorder. * The incidence rate for excoriation disorder is high within the population. * Diagnostic criteria for the disease have already been proposed. * The classification of excoriation disorder as a separate condition would lead to better studies and better treatment outcomes. * Classification as a separate condition would lead to more awareness of the disorder and encourage more people to obtain treatment.[8] However, a review of the scientific literature by Jenkins et al. on excoriation disorder as a separate category in the DSM-5 concluded that such a distinction requires more evidence.[13] Because excoriation disorder is different from other conditions and disorders that cause picking of the skin, it is important that any diagnosis of excoriation disorder take into account various other medical conditions as possible causes before diagnosing the patient with excoriation disorder.[3] There are a variety of conditions that cause itching and skin picking including: eczema, psoriasis, diabetes, liver disease, Hodgkin's disease, polycythemia vera, systemic lupus, and Prader-Willi syndrome.[3] In order to better understand excoriation disorder, researchers have developed a variety of scales to categorize skin-picking behavior. These include the Skin-Picking Impact Scale (SPIS), and The Milwaukee Inventory for the Dimensions of Adult Skin-picking.[7] The SPIS was created to measure how skin picking affects the individual socially, behaviorally, and emotionally.[14] As of the release of the fifth Diagnostic and Statistical Manual of Mental Disorders in May 2013, this disorder is classified as its own separate condition under "Obsessive Compulsive and Related Disorders" and is termed "excoriation (skin-picking) disorder". The diagnostic material is as follows:[15] 1. Repeated picking of the skin, resulting in injuries 2. Recurring attempts to stop picking, relapses continually occur 3. Picking causes a substantial amount of distress and substantially impairs everyday functioning 4. The picking is not caused or cannot be better explained by physiological effects of a substance or a medical disorder 5. The picking is not more accurately attributed to another mental disorder ### Classification[edit] Since the DSM-5 (2013), excoriation disorder is classified as "L98.1 Excoriation (skin-picking) disorder" in ICD-10;[16] and is no longer classified in "Impulse control disorder" (f63). Excoriation disorder is defined as "repetitive and compulsive picking of skin which results in tissue damage".[3] Its most official name had been "dermatillomania" for some time. As of the release of the fifth Diagnostic and Statistical Manual of Mental Disorders in May 2013, excoriation disorder is classified as its own separate condition under "Obsessive Compulsive and Related Disorders" and is termed "excoriation (skin-picking) disorder". #### Similarities with other conditions[edit] The inability to control the urge to pick is similar to the urge to compulsively pull one's own hair, i.e., trichotillomania. Researchers have noted the following similarities between trichotillomania and excoriation disorder: the symptoms are ritualistic but there are no preceding obsessions; there are similar triggers for the compulsive actions; both conditions appear to play a role in modifying the arousal level of the subject; and the age of onset for both conditions is similar.[8] There is also a high level of comorbidity between those that have trichotillomania and those that have excoriation disorder.[8] A notable difference between these conditions is that skin picking seems to be dominated by females whereas trichotillomania is more evenly distributed across genders.[8] Research has also suggested that excoriation disorder may be thought of as a type of obsessive compulsive disorder (OCD).[6] Excoriation disorder and OCD are similar in that they both involve "repetitive engagement in behaviors with diminished control" and also both generally decrease anxiety.[3] Nevertheless, Odlaug and Grant have suggested that excoriation disorder is more akin to substance abuse disorder than OCD.[3] They argue that excoriation disorder differs from OCD in the following fundamental ways: * There is a much greater share of females with excoriation disorder. * Excoriation disorder may be inherently pleasurable whereas OCD is not. * The treatments that are generally effective for patients with OCD (i. e., SSRIs and exposure therapy) are not as successful in patients with excoriation disorder. * Unlike OCD, picking the skin is rarely driven by obsessive thoughts. Odlaug and Grant have recognized the following similarities between individuals with dermatillomania and patients with addictions: * Compulsion to engage in the negative behavior despite knowledge of the harm. * Lack of control over the problematic behavior. * Strong urge to engage in the behavior prior to engagement. * Feeling of pleasure while engaging in the behavior or a feeling of relief or reduced anxiety after engaging in the behavior.[3] One study that supported the addiction theory of picking found that 79% of patients with excoriation disorder reported a pleasurable feeling when picking.[3] Odlaug and Grant also argue that dermatillomania could have several different psychological causes, which would explain why some patients seem more likely to have symptoms of OCD, and others, of an addiction. They suggest that treating certain cases of excoriation as an addiction may yield more success than treating them as a form of OCD.[3] ## Treatment[edit] Knowledge about effective treatments for excoriation disorder is sparse, despite the prevalence of the condition.[7][5] There are two major classes of therapy for excoriation disorder: pharmacological and behavioral.[3][5] Individuals with excoriation disorder often do not seek treatment for their condition, largely due to feelings of embarrassment, alienation, lack of awareness, or belief that the condition cannot be treated. One study found that only 45% of individuals with excoriation disorder ever sought treatment, and only 19% ever received dermalogical treatment. Another study found that only 30% of individuals with this disorder sought treatment.[3] ### Medication[edit] There are several different classes of pharmacological treatment agents that have some support for treating excoriation disorder: SSRIs; opioid antagonists; anti-epileptic agents; and glutamatergic agents.[3][5] In addition to these classes of drugs, some other pharmacological products have been tested in small trials as well.[5] Antipsychotic, antianxiety, antidepressant, and antiepileptic medications have all been used to treat skin picking, with varying degrees of success.[17] SSRIs have shown to be effective in the treatment of OCD, which serves as an argument in favor of treating excoriation disorder with the same therapy. Unfortunately, clinical studies have not provided clear support for this, because there have not been large double-blind placebo-controlled trials of SSRI therapy for excoriation disorder.[3][7] In fact, in a meta-analysis of pharmacological treatments of excoriation disorders, it was found that selective serotonin reuptake inhibitors (SSRIs) and lamotrigine were no more effective than a placebo for longterm effects.[18] Reviews of treatment of excoriation disorder have shown that the following medications may be effective in reducing picking behavior: doxepin, clomipramine, naltrexone, pimozide, and olanzapine.[7] Small studies of fluoxetine, an SSRI, in treating excoriation disorder showed that the drug reduced certain aspects of skin picking compared with a placebo, but full remission was not observed.[3] One small study of patients with excoriation disorder treated with citalopram, another SSRI, showed that those who took the drug significantly reduced their scores on the Yale-Brown Obsessive Compulsive Scale compared with a placebo, but that there was no significant decrease on the visual-analog scale of picking behavior.[3] While there have been no human studies of opioid antagonists for the treatment of excoriation disorder, there have been studies showing that these products can reduce self-chewing in dogs with acral lick, which some have proposed is a good animal model for body-focused repetitive behavior.[3] Furthermore, case reports support the use of these opioid antagonists to treat excoriation disorder.[3] Opioid antagonists work by affecting dopamine circuitry, thereby decreasing the pleasurable effects of picking.[3] Another class of possible pharmacological treatments are glutamatergic agents such as n-acetyl cysteine (NAC). These products have shown some ability to reduce other problematic behaviors such as cocaine addiction and trichotillomania.[3] Some case studies and some small studies of NAC have shown a decrease in picking by treatment with NAC compared with placebo.[3] Excoriation disorder and trichotillomania have been treated with inositol.[19] Topiramate, an anti-epileptic drug, has been used to treat excoriation disorder; in a small study of individuals with Prader–Willi syndrome, it was found to reduce skin picking.[7] ### Counseling[edit] Behavioral treatments include habit reversal training, cognitive-behavioral therapy, acceptance-enhanced behavior therapy[3][6] and acceptance and commitment therapy (ACT).[20] Several studies have shown that habit reversal training associated with awareness training reduces skin-picking behavior in those individuals with excoriation disorder that do not have psychological disabilities.[7] Habit reversal training can include awareness enhancement and competing response training.[7] For example, in one study the competing response training required participants to make a closed fist for one minute instead of picking or in response to a condition that usually provokes picking behavior.[7] ### Developmentally disabled[edit] There are several different behavioral interventions that have been tested to treat excoriation disorder in the developmentally disabled. One method is to have individuals wear a form of protective clothing that limits the ability of the patient to pick at their body, e.g., gloves or face mask.[7] Other behavioral treatments attempt to change behavior through providing different incentives. Under Differential Reinforcement of Other Behavior (DRO), a patient is rewarded if able to abstain from the picking behavior for a certain amount of time.[7] In contrast to DRO, Differential Reinforcement of Incompatible Behavior (DRI) rewards an individual for engaging in an alternative behavior that cannot physically occur at the same time as the problem behavior (e.g. sitting on your hands instead of picking at your skin).[7] Lastly, differential reinforcement of alternative behavior rewards behavior that is not necessarily incompatible with the target behavior but serves the same function as the target behavior (e.g., providing people with a competing behavior to occupy their time instead of skin picking).[7] All of these techniques have been reported to have some success in small studies, but none has been tested in large enough populations to provide definitive evidence of their effectiveness.[7] ### Biofeedback[edit] Tentative evidence suggests that devices that provide feedback when the activity occurs can be useful.[21] ## Prognosis[edit] Typically, individuals with excoriation disorder find that the disorder interferes with daily life. Hindered by shame, embarrassment, and humiliation, they may take measures to hide their disorder by not leaving home, wearing long sleeves and pants even in heat, or covering visible damage to skin with cosmetics and/or bandages. When untreated, excoriation disorder can last between anywhere from 5 to 21 years. However, many doctors consider this disorder to be a permanent diagnosis.[22] ## Epidemiology[edit] The prevalence of excoriation disorder is not well understood.[3] Estimates of prevalence of the condition range from 1.4 to 5.4% in the general population. One U.S. telephone survey found that 16.6% of respondents "picked their skin to the point of noticeable tissue damage" and that 1.4% would qualify as meeting the requirements of excoriation disorder. Another community survey found a rate of 5.4% had excoriation disorder. A survey of college students found a rate of 4%.[3] One study found that among non-disabled adults, 63% of individuals engaged in some form of skin picking and 5.4% engaged in serious skin picking.[7] Lastly, a survey of dermatology patients found that 2% suffered from excoriation disorder.[3] In some patients excoriation disorder begins with the onset of acne in adolescence, but the compulsion continues even after the acne has gone away. Skin conditions such as keratosis pilaris, psoriasis, and eczema can also provoke the behavior. In patients with acne, the grooming of the skin is disproportionate to the severity of the acne.[3] Certain stressful events including marital conflicts, deaths of friends or family, and unwanted pregnancies have been linked to the onset of the condition.[3] If excoriation disorder does not occur during adolescence another common age of onset is between the ages of 30 to 45.[3] Additionally, many cases of excoriation disorder have been documented to begin in children under the age of 10. One small survey of patients with excoriation disorder found that 47.5% of them had an early onset of excoriation disorder that began before age 10.[3] Traumatic childhood events may initiate the behavior. Excoriation disorder is statistically more common in females than in males.[3][6] Excoriation disorder has a high rate of comorbidity with other psychiatric conditions, especially with mood and anxiety disorders .[8] One survey of patients with excoriation disorder found that 56.7% also had a DSM-IV Axis-I disorder and 38% had alcohol- or drug-abuse problems.[3] Studies have shown the following rates of psychiatric conditions found in patients with excoriation disorder: trichotillomania (38.3%), substance abuse (38%), major depressive disorder (approximately 31.7% to 58.1%), anxiety disorders (approximately 23% to 56%), obsessive-compulsive disorder (approximately 16.7% to 68%), and body dysmorphic disorder (approximately 26.8% to 44.9%).[3] There are also higher rates of excoriation disorder in patients in psychiatric facilities; a study of adolescent psychiatric inpatients found that excoriation disorder was present in 11.8% of patients.[3] It is also present at high rates with some other conditions: 44.9% of patients with body dysmorphic disorder also have excoriation disorder; 8.9% of patients with OCD have excoriation disorder; and 8.3% of patients with trichotillomania have excoriation disorder.[3] Skin picking is also common in those with certain developmental disabilities; for example, Prader–Willi syndrome and Smith–Magenis syndrome.[7] Studies have shown that 85% of people with Prader–Willi syndrome also engage in skin-picking.[7] Children with developmental disabilities are also at an increased risk for excoriation disorder.[7] Excoriation disorder also correlates with "social, occupational, and academic impairments, increased medical and mental health concerns (including anxiety, depression, obsessive–compulsive disorder) ... and financial burden".[7] Excoriation disorder also has a high degree of comorbidity with occupational and marital difficulties.[8] Substance abuse is often present, and individuals with excoriation disorder are twice as likely to have first-degree relatives who have substance abuse disorders than those without the condition.[3] Some cases of body-focused repetitive behaviors found in identical twins also suggest a hereditary factor.[23] ## History[edit] The first known mention of excoriation disorder in the print can be found in 1898 by the French dermatologist Louis-Anne-Jean Brocq, describing an adolescent female patient who had uncontrolled picking of acne.[3][24] ## Society and culture[edit] Excoriation disorder has been the subject of several episodes of Obsessed, a television documentary series that focuses on treatment of anxiety disorders. Excoriation disorder is shown as a symptom of Nina Sayers' anxiety and OCD in the movie Black Swan. ## See also[edit] * Dermatophagia * Morgellons ## References[edit] 1. ^ The term derives from the Greek: δέρμα derma ("skin"), τίλλειν tillein ("to pull"), and μανία mania ("madness, frenzy"). 2. ^ Feusner JD, Hembacher E, Phillips KA (September 2009). "The mouse who couldn't stop washing: pathologic grooming in animals and humans". CNS Spectrums. 14 (9): 503–13. doi:10.1017/s1092852900023567. PMC 2853748. PMID 19890232. 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 ag ah ai aj ak al am an ao ap aq ar as at au av Odlaug BL, Grant JE (September 2010). "Pathologic skin picking". The American Journal of Drug and Alcohol Abuse. 36 (5): 296–303. doi:10.3109/00952991003747543. PMID 20575652. 4. ^ Deckersbach, Thilo; Wilhelm, Sabine; Keuthen, Nancy J.; Baer, Lee; Jenike, Michael A. (July 1, 2002). "Cognitive-Behavior Therapy for Self-Injurious Skin Picking". Behavior Modification. 26 (3): 361–377. doi:10.1177/0145445502026003004. ISSN 0145-4455. PMID 12080906. 5. ^ a b c d e f g h Lochner, Christine; Roos, Annerine; Stein, Dan J (2017-07-14). "Excoriation (skin-picking) disorder: a systematic review of treatment options". Neuropsychiatric Disease and Treatment. 13: 1867–1872. doi:10.2147/NDT.S121138. ISSN 1176-6328. PMC 5522672. PMID 28761349. 6. ^ a b c d e * Dell'Osso B, Altamura AC, Allen A, Marazziti D, Hollander E (December 2006). "Epidemiologic and clinical updates on impulse control disorders: a critical review". European Archives of Psychiatry and Clinical Neuroscience. 256 (8): 464–75. doi:10.1007/s00406-006-0668-0. PMC 1705499. PMID 16960655. 7. ^ a b c d e f g h i j k l m n o p q r s t u Lang R, Didden R, Machalicek W, Rispoli M, Sigafoos J, Lancioni G, Mulloy A, Regester A, Pierce N, Kang S (2010). "Behavioral treatment of chronic skin-picking in individuals with developmental disabilities: a systematic review". Research in Developmental Disabilities. 31 (2): 304–15. doi:10.1016/j.ridd.2009.10.017. PMID 19963341. 8. ^ a b c d e f g h i Stein DJ, Grant JE, Franklin ME, Keuthen N, Lochner C, Singer HS, Woods DW (June 2010). "Trichotillomania (hair pulling disorder), skin picking disorder, and stereotypic movement disorder: toward DSM-V". Depression and Anxiety. 27 (6): 611–26. doi:10.1002/da.20700. PMID 20533371. 9. ^ Causes of Skin Picking Archived 2012-06-11 at the Wayback Machine, including biological and environmental factors. 10. ^ Yalçin M, Tellioğlu E, Yildirim DU, Savrun BM, Özmen M, Aydemir EH (December 2015). "Psychiatric Features in Neurotic Excoriation Patients: The Role of Childhood Trauma". Noro Psikiyatri Arsivi. 52 (4): 336–341. doi:10.5152/npa.2015.9902. PMC 5353104. PMID 28360736. 11. ^ Schienle, Anne; Wabnegger, Albert (1 April 2020). "Two subtypes of pathological skin-picking: Evidence from a voxel-based morphometry study". Journal of Obsessive-Compulsive and Related Disorders. 25: 100534. doi:10.1016/j.jocrd.2020.100534. ISSN 2211-3649. Retrieved 21 December 2020. 12. ^ a b Monzani, Benedetta; Rijsdijk, Fruhling; Cherkas, Lynn; Harris, Juliette; Keuthen, Nancy; Mataix-Cols, David (2012-05-22). "Prevalence and heritability of skin picking in an adult community sample: A twin study". American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 159B (5): 605–610. doi:10.1002/ajmg.b.32067. ISSN 1552-4841. 13. ^ a b Jenkins, Zoe; Zavier, Hyacinta; Phillipou, Andrea; Castle, David (September 2019). "Should skin picking disorder be considered a diagnostic category? A systematic review of the evidence". The Australian and New Zealand Journal of Psychiatry. 53 (9): 866–877. doi:10.1177/0004867419834347. ISSN 1440-1614. PMID 30895799. 14. ^ Keuthen NJ, Deckersbach T, Wilhelm S, Engelhard I, Forker A, O'Sullivan RL, Jenike MA, Baer L (2001). "The Skin Picking Impact Scale (SPIS): scale development and psychometric analyses". Psychosomatics. 42 (5): 397–403. doi:10.1176/appi.psy.42.5.397. PMID 11739906. Archived from the original on 2012-07-12. Retrieved 2011-10-01. 15. ^ "Excoriation Disorder: Practice Essentials, Background, Pathophysiology and Etiology". 2018-07-10. Cite journal requires `\|journal=` (help) 16. ^ Black, Donald W.; Grant, Jon E. (2014). DSM-5 Guidebook: The Essential Companion to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Pub. p. 870. ISBN 978-1585624652. 17. ^ "Excoriation Disorder: Practice Essentials, Background, Pathophysiology and Etiology". emedicine.medscape.com. 2018-07-10. Retrieved 2018-12-01. 18. ^ Schumer, Maya C.; Bartley, Christine A.; Bloch, Michael H. (April 2016). "Systematic Review of Pharmacological and Behavioral Treatments for Skin Picking Disorder". Journal of Clinical Psychopharmacology. 36 (2): 147–152. doi:10.1097/JCP.0000000000000462. ISSN 0271-0749. PMC 4930073. PMID 26872117. 19. ^ Torales J, Barrios I, Villalba J (2017). "Alternative Therapies for Excoriation (Skin Picking) Disorder: A Brief Update". Advances in Mind-Body Medicine. 31 (1): 10–13. PMID 28183072. 20. ^ Ruiz, F. J. (2010). "A review of Acceptance and Commitment Therapy (ACT) empirical evidence: Correlational, experimental psychopathology, component and outcome studies". International Journal of Psychology and Psychological Therapy. 10 (1): 125–62. 21. ^ Torales J, Barrios I, Villalba J (2017). "Alternative Therapies for Excoriation (Skin Picking) Disorder: A Brief Update". Advances in Mind-Body Medicine. 31 (1): 10–13. PMID 28183072. 22. ^ Craig-Müller, Sören; Reichenberg, Jason (July 4, 2015). "The Other Itch That Rashes: a Clinical and Therapeutic Approach to Pruritus and Skin Picking Disorders". Allergic Skin Diseases. 23. ^ Monzani, Benedetta; Rijsdijk, Fruhling; Cherkas, Lynn; Harris, Juliette; Keuthen, Nancy; Mataix-Cols, David (2012-05-22). "Prevalence and heritability of skin picking in an adult community sample: A twin study". American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 159B (5): 605–610. doi:10.1002/ajmg.b.32067. ISSN 1552-4841. PMID 22619132. 24. ^ Brocq ML (1898). "L'Acné excoriée des jeunes filles et son traitement" [Acne excoriee of young women and their treatment]. Journal des Practiciens, Revue Générale de Clinique et de Thérapeutique. 12: 193–197. ## Further reading[edit] * Grant JE, Odlaug BL (August 2009). "Update on pathological skin picking". Current Psychiatry Reports. 11 (4): 283–8. doi:10.1007/s11920-009-0041-x. PMID 19635236. * Singer HS (2011). Stereotypic movement disorders. Handbook of Clinical Neurology. 100. pp. 631–9. doi:10.1016/B978-0-444-52014-2.00045-8. ISBN 9780444520142. PMID 21496612. * Stein DJ, Grant JE, Franklin ME, Keuthen N, Lochner C, Singer HS, Woods DW (June 2010). "Trichotillomania (hair pulling disorder), skin picking disorder, and stereotypic movement disorder: toward DSM-V". Depression and Anxiety. 27 (6): 611–26. doi:10.1002/da.20700. PMID 20533371. * Stratton M (February 2018). "Stop Picking On Me". Cite journal requires `\|journal=` (help) ## External links[edit] Classification D * ICD-10: L98.1 * ICD-9-CM: 312.3 * MeSH: D007174 * DiseasesDB: 29765 External resources * eMedicine: article/1122042 * 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 * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Excoriation disorder	c1696701	6,044	wikipedia	https://en.wikipedia.org/wiki/Excoriation_disorder	2021-01-18T19:06:00	{"umls": ["C1696701"], "icd-9": ["312.3"], "icd-10": ["L98.1"], "wikidata": ["Q904200"]}
A rare aortic arch defect characterized by variable degrees of dysphagia due to compression of the esophagus from an aberrant right subclavian artery (arteria lusoria), which arises as the fourth branch, distal to the left subclavian artery, from the aortic arch. In most cases, the aberrant vessel then passes posterior to the esophagus, less frequently between the trachea and esophagus, or anterior to the trachea. Children may also present with stridor and recurrent chest infections. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Dysphagia lusoria	c0267073	6,045	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99082	2021-01-23T17:41:09	{"umls": ["C0267073"], "icd-10": ["Q25.4"]}
Schatzki ring Endoscopic image of Schatzki ring, seen in the esophagus with the gastro-esophageal junction in the background. SpecialtyMedical genetics A Schatzki ring or Schatzki–Gary ring is a narrowing of the lower esophagus that can cause difficulty swallowing (dysphagia). The narrowing is caused by a ring of mucosal tissue (which lines the esophagus) or muscular tissue.[1] A Schatzki ring is a specific type of "esophageal ring", and Schatzki rings are further subdivided into those above the esophagus/stomach junction (A rings),[2] and those found at the squamocolumnar junction in the lower esophagus (B rings).[3][2] Patients with Schatzki rings can develop intermittent difficulty swallowing or, more seriously, a completely blocked esophagus. The ring is named after the German-American physician Richard Schatzki. ## Contents * 1 Signs and symptoms * 1.1 Other associations * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Not all patients with Schatzki rings have symptoms; barium swallow tests of the esophagus sometimes show Schatzki rings in patients with no swallowing difficulties.[citation needed] When Schatzki rings cause symptoms, they usually result in episodic difficulties with swallowing (dysphagia) solid foods, or a sensation that the food "sticks" while swallowing, especially if the food is not chewed thoroughly. Patients usually are able to regurgitate or force through the food material and resume eating. However, complete obstruction of the esophagus by a bolus of food (often called steakhouse syndrome) can occur. This can cause crushing chest pain and may need immediate treatment with endoscopy, which is the use of a specialized fibre-optic camera in order to remove the lodged food.[4] After the obstruction is located, snares or forceps are inserted to pull the food out of the esophagus or to push it into the stomach. The latter is done with caution, usually when the anatomy of the structures around the obstruction is already known.[citation needed] ### Other associations[edit] * Schatzki rings can be associated with swallow syncope, a rare variety of syncope.[5] * Schatzki rings are associated with lesser incidence of Barrett's esophagus, which is considered to be a pre-cancerous condition of the esophagus in some cases.[6] ## Cause[edit] Although many hypotheses have been proffered, the cause of Schatzki rings remains uncertain; both congenital and acquired factors may be involved.[citation needed] ## Diagnosis[edit] Schatzki B ring at barium swallow. A Schatzki ring is usually diagnosed by esophagogastroduodenoscopy or barium swallow. Endoscopy usually shows a ring within the lumen of the esophagus which can be of variable size (see picture). The ring is usually located a few centimetres above the gastro-esophageal junction, where the esophagus joins the stomach. Schatzki rings can often resemble a related entity called an esophageal web. Esophageal webs also contain extra mucosal tissue, but do not completely encircle the esophagus.[citation needed] Endoscopies and barium swallows done for other reasons often reveal unsuspected Schatzki rings,[7] meaning that many Schatzki rings are asymptomatic.[citation needed] Two varieties of Schatzki rings have been described. The original description by Schatzki and Gary was of a ring of fibrous tissue seen on autopsy; this is the less common type of Schatzki ring.[1] More commonly, the ring consists of the same mucosal tissue that lines the entire esophagus. ## Treatment[edit] Asymptomatic Schatzki rings seldom worsen over time, and need no treatment.[citation needed] Symptomatic Schatzki rings may be treated with esophageal dilatation, using bougie or balloon dilators. These have been found to be equally effective.[8] Bougie dilatation involves passage of long dilating tubes of increasing size down the esophagus to stretch the area of narrowing, either over a guidewire passed into the stomach by endoscopy (the Savary-Gillard system) or using mercury-weighted dilators (the Maloney system). This is usually done with intravenous sedation to reduce discomfort. Dilatation can produce some temporary irritation. A short course of proton pump inhibitor therapy may decrease aggravation by stomach acid reflux into the esophagus. The duration of the benefit of dilation varies, but may be from months to years. Dilation may be repeated if narrowing recurs.[citation needed] ## Epidemiology[edit] About 6 to 14 percent of patients who receive a routine barium swallow test of the esophagus are found to have a Schatzki ring.[9] ## See also[edit] * Dysphagia * Esophageal web * Esophageal dilatation ## References[edit] 1. ^ a b Schatzki, Richard; J. E. Gary (December 1953). "Dysphagia due to a diaphragm-like localized narrowing in the lower esophagus (lower esophageal ring)". The American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine. 70 (6): 911–22. PMID 13104726. 2. ^ a b Kumar, Vinay; Abbas, Abul; Aster, Jon (2015). Robbins and Cotran Pathologic Basis of Disease (Ninth ed.). Philadelphia, PA: Elsevier Saunders. p. 753. ISBN 978-1-4557-2613-4. 3. ^ "Obstruction: Esophageal Disorders: Merck Manual Home Health Handbook". 4. ^ Stadler, J.; A. H. Hölscher; H. Feussner; J. Dittler; J. R. Siewert (December 1989). "The "steakhouse syndrome". Primary and definitive diagnosis and therapy". Surgical Endoscopy. 3 (4): 195–8. doi:10.1007/BF02171545. PMID 2623551. 5. ^ Gawrieh, Samer; Ty Carroll; Walter J. Hogan; Konrad H. Soergel; Reza Shaker (October 2005). "Swallow syncope in association with Schatzki ring and hypertensive esophageal peristalsis: report of three cases and review of the literature". Dysphagia. 20 (4): 273–7. doi:10.1007/s00455-005-0024-y. PMID 16633871. 6. ^ Mitre, Marcia C.; David A. Katzka; Colleen M. Brensinger; James D. Lewis; Ricardo J. Mitre; Gregory G. Ginsberg (May 2004). "Schatzki ring and Barrett's esophagus: do they occur together?". Digestive Diseases and Sciences. 49 (5): 770–3. doi:10.1023/B:DDAS.0000030087.07078.8a. PMID 15259497. 7. ^ Pezzullo, john C.; Ann M. Lewicki (September 2003). "Schatzki ring, statistically reexamined". Radiology. 228 (3): 609–13. doi:10.1148/radiol.2283021162. PMID 12869689. Retrieved 2006-07-20. 8. ^ Scolapio, James S.; Tousif M. Pasha; Christopher J. Gostout; Douglas W. Mahoney; Alan R. Zinsmeister; Beverly J. Ott; Keith D. Lindor (July 1999). "A randomized prospective study comparing rigid to balloon dilators for benign esophageal strictures and rings". Gastrointestinal Endoscopy. 50 (1): 13–7. doi:10.1016/S0016-5107(99)70337-8. PMID 10385715. 9. ^ KEYTING, WS; BAKER, GM; MCCARVER, RR; DAYWITT, AL (December 1960). "The lower esophagus". The American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine. 84: 1070–5. PMID 13752844. ## External links[edit] Classification D * ICD-10: K22.2, Q39.3 * ICD-9-CM: 530.3, 750.3 * MeSH: C562765 * DiseasesDB: 31504 External resources * MedlinePlus: 000208 * eMedicine: med/2069 * 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 Congenital malformations and deformations of digestive system Upper GI tract Tongue, mouth and pharynx * Cleft lip and palate * Van der Woude syndrome * tongue * Ankyloglossia * Macroglossia * Hypoglossia Esophagus * EA/TEF * Esophageal atresia: types A, B, C, and D * Tracheoesophageal fistula: types B, C, D and E * esophageal rings * Esophageal web (upper) * Schatzki ring (lower) Stomach * Pyloric stenosis * Hiatus hernia Lower GI tract Intestines * Intestinal atresia * Duodenal atresia * Meckel's diverticulum * Hirschsprung's disease * Intestinal malrotation * Dolichocolon * Enteric duplication cyst Rectum/anal canal * Imperforate anus * Rectovestibular fistula * Persistent cloaca * Rectal atresia Accessory Pancreas * Annular pancreas * Accessory pancreas * Johanson–Blizzard syndrome * Pancreas divisum Bile duct * Choledochal cysts * Caroli disease * Biliary atresia Liver * Alagille syndrome * Polycystic liver disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Schatzki ring	c0341137	6,046	wikipedia	https://en.wikipedia.org/wiki/Schatzki_ring	2021-01-18T18:56:02	{"mesh": ["C562765"], "umls": ["C0341137"], "icd-9": ["750.3", "530.3"], "icd-10": ["Q39.3", "K22.2"], "wikidata": ["Q628052"]}
Johnston and Green (1965) presented 5 cases of which 2 were black brother and sister. Chromosome studies were normal. The parents and 5 other sibs appeared to be unaffected. Two sibs died in early infancy. In one, mongolism was diagnosed. Although bronchopulmonary suppuration largely determines the degree of respiratory disability, infection is not responsible for the underlying lesion of the tracheobronchial tree. The characteristic bronchographic picture led several workers to call the disorder 'trachiectasis with multiple diverticula.' The appearance is created by enlargement of the airways and musculomembranous tissue projecting like corrugations between the cartilaginous rings. The black patient reported by Aaby and Blake (1966) probably suffered from the Ehlers-Danlos syndrome. Pulmonary \- Trachiectasis \- Diverticulosis of trachea \- Bronchiectasis \- Bronchopulmonary infection Radiology \- Musculomembranous tissue projects like corrugations between tracheal cartilaginous rings Misc \- Death in infancy Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	TRACHEOBRONCHOMEGALY	c0040587	6,047	omim	https://www.omim.org/entry/275300	2019-09-22T16:21:36	{"mesh": ["D014137"], "omim": ["275300"], "orphanet": ["3347"]}
A rare, genetic, skin tumor disorder characterized by childhood-onset of multiple, benign, asymptomatic, white to flesh-colored papules predominently located on the face, ears, neck and trunk, not associated with systemic organ involvement, associated malignancies or FLCN gene locus mutation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Familial multiple discoid fibromas	c1860850	6,048	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=538756	2021-01-23T18:48:36	{"mesh": ["C536847"], "omim": ["190340"], "icd-10": ["D23.2"], "synonyms": ["Familial multiple trichodiscomas"]}
Plasmablastic lymphoma is an aggressive form of non-Hodgkin lymphoma. Although the condition most commonly occurs in the oral cavity, it can be diagnosed in many other parts of the body such as the gastrointestinal tract, lymph nodes, and skin. The exact underlying cause of plasmablastic lymphoma is poorly understood; however, it is often associated with suppression of the immune system (i.e. HIV infection, immunosuppressive therapy). There is currently no standard therapy for plasmablastic lymphoma. Treatment usually consists of chemotherapy with or without radiation therapy and hematopoietic stem cell transplantation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Plasmablastic lymphoma	c3472614	6,049	gard	https://rarediseases.info.nih.gov/diseases/12125/plasmablastic-lymphoma	2021-01-18T17:58:17	{"mesh": ["D000069293"], "orphanet": ["289666"], "synonyms": []}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article relies too much on references to primary sources. Please improve this by adding secondary or tertiary sources. (May 2015) (Learn how and when to remove this template message) This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (March 2015) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Anterior cutaneous nerve entrapment syndrome (ACNES) is a nerve entrapment condition that causes chronic pain of the abdominal wall. It occurs when nerve endings of the lower thoracic intercostal nerves (7–12) are 'entrapped' in abdominal muscles, causing a severe localized nerve (neuropathic) pain that is usually experienced at the front of the abdomen. ACNES syndrome is frequently overlooked and unrecognized, although the incidence is estimated to be 1:2000 patients.[1] The relative unfamiliarity with this condition often leads to significant diagnostic delays and misdiagnoses, often resulting in unnecessary diagnostic interventions and futile procedures.[2] Physicians often misdiagnose ACNES as irritable bowel syndrome or "functional disorders", as symptoms of the condition are not dispositive.[3][4] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Treatment * 4 Epidemiology * 5 References ## Signs and symptoms[edit] Affected individuals typically experience limited relief from standard pain relieving medication, with the exception of some neuroleptic agents. Patients frequently experience 'pseudovisceral' phenomena or symptoms of altered autonomic nervous system function including nausea, bloating, abdominal swelling, loss of appetite with consecutively lowered body weight or an altered defecation process.[5] Pain is typically related to tensing the abdominal wall muscles, so any type of movement is prone to aggravate pain. Lying quietly can be the least painful position. Most patients report that they cannot sleep on the painful side.[6] ## Diagnosis[edit] Once ACNES is considered based on the patient's history, the diagnosis can be made via a thorough physical examination: looking for a painful spot, which worsens by tensing the abdominal muscles with lifting the head and straightened legs (Carnett's sign).[7] Almost always, a small area of maximal pain is covered by a larger area of altered skin sensibility with somatosensory disturbances such as hypoesthesia as well as hyperesthesia or hyperalgesia and change of cool perception. Pinching the skin between thumb and index finger is extremely painful compared to the opposite non-involved side.[8] Confirmation of a diagnosis of ACNES is warranted using an abdominal wall infiltration with a local anesthetic agent near the painful spot.[9] ## Treatment[edit] Treatment consists of several such anesthetic injections, sometimes combined with corticosteroids. Such an approach yields persistent pain relief in two-thirds of patients. This beneficial effect on pain has been demonstrated in a prospective double blind trial.[10] The physical volume of the injection may also break apart the adhesions or fibrosis responsible for the entrapment symptoms.[11] Patients who do not respond to a stratagem of repetitive local trigger point injections can be offered a surgical approach. Terminal branches of an intercostal nerve are removed at the level of the anterior sheath of the rectus abdominal muscle ('anterior neurectomy'). Several larger series demonstrated a successful response in approximately two out of three patients, which was confirmed in another prospective double blind surgical trial: 73% of the patients who underwent a neurectomy were pain free, compared to 18% in the non-nerve resected group.[12] Patients not responding to an anterior neurectomy, or those in whom the pain syndrome recurs after an initial pain free period (10%) may choose to undergo secondary surgery. This involves a repeated exploration combined with a posterior neurectomy. This procedure has been shown to be beneficial in 50% of cases.[13][14] ## Epidemiology[edit] This syndrome is predominantly found in young women, but also occurs in children, teenagers and octogenarians.[15] ## References[edit] 1. ^ Van Assen, T.; Brouns, J. A. G. M.; Scheltinga, M. R.; Roumen, R. M. (2015). "Incidence of abdominal pain due to the anterior cutaneous nerve entrapment syndrome in an emergency department". Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 23: 19. doi:10.1186/s13049-015-0096-0. PMC 4327965. PMID 25887961. 2. ^ Srinivasan, R; Greenbaum, D. S. (2002). "Chronic abdominal wall pain: A frequently overlooked problem. Practical approach to diagnosis and management". The American Journal of Gastroenterology. 97 (4): 824–30. PMID 12003414. 3. ^ Van Assen, T; De Jager-Kievit, J. W.; Scheltinga, M. R.; Roumen, R. M. (2013). "Chronic abdominal wall pain misdiagnosed as functional abdominal pain". The Journal of the American Board of Family Medicine. 26 (6): 738–44. doi:10.3122/jabfm.2013.06.130115. PMID 24204070. 4. ^ Van Assen, T; Boelens, O. B.; Kamphuis, J. T.; Scheltinga, M. R.; Roumen, R. M. (2012). "Construction and validation of a questionnaire distinguishing a chronic abdominal wall pain syndrome from irritable bowel syndrome". Frontline Gastroenterology. 3 (4): 288–294. doi:10.1136/flgastro-2012-100207. PMC 3730810. PMID 23914291. 5. ^ Applegate WV (1972). "Abdominal cutaneous nerve entrapment syndrome". Surgery. 71 (1): 118–24. PMID 4332389. 6. ^ Scheltinga, M. R.; Boelens, O. B.; Tjon a Ten, W. E.; Roumen, R. M. (2011). "Surgery for refractory anterior cutaneous nerve entrapment syndrome (ACNES) in children". Journal of Pediatric Surgery. 46 (4): 699–703. doi:10.1016/j.jpedsurg.2010.08.054. PMID 21496540. 7. ^ Carnett J. (1926). "Intercostal neuralgia as a cause of abdominal pain and tenderness". Surg Gynecol Obstet. 42: 8. 8. ^ Van Assen, T; Boelens, O. B.; Van Eerten, P. V.; Perquin, C; Scheltinga, M. R.; Roumen, R. M. (2015). "Long-term success rates after an anterior neurectomy in patients with an abdominal cutaneous nerve entrapment syndrome". Surgery. 157 (1): 137–43. doi:10.1016/j.surg.2014.05.022. PMID 25444218. 9. ^ Boelens, O. B.; Scheltinga, M. R.; Houterman, S; Roumen, R. M. (2011). "Management of anterior cutaneous nerve entrapment syndrome in a cohort of 139 patients". Annals of Surgery. 254 (6): 1054–8. doi:10.1097/SLA.0b013e31822d78b8. PMID 21881494. 10. ^ Boelens, O. B.; Scheltinga, M. R.; Houterman, S; Roumen, R. M. (2013). "Randomized clinical trial of trigger point infiltration with lidocaine to diagnose anterior cutaneous nerve entrapment syndrome". British Journal of Surgery. 100 (2): 217–21. doi:10.1002/bjs.8958. PMID 23180371. 11. ^ Akhnikh, S; De Korte, N; De Winter, P (2014). "Anterior cutaneous nerve entrapment syndrome (ACNES): The forgotten diagnosis". European Journal of Pediatrics. 173 (4): 445–9. doi:10.1007/s00431-013-2140-2. PMID 24197667. 12. ^ Boelens, O. B.; Van Assen, T; Houterman, S; Scheltinga, M. R.; Roumen, R. M. (2013). "A double-blind, randomized, controlled trial on surgery for chronic abdominal pain due to anterior cutaneous nerve entrapment syndrome". Annals of Surgery. 257 (5): 845–9. doi:10.1097/SLA.0b013e318285f930. PMID 23470571. 13. ^ Van Assen, T; Boelens, O. B.; Van Eerten, P. V.; Scheltinga, M. R.; Roumen, R. M. (2014). "Surgical options after a failed neurectomy in anterior cutaneous nerve entrapment syndrome". World Journal of Surgery. 38 (12): 3105–11. doi:10.1007/s00268-014-2737-2. PMID 25189442. 14. ^ Roumen, R. M.; Scheltinga, M. R. (2006). "Abdominal intercostal neuralgia: A forgotten cause of abdominal pain". Nederlands Tijdschrift voor Geneeskunde. 150 (35): 1909–15. PMID 16999272. 15. ^ Lindsetmo, R. O.; Stulberg, J (2009). "Chronic abdominal wall pain--a diagnostic challenge for the surgeon". The American Journal of Surgery. 198 (1): 129–34. doi:10.1016/j.amjsurg.2008.10.027. PMID 19555786. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Anterior cutaneous nerve entrapment syndrome	c0702166	6,050	wikipedia	https://en.wikipedia.org/wiki/Anterior_cutaneous_nerve_entrapment_syndrome	2021-01-18T18:55:40	{"mesh": ["D000152"], "icd-10": ["G58.0"], "orphanet": ["51890"], "synonyms": ["ACNES", "Intercostal nerve syndrome", "Rectus abdominis syndrome"], "wikidata": ["Q19765925"]}
A number sign (#) is used with this entry because parietal foramina-1 (PFM1) is caused by heterozygous mutation in the MSX2 gene (123101) on chromosome 5q35. Description Parietal foramina are symmetric, oval defects in the parietal bone situated on each side of the sagittal suture and separated from each other by a narrow bridge of bone. The size of the openings decrease with age and considerable intrafamilial variability is observed (summary by Spruijt et al., 2005). ### Genetic Heterogeneity of Parietal Foramina See also PFM2 (609597) and the 11p11.2 deletion syndrome (601224), in which parietal foramina are caused by haploinsufficiency of the ALX4 gene (605420) on chromosome 11p. A third locus for PFM (PFM3; 609566) has been mapped to chromosome 4q21-q23. Clinical Features Goldsmith (1922) called this condition 'Catlin marks' because he observed 16 instances in 5 generations of the Catlin family. This, like Hartnup disease, Cowden syndrome, Lutheran trait, and Hageman factor, is one of the few examples of hereditary traits named for the family in which it was first observed. Lother (1959) described 5 cases in 2 generations. Many of the affected persons in Goldsmith's family had circumscribed aplasia of the scalp and the same was true of Lother's family (see 107600). Kite (1961) observed association with seizures. The possibility of confusion with aboriginal trephination was pointed out by Powell (1970). Clefts of the lip and/or palate were present in cases reported by Hollender (1967), Irvine and Taylor (1936), and others. Little et al. (1990) suggested that hereditary cranium bifidum is the same entity as symmetric parietal foramina. They described a family with serial radiographs that documented the development of parietal foramina in late childhood and adulthood from apparent cranium bifidum and parietal foramina during infancy and early childhood. They concluded that the 2 manifestations are merely a function of age. Murphy and Gooding (1970) demonstrated, in a single patient, progression from apparent cranium bifidum during early childhood to parietal foramina during mid-childhood and adulthood. Normally, components of the calvaria (frontal and parietal bones), which are formed by intramembranous ossification, grow and migrate toward each other to eventually enclose the brain during fetal development. A wide opening between these bones, a fontanel, normally occurs superiorly in term infants, posteriorly and anteriorly, and persists into adulthood only rarely. Cranium bifidum, literally 'cleft skull,' is characterized by the persistence of wide fontanel, bilaterally or in the midline, posteriorly or anteriorly, into childhood. During mid-childhood, these areas usually close, leaving only symmetric openings (foramina) in the frontal or parietal regions. Terrafranca and Zellis (1953) described mother and 2 children with cranium bifidum. In one of the children a medial defect in the frontal bone was accompanied by symmetrical parietal lacunae like those in parietal foramina, as well as cervical (C5-C7) and lumbosacral (L5-S1) spina bifida occulta. The other offspring had an identical frontal defect but less conspicuous parietal foramina and no spina bifida. The mother had a U-shaped frontal defect astride the metopic suture. Little et al. (1990) reviewed other families. Chrzanowska et al. (1998) reported a patient with a 'new' branchial syndrome that included the features of parietal foramina; Rauch et al. (1998) considered the patient to represent a case of the FG syndrome (305450). Spruijt et al. (2005) reported a girl born with a large skull defect, who at 2 months of age had a 5 by 3 cm posterior cranial skull defect. At 10 months of age, the skull defect was much smaller due to a midsagittal bony bridge in the middle of the defect, resulting in bilateral symmetrical foramina of approximately 2 cm in diameter each. The patient's clavicles were normal both on physical and radiographic examination. On CT scan, the father was found to have bilateral skull defects of 1.5 cm in diameter separated by a bony bridge in the same posterior position of the skull as the proband; he had no clavicular defects, and he recalled being told that he had late milk tooth eruption, although he had normal permanent dentition. The grandparents were not available for examination, but neither had a history of a skull defect as a child. Molecular Genetics In affected members of 3 unrelated families with PFM1, Wilkie et al. (2000) identified 3 different heterozygous mutations in the MSX2 gene (123101.0002-123101.0004). One was a deletion of approximately 206 kb including the entire gene, and the others were intragenic mutations of the DNA-binding homeodomain that predicted disruption of critical intramolecular and DNA contacts. Mouse Msx2 protein with either of the homeodomain mutations exhibited more than 85% reduction in binding to an optimal MSX2 DNA-binding site. These findings contrasted with the previously described MSX2 homeodomain mutation (P148H; 123101.0001), associated with craniosynostosis, which binds with enhanced affinity to the same target. In the affected father of a child with parietal foramina, Spruijt et al. (2005) identified an 8-bp deletion in the MSX2 gene (123101.0008). DNA analysis was refused for the proband and her grandparents. Among 5 unrelated families and 6 sporadic cases with parietal foramina, Mavrogiannis et al. (2006) identified 2 different heterozygous mutations in the MSX2 gene in 2 families and 2 different heterozygous mutations in the ALX4 gene (605420.0006; 605420.0007) in 1 family and 1 sporadic case, respectively. Combined with previous reports, mutations in the ALX4 or MSX2 genes had been identified in 11 of 13 familial PFM cases and 1 of 6 sporadic PFM cases. There were no significant genotype/phenotype correlations. Mavrogiannis et al. (2006) concluded that PFM caused by ALX4 and MSX2 have a similar prevalence and are clinically indistinguishable. INHERITANCE \- Autosomal dominant HEAD & NECK Mouth \- Cleft lip \- Cleft palate SKELETAL Skull \- Symmetrical, oval parietal bone defects \- Cranium bifidum SKIN, NAILS, & HAIR Skin \- Scalp defect NEUROLOGIC Central Nervous System \- Headache \- Seizures MISCELLANEOUS \- Genetic heterogeneity \- Parietal foramina-2 (PFM2, 609597 ) are caused by mutations in the ALX4 gene ( 605420 ) \- See also PFM3 on chromosome 4q21-q23 ( 609566 ) MOLECULAR BASIS \- Caused by mutation in the msh homeobox 2 gene (MSX2, 123101.0002 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	PARIETAL FORAMINA 1	c1868598	6,051	omim	https://www.omim.org/entry/168500	2019-09-22T16:36:34	{"doid": ["0060285"], "mesh": ["C566826"], "omim": ["168500"], "orphanet": ["60015"], "synonyms": ["Alternative titles", "PFM", "PARIETAL FORAMINA, SYMMETRIC", "FORAMINA PARIETALIA PERMAGNA", "CATLIN MARKS", "CRANIUM BIFIDUM OCCULTUM", "CRANIUM BIFIDUM, HEREDITARY"], "genereviews": ["NBK1128"]}
Auditory processing disorder Other namesCentral auditory processing disorder SpecialtyAudiology, neurology[1] Auditory processing disorder (APD), rarely known as King-Kopetzky syndrome or auditory disability with normal hearing (ADN), is an umbrella term for a variety of disorders that affect the way the brain processes auditory information.[2] Individuals with APD usually have normal structure and function of the outer, middle, and inner ear (peripheral hearing). However, they cannot process the information they hear in the same way as others do, which leads to difficulties in recognizing and interpreting sounds, especially the sounds composing speech. It is thought that these difficulties arise from dysfunction in the central nervous system. The American Academy of Audiology notes that APD is diagnosed by difficulties in one or more auditory processes known to reflect the function of the central auditory nervous system.[2] It can affect both children and adults. Although the actual prevalence is currently unknown, it has been estimated to be 2–7% in children in US and UK populations.[3] APD can continue into adulthood. Cooper and Gates (1991) estimated the prevalence of adult APD to be 10 to 20%. It has been reported that males are twice as likely to be affected by the disorder as females,[4][5] and that prevalence is higher in the elderly and increases with age.[6] ## Contents * 1 Signs and symptoms * 1.1 Relation to attention deficit hyperactivity disorder * 1.2 Relation to specific language impairment and developmental dyslexia * 2 Causes * 2.1 Acquired * 2.2 Genetics * 2.3 Developmental * 2.4 Somatic * 3 Diagnosis * 3.1 Definitions * 3.2 Types of testing * 3.3 Modality-specificity and controversies * 3.4 Characteristics * 3.5 Subcategories * 4 Treatment * 5 History * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Many people experience problems with learning and day-to-day tasks with difficulties over time. Adults with this disorder[7] can experience the signs and symptoms below: * talk louder than necessary * talk softer than necessary * have trouble remembering a list or sequence * often need words or sentences repeated * have poor ability to memorize information learned by listening * interpret words too literally * need assistance hearing clearly in noisy environments * rely on accommodation and modification strategies * find or request a quiet work space away from others * request written material when attending oral presentations * ask for directions to be given one step at a time ### Relation to attention deficit hyperactivity disorder[edit] It has been discovered that APD and ADHD present overlapping symptoms. Below is a ranked order of behavioral symptoms that are most frequently observed in each disorder. Professionals evaluated the overlap of symptoms between the two disorders. The order below is of symptoms that are almost always observed.[8] This chart shows that although the symptoms listed are different, it is easy to get confused between many of them. ADHD APD 1\. Inattentive 1\. Difficult hearing in background noise 2\. Distracted 2\. Difficulty following oral instructions 3\. Hyperactive 3\. Poor listening skills 4\. Fidgety or restless 4\. Academic difficulties 5\. Hasty or impulsive 5\. Poor auditory association skills 6\. Interrupts or intrudes 6\. Distracted 7\. Inattentive There is a co-occurrence between ADHD and APD. A systematic review published in 2018[9] detailed one study that showed 10% of children with APD have confirmed or suspected ADHD. It also stated that it's sometimes difficult to distinguish the two, since characteristics and symptoms between APD and ADHD tend to overlap. The systematic review mentioned here described this overlap between APD and other behavioral disorders and whether or not it was easy to distinguish those children that solely had auditory processing disorder.[citation needed] ### Relation to specific language impairment and developmental dyslexia[edit] There has been considerable debate over the relationship between APD and Specific language impairment (SLI). SLI is diagnosed when a child has difficulties with understanding or producing spoken language for no obvious cause. The problems cannot be explained in terms of peripheral hearing loss. The child is typically late in starting to talk, and may have problems in producing speech sounds clearly, and in producing or understanding complex sentences. Some theoretical accounts of SLI regard it as the result of auditory processing problems.[10][11] However, this view of SLI is not universally accepted, and others regard the main difficulties in SLI as stemming from problems with higher-level aspects of language processing. Where a child has both auditory and language problems, it can be hard to sort out cause-and-effect.[11] Similarly with developmental dyslexia, there has been considerable interest in the idea that for some children reading problems are downstream consequences of difficulties in rapid auditory processing. Again, cause and effect can be hard to unravel. This is one reason why some experts have recommended using non-verbal auditory tests to diagnose APD.[12] Specifically regarding the neurological factors of dyslexia, the disorder has been linked to polymicrogyria which causes cell migrational problems. This relates to APD because children that have polymicrogyri almost always present deficits on APD testing.[3] It has also been suggested that APD may be related to cluttering,[13] a fluency disorder marked by word and phrase repetitions. It has been found that a higher than expected proportion of individuals diagnosed with SLI and dyslexia on the basis of language and reading tests also perform poorly on tests in which auditory processing skills are tested.[14] APD can be assessed using tests that involve identifying, repeating or discriminating speech, and a child may do poorly because of primary language problems.[15] In a study comparing children with a diagnosis of dyslexia and those with a diagnosis of APD, they found the two groups could not be distinguished.[11][16][17] obtained similar findings in studies comparing children diagnosed with SLI or APD.[18][19] The two groups had very similar profiles. This raises the worrying possibility that the diagnosis that a child receives may be largely a function of the specialist they see: the same child who would be diagnosed with APD by an audiologist may be diagnosed with SLI by a speech-language therapist or with dyslexia by a psychologist.[12] ## Causes[edit] ### Acquired[edit] Acquired APD can be caused by any damage to or dysfunction of the central auditory nervous system and can cause auditory processing problems.[20][21] For an overview of neurological aspects of APD, see Griffiths.[22] ### Genetics[edit] Some studies indicated an increased prevalence of a family history of hearing impairment in these patients. The pattern of results is suggestive that Auditory Processing Disorder may be related to conditions of autosomal dominant inheritance.[23][24][25] The ability to listen to and comprehend multiple messages at the same time is a trait that is heavily influenced by our genes, say federal researchers.[26] These "short circuits in the wiring" sometimes run in families or result from a difficult birth, just like any learning disability.[27] Auditory processing disorder can be associated with conditions affected by genetic traits, such as various developmental disorders. Inheritance of Auditory Processing Disorder refers to whether the condition is inherited from your parents or "runs" in families.[28] Central auditory processing disorder may be hereditary neurological traits from the mother or the father.[29] ### Developmental[edit] In the majority of cases of developmental APD, the cause is unknown. An exception is acquired epileptic aphasia or Landau-Kleffner syndrome, where a child's development regresses, with language comprehension severely affected.[30] The child is often thought to be deaf, but normal peripheral hearing is found. In other cases, suspected or known causes of APD in children include delay in myelin maturation,[31] ectopic (misplaced) cells in the auditory cortical areas,[32] or genetic predisposition.[33] In a family with autosomal dominant epilepsy, seizures which affected the left temporal lobe seemed to cause problems with auditory processing.[34] In another extended family with a high rate of APD, genetic analysis showed a haplotype in chromosome 12 that fully co-segregated with language impairment.[35] Hearing begins in utero, but the central auditory system continues to develop for at least the first decade.[36] There is considerable interest in the idea that disruption to hearing during a sensitive period may have long-term consequences for auditory development.[37] One study showed thalamocortical connectivity in vitro was associated with a time sensitive developmental window and required a specific cell adhesion molecule (lcam5) for proper brain plasticity to occur.[38] This points to connectivity between the thalamus and cortex shortly after being able to hear (in vitro) as at least one critical period for auditory processing. Another study showed that rats reared in a single tone environment during critical periods of development had permanently impaired auditory processing.[39] ‘Bad’ auditory experiences, such as temporary deafness by cochlear removal in rats leads to neuron shrinkage.[36] In a study looking at attention in APD patients, children with one ear blocked developed a strong right-ear advantage but were not able to modulate that advantage during directed-attention tasks.[40] In the 1980s and 1990s, there was considerable interest in the role of chronic Otitis media (middle ear disease or 'glue ear') in causing APD and related language and literacy problems. Otitis media with effusion is a very common childhood disease that causes a fluctuating conductive hearing loss, and there was concern this may disrupt auditory development if it occurred during a sensitive period.[41] Consistent with this, in a sample of young children with chronic ear infections recruited from a hospital otolargyngology department, increased rates of auditory difficulties were found later in childhood.[42] However, this kind of study will suffer from sampling bias because children with otitis media will be more likely to be referred to hospital departments if they are experiencing developmental difficulties. Compared with hospital studies, epidemiological studies, which assesses a whole population for otitis media and then evaluate outcomes, have found much weaker evidence for long-term impacts of otitis media on language outcomes.[43] ### Somatic[edit] It seems that somatic anxiety (that is, physical symptoms of anxiety such as butterflies in the stomach or cotton mouth) and situations of stress may be determinants of speech-hearing disability.[44][45] ## Diagnosis[edit] Questionnaires can be used for the identification of persons with possible auditory processing disorders, as these address common problems of listening. They can help in the decision for pursuing clinical evaluation. One of the most common listening problems is speech recognition in the presence of background noise.[46][47] According to the respondents who participated in a study by Neijenhuis, de Wit, and Luinge (2017),[48] the following symptoms are characteristic in children with listening difficulties, and they are typically problematic with adolescents and adults. They include: * Difficulty hearing in noise * Auditory attention problems * Better understanding in one on one situations * Difficulties in noise localization * Difficulties in remembering oral information According to the New Zealand Guidelines on Auditory Processing Disorders (2017)[49] a checklist of key symptoms of APD or comorbidities that can be used to identify individuals who should be referred for audiological and APD assessment includes, among others: * Difficulty following spoken directions unless they are brief and simple * Difficulty attending to and remembering spoken information * Slowness in processing spoken information * Difficulty understanding in the presence of other sounds * Overwhelmed by complex or “busy” auditory environments e.g. classrooms, shopping malls * Poor listening skills * Insensitivity to tone of voice or other nuances of speech * Acquired brain injury * History of frequent or persistent middle ear disease (otitis media, ‘glue ear’). * Difficulty with language, reading or spelling * Suspicion or diagnosis of dyslexia * Suspicion or diagnosis of language disorder or delay Finally, the New Zealand guidelines state that behavioral checklists and questionnaires should only be used to provide guidance for referrals, for information gathering (for example, prior to assessment or as outcome measures for interventions), and as measures to describe the functional impact of auditory processing disorder. They are not designed for the purpose of diagnosing auditory processing disorders. The New Zealand guidelines indicate that a number of questionnaires have been developed to identify children who might benefit from evaluation of their problems in listening. Examples of available questionnaires include the Fisher’s Auditory Problems Checklist,[50] the Children’s Auditory Performance Scale,[51] the Screening Instrument for Targeting Educational Risk,[52] and the Auditory Processing Domains Questionnaire [53] among others. All of the previous questionnaires were designed for children and none are useful for adolescents and adults.[citation needed] The University of Cincinnati Auditory Processing Inventory (UCAPI) [54] [55] was designed for use with adolescents and adults seeking testing for evaluation of problems with listening and/or to be used following diagnosis of an auditory processing disorder to determine the subject’s status. Following a model described by Zoppo et al. (2015[56]) a 34-item questionnaire was developed that investigates auditory processing abilities in each of the six common areas of complaint in APD (listening and concentration, understanding speech, following spoken instructions, attention, and other.) The final questionnaire was standardized on normally achieving young adults ranging from 18 to 27 years of age. Validation data was acquired from subjects with language-learning or auditory processing disorders who were either self-reported or confirmed by diagnostic testing. A UCAPI total score is calculated by combining the totals from the six listening conditions and provides an overall value to categorize listening abilities. Additionally, analysis of the scores from the six listening conditions provides an auditory profile for the subject. Each listening condition can then be utilized by the professional in making recommendation for diagnosing problem of learning through listening and treatment decisions. The UCAPI provides information on listening problems in various populations that can aid examiners in making recommendations for assessment and management. APD has been defined anatomically in terms of the integrity of the auditory areas of the nervous system.[57] However, children with symptoms of APD typically have no evidence of neurological disease and the diagnosis is made on the basis of performance on behavioral auditory tests. Auditory processing is "what we do with what we hear",[58] and in APD there is a mismatch between peripheral hearing ability (which is typically normal) and ability to interpret or discriminate sounds. Thus in those with no signs of neurological impairment, APD is diagnosed on the basis of auditory tests. There is, however, no consensus as to which tests should be used for diagnosis, as evidenced by the succession of task force reports that have appeared in recent years. The first of these occurred in 1996.[59] This was followed by a conference organized by the American Academy of Audiology.[60] Experts attempting to define diagnostic criteria have to grapple with the problem that a child may do poorly on an auditory test for reasons other than poor auditory perception: for instance, failure could be due to inattention, difficulty in coping with task demands, or limited language ability. In an attempt to rule out at least some of these factors, the American Academy of Audiology conference explicitly advocated that for APD to be diagnosed, the child must have a modality-specific problem, i.e. affecting auditory but not visual processing. However, a committee of the American Speech-Language-Hearing Association subsequently rejected modality-specificity as a defining characteristic of auditory processing disorders.[61] ### Definitions[edit] in 2005 The American Speech-Language-Hearing Association (ASHA) published "Central Auditory Processing Disorders" as an update to the 1996 "Central Auditory Processing: Current Status of Research and Implications for Clinical Practice".[61] The American Academy of Audiology has released more current practice guidelines related to the disorder.[2] ASHA formally defines APA as "a difficulty in the efficiency and effectiveness by which the central nervous system (CNS) utilizes auditory information."[62] In 2018, the British Society of Audiology published a 'position statement and practice guidance' on Auditory Processing Disorder (APD) updated its definition of APD. According to the Society, APD refers to the inability to process speech and on-speech sounds.[63] Auditory processing disorder can be developmental or acquired. It may result from ear infections, head injuries or neurodevelopmental delays that affect processing of auditory information. This can include problems with: "...sound localization and lateralization (see also binaural fusion); auditory discrimination; auditory pattern recognition; temporal aspects of audition, including temporal integration, temporal discrimination (e.g., temporal gap detection), temporal ordering, and temporal masking; auditory performance in competing acoustic signals (including dichotic listening); and auditory performance with degraded acoustic signals".[59] The Committee of UK Medical Professionals Steering the UK Auditory Processing Disorder Research Program have developed the following working definition of Auditory Processing Disorder: "APD results from impaired neural function and is characterized by poor recognition, discrimination, separation, grouping, localization, or ordering of speech sounds. It does not solely result from a deficit in general attention, language or other cognitive processes."[64] ### Types of testing[edit] 1. The SCAN-C[65] for children and SCAN-A [66] for adolescents and adults are the most common tools for screening and diagnosing APD in the USA. Both tests are standardized on a large number of subjects and include validation data on subjects with auditory processing disorders. The SCAN test batteries include screening tests: norm-based criterion-referenced scores; diagnostic tests: scaled scores, percentile ranks and ear advantage scores for all tests except the Gap Detection test. The four tests include four subsets on which the subject scores are derived include: discrimination of monaurally presented single words against background noise (speech in noise), acoustically degraded single words (filtered words), dichotically presented single words and sentences. 2. Random Gap Detection Test (RGDT) is also a standardized test. It assesses an individual’s gap detection threshold of tones and white noise. The exam includes stimuli at four different frequencies (500, 1000, 2000, and 4000 Hz) and white noise clicks of 50 ms duration. It is a useful test because it provides an index of auditory temporal resolution. In children, an overall gap detection threshold greater than 20 ms means they have failed and may have an auditory processing disorder based on abnormal perception of sound in the time domain.[67][68] 3. Gaps in Noise Test (GIN) also measures temporal resolution by testing the patient's gap detection threshold in white noise.[69] 4. Pitch Patterns Sequence Test (PPT) and Duration Patterns Sequence Test (DPT) measure auditory pattern identification. The PPS has s series of three tones presented at either of two pitches (high or low). Meanwhile, the DPS has a series of three tones that vary in duration rather than pitch (long or short). Patients are then asked to describe the pattern of pitches presented.[70] 5. Masking Level Difference (MLD) at 500 Hz measures overlapping temporal processing, binaural processing, and low-redundancy by measuring the difference in threshold of an auditory stimulus when a masking noise is presented in and out of phase.[71] ### Modality-specificity and controversies[edit] This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Auditory processing disorder" – news · newspapers · books · scholar · JSTOR (November 2019) The issue of modality-specificity has led to considerable debate among experts in this field. Cacace and McFarland have argued that APD should be defined as a modality-specific perceptual dysfunction that is not due to peripheral hearing loss.[72][73] They criticise more inclusive conceptualizations of APD as lacking diagnostic specificity.[74] A requirement for modality-specificity could potentially avoid including children whose poor auditory performance is due to general factors such as poor attention or memory.[72][73] Others, however, have argued that a modality-specific approach is too narrow, and that it would miss children who had genuine perceptual problems affecting both visual and auditory processing. It is also impractical, as audiologists do not have access to standardized tests that are visual analogs of auditory tests.[75] The debate over this issue remains unresolved between modality-specific researchers such as Cacace, and associations such as the American Speech-Language-Hearing Association (among others).[61] It is clear, however, that a modality-specific approach will diagnose fewer children with APD than a modality-general one, and that the latter approach runs a risk of including children who fail auditory tests for reasons other than poor auditory processing.[63][61] Although modality-specific testing has been advocated for well over a decade, the visual analog of APD testing has met with sustained resistance from the fields of optometry and ophthalmology.[citation needed][editorializing] Another controversy concerns the fact that most traditional tests of APD use verbal materials.[12] The British Society of Audiology[63] has embraced Moore's (2006) recommendation that tests for APD should assess processing of non-speech sounds.[12] The concern is that if verbal materials are used to test for APD, then children may fail because of limited language ability. An analogy may be drawn with trying to listen to sounds in a foreign language. It is much harder to distinguish between sounds or to remember a sequence of words in a language you do not know well: the problem is not an auditory one, but rather due to lack of expertise in the language.[63] In recent years there have been additional criticisms of some popular tests for diagnosis of APD. Tests that use tape-recorded American English have been shown to over-identify APD in speakers of other forms of English.[76] Performance on a battery of non-verbal auditory tests devised by the Medical Research Council's Institute of Hearing Research was found to be heavily influenced by non-sensory task demands, and indices of APD had low reliability when this was controlled for.[77][78] This research undermines the validity of APD as a distinct entity in its own right and suggests that the use of the term "disorder" itself is unwarranted. In a recent review of such diagnostic issues, it was recommended that children with suspected auditory processing impairments receive a holistic psychometric assessment including general intellectual ability, auditory memory, and attention, phonological processing, language, and literacy.[79] The authors state that "a clearer understanding of the relative contributions of perceptual and non-sensory, unimodal and supramodal factors to performance on psychoacoustic tests may well be the key to unravelling the clinical presentation of these individuals."[79] Depending on how it is defined, APD may share common symptoms with ADD/ADHD, specific language impairment, and autism spectrum disorders. A review showed substantial evidence for atypical processing of auditory information in children with autism.[80] Dawes and Bishop noted how specialists in audiology and speech-language pathology often adopted different approaches to child assessment, and they concluded their review as follows: "We regard it as crucial that these different professional groups work together in carrying out assessment, treatment and management of children and undertaking cross-disciplinary research."[15] In practice, this seems rare.[according to whom?] To ensure that APD is correctly diagnosed, the examiners must differentiate APD from other disorders with similar symptoms. Factors that should be taken into account during the diagnosis are: attention, auditory neuropathy, fatigue, hearing and sensitivity, intellectual and developmental age, medications, motivation, motor skills, native language and language experience, response strategies and decision-making style, and visual acuity.[81] It should also be noted that children under the age of seven cannot be evaluated correctly because their language and auditory processes are still developing. In addition, the presence of APD cannot be evaluated when a child's primary language is not English.[82][ambiguous] ### Characteristics[edit] The American Speech-Language-Hearing Association [83] state that children with (Central) Auditory Processing Disorder often: * have trouble paying attention to and remembering information presented orally, and may cope better with visually acquired information * have problems carrying out multi-step directions given orally; need to hear only one direction at a time * have poor listening skills * need more time to process information * have difficulty learning a new language * have difficulty understanding jokes, sarcasm, and learning songs or nursery rhymes * have language difficulties (e.g., they confuse syllable sequences and have problems developing vocabulary and understanding language) * have difficulty with reading, comprehension, spelling, and vocabulary APD can manifest as problems determining the direction of sounds, difficulty perceiving differences between speech sounds and the sequencing of these sounds into meaningful words, confusing similar sounds such as "hat" with "bat", "there" with "where", etc. Fewer words may be perceived than were actually said, as there can be problems detecting the gaps between words, creating the sense that someone is speaking unfamiliar or nonsense words. In addition, it is common for APD to cause speech errors involving the distortion and substitution of consonant sounds.[84] Those suffering from APD may have problems relating what has been said with its meaning, despite obvious recognition that a word has been said, as well as repetition of the word. Background noise, such as the sound of a radio, television or a noisy bar can make it difficult to impossible to understand speech, since spoken words may sound distorted either into irrelevant words or words that don't exist, depending on the severity of the auditory processing disorder.[85] Using a telephone can be problematic for someone with auditory processing disorder, in comparison with someone with normal auditory processing, due to low quality audio, poor signal, intermittent sounds and the chopping of words. Many who have auditory processing disorder subconsciously develop visual coping strategies, such as lip reading, reading body language, and eye contact, to compensate for their auditory deficit, and these coping strategies are not available when using a telephone.[citation needed] As noted above, the status of APD as a distinct disorder has been queried, especially by speech-language pathologists[86] and psychologists,[87] who note the overlap between clinical profiles of children diagnosed with APD and those with other forms of specific learning disability. Many audiologists, however, would dispute that APD is just an alternative label for dyslexia, SLI, or ADHD, noting that although it often co-occurs with these conditions, it can be found in isolation.[88] ### Subcategories[edit] Based on sensitized measures of auditory dysfunction and on psychological assessment, patients can be subdivided into seven subcategories:[89] 1. middle ear dysfunction 2. mild cochlear pathology 3. central/medial olivocochlear efferent system (MOCS) auditory dysfunction 4. purely psychological problems 5. multiple auditory pathologies 6. combined auditory dysfunction and psychological problems 7. unknown Different subgroups may represent different pathogenic and aetiological factors. Thus, subcategorization provides further understanding of the basis of Auditory Processing Disorder, and hence may guide the rehabilitative management of these patients. This was suggested by Professor Dafydd Stephens and F Zhao at the Welsh Hearing Institute, Cardiff University.[90] ## Treatment[edit] See also: Alternative therapies for developmental and learning disabilities Treatment of APD typically focuses on three primary areas: changing learning environment, developing higher-order skills to compensate for the disorder, and remediation of the auditory deficit itself.[91] However, there is a lack of well-conducted evaluations of intervention using randomized controlled trial methodology. Most evidence for effectiveness adopts weaker standards of evidence, such as showing that performance improves after training. This does not control for possible influences of practice, maturation, or placebo effects. Recent research has shown that practice with basic auditory processing tasks (i.e. auditory training) may improve performance on auditory processing measures[92][93] and phonemic awareness measures.[94] Changes after auditory training have also been recorded at the physiological level.[95][96] Many of these tasks are incorporated into computer-based auditory training programs such as Earobics and Fast ForWord, an adaptive software available at home and in clinics worldwide, but overall, evidence for effectiveness of these computerised interventions in improving language and literacy is not impressive.[97] One small-scale uncontrolled study reported successful outcomes for children with APD using auditory training software.[98] Treating additional issues related to APD can result in success. For example, treatment for phonological disorders (difficulty in speech) can result in success in terms of both the phonological disorder as well as APD. In one study, speech therapy improved auditory evoked potentials (a measure of brain activity in the auditory portions of the brain).[99] While there is evidence that language training is effective for improving APD, there is no current research supporting the following APD treatments: * Auditory Integration Training typically involves a child attending two 30-minute sessions per day for ten days.[100] * Lindamood-Bell Learning Processes (particularly, the Visualizing and Verbalizing program) * Physical activities that require frequent crossing of the midline (e.g., occupational therapy) * Sound Field Amplification * Neuro-Sensory Educational Therapy * Neurofeedback However, use of an individual FM transmitter/receiver system by teachers and students has been shown to produce significant improvements with children over time.[101] ## History[edit] Samuel J. Kopetzky, who first described the condition in 1948. P. F. King, first discussed the etiological factors behind it in 1954.[102] Helmer Myklebust's 1954 study, "Auditory Disorders in Children".[103] suggested auditory processing disorder was separate from language learning difficulties. His work sparked interest in auditory deficits after acquired brain lesions affecting the temporal lobes[104][105] and led to additional work looking at the physiological basis of auditory processing,[106] but it was not until the late seventies and early eighties that research began on APD in depth. In 1977, the first conference on the topic of APD was organized by Robert W. Keith, Ph.D. at the University of Cincinnati. The proceedings of that conference was published by Grune and Stratton under the title "Central Auditory Dysfunction" (Keith RW Ed.) That conference started a new series of studies focusing on APD in children.[107][108][109][110][111] Virtually all tests currently used to diagnose APD originate from this work. These early researchers also invented many of the auditory training approaches, including interhemispheric transfer training and interaural intensity difference training. This period gave us a rough understanding of the causes and possible treatment options for APD. Much of the work in the late nineties and 2000s has been looking to refining testing, developing more sophisticated treatment options, and looking for genetic risk factors for APD. Scientists have worked on improving behavioral tests of auditory function, neuroimaging, electroacoustic, and electrophysiologic testing.[112][113] Working with new technology has led to a number of software programs for auditory training.[114][115] With global awareness of mental disorders and increasing understanding of neuroscience, auditory processing is more in the public and academic consciousness than ever before.[116][117][118][119] ## See also[edit] * Cocktail party effect * Dafydd Stephens * Hearing loss * List of eponymous diseases * Amblyaudia * Auditory verbal agnosia * Cortical deafness * Echoic memory * Language processing * Selective auditory attention * Sensory processing disorders * Selective mutism * Spatial hearing loss * Music-specific disorders ## References[edit] 1. ^ Griffiths, Timothy (2002). "Central Auditory Pathologies". British Medical Bulletin. 63 (63): 107–120. doi:10.1093/bmb/63.1.107. PMID 12324387. 2. ^ a b c American Academy of Audiology. 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PMID 22212767. 99. ^ Leite RA, Wertzner HF, Matas CG (2010). "Long latency auditory evoked potentials in children with phonological disorder". Pró-fono : Revista de Atualização Científica. 22 (4): 561–6. doi:10.1590/s0104-56872010000400034. PMID 21271117. 100. ^ Mudford OC, Cullen C (2004). "Auditory integration training: a critical review". In Jacobson JW, Foxx RM, Mulick JA (eds.). Controversial Therapies for Developmental Disabilities. Routledge. pp. 351–62. ISBN 978-0-8058-4192-3. 101. ^ Sharma, Mridula & Purdy, Suzanne & Kelly, Andrea (2012). "A Randomized Control Trial of Interventions In School-Aged Children with Auditory Processing Disorders". International Journal of Audiology. 51 (7): 506–18. doi:10.3109/14992027.2012.670272. PMID 22512470. S2CID 25414619.CS1 maint: multiple names: authors list (link) 102. ^ "Is there an association between noise exposure and King Kopetzky Syndrome?". Noise and Health. Retrieved 31 July 2010. 103. ^ Myklebust, H. (1954). Auditory disorders in children. New York: Grune & Stratton. 104. ^ Bocca E, Calearo C, Cassinari V (1954). "A new method for testing hearing in temporal lobe tumours; preliminary report". Acta Oto-Laryngologica. 44 (3): 219–21. doi:10.3109/00016485409128700. PMID 13197002. 105. ^ Bocca E, Calearo C, Cassinari V, Migliavacca F (1955). "Testing "cortical" hearing in temporal lobe tumours". Acta Oto-Laryngologica. 45 (4): 289–304. doi:10.3109/00016485509124282. PMID 13275293. 106. ^ Kimura, Doreen (1961). "Cerebral dominance and the perception of verbal stimuli". Canadian Journal of Psychology. 15 (3): 166–171. doi:10.1037/h0083219. ISSN 0008-4255. 107. ^ Katz, J., & Illmer, R. (1972). Auditory perception in children with learning disabilities. In J. Katz (Ed.), Handbook of clinical audiology (pp. 540–563). Baltimore: Williams & Wilkins. 108. ^ Keith, Robert W. (1977). Central auditory dysfunction: University of Cincinnati Medical Center Division of Audiology and Speech Pathology symposium. New York: Grune & Stratton. ISBN 978-0-8089-1061-9. OCLC 3203948. 109. ^ Sweetow RW, Reddell RC (1978). "The use of masking level differences in the identification of children with perceptual problems". J Am Audiol Soc. 4 (2): 52–6. PMID 738915. 110. ^ Manning WH, Johnston KL, Beasley DS (February 1977). "The performance of children with auditory perceptual disorders on a time-compressed speech discrimination measure". J Speech Hear Disord. 42 (1): 77–84. doi:10.1044/jshd.4201.77. PMID 839757. 111. ^ Willeford, J. A. (1977). "Assessing central auditory behavior in children A test battery approach". In Keith, Robert W. (ed.). Central auditory dysfunction. New York: Grune & Stratton. pp. 43–72. ISBN 978-0-8089-1061-9. OCLC 3203948. 112. ^ Jerger J, Thibodeau L, Martin J, et al. (September 2002). "Behavioral and electrophysiologic evidence of auditory processing disorder: a twin study". J Am Acad Audiol. 13 (8): 438–60. doi:10.1055/s-0040-1716007. PMID 12371661. 113. ^ Estes RI, Jerger J, Jacobson G (February 2002). "Reversal of hemispheric asymmetry on auditory tasks in children who are poor listeners". J Am Acad Audiol. 13 (2): 59–71. doi:10.1055/s-0040-1715949. PMID 11895008. 114. ^ Chermak GD, Musiek FE (2002). "Auditory training: Principles and approaches for remediation and managing auditory processing disorders". Seminars in Hearing. 23 (4): 287–295. doi:10.1055/s-2002-35878. ISSN 0734-0451. 115. ^ Musiek F (June 1999). "Habilitation and management of auditory processing disorders: overview of selected procedures". J Am Acad Audiol. 10 (6): 329–42. PMID 10385875. 116. ^ Jerger J, Musiek F (October 2000). "Report of the Consensus Conference on the Diagnosis of Auditory Processing Disorders in School-Aged Children" (PDF). J Am Acad Audiol. 11 (9): 467–74. PMID 11057730. Archived from the original (PDF) on 2013-06-21. Retrieved 2012-05-24. 117. ^ Keith, Robert W. (1981). Central auditory and language disorders in children. San Diego, CA: College-Hill Press. ISBN 978-0-933014-74-9. OCLC 9258682. 118. ^ Katz, Jack; Henderson, Donald; Stecker, Nancy Austin (1992). Central auditory processing: a transdisciplinary view. St. Louis, MO: Mosby Year Book. ISBN 978-1-55664-372-9. OCLC 2587728. 119. ^ Katz, Jack; Stecker, Nancy Austin (1998). Central auditory processing disorders: mostly management. Boston: Allyn and Bacon. ISBN 978-0-205-27361-4. OCLC 246378171. ## External links[edit] * Auditory processing disorder: An overview for the clinician * American Speech-Language-Hearing Association (ASHA) Classification D * ICD-10: H93.2 * ICD-9-CM: 388.45 388.40 * MeSH: D001308 * v * t * e Disorders of hearing and balance Hearing Symptoms * Hearing loss * Excessive response * Tinnitus * Hyperacusis * Phonophobia Disease Loss * Conductive hearing loss * Otosclerosis * Superior canal dehiscence * Sensorineural hearing loss * Presbycusis * Cortical deafness * Nonsyndromic deafness Other * Deafblindness * Wolfram syndrome * Usher syndrome * Auditory processing disorder * Spatial hearing loss Tests * Hearing test * Rinne test * Tone decay test * Weber test * Audiometry * pure tone * visual reinforcement Balance Symptoms * Vertigo * nystagmus Disease * Balance disorder * Peripheral * Ménière's disease * Benign paroxysmal positional vertigo * Labyrinthitis * Labyrinthine fistula Tests * Dix–Hallpike test * Unterberger test * Romberg's test * Vestibulo–ocular reflex * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Auditory processing disorder	c0004310	6,052	wikipedia	https://en.wikipedia.org/wiki/Auditory_processing_disorder	2021-01-18T19:00:28	{"mesh": ["D001308"], "icd-9": ["388.40", "388.45"], "icd-10": ["H93.25"], "wikidata": ["Q433152"]}
Partial pulmonary venous return (PAPVR) is a form of congenital pulmonary venous return (see this term) where one or a few of the pulmonary veins drain into the right atrium or one of its tributaries instead of the left atrium. Some patients can be asymptomatic while others can manifest with non-specific signs such as frequent respiratory infections, fatigue and exertional dyspnea. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Congenital partial pulmonary venous return anomaly	c0158634	6,053	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99124	2021-01-23T17:01:34	{"umls": ["C0158634"], "icd-10": ["Q26.3"]}
Wooden chest syndrome is a rigidity of the chest following the administration of high doses of opioids during anaesthesia.[1] Wooden chest syndrome describes marked muscle rigidity — especially involving the thoracic and abdominal muscles — that is an occasional adverse effect associated with the intravenous administration of lipophilic synthetic opioids such as fentanyl. It can make ventilation difficult, and seems to be reversed by naloxone.[2] Hypoxemia, hypertension, pulmonary hypertension, respiratory acidosis and increased intracranial pressure may supervene.[3] One recent study hypothesized that chest wall rigidity might be at least partially responsible for some deaths related to intravenous injection of fentanyl, which increasingly is appearing in samples of heroin.[2] ## References[edit] 1. ^ Chambers, David; Huang, Christopher; Matthews, Gareth (2014). "Anaesthesia and the Lung". Basic Physiology for Anaesthetists (illustrated ed.). Cambridge: Cambridge University Press. p. 107. ISBN 9781107637825. Retrieved 2015-01-31. 2. ^ a b Gussow, Leon (March 25, 2016). "Is possible chest wall rigidity after illicit intravenous fentanyl administration clinically significant?". The Poison Review. Retrieved 2018-04-01. 3. ^ Tanus-Santos, Jose Eduardo (30 November 1998). "Fentanyl is not best anaesthetic induction agent in rapid sequence intubation". The BMJ. Retrieved 2018-04-01. This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Wooden chest syndrome	None	6,054	wikipedia	https://en.wikipedia.org/wiki/Wooden_chest_syndrome	2021-01-18T18:34:32	{"wikidata": ["Q16873382"]}
Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare immunodeficiency syndrome, with susceptibility to mycobacteria, such as the vaccine against tuberculosis (bacillus Calmette-Guérin (BCG) and environmental mycobacteria. It is characterized by severe, recurrent infections, either systemic (widespread) or localized. It has many subtypes. The most serious types are the autosomal recessive complete interferon gamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2) deficiencies. MSMD due to partial IFN-gammaR1, partial IFN-gammaR2, complete IL-12R-beta1, complete IL12B, complete ISG15, partial STAT1 and partial IRF8 deficiencies and MSMD due to partial X-linked recessive (XR) mutations are less severe subtypes. Only about half of patients with MSMD have an identified genetic cause. Nine genes are known to be responsible for MSMD. Seven of them are inherited in an autosomal recessive or autosomal dominant pattern (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, IRF8 and ISG15 genes) and 2 are X-linked (IKBKG and CYBB genes). BCG vaccination should be avoided in those with MSMD. Treatment includes antibiotics and surgery for lymph node removal in some cases. Hematopoietic stem cell transplantation (HSCT) may be considered in specific cases. Prognosis depends on the specific mutation and the associated disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Mendelian susceptibility to mycobacterial diseases	c3266863	6,055	gard	https://rarediseases.info.nih.gov/diseases/12977/mendelian-susceptibility-to-mycobacterial-diseases	2021-01-18T17:59:09	{"mesh": ["D009165"], "orphanet": ["748"], "synonyms": ["Idiopathic infection caused by BCG or atypical mycobacteria", "Mendelian susceptibility to atypical mycobacteria", "Mendelian susceptibility to mycobacterial diseases", "Mendelian susceptibility to mycobacterial infections", "MSMD"]}
Rare psychological or neurological condition Athymhormic syndrome SpecialtyPsychiatry Athymhormic syndrome (from Ancient Greek θυμός thūmós, "mood" or "affect", and hormḗ, "impulse", "drive" or "appetite"), psychic akinesia, or auto-activation deficit (AAD) is a rare psychopathological and neurological syndrome characterized by extreme passivity, apathy, blunted affect and a profound generalized loss of self-motivation and conscious thought. For example, a patient spent 45 minutes with his hands on a lawn mower, totally unable to initiate the act of mowing. This “kinetic blockade” disappeared instantaneously when his son told him to move.[1] The existence of such symptoms in patients after damage to certain structures in the brain has been used in support of a physical model of motivation in human beings, wherein the limbic loop of the basal ganglia is the initiator of directed action and thought.[2] First described by French neurologist Dominique Laplane in 1982 as "PAP syndrome" (French: perte d'auto-activation psychique, or "loss of psychic autoactivation"), the syndrome is believed to be due to damage to areas of the basal ganglia or frontal cortex, specifically the striatum and globus pallidus, responsible for motivation and executive functions.[3] It may occur without any preexisting psychiatric condition. ## Contents * 1 Symptoms * 2 Diagnosis * 3 See also * 4 References ## Symptoms[edit] It is characterized by an absence of voluntary motion without any apparent motor deficit, and patients often describe a complete mental void or blank. This is accompanied by reduced affect or emotional concern (athymhormy) and often by compulsions, repetitive actions, or tics. After stimulation from the outside, such as a direct command, the patient is able to move normally and carry out complex physical and mental tasks for as long as they are prompted to continue. The symptoms may be differentiated from depression because depression requires the existence of sadness or negative thoughts, while athymhormic patients claim to have complete lack of thoughts, positive or negative. ## Diagnosis[edit] This section is empty. You can help by adding to it. (August 2018) ## See also[edit] * Aboulia * Akinetic mutism * Athymhormia * Huntington's disease * Progressive supranuclear palsy ## References[edit] 1. ^ Laplane, D.; Dubois, B. (2001). "Auto‐Activation deficit: A basal ganglia related syndrome". Mov. Disord. 16 (5): 810–814. doi:10.1002/mds.1185. PMID 11746609. 2. ^ Habib, M. (2004). "Athymhormia and Disorders of Motivation in Basal Ganglia Disease". The Journal of Neuropsychiatry and Clinical Neurosciences. 16 (4): 509–524. doi:10.1176/jnp.16.4.509. PMID 15616180. 3. ^ Bogousslavsky, J.; Cummings, J.L. (2000). Behavior and Mood Disorders in Focal Brain Lesions. Cambridge University Press. ISBN 9780521774826. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Athymhormic syndrome	None	6,056	wikipedia	https://en.wikipedia.org/wiki/Athymhormic_syndrome	2021-01-18T19:05:39	{"wikidata": ["Q4815725"]}
Eosinophilic cystitis SpecialtyUrology Eosinophilic cystitis is a rare condition where eosinophiles are present in the bladder wall.[1] Signs and symptoms are similar to a bladder infection.[1] Its cause is not entirely clear; however, may be linked to food allergies, infections, and medications among others.[2] ## Management[edit] Treatment involves avoiding the trigger if that can be determined.[1] ## Prognosis[edit] Long term outcomes in children are generally good.[1] ## References[edit] 1. ^ a b c d Kramer, ed. by A. Barry Belman; Lowell R. King; Stephen A. (2002). Clinical pediatric urology (4. ed.). London: Dunitz. p. 338. ISBN 9781901865639.CS1 maint: extra text: authors list (link) 2. ^ Popescu, OE; Landas, SK; Haas, GP (Feb 2009). "The spectrum of eosinophilic cystitis in males: case series and literature review". Archives of Pathology & Laboratory Medicine. 133 (2): 289–94. doi:10.1043/1543-2165-133.2.289 (inactive 2021-01-10). PMID 19195972.CS1 maint: DOI inactive as of January 2021 (link) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Eosinophilic cystitis	c0742965	6,057	wikipedia	https://en.wikipedia.org/wiki/Eosinophilic_cystitis	2021-01-18T18:30:16	{"gard": ["6346", "6347"], "umls": ["C0742965"], "wikidata": ["Q16969155"]}
BNAR syndrome is a very rare multiple congenital anomaly syndrome characterized by a bifid nose (see this term) (with bulbous nasal tip but not associated with hypertelorism) with or without the presence of anal defects (i.e. anteriorly placed anus, rectal stenosis or atresia) and renal dysplasia (unilateral or bilateral renal agenesis, see these terms) and without intellectual disability. BNAR syndrome is phenotypically related to Fraser syndrome and oculotrichoanal syndrome (see these terms). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	BNAR syndrome	c2750433	6,058	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=217266	2021-01-23T18:53:40	{"gard": ["10595"], "mesh": ["C567672"], "omim": ["608980"], "umls": ["C2750433"], "icd-10": ["Q87.8"], "synonyms": ["Bifid nose with or without anorectal and renal anomalies"]}
A number sign (#) is used with this entry because of evidence that glucocorticoid deficiency-5 (GCCD5) is caused by homozygous mutation in the TXNRD2 gene (606448) on chromosome 22q11. One such family has been reported. Description Familial glucocorticoid deficiency-5 is characterized by resistance to adrenocorticotropic hormone (ACTH) and isolated glucocorticoid deficiency, with typical biochemical findings of low serum cortisol levels and high plasma ACTH. Patients commonly present with hyperpigmentation (Prasad et al., 2014). For a discussion of genetic heterogeneity of familial glucocorticoid deficiency, see GCCD1 (202200). Clinical Features Prasad et al. (2014) reported a large consanguineous Kashmiri family in which 7 members had isolated glucocorticoid deficiency. The index patient was diagnosed at age 10.8 years, after hyperpigmentation occurred during febrile illnesses. Laboratory evaluation revealed low serum cortisol with elevated plasma ACTH, consistent with ACTH resistance. Her sister was subsequently diagnosed at age 4.5 years, with a 2-year history of hyperpigmentation. The proband had 4 children, 3 of whom were screened at birth and diagnosed with glucocorticoid deficiency between the ages of 1 month and 7 years, including 1 girl whose ACTH level was initially elevated but normalized for a time before she was diagnosed at age 6.9 years. The fourth child had elevated ACTH levels in infancy but later showed normalization and was clinically well at age 7.4 years. The proband's sister had a son who presented at age 1 month with cardiac failure due to truncus arteriosus and ventricular septal defect. During that hospitalization he was also diagnosed with isolated glucocorticoid deficiency. All affected individuals demonstrated a poor cortisol response to ACTH stimulation, requiring glucocorticoid replacement therapy, and all had normal mineralocorticoid production. Molecular Genetics In 7 affected members of a consanguineous Kashmiri family with isolated glucocorticoid deficiency, who were negative for mutation in known GCCD-associated genes, Prasad et al. (2014) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the TXNRD2 gene (Y447X; 606448.0001). The mutation segregated with disease in the family, and family members who were heterozygous for the change were clinically unaffected. The authors noted that none of the family members, heterozygous or homozygous, had any evidence of cardiomyopathy or conduction disease. INHERITANCE \- Autosomal recessive SKIN, NAILS, & HAIR Skin \- Hyperpigmentation during febrile illness ENDOCRINE FEATURES \- Low serum cortisol \- Elevated plasma ACTH \- ACTH resistance MISCELLANEOUS \- Laboratory abnormalities noted in infancy may normalize transiently in childhood \- Based on report of 1 large consanguineous Kashmiri family (last curated December 2017) MOLECULAR BASIS \- Caused by mutation in the thioredoxin reductase-2 gene (TXNRD2, 606448.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	GLUCOCORTICOID DEFICIENCY 5	c4049650	6,059	omim	https://www.omim.org/entry/617825	2019-09-22T15:44:41	{"mesh": ["C565974"], "omim": ["202200", "617825"], "orphanet": ["361"], "synonyms": []}
A number sign (#) is used with this entry because of evidence that Salih myopathy (SALMY), also known as early-onset myopathy with fatal cardiomyopathy (EOMFC), is caused by homozygous or compound heterozygous mutation in the gene encoding titin (TTN; 188840) on chromosome 2q31. Clinical Features Carmignac et al. (2007) reported 5 patients from 2 consanguineous families of Moroccan and Sudanese origin, respectively, with congenital myopathy and fatal dilated cardiomyopathy. All patients showed delayed motor development with symmetric, generalized muscle weakness predominantly of proximal and distal lower limbs. The 3 male sibs of the Moroccan family showed onset in infancy, whereas the 2 sibs of the Sudanese family had onset at birth with neonatal hypotonia. Other features included facial muscle weakness, ptosis, and relative calf hypertrophy. Progressive dilated cardiomyopathy with rhythm disturbances developed between ages 5 and 12 years. Death from cardiomyopathy occurred in all 5 patients; 4 survived into their teenage years. Skeletal muscle biopsies showed minicore-like lesions with mitochondrial depletion and sarcomere disorganization, centralized nuclei, and type 1 fiber predominance. Dystrophic changes were more apparent in the second decade. Cardiac muscle biopsies showed disruption of myocardial architecture, nuclear hypertrophy, and endomysial fibrosis. All parents were clinically unaffected. By Sanger sequencing of the 6 M-line-encoding exons (Mex1-Mex6) in the TTN gene in 31 patients from 23 families segregating congenital core myopathy and primary heart disease, Chauveau et al. (2014) identified homozygous or compound heterozygous mutations in 5 patients from 4 families. The severity of the phenotype varied among the families. All 5 patients had congenital or infantile muscle weakness with axial and distal joint contractures and relatively preserved respiratory function. Muscle biopsies in all showed type 1 fiber predominance or uniformity, and minicore myopathy with central nuclei. In family 1, 2 brothers, born to consanguineous Turkish parents, had moderate to severe elbow and joint contractures. The older brother had an asymptomatic dilated cardiomyopathy at age 19, and his brother had a normal echocardiogram at age 16 years. The patient in family 2 presented with atrial septal defect (ASD) and neonatal hypotonia. She did not walk until age 2 years. She developed elbow and ankle contractures at age 6 and dilated cardiomyopathy at age 16. She also had cardiac septal involvement. The authors considered her phenotype typical of Emery-Dreifuss muscular dystrophy (see 310300). The patient in family 3 presented with ASD and ventricular septal defects (VSD) that required correction in his first year. He developed severe dilated cardiomyopathy at age 13 and underwent cardiac transplantation at age 14. He had mild ankle contractures as well as a cleft soft palate, short webbed neck, hypertelorism, and radioulnar synostosis. Family 4 included 1 affected girl and a female pregnancy termination. The girl was born with a VSD and neonatal hypotonia. She had arthrogryposis, dislocated hips with dysplasia, and elbow, hip, and knee contractures. She had left ventricular noncompaction and required heart transplant at age 4 years. The patients in families 2, 3, and 4 manifested severe scoliosis. None of the parents had any manifestations of myopathy or cardiomyopathy. Molecular Genetics By linkage analysis, followed by candidate gene sequencing, Carmignac et al. (2007) identified 2 different homozygous deletions in the TTN gene (188840.0012 and 188840.0013, respectively) in affected members of 2 unrelated families with early-onset myopathy and fatal cardiomyopathy. The deletions resulted in truncation of the C terminus of the protein, absence of which had been expected to be lethal, and disruption of the sarcomeric M-line protein complex. The consanguineous parents of each family were heterozygous for the respective deletions and were clinically unaffected. Chauveau et al. (2014) identified 7 novel homozygous or compound heterozygous TTN mutations (5 in the M-line and 5 truncating) in 4 of 23 families with Salih myopathy. INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Facial muscle weakness Eyes \- Ptosis CARDIOVASCULAR Heart \- Dilated cardiomyopathy \- Arrhythmia \- Cardiac septal defects SKELETAL \- Joint contractures Spine \- Scoliosis MUSCLE, SOFT TISSUES \- Delayed motor development \- Muscle weakness, generalized, proximal and distal \- Calf hypertrophy \- Muscle biopsy shows centralized nuclei \- Type 1 fiber predominance \- Minicore-like lesions with mitochondrial depletion and sarcomeric disorganization \- Disruption of the M-line \- Dystrophic changes occur later LABORATORY ABNORMALITIES \- Serum creatine kinase may be increased MISCELLANEOUS \- Muscle involvement shows onset at birth or in infancy \- Cardiac involvement occurs between 5 and 12 years \- Sudden death due to cardiomyopathy MOLECULAR BASIS \- Caused by mutation in the titin gene (TTN, 188840.0012 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	SALIH MYOPATHY	c2673677	6,060	omim	https://www.omim.org/entry/611705	2019-09-22T16:03:03	{"mesh": ["C567129"], "omim": ["611705"], "orphanet": ["289377"], "synonyms": ["Alternative titles", "MYOPATHY, EARLY-ONSET, WITH FATAL CARDIOMYOPATHY"], "genereviews": ["NBK83297"]}
Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature due to pre- and postnatal growth delay, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to certain cancers. ## Epidemiology The prevalence is unknown, but around 300 cases have been reported so far. ## Clinical description The skin is usually normal at birth but erythema develops on the cheeks at 3-6 months of age and subsequently spreads to the extremities and buttocks. The trunk and abdomen are generally spared. During the course of the disease, cutaneous atrophy with reticulated areas of hypo- and hyperpigmentation and persistent telangiectasias develop. Other cutaneous manifestations include dental anomalies, nail dystrophy and palmo-plantar hyperkeratotic lesions. The extracutaneous manifestations are clinically heterogeneous and two subforms of RTS have been defined: RTS type 1 (RTS1; see this term) characterized by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTS type 2 (RTS2; see this term) characterized by poikiloderma, congenital bone defects (frontal bossing, saddle nose and radial ray defects: thumb hypo- or aplasia or radial aplasia) and an increased risk of osteosarcoma (see this term) in childhood and cutaneous squamous cell carcinoma later in life. Gastrointestinal (chronic emesis and diarrhea), respiratory, and benign and malignant hematological manifestations (anemia, neutropenia and myelodysplasia), as well as hypogonadism and osteopenia, have been reported in some patients. ## Etiology RTS2 is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (8q24.3; detected in 60-65% of RTS patients), whereas the etiology in RTS1 remains unknown. ## Diagnostic methods Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. ## Differential diagnosis The differential diagnosis should include other causes of childhood poikiloderma and other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, xeroderma pigmentosum, Kindler syndrome, poikiloderma with neutropenia, and dyskeratosis congenita; see these terms), and the allelic disorders, RAPADILINO syndrome (in which radial ray defects are a constant feature, poikiloderma is absent and the risk of malignancy is lower) and Baller-Gerold syndrome (which is associated with craniosynostosis; see these terms). ## Genetic counseling RTS is transmitted in an autosomal recessive manner. Genetic counseling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTS2. ## Management and treatment Management should include laser treatment for the telangiectatic lesions, annual ophthalmic examinations and a radiological survey in case of bone pain, limping or fractures (indicators of osteosarcoma). RTS patients may show increased susceptibility to the adverse effects of chemotherapy, and a higher risk of a secondary malignancy (5% risk of developing skin cancer). ## Prognosis The prognosis in RTS is variable: life expectancy is normal in the absence of cancer, whereas outcomes in patients with malignant pathologies depend on the quality and frequency of cancer screening and treatment. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Rothmund-Thomson syndrome	c0032339	6,061	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2909	2021-01-23T17:07:45	{"gard": ["4392"], "mesh": ["D011038"], "omim": ["268400"], "umls": ["C0032339"], "icd-10": ["Q82.8"], "synonyms": ["Poikiloderma of Rothmund-Thomson", "RTS"]}
Mucopolysaccharidosis type 2 (MPS2, see this term), severe form (MPS2S), is associated with a massive accumulation of glycosaminoglycans and a wide variety of symptoms including a rapidly progressive cognitive decline; it is most often fatal in the second or third decade. ## Epidemiology Prevalence of MPS2 at birth in Europe is 1/166,000, the severe form accounts for at least two-thirds of all cases. ## Clinical description MPS2S presents with the spectrum of symptoms observed in all MSP2 (see this term) cases, often with an earlier presentation. MPS2S patients have a decrease in growth rate in early to mid-childhood, along with respiratory difficulties and a thickening of lips and nostrils as well as an enlarged and protruding tongue (distinctive facies), which may become evident between 2-4 years of age. Psychomotor milestones are delayed, and regression often occurs. Between the ages of 2-6 years patients begin to exhibit aggressive behavior and hyperactivity, often lacking any sense of danger as they follow a course of progressive cognitive decline. Vision may be affected, and progressive hearing loss occurs in most cases. Myocardial thickening and cardiac valve dysfunction are common. Approximately 60-80 % of patients with MPS2 have the severe form of the disease with neurological implications. ## Etiology MPS2 results from iduronate-2-sulfatase (I2S) deficiency, which leads to lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate and heparan sulfate. MPS2S appears to be associated with a complete absence of functional enzyme due to nonsense mutations or complete gene deletions or rearrangements. In most cases, however, prognosis cannot be established by genotype alone. ## Diagnostic methods Diagnosis is based on detection of increased levels of DS and HS in the urine and confirmed by the demonstration of the enzyme deficiency in the serum, leukocytes or fibroblasts, or in dried blood spot samples. Enzymatic activity of another sulfatase should also be assessed. Genetic testing is possible; sequencing must include the entire IDS gene including its promoter region. ## Management and treatment Regular evaluation of patients should be followed by palliative care as is necessary. Cranial shunting to relieve hydrocephalus is often required. Weekly intravenous infusion with recombinant enzyme preparations has been shown to help with somatic symptoms. Intrathecal administration of enzyme replacement therapy holds promise to treat neurological aspects of MSP2; testing of such treatments is ongoing. ## Prognosis Prognosis is poor. MPS2S is most often fatal within the second or third decade of life, due to obstructive airway disease, infection, or cardiac failure due to valve dysfunction, pulmonary hypertension or cardiomyopathy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Mucopolysaccharidosis type 2, severe form	c0026705	6,062	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=217085	2021-01-23T18:09:55	{"mesh": ["D016532"], "omim": ["309900"], "icd-10": ["E76.1"], "synonyms": ["Hunter syndrome type A", "Iduronate 2-sulfatase deficiency type A", "MPS2A", "MPSIIA", "Mucopolysaccharidosis type 2A", "Mucopolysaccharidosis type II, severe form", "Mucopolysaccharidosis type IIA"]}
A genetic syndrome with limb reduction defects characterized by skeletal abnormalities of the upper limbs and mild-to-severe congenital cardiac defects. ## Epidemiology Holt-Oram syndrome (HOS) prevalence is estimated at 1/ 100,000 live births (in Hungary), but various cases have been published worldwide. ## Clinical description The clinical picture of HOS covers a wide spectrum of upper extremity defects, always including the radial ray, and cardiac defects. Radial ray upper limb anomalies include carpal bone malformation(s) as well as triphalangeal or absent thumb(s), phocomelia, hypoplasia or aplasia involving the radius often resulting in unequal arm lengths, transverse upper limb defects including abnormal forearm pronation and supination. Patients may have more severe left than right upper-limb abnormalities. Most frequent congenital cardiac malformations observed are atrial septal defect, ostium secundum type (ASD) and ventricular septal defect (VSD). Conduction abnormalities like paroxysmal atrial fibrillation, sometimes associated with various degrees of atrioventricular block, have been reported. Other variable anomalies reported include craniofacial, axillary, tracheal, vertebral and lower-limb anomalies, as well as deafness, abdominal situs inversus and renal abnormalities, but in many cases these findings reflect phenocopy syndromes rather than HOS itself. ## Etiology HOS is caused by a mutation in the TBX5 gene located on the long arm of chromosome 12 (12q24.1). The TBX5 gene encodes T-box5, a transcription factor regulating the expression of other genes in developing heart and limbs. More than 85% of the clinically diagnosed HOS individuals carry a TBX5 mutation. ## Diagnostic methods Diagnosis of HOS is based on clinical findings and family history. It can be confirmed by molecular genetic analyses. ## Differential diagnosis Differential diagnosis includes heart-hand syndrome type 2, heart-hand syndrome type 3, brachydactyly-long thumb, SAL4-related disorders (Okihiro and acro-renal-ocular syndrome), ulnar-mammary syndrome, Slovenian type heart-hand syndrome, Fanconi anemia, distal 22q11.2 microdeletion syndrome, VACTERL association, thalidomide embryopathy, fetal valproate syndrome. ## Antenatal diagnosis Prenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known HOS mutation. In women with HOS, cardiac defects should be evaluated by a cardiologist to determine what monitoring and care may be needed during pregnancy. ## Genetic counseling The majority of the HOS mutations occur de novo. HOS is inherited in an autosomal dominant manner with complete penetrance for upper-limb malformations, and 75% penetrance for congenital heart malformations and with variable expressivity leading to a wide spectrum of phenotypes. Genetic counseling should be offered to parents with a TBX5 mutation informing them of their 50% risk of transmitting it on to their children. Molecular genetic testing is not sufficient to precisely predict the severity of upper-limb and congenital heart anomalies. ## Management and treatment Management is multidisciplinary and includes geneticists, cardiologists, orthopedic surgeons and pediatric orthopedics as well as social support networks. Patients with advanced heart block may require a permanent pacemaker. An echocardiogram is recommended every one to five years if cardiac defects are present. Electrocardiograms (EKGs) are recommended annually for adults. ## Prognosis Prognosis is variable. Functional impact in everyday life is based on the type and severity of upper-limb anomalies. Life expectancy depends on the severity of cardiac anomalies. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Holt-Oram syndrome	c0265264	6,063	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=392	2021-01-23T18:24:10	{"gard": ["6666"], "mesh": ["C535326"], "omim": ["142900"], "umls": ["C0265264"], "icd-10": ["Q87.2"], "synonyms": ["Atriodigital dysplasia type 1", "HOS", "Heart-hand syndrome type 1"]}
Salivary peroxidase is polymorphic; leukocyte peroxidase is not (Azen, 1977). Azen concluded that homozygosity for a recessive gene determines a phenotype of fast electrophoretic mobility (SAPX-1). SAPX-2 and SAPX-3 phenotypes are each determined by a dominant allele at the locus of the recessive allele. Furthermore, Azen (1977) found precise correlation between acid protein types (Pa; 168730) and peroxidase types. This suggested to him that the peroxidase polymorphism is due not to mutation in its structural gene but to modification of the SAPX-1 gene product by the products of the Pa locus. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	PEROXIDASE, SALIVARY	c1868425	6,064	omim	https://www.omim.org/entry/170990	2019-09-22T16:36:23	{"omim": ["170990"]}
A number sign (#) is used with this entry because this form of limb-girdle muscular dystrophy-dystroglycanopathy (type C4; MDDGC4), also known as LGMDR13 and LGMD2M, is caused by homozygous or compound heterozygous mutation in the gene encoding fukutin (FKTN; 607440) on chromosome 9q31. Mutation in the FKTN gene can also cause a severe muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A4; MDDGA4; 253800) and a form of congenital muscular dystrophy-dystroglycanopathy without mental retardation (type B4; MDDGB4; 613152). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308). Description MDDGC4 is an autosomal recessive muscular dystrophy with onset in infancy or early childhood. Cognition and brain structure are usually normal (Godfrey et al., 2006). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009). Clinical Features Godfrey et al. (2006) reported 3 children from 2 unrelated families with autosomal recessive limb-girdle muscular dystrophy. All developed hypotonia and muscle weakness in infancy between ages 4 and 10 months. Two patients presented with severe acute motor deterioration after febrile viral illnesses; the third patient already had motor symptoms but also showed deterioration after a febrile illness at age 3 years. The patients showed mainly proximal muscle weakness with delayed motor development, decreased endurance, frequent falls, proximal muscle weakness, hypertrophy of lower limb muscles, and increased serum creatine kinase. All 3 patients eventually achieved independent ambulation. Skeletal muscle biopsies showed virtually absent glycosylation of alpha-dystroglycan and dystrophic features with mild macrophage infiltration. All patients had normal intellectual development and normal brain structure, and responded favorably to steroid treatment. Godfrey et al. (2007) identified 5 patients with FKTN-related limb-girdle muscular dystrophy, including 2 pairs of sibs, among 92 probands with muscular dystrophy and evidence of a dystroglycanopathy. Age at onset ranged from 4 months to 4 years, and all had normal cognition. Motor achievement varied: 3 achieved walking, and 2 running. Two patients had contractures, and most had muscle hypertrophy. Brain MRI was essentially normal, but 1 patient had mild hydrocephalus. Some of the patients had been reported by Godfrey et al. (2006). Puckett et al. (2009) reported 2 brothers of Japanese and Caucasian ancestry with limb-girdle muscular dystrophy. The younger brother showed poor growth in infancy and muscle weakness at 21 months. Physical examination showed pectus excavatum, modified Gowers maneuver, and decreased deep tendon reflexes. There was no evidence of calf hypertrophy or cardiac involvement, and cognitive and motor development were normal. Although calf hypertrophy was evident within the next year, the patient's physical examination was unchanged at age 5 years. The older brother was referred at age 4 years. He had normal motor development and subtle muscle abnormalities, including mild hypotonia, decreased muscle strength, calf hypertrophy, partial Gowers maneuver, and decreased deep tendon reflexes. He later developed lumbar lordosis, pectus excavatum, and waddling gait. Both patients had increased serum creatine kinase. Both remained ambulant at ages 4 and 6 years. Skeletal muscle biopsy of 1 patient showed mild dystrophic changes, with small numbers of necrotic and regenerating myofibers and hypoglycosylated alpha-dystroglycan. Vuillaumier-Barrot et al. (2009) reported a girl, born of consanguineous Turkish parents, with a moderately severe form of muscular dystrophy. She had delayed motor development, pes equinovarus, increased serum creatine kinase, generalized proximal muscle weakness, and diffuse muscle wasting of the calves. The disorder was progressive, and she lost ambulation at 11 years and developed contractures. Intelligence and brain MRI were normal. Muscle biopsy showed dystrophic changes and decreased glycosylated alpha-dystroglycan. Genetic analysis revealed a homozygous R307Q mutation in the FKTN gene (607440.0009). The authors also reported an unrelated French boy with FKTN-related muscular dystrophy who began to walk at 15 months and had increased serum creatine kinase. At age 7 years, he had calf hypertrophy and normal gait, and complained of episodic myalgia after effort. He was able to run, swim, and ride a bicycle without difficulty. Both patients had normal brain MRI and intelligence, and neither had signs of cardiac involvement. Molecular Genetics In 3 patients with limb-girdle muscular dystrophy, Godfrey et al. (2006) identified compound heterozygosity for 2 mutations in the FKTN gene (607440.0005; 607440.0008; 607440.0009). The authors noted that the phenotype was much less severe than that observed in the allelic disorder Fukuyama congenital muscular dystrophy (FCMD; 253800). In 2 brothers of Japanese and Caucasian ancestry with limb-girdle muscular dystrophy, Puckett et al. (2009) identified compound heterozygosity for 2 mutations in the FKTN gene (A114T, 607440.0014 and F176S, 607440.0015). One of the mutations (A114T) had been reported in 2 sibs with limb-girdle muscular dystrophy (Godfrey et al., 2007). Mercuri et al. (2009) identified compound heterozygosity for 2 mutations in the FKTN gene (R307Q; 607440.0009 and 42delG; 607440.0019) in 1 of 81 Italian patients with congenital muscular dystrophy associated with defective glycosylation of alpha-dystroglycan. The patient did not have mental retardation and had no structural brain abnormalities. Nomenclature Godfrey et al. (2006) originally referred to this disorder as LGMD2L. However, since an LGMD locus on chromosome 11p13-p12 had already been designated LGMD2L (see Jarry et al., 2007; 611307), LGMD due to mutation in the FKTN gene was referred to as 'LGMD2M.' The disorder is now designated MDDGC4. INHERITANCE \- Autosomal recessive CHEST External Features \- Pectus excavatum SKELETAL \- Contractures Spine \- Lordosis Feet \- Pes equinovarus (1 patient) MUSCLE, SOFT TISSUES \- Muscular dystrophy \- Hypotonia \- Delayed motor development \- Proximal muscle weakness \- Gowers sign \- Muscle hypertrophy \- Patients achieve independent ambulation, but may lose it \- Dystrophic features seen on muscle biopsy \- Abnormal glycosylation of alpha-dystroglycan seen on muscle biopsy NEUROLOGIC Central Nervous System \- No central nervous system abnormalities Peripheral Nervous System \- Hyporeflexia LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Onset in infancy \- Variable severity \- Progressive disorder \- Symptoms are aggravated by febrile illness \- Good response to steroid treatment MOLECULAR BASIS \- Caused by mutation in the fukutin gene (FKTN, 607440.0005 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 4	c1969040	6,065	omim	https://www.omim.org/entry/611588	2019-09-22T16:03:06	{"doid": ["0110296"], "mesh": ["C566912"], "omim": ["611588"], "orphanet": ["206554"], "synonyms": ["Alternative titles", "MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 13", "MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2M"]}
Gartner's duct cyst Gross pathology of Gartner's duct cyst SpecialtyGynecology A Gartner's duct cyst (sometimes incorrectly referred to as vaginal inclusion cyst) is a benign vaginal cyst that originates from the Gartner's duct, which is a vestigial remnant of the mesonephric duct (wolffian duct) in females.[1][2] They are typically small asymptomatic cysts that occur along the lateral walls of the vagina, following the course of the duct. They can present in adolescence with painful menstruation (dysmenorrhea) or difficulty inserting a tampon. They can also enlarge to substantial proportions and be mistaken for urethral diverticulum or cystocele.[3][4] In some rare instances, they can be congenital.[2] There is a small association between Gartner's duct cysts and metanephric urinary anomalies, such as ectopic ureter and ipsilateral renal hypoplasia.[5] Symptoms of a Gartner's duct cyst include: infections, bladder dysfunction, abdominal pain, vaginal discharge, and urinary incontinence.[6] The size of the cyst is usually less than 2 cm. On T2-weighted imaging, it manifests as hyperintense signal as most of its contents are fluid in nature. If the contents of the cyst are blood or protenanous, it will show high T1 signal and low T2 signal.[7] ## References[edit] 1. ^ Hoogendam JP, Smink M (April 2017). "Gartner's Duct Cyst". The New England Journal of Medicine. 376 (14): e27. doi:10.1056/NEJMicm1609983. PMID 28379795. 2. ^ a b Tiwari C, Shah H, Desale J, Waghmare M (2017). "Neonatal Gartner Duct Cyst: Two Case Reports and Literature Review". Developmental Period Medicine. 21 (1): 35–37. PMID 28551690. 3. ^ Eilber KS, Raz S (September 2003). "Benign cystic lesions of the vagina: a literature review". The Journal of Urology. 170 (3): 717–22. doi:10.1097/01.ju.0000062543.99821.a2. PMID 12913681. 4. ^ Arumugam A, Kumar G, Si L, Vijayananthan A (October 2007). "Gartner duct cyst in pregnancy presenting as a prolapsing pelvic mass". Biomedical Imaging and Intervention Journal. 3 (4): e46. doi:10.2349/biij.3.4.e46. PMC 3097688. PMID 21614298. 5. ^ Currarino G (November 1982). "Single vaginal ectopic ureter and Gartner's duct cyst with ipsilateral renal hypoplasia and dysplasia (or agenesis)". The Journal of Urology. 128 (5): 988–93. doi:10.1016/S0022-5347(17)53311-X. PMID 7176066. 6. ^ Rios SS, Pereira LC, Santos CB, Chen AC, Chen JR, de Fátima B, Vogt M (June 2016). "Conservative treatment and follow-up of vaginal Gartner's duct cysts: a case series". Journal of Medical Case Reports. 10 (1): 147. doi:10.1186/s13256-016-0936-1. PMC 4890494. PMID 27256294. 7. ^ Chaudhari VV, Patel MK, Douek M, Raman SS (November 2010). "MR imaging and US of female urethral and periurethral disease". Radiographics. 30 (7): 1857–74. doi:10.1148/rg.307105054. PMID 21057124. ## External links[edit] Classification D * ICD-10: Q52.4 * ICD-9-CM: 752.41 * DiseasesDB: 30725 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Gartner's duct cyst	c0221366	6,066	wikipedia	https://en.wikipedia.org/wiki/Gartner%27s_duct_cyst	2021-01-18T18:49:51	{"wikidata": ["Q5524429"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive intellectual developmental disorder-70 (MRT70) is caused by homozygous mutation in the RSRC1 gene (613352) on chromosome 3q25. Description MRT70 is characterized primarily by impaired intellectual development. Mild facial dysmorphism, febrile seizures, and behavioral abnormalities have been reported in some patients (Maddirevula et al., 2018; Perez et al., 2018). Clinical Features Maddirevula et al. (2018) described 3 affected children from a consanguineous Malaysian family with cognitive impairment, no dysmorphic features, and normal brain MRIs. One sib was reported to have had febrile seizures. Perez et al. (2018) described a consanguineous Bedouin kindred with 5 children who presented with apparently autosomal recessive severe global developmental delay with no regression, impaired intellectual development with speech delay, aberrant behavior, and mild generalized hypotonia. All patients had mild to moderate intellectual disability with walking at age 3 to 4 years and verbal expression of only a few single words even in adolescence. These patients had mild facial dysmorphisms described as a broad nasal bridge, slight hypertelorism, and retrognathia with an open mouth and drooling. All children had febrile seizures during childhood, and one developed focal seizures with impaired awareness that occasionally progressed to bilateral tonic-clonic seizures that were effectively treated with valproic acid. While all affected individuals had deficits in fine motor skills and incontinence, none had abnormalities in coordination. Behavioral abnormalities included temper tantrums, self-harm infliction, and attention deficit hyperactivity disorder (ADHD). One of the 5 sibs had autistic features. The remainder of physical and neurologic exams, ophthalmologic and hearing tests, and brain MRIs were normal. Inheritance The transmission pattern of MRT70 in the families reported by Maddirevula et al. (2018) and Perez et al. (2018) was consistent with autosomal recessive inheritance. Molecular Genetics Maddirevula et al. (2018) reported 3 sibs with MRT70 with a homozygous nonsense mutation in the RSRC1 gene (R90X; 613352.0001). Perez et al. (2018) reported 5 sibs with MRT70 with a homozygous nonsense mutation in the RSRC1 gene (R69X; 613352.0002). INHERITANCE \- Autosomal recessive HEAD & NECK Face \- Retrognathia Eyes \- Hypertelorism Nose \- Broad nasal bridge GENITOURINARY Bladder \- Incontinence NEUROLOGIC Central Nervous System \- Intellectual disability, mild-to-moderate \- Motor developmental delay \- Speech delay \- Febrile seizures (in childhood) \- Deficits in fine motor skills Behavioral Psychiatric Manifestations \- Temper tantrums \- Self-harm behaviors \- Attention deficit hyperactivity disorder (ADHD) \- Autistic features (in 1 patient) MISCELLANEOUS \- Five Bedouin sibs and 3 Malaysian sibs have been reported (last curated April 2019) \- Variable features may be present MOLECULAR BASIS \- Caused by mutation in the arginine/serine-rich coiled-coil protein 1 gene (RSRC1, 613352.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 70	None	6,067	omim	https://www.omim.org/entry/618402	2019-09-22T15:42:08	{"omim": ["618402"], "orphanet": ["88616"], "synonyms": ["Alternative titles", "NS-ARID", "AR-NSID", "MENTAL RETARDATION, AUTOSOMAL RECESSIVE 70"]}
## Clinical Features Mievis et al. (1996) described a possibly distinct syndrome in 2 brothers born of nonconsanguineous healthy parents. The older brother exhibited short stature, slender trunk with a low chest circumference, relatively large head, triangular face, and retromicrognathia. At 10.5 years of age, his height was 104 cm. Roentgenographic studies showed delay in epiphyseal maturation, unusual form of metaphyses, and narrow thoracic cage. The second brother, who had similar manifestations and horseshoe kidney, died immediately after birth. Histologic analysis showed growth plates with thick and dense islets of calcified cartilage. Mievis et al. (1996) suggested that this complex is different from low birth weight syndromes, e.g., Russell-Silver syndrome (268650) and 3M syndrome (273750), and from other metaphyseal chondrodysplasias. Autosomal or X-linked recessive inheritance is possible. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Slender trunk HEAD & NECK Head \- Large head Face \- Triangular face \- Retromicrognathia CHEST External Features \- Low chest circumference \- Narrow thoracic cage GENITOURINARY Kidneys \- Horseshoe kidney SKELETAL Limbs \- Delayed epiphyseal maturation \- Unusual metaphyses \- Thick growth plates with dense islets of calcified cartilage MISCELLANEOUS \- Possible X-linked inheritance ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	SHORT STATURE SYNDROME, BRUSSELS TYPE	c1832439	6,068	omim	https://www.omim.org/entry/601350	2019-09-22T16:14:59	{"mesh": ["C537121"], "omim": ["601350"], "orphanet": ["2867"]}
Poland syndrome Other namesPoland's syndrome, Poland's syndactyly, Poland sequence, Poland's anomaly, unilateral defect of pectoralis major and syndactyly of the hand[1] Missing right breast and right pectoralis major muscle in Poland syndrome[2] SpecialtyMedical genetics SymptomsUnderdeveloped chest muscle and short webbed fingers on one side[3][1] Usual onsetAt birth[1] CausesUnknown[1] Diagnostic methodBased on symptoms[4] Differential diagnosisMoebius syndrome, Hanhart syndrome[4] TreatmentSurgical correction[3] Frequency1 in 20,000 newborns[1] Poland syndrome is a birth defect characterized by an underdeveloped chest muscle and short webbed fingers on one side of the body.[3][1] Short ribs, less fat, and breast and nipple abnormalities may also occur on that side.[1] Typically the right side is involved.[3] People generally have normal movement and health.[1] The cause is unknown.[1] One theory is that it is due to disruption of blood flow during development before birth.[1] The condition is generally not inherited from a person's parents.[1] No genes that contribute to the disorder have been identified.[1] Diagnosis is based on symptoms.[4] Often people remain undiagnosed and some may not realize they are affected until puberty.[3] Treatment depends on the severity and may include surgical correction.[3] About 1 in 20,000 newborns are affected.[1] Males are affected twice as often as females.[1] It is named after Alfred Poland, who described the condition when he was a student in 1841.[4][5] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 4.1 Technique * 4.2 Surgery * 5 Epidemiology * 6 History * 7 Notable cases * 8 References * 9 External links ## Signs and symptoms[edit] Right hand symbrachydactyly in Poland syndrome[2] Male with Poland syndrome showing absent left pectoral A list of the common side effects broken down by frequency.[3] Very frequent * Abnormal gastrointestinal tract * Absent pectoral muscles * Brachydactyly (Short fingers) * Dextrocardia * Diaphragmatic hernia/defect * Humerus absent/abnormal * Liver/biliary tract anomalies * Maternal diabetes * Oligodactyly/missing fingers * Radius absent/abnormal * Rhizomelic micromelia (relatively shorter proximal segment of the limbs compared to the middle and the distal segments) * Sparsity or abnormality of axillary hair on affected side * Syndactyly of fingers (webbing) * Ulna absent/abnormal * Upper limb asymmetry * Abnormal rib * Simian crease on affected side Frequent * Hypoplastic/absent nipples * Scapula anomaly Occasional * Agenesis/hypoplasia of kidneys * Encephalocele/exencephaly * Abnormal morphology of hypothalamic-hypophyseal axis * Abnormal function of hypothalamic-hypophyseal axis * Microcephaly * Preaxial polydactyly * Ureteric anomalies (reflux/duplex system) * Vertebral segmentation anomaly It is usually considered a unilateral condition. Some have claimed that the term can be applied in bilateral presentation,[6] but others recommend using alternate terminology in those cases.[1] ## Causes[edit] The cause of Poland syndrome is unknown. However, an interruption of the embryonic blood supply to the arteries that lie under the collarbone (subclavian arteries) at about the 46th day of embryonic development is the prevailing theory.[7] The subclavian arteries normally supply blood to embryonic tissues that give rise to the chest wall and hand. Variations in the site and extent of the disruption may explain the range of signs and symptoms that occur in Poland syndrome. Abnormality of an embryonic structure called the apical ectodermal ridge, which helps direct early limb development, may also be involved in this disorder.[8] ## Diagnosis[edit] The person's largest cavernous malformation is shown in the left frontal pole. This lesion has classic signs of hemorrhage (white arrows). More lesions compatible with cavernous malformations in other areas of the brain can also be observed (arrowheads). Poland syndrome.[2] Mammogram showing absence of the pectoralis major muscle and distortion on the left side. Right side is normal. Poland syndrome is usually diagnosed at birth, based upon the physical characteristics. Imaging techniques such as a CT scan may reveal the extent to which the muscles are affected.[9] The syndrome varies in severity and as such is often not reported until puberty, when lopsided growth becomes apparent.[10] ## Treatment[edit] ### Technique[edit] The complete or partial absence of the pectoralis muscle is the malformation that defines Poland syndrome. It can be treated by inserting a custom implant designed by CAD (computer aided design).[11] A 3D reconstruction of the patient's chest is performed from a medical scanner to design a virtual implant perfectly adapted to the anatomy of each one.[12] The implant is made of medical silicone unbreakable rubber. This treatment is purely cosmetic and does not make up for the patient's imbalanced upper body strength.[citation needed] The Poland syndrome malformations being morphological, correction by custom implant is a first-line treatment.[13] This technique allows a wide variety of patients to be treated with good outcomes. Poland Syndrome can be associated with bones, subcutaneous and mammary atrophy: if the first, as for pectus excavatum, is successfully corrected by a custom implant, the others can require surgical intervention such as lipofilling or silicone breast implant, in a second operation.[citation needed] ### Surgery[edit] The surgery takes place under general anaesthesia and lasts less than 1 hour. The surgeon prepares the locus to the size of the implant after performing an 8-cm axillary incision and inserts the implant beneath the skin. The closure is made in two planes.[citation needed] The implant will replace the pectoralis major muscle, thus enabling the thorax to be symmetrical and, in women, the breast as well. If necessary, especially in the case of women, a second operation will complement the result by the implantation of a breast implant and / or lipofilling.[citation needed] Lipomodelling is progressively used in the correction of breast and chest wall deformities. In Poland syndrome, this technique appears to be a major advance that will probably revolutionize the treatment of severe cases. This is mainly due to its ability to achieve previously unachievable quality of reconstruction with minimal scarring.[14] ## Epidemiology[edit] Poland syndrome affects males three times as often as females and affects the right side of the body twice as often as the left.[15] The incidence is estimated to range from one in 7,000 to one in 100,000 live births.[16] ## History[edit] Alfred Poland's original description of the syndrome. It was named in 1962 by Patrick Clarkson, a New Zealand-born British plastic surgeon working at Guy's Hospital and Queen Mary's Hospital, London. He noticed that three of his patients had both a hand deformity and an underdeveloped breast on the same side. He discussed this with his colleague at Guy's Hospital, Dr Philip Evans, who agreed that the syndrome was "not widely appreciated". Clarkson found a reference to a similar deformity published by Alfred Poland, over a hundred years earlier in Guy's Hospital reports, in 1841.[17] Clarkson was able to find the hand specimen dissected by Poland, which was still held in the hospital pathology museum.[citation needed] Poland had dissected a convict known as George Elt, who was said to be unable to draw his hand across his chest. Poland noted the chest wall deformity, and this was illustrated in his article; the hand was also dissected and preserved for posterity in Guy's Hospital museum where it remains today. It cannot be truly said that Poland described this syndrome because he only described one isolated case. Clarkson published his series of three cases and named the syndrome after Poland in his article.[18] According to the National Institute of Healh, Poland Syndrome affects 1 in 20,000 newborns (more males than females).[19] ## Notable cases[edit] * TV presenter Jeremy Beadle (1948–2008) was known for having this condition. His Poland syndrome manifested itself in the form of his disproportionately small right hand.[20] * Olympic boxer Jérôme Thomas is also affected by Poland syndrome, as his left arm and hand are significantly shorter and smaller than his right. Thomas also lacks a left pectoral muscle. * PGA Tour golfer Bryce Molder has Poland syndrome, with an absent left pectoral muscle and a small left hand. Several surgeries in his childhood repaired syndactyly on the left hand.[21] * Actor Ted Danson, famous for starring in the TV show Cheers, admitted he had the condition in 2000 to Orange Coast magazine and said that he was bullied as a child because of it.[22] * Formula One World Champion Fernando Alonso is affected by Poland syndrome; he is missing the right pectoral muscle.[23] * Cricketer Lewis Hatchett was born with Poland syndrome.[24] * Australian Paralympian Mathew Silcocks is affected by Poland syndrome.[25] * Hailey Dawson of Nevada (born 2010) has a missing right pectoral muscle and is missing three fingers on her right hand due to the condition. She has thrown out the ceremonial first pitch at all 30 Major League Baseball parks, using a 3D-printed robotic right hand fitted for her by engineers at the University of Nevada, Las Vegas. [26][27][28] ## References[edit] 1. ^ a b c d e f g h i j k l m n o Reference, Genetics Home (9 October 2018). "Poland syndrome". Genetics Home Reference. 2. ^ a b c Lizarraga, Karlo J; De Salles, Antonio AF (20 September 2011). "Multiple cavernous malformations presenting in a patient with Poland syndrome: A case report". Journal of Medical Case Reports. 5 (1): 469. doi:10.1186/1752-1947-5-469. PMC 3195104. PMID 21933407. 3. ^ a b c d e f g "Poland syndrome". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2016. Retrieved 16 October 2018. 4. ^ a b c d "Poland Syndrome". NORD (National Organization for Rare Disorders). 2007. Retrieved 16 October 2018. 5. ^ Weinzweig, Jeffrey (2010). Plastic Surgery Secrets Plus E-Book. Elsevier Health Sciences. p. 774. ISBN 978-0323085908. 6. ^ Karnak I., Tanyel F. C., Tunçbilek E., Unsal M., Büyükpamukçu N. (February 1998). "Bilateral Poland anomaly". Am. J. Med. Genet. 75 (5): 505–07. doi:10.1002/(SICI)1096-8628(19980217)75:5<505::AID-AJMG9>3.0.CO;2-L. PMID 9489794.CS1 maint: uses authors parameter (link) 7. ^ Poullin P., Toussirot E., Schiano A., Serratrice G. (1992). "[Complete and dissociated forms of Poland's syndrome (5 cases)]". Rev Rhum Mal Osteoartic. 59 (2): 114–20. PMID 1604222.CS1 maint: uses authors parameter (link) 8. ^ "Poland Syndrome". Genetics Home Reference. Retrieved 12 December 2014. 9. ^ "Poland Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2018-03-18. 10. ^ "Poland syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-03-18. 11. ^ J.-P. Chavoin; A. André; E. Bozonnet; A. Teisseyre; J. Arrue; B. Moreno; D. Glangloff; J-.L. Grolleau; I. Garrido (2010). "Mammary implant selection or chest implants fabrication with computer help". Annales de Chirurgie Plastique Esthétique. 55: 471–480. 12. ^ "Pectus Excavatum & Poland Syndrome treatment". AnatomikModeling. 13. ^ Chichery A.; Jalbert F.; Foucras L.; Grolleau J.-L.; Chavoin J.-P. (2006). "Syndrome de Poland". EMC - Techniques Chirurgicales - Chirurgie Plastique Reconstructrice et Esthétique. 1 (3): 1–17. doi:10.1016/S1286-9325(06)44494-0. 14. ^ Emmanuel Delay, Libor Streit, Gilles Toussoun, Sophie La Marca, C. Ho Quoc. (January 2013). "Lipomodelling: An important advance in breast surgery". Acta Chirurgiae Plasticae. 55 (2): 34–43. PMID 24467681 – via ResearchGate.CS1 maint: multiple names: authors list (link) 15. ^ "Learning about Poland Anomaly". Retrieved 2007-02-09. 16. ^ Fokin A, Robicsek F (2002). "Poland's syndrome revisited". Ann Thorac Surg. 74 (6): 2218–25. doi:10.1016/S0003-4975(02)04161-9. PMID 12643435. 17. ^ Poland A. (1841). "Deficiency of the pectoral muscles". Guy's Hospital Reports. VI: 191–193. "Plate". Cite journal requires `\|journal=` (help) 18. ^ Clarkson P. (1962). "Poland's syndactyly". Guys Hosp Rep. 111: 335–46. PMID 14021589. 19. ^ "Meet the pint-sized baseball fan throwing out first pitches at every MLB stadium in America: Hailey Dawson, 8, is pitching with a ROBOTIC HAND made by a 3D printer after being born with a rare syndrome". www.msn.com. Retrieved 2018-07-13. 20. ^ Burt, Jennifer (1997-10-20). "Jeremy is a role model for children". Leicester (UK) Mercury. 21. ^ "Bryce Molder". PGA Tour. Archived from the original on January 6, 2011. Retrieved 6 Jan 2011. 22. ^ Communications, Emmis (1 May 2000). "Orange Coast Magazine". Emmis Communications. Retrieved 25 July 2018 – via Google Books. 23. ^ "Poland Syndrome". Dovemed. Retrieved 31 March 2016. 24. ^ "Hatchett retires after defying the odds". ESPN Cricinfo. 2016-09-24. Retrieved 24 September 2016. 25. ^ "Mathew Silcocks \| APC Corporate". Archived from the original on 12 July 2012. 26. ^ "9-Year-Old Hailey Dawson Throws Out First Pitch At Camden Yards After Completing 'Journey To 30'". WJZ-TV. August 2, 2019. Retrieved October 3, 2019. 27. ^ Footer, Alyson (October 28, 2017). "Girl with robotic hand throws inspiring first pitch". MLB.com. Retrieved July 1, 2018. 28. ^ Bella, Cheryl (March 15, 2018). "Young Baseball Fan Starts 'Journey to 30' with Pitch for Padres". University of Nevada, Las Vegas. Retrieved July 1, 2018. ## External links[edit] Classification D * ICD-10: Q79.8 * ICD-9-CM: 756.89 * OMIM: 173800 * MeSH: D011045 * DiseasesDB: 31679 * SNOMED CT: 38371006 External resources * eMedicine: plastic/132 * Orphanet: 2911 * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Poland syndrome	c1868156	6,069	wikipedia	https://en.wikipedia.org/wiki/Poland_syndrome	2021-01-18T18:35:06	{"gard": ["7412"], "mesh": ["C566793", "D011045"], "umls": ["C1868156"], "icd-9": ["756.89"], "orphanet": ["2911"], "wikidata": ["Q633859"]}
A number sign (#) is used with this entry because of evidence that metachromatic leukodystrophy due to saposin B deficiency is caused by homozygous or compound heterozygous mutation in the prosaposin gene (PSAP; 176801) on chromosome 10q22. This disorder is genetically distinct from metachromatic leukodystrophy (MLD; 250100) due to deficiency of arylsulfatase A (ARSA; 607574). Clinical Features Shapiro et al. (1979) and Hahn et al. (1982) described 3 patients from 2 families with metachromatic leukodystrophy and normal arylsulfatase A activity. Stevens et al. (1981) defined this biochemically distinct form of metachromatic leukodystrophy in 2 sibs of consanguineous Mexican-American parents. The clinical picture was that of juvenile MLD. Instead of the expected profound deficiency of arylsulfatase A, their enzyme levels were about half-normal, and the enzyme from fibroblasts had properties identical to those of normal fibroblasts. Nevertheless, hydrolysis of cerebroside sulfate by growing fibroblasts was markedly attenuated. Supplementation of the fibroblasts with the cerebroside sulfatase activator saposin B normalized the response in the loading test. The cerebroside sulfatase activator was purified and characterized as a heat stable, low molecular weight, anionic, lysosomal protein that exerts its effects by interacting with and dispersing the hydrophobic sulfatide (Fischer and Jatzkewitz, 1977). A bile salt such as sodium taurodeoxycholate or sodium cholate could substitute for the activator, indicating its essentially detergent mechanism of action. With a monoclonal antibody, Inui et al. (1983) demonstrated little or no CRM for the activator protein. They also demonstrated that sulfatide metabolism in cultured cells from the patient of Shapiro et al. (1979) could be corrected not only by the sulfatide sulfatase activator protein but also by the activator protein for GM1 ganglioside beta-galactosidase, indicating possible identity of these proteins. Wenger et al. (1989) described a fourth case of saposin B deficiency. The infant, who was unusually severely affected, was born of Nigerian parents. Rafi et al. (1992) demonstrated that cultured cells deficient in SAPB had correction of sulfatide metabolism when transfected with a virally transferred prosaposin cDNA; the cells produced normal levels of mature SAPB. Henseler et al. (1996) reported a Turkish boy, born of consanguineous parents, with juvenile metachromatic leukodystrophy. He acquired the ability to walk autonomously at age 14 months, but later developed motor difficulties and ceased walking at age 24 months. Clinical examination at age 25 months showed signs of peripheral neuropathy and slight psychologic delay. Laboratory studies showed normal arylsulfatase A activity with increased urinary excretion of sulfatides and globotriaosylceramide. Cultured fibroblasts of the patient metabolized very little endocytosed-labeled sulfatide in a sulfatide-loading experiment; normal catabolism was restored when mature saposin B was added to the culture medium. Wrobe et al. (2000) reported a 4-year-old girl of Spanish ancestry with saposin B deficiency. At the age of 2 years, she showed severe motor deterioration, hypotonia, weakness, and signs of CNS demyelination and polyneuropathy. At 4 years of age, nerve conduction was severely decreased, and sural nerve biopsy showed active demyelination and metachromatic deposits in macrophages. A bone marrow transplant (BMT) was attempted at the age of 4 years 9 months, but the child died 2 months postengraftment. Her younger sister, aged 2 years, also showed moderate hypotonia, patellar hyperreflexia, and signs of initial occipital demyelination, and BMT was performed at the age of 2 years 8 months. Kuchar et al. (2009) reported a boy with saposin B deficiency. He presented at age 9 months with signs of a mild, right-sided spastic hemiparesis. By age 2 years, he lost the previously acquired ability to walk a few steps, and showed decreased muscle strength with hyporeflexia. At age 43 months, he developed seizures, lost speech, and had spastic tetraparesis with almost no use of his hands. There was a progressive deterioration, and he was severely disabled at age 6 years with unreactive pupils. Brain MRI showed extensive white matter lesions and evidence of an old infarction. Urine analysis showed increased levels of sulfatide, similar to those seen in metachromatic leukodystrophy. Genetic analysis identified compound heterozygosity for 2 mutations in the PSAP gene (176801.0014 and 176801.0015), resulting in complete loss of 1 allele and generation of transcripts with deletions affecting only the SapB domain from the other allele. Clinical Management Landrieu et al. (1998) performed allogenic bone marrow transplantation in a 2-year-old boy with metachromatic leukodystrophy due to saposin B deficiency, and with involvement mainly of the peripheral nervous system. Transient deterioration was observed, followed by continuous improvement of peripheral nervous system functions. These findings were supported by nerve conduction velocity measurements, but the symptoms ultimately worsened. Magnetic resonance imaging showed persistent white matter lesions and progressive pontocerebellar atrophy. Molecular Genetics In a Turkish boy with metachromatic leukodystrophy due to saposin B deficiency, Henseler et al. (1996) identified a homozygous mutation in the PSAP gene (176801.0006). In a 4-year-old girl of Spanish ancestry with saposin B deficiency, Wrobe et al. (2000) identified a mutation in the PSAP gene (176801.0007). INHERITANCE \- Autosomal recessive ABDOMEN Gastrointestinal \- Dysphagia GENITOURINARY Bladder \- Incontinence MUSCLE, SOFT TISSUES \- Hypotonia \- Weakness NEUROLOGIC Central Nervous System \- Developmental delay, progressive \- Psychomotor regression \- Spasticity \- Spastic quadriparesis \- Hyperreflexia \- Extensor plantar responses \- Seizures \- Hyporeflexia \- Ataxic gait \- Cognitive decline \- Loss of speech \- Dysarthria \- Periventricular white matter abnormalities \- Demyelination Peripheral Nervous System \- Peripheral neuropathy \- Decreased nerve conduction velocities \- Hyporeflexia LABORATORY ABNORMALITIES \- Normal or mildly decreased arylsulfatase A activity \- Saposin B deficiency \- Submucosal macrophages filled with sphingolipids \- Increased urinary sulfatides MISCELLANEOUS \- Variable severity \- Variable age at onset (infant to adult) \- Disease course depends on age at onset MOLECULAR BASIS \- Caused by mutation in the prosaposin gene (PSAP, 176801.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	METACHROMATIC LEUKODYSTROPHY DUE TO SAPOSIN B DEFICIENCY	c0023522	6,070	omim	https://www.omim.org/entry/249900	2019-09-22T16:25:29	{"doid": ["10581"], "mesh": ["D007966"], "omim": ["249900"], "orphanet": ["512"], "synonyms": ["Alternative titles", "METACHROMATIC LEUKODYSTROPHY DUE TO CEREBROSIDE SULFATASE ACTIVATOR DEFICIENCY", "SAPOSIN B DEFICIENCY"]}
Armillaria root rot Armillaria luteobubalina, widespread in Australia, is a primary cause of Eucalyptus tree death and forest dieback resulting from Armillaria root rot. Causal agentsSeveral species of the genus Armillaria HostsSeveral tree species Armillaria root rot is a fungal root rot caused by several different members of the genus Armillaria. The symptoms are variable depending on the host infected, ranging from stunted leaves to chlorotic needles and dieback of twigs and branches. However, all infected hosts display symptoms characteristic of being infected by a white rotting fungus. The most effective ways of management focus on limiting the spread of the fungus, planting resistant species, and removing infected material. This disease poses a threat to the lumber industry as well as affecting recreational areas. ## Contents * 1 Hosts and symptoms * 2 Disease cycle * 3 Environment * 4 Management * 5 Importance * 6 References ## Hosts and symptoms[edit] Because this disease is caused by multiple species within the genus Armillaria, it has an extremely broad host range. Hundreds of trees and shrubs are susceptible to root rot to varying degrees. In fact, the only two genera of tree known to be resistant to Armillaria root rot are larch and birch. Further investigation is being conducted for additional species, but at this time there is no further evidence leading to the belief that more exist. While Armillaria is a significant and damaging pathogen of tree hosts, it also has many agronomic hosts such as grapevines, berries, roses, stone fruits, and rosaceous plants, although the fungus is primarily native to areas where it can use forest trees as a host. On hosts such as these, infection causes death of the cambium and further decay of the xylem. Vines or stems from these plants, once infected, may remain a potential source for inoculum for up to ten years and can infect neighboring plants.[1] As a result of the multitude of possible hosts, symptoms also range a great deal from one infection to another. All infected hosts do however display symptoms common to white rotting fungi. These include light or bleached wood as a result of the degradation of essential cell wall compounds such as lignin and hemicellulose. In addition to these, the host will show above-ground symptoms due to fungal infection of the vasculature. These include chlorosis in the needles as well as dieback of twigs and branches. The extent of these symptoms varies with the degree of infection as well as the susceptibility of the host. In addition to these symptoms, the trunks of conifers will also exude excess resin in a process known as resinopsis which results in a layer of resin, debris, and fungal tissue forming around infected roots.[2] Deciduous trees occasionally develop sunken cankers but most often fail to exhibit these symptoms on the trunk, and will instead simply display the other symptoms. In addition to these symptoms, signs of the infectious organism are very evident in the host. Upon removal of the bark, white mycelial mats are visible along with rhizomorphs, a distinctive reproductive structure. Clusters of mushrooms will also form at the base of the infected tree, indicating an infection. However, fruiting is not consistent year-to-year and the mushrooms frequently resemble other species to the untrained eye. Therefore, the presence of mushrooms should not constitute the only diagnostic indicator when identifying the disease. As the name suggests, the caps of these mushrooms are a honey, or light brown color, and the gills of the mushroom and spore print are white.[3] The stem is typically a mottled white and brown, with a ring on the stem, too. Honey mushrooms are edible, but because of their tendency to look so similar to other species, only the very experienced should collect them. Also, zone lines of melanized fungal cells may be visible within infected wood. ## Disease cycle[edit] Diagramatic illustration of white root rot disease cycle. Black root-like rhizomorphs on an unidentified European Armillaria species For the most part, this fungus exhibits a life cycle characteristic of basidiomycetes. It reproduces sexually with the mating of hyphae and produces a basidiocarp at the base of the infected host. This basidiocarp produces basidiospores that will further infect new hosts. However, Armillaria rarely spreads using this method in nature, possibly as a result of the spores being ineffective. In contrast, it will spread either through rhizomorphs or direct mycelial contact.[4] In the case of mycelial contact, the roots of an infected host grow near enough to a new host that mycelia simply grow onto the new host and infect. Rhizomorphs are string-like masses of hyphae utilized if no new hosts are nearby and spread by probing through the soil towards uninfected roots. ## Environment[edit] Armillaria infects trees in temperate and tropical regions. Armillaria commonly infects stressed trees that have been weakened by insects, other pathogens and/or climate stresses. It can also kill healthy trees especially in dry areas, like coniferous forests in the western United States. This fungus is found worldwide, but prefers cool soils and climates. ## Management[edit] Plant varieties that are resistant to Armillaria or species are resistant to other environmental or biological stressors. If the infected area has been cleared of trees, plants that are not vulnerable to the disease should be planted for five or so years until Armillaria is eradicated. Stump removal is also an effective management tool but can be expensive. Another way to reduce susceptibility is to maintain plant health by regular fertilization (if needed), watering during droughts, and trying not to create wounds on the plant. Fumigation can also be used to reduce the amount of inoculum.[5] Cultural practices can also be effective for preventing the spread of Armillaria. High temperatures interfere with the progression of this disease; if soil temperatures reach 79 °F (26 °C), then the growth of Armillaria in the soil will be limited.[6] Using collar excavation to expose primary roots directly below the crown to the continuous cycle of solar heating and air may reduce the colonization from Armillaria in trees that are already infected.[7] This is called root collar excavation (RCE), and while it has been applied to citrus orchards and grapevines, this method has high labor costs and involvement due to the difficulty of carefully exposing these primary roots. ## Importance[edit] This disease poses a serious threat to the timber industry in that it affects nearly every cultivated species of hardwood and proves very difficult to remove once it has entered an area. The ability to spread using rhizomorphs as well as through mycelial contact allow the fungus to spread over very large areas and between many individuals. In fact, Armillaria is recognized as the largest living organism due to its clonal method of spreading. Infection is especially strong where environmental conditions are optimal and a large amount of possible hosts exist. This essentially is anywhere hardwoods are found growing. It has been found in every state in the United States of America as well as on several other continents including Australia,[8] Europe, and Asia.[9] ## References[edit] Wikimedia Commons has media related to Armillaria root rot. 1. ^ "Armillaria Root Rot in Grapes – Grapes". grapes.extension.org. Retrieved 2020-04-30. 2. ^ Williams, R.E.; Shaw III, C.G.; Wargo, P.M.; Sites, W.H. (1989). Armillaria Root Disease. Forest Insect and Disease Leaflet, 78. Washington, D.C.: USDA Forest Service. Archived from the original on 26 October 2010. Retrieved 30 October 2010. 3. ^ Worrall, J. (2004). "Armillaria root disease". The Plant Health Instructor. doi:10.1094/PHI-I-2004-0706-01. ISSN 1935-9411. 4. ^ Worall, James J. (2010). "Armillaria Root Disease". Forest & Shade Tree Pathology. Archived from the original on 21 November 2010. Retrieved 30 October 2010. 5. ^ Department of Crop Sciences, University of Illinois at Urbana-Champaign (2000). Armillaria Root Rot of Trees and Shrubs (PDF). Report on Plant Disease, 602. Urbana, Illinois: University of Illinois Extension. Retrieved 30 October 2010. 6. ^ "Armillaria Root Rot". Penn State Extension. Retrieved 2020-04-30. 7. ^ "Armillaria root rot \| College of Agriculture, Forestry and Life Sciences \| Clemson University, South Carolina". www.clemson.edu. Retrieved 2020-04-30. 8. ^ Coetzee, Martin P. A.; Wingfield, Brenda D.; Harrington, Thomas C.; Steimel, Joe; Coutinho, Teresa A.; Wingfield, Michael J. (2001). "The root rot fungus Armillaria mellea introduced into South Africa by early Dutch settlers" (PDF). Molecular Ecology. 10 (2): 387–96. doi:10.1046/j.1365-294X.2001.01187.x. PMID 11298953. S2CID 714873. Retrieved 30 October 2010. 9. ^ Davari, M.; Askari, B. (2005). "Armillaria mellea as a cause of oak decline in Hatam-baigh forest of Iran". Communications in Agricultural and Applied Biological Sciences. 70 (3): 295–304. PMID 16637190. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Armillaria root rot	None	6,071	wikipedia	https://en.wikipedia.org/wiki/Armillaria_root_rot	2021-01-18T19:04:36	{"wikidata": ["Q4793483"]}
Cerulean cataracts are opaque areas that develop in the lens of the eye that often have a bluish or whitish color. They may be present at birth or develop in very early childhood, but may not be diagnosed until adulthood. They are usually bilateral and progressive. Infants can be asymptomatic, but may also be visually impaired from birth and develop nystagmus and amblyopia. In adulthood, the cataracts may progress, making lens removal necessary. Cerulean cataracts may be caused by mutations in several genes, including the CRYBB2, CRYGD, and MAF genes, and are inherited in an autosomal dominant manner. No treatment is known to prevent cerulean cataracts, but frequent evaluations and cataract surgery are typically required to prevent amblyopia as the opacities progress. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Cerulean cataract	c0344523	6,072	gard	https://rarediseases.info.nih.gov/diseases/9508/cerulean-cataract	2021-01-18T18:01:32	{"mesh": ["C537955"], "omim": ["115660", "601547", "608983", "610202"], "umls": ["C0344523"], "orphanet": ["98989"], "synonyms": ["Cataract, congenital, cerulean type 1", "CCA1", "Cataract, congenital, blue dot type 1"]}
Look up dysorgasmia in Wiktionary, the free dictionary. Dysorgasmia is the experience of pain after an orgasm, usually in the abdomen. The condition may be experienced during or after orgasm, sometimes as late as several hours after the orgasm occurred. Both men and women can experience orgasmic pain. The term is sometimes used interchangeably with painful ejaculation when experienced by a man, but ejaculatory pain is only a subtype of male dysorgasmia as men can experience pain without ejaculating.[1] The phenomenon is poorly understood[1] and underresearched.[2] Dysorgasmia can come as a side effect of surgical interventions such as prostatectomy.[3] ## See also[edit] * Dyspareunia, pain during sex ## References[edit] 1. ^ a b Chiles, Kelly A. (January 19, 2017). "Musings on Male Dysorgasmia". The Journal of Sexual Medicine. 14 (4): 489–490. doi:10.1016/j.jsxm.2017.01.019. 2. ^ "Smärtsamma orgasmer?". Expressen. December 9, 2017. Retrieved 2020-10-15. 3. ^ Matsushita, Kazuhito; Tal, Raanan; Mulhall, John P (March 2012). "The Evolution of Orgasmic Pain (Dysorgasmia) Following Radical Prostatectomy". The Journal of Sexual Medicine. 9 (5): 1454–8. doi:10.1111/j.1743-6109.2012.02699.x. PMID 22458302 – via ResearchGate. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Dysorgasmia	None	6,073	wikipedia	https://en.wikipedia.org/wiki/Dysorgasmia	2021-01-18T18:53:01	{"wikidata": ["Q97366766"]}
Fused manidbular incisors is an extremely rare dental anomaly that is characterized by the union of two, normally separated, incisor tooth germs of the primary dentition. It is frequently associated with hypodontia (see this term) and an increased risk of pulp exposure. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Fused mandibular incisors	c3494175	6,074	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2287	2021-01-23T17:55:27	{"gard": ["2419"], "mesh": ["D005671", "C535997"], "omim": ["147251"], "umls": ["C2931081", "C3494175"], "icd-10": ["K00.2"]}
Braun and Bayer (1962) described a sibship of 12 containing 5 affected brothers. Two brothers, 5 sisters and both parents were normal. Parental consanguinity was denied. Whereas 2 of the affected sibs had urinary tract and digital anomalies, bifid uvula, nephrosis and deafness, 1 brother was deaf and had digital anomalies only, and 2 brothers had nephrosis only. The digital anomaly consisted of short and bifid distal phalanges of thumbs and big toes, for which no photographs or roentgenograms were published. Deafness was conductive, with no malformations of the middle ear bone (one of the affected sibs was autopsied). A female relative was known to be deaf. The author suggested either autosomal recessive or X-linked dominant inheritance (the mother had renal complications and hypertension during her pregnancies) of this syndrome, which was not previously described in the literature. HEENT \- Bifid uvula Limbs \- Digital malformations \- Short bifid distal phalanges of thumbs and big toes Inheritance \- Autosomal recessive vs. X-linked dominant GU \- Nephrosis \- Urinary tract anomalies Ears \- Hearing loss ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	NEPHROSIS WITH DEAFNESS AND URINARY TRACT AND DIGITAL MALFORMATIONS	c1850552	6,075	omim	https://www.omim.org/entry/256200	2019-09-22T16:24:24	{"mesh": ["C536402"], "omim": ["256200"], "orphanet": ["2669"]}
"Laurence-Moon-Biedl syndrome" and "Laurence-Moon-Biedl-Bardet" redirect here. Not to be confused with Laurence–Moon syndrome. Bardet–Biedl syndrome Other namesBiedl-Bardet Syndrome [1] This condition is often inherited via autosomal recessive manner (including digenic recessive); but epigenetic phennomena also cause some of the variation seen in BBS SpecialtyMedical genetics Bardet–Biedl syndrome (BBS) is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized by rod/cone dystrophy, polydactyly, central obesity, hypogonadism, and kidney dysfunction in some cases.[2] Historically, slower mental processing has also been considered a principal symptom but is now not regarded as such. ## Contents * 1 Signs and symptoms * 1.1 Relation to other rare genetic disorders * 2 Pathophysiology * 3 Diagnosis * 4 Eponym * 5 References * 6 External links ## Signs and symptoms[edit] Bardet–Biedl syndrome is a pleiotropic disorder with variable expressivity and a wide range of clinical variability observed both within and between families. The most common clinical features are rod–cone dystrophy, with childhood-onset night-blindness followed by increasing visual loss; postaxial polydactyly; truncal obesity that manifests during infancy and remains problematic throughout adulthood; varying degrees of learning disabilities; male hypogenitalism and complex female genitourinary malformations; and renal dysfunction, a major cause of morbidity and mortality. There is a wide range of secondary features that are sometimes associated with BBS[3]:147–148 including[3]:153–154 * Strabismus, cataracts, astigmatism, pigmentary retinopathy, poor visual acuity, low vision, and/or blindness caused by an impaired photoreceptor transport mechanism in the retina.[4] * "Brachydactyly, syndactyly of both the hands and feet is common, as is partial syndactyl (most usually between the second and third toes)" * Polyuria/polydipsia (nephrogenic diabetes insipidus) * Ataxia/poor coordination/imbalance * Mild hypertonia (especially lower limbs) * Diabetes mellitus * Hepatic involvement * Anosmia * Auditory deficiencies * Hirschsprung disease and subsequent bowel obstruction has been described.[5] * Hypertrophy of interventricular septum and left ventricle and dilated cardiomyopathy. * Hypogonadism, kidney failure, urogenital sinuses, ectopic urethra, uterus duplex, septate vagina, and hypoplasia of the uterus, ovaries, and fallopian tubes * Speech disorder/delay * Developmental delay, especially of fine and gross motor skills[citation needed] ### Relation to other rare genetic disorders[edit] Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely varying, phenotypically observed disorders. BBS is one such syndrome that has now been identified to be caused by defects in the cellular ciliary structure. Thus, BBS is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, polycystic kidney and liver disease, nephronophthisis, Alström syndrome, Meckel–Gruber syndrome and some forms of retinal degeneration.[6] ## Pathophysiology[edit] The detailed biochemical mechanism that leads to BBS is still unclear. The gene products encoded by these BBS genes, called BBS proteins, are located in the basal body and cilia of the cell.[7] Using the round worm C. elegans as a model system, biologists found that BBS proteins are involved in a process called intraflagellar transport (IFT), a bi-directional transportation activity within the cilia along the long axis of the ciliary shaft that is essential for ciliogenesis and the maintenance of cilia.[8] Recent biochemical analysis of human BBS proteins revealed that BBS proteins are assembled into a multiple protein complex, called "BBSome". BBSome is proposed to be responsible for transporting intracellular vesicles to the base of the cilia and to play an important role in the ciliary function.[citation needed] Since abnormalities of cilia are known to be related to a wide range of disease symptoms including those commonly seen in BBS patients, it is now widely accepted that mutated BBS genes affect normal cilia function, which, in turn, causes BBS.[citation needed] A theory that photoreceptor cells are nourished by the IFT of retinal cilia now offers a potential explanation for the retinal dystrophy common in BBS patients after their early years of life.[9][10] Genes involved include: * BBsome: BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, TTC8/BBS8, BBS10, TRIM32/BBS11 BBS12, CCDC28B, CEP290, TMEM67, MKS1, MKKS[11] * chaperone: BBS6[citation needed] ## Diagnosis[edit] The diagnosis of BBS is established by clinical findings and family history. Molecular genetic testing can be used to confirm the diagnosis. Multigene panels offer the most effective approach in achieving molecular confirmation of BBS. ## Eponym[edit] The syndrome is named after Georges Bardet and Arthur Biedl.[12][why?] The first known case was reported by Laurence and Moon in 1866 at the Ophthalmic Hospital in South London. Laurence–Moon–Biedl–Bardet syndrome is no longer considered as valid terms in that patients of Laurence and Moon had paraplegia but no polydactyly or obesity, which are the key elements of the Bardet–Biedl syndrome. Laurence–Moon syndrome is usually considered a separate entity. However, some recent research suggests that the two conditions may not be distinct.[13] As of 2012[update], 14[11] (or 15)[14] different BBS genes had been identified. ## References[edit] 1. ^ "Bardet-Biedl syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 13 August 2019. 2. ^ Beales P, Elcioglu N, Woolf A, Parker D, Flinter F (1 June 1999). "New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey". J. Med. Genet. 36 (6): 437–46. doi:10.1136/jmg.36.6.437 (inactive 2021-01-15). PMC 1734378. PMID 10874630. Archived from the original on 2008-03-14. Retrieved 2007-10-11.CS1 maint: DOI inactive as of January 2021 (link) 3. ^ a b Ross, Allison; Beales, Philip L; Hill, Josephine (2008). The Clinical, Molecular, and Functional Genetics of Bardet–Biedl Syndrome, in Genetics of Obesity Syndromes. Oxford University Press. doi:10.1093/med/9780195300161.001.0001. ISBN 978-0-19-530016-1. Retrieved 2009-07-01. 4. ^ Abd-El-Barr, MM; Sykoudis K; Andrabi S; Eichers ER; Pennesi ME; Tan PL; Wilson JH; Katsanis N; Lupski JR; Wu SM. (December 2007). "Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet–Biedl syndrome". Vision Res. 47 (27): 3394–407. doi:10.1016/j.visres.2007.09.016. PMC 2661240. PMID 18022666. 5. ^ Ramji AN. Sigmoid volvulus in bardet-biedl syndrome: serendipity or a new association? Int Surg J 2019;6:1388-91. 6. ^ Badano JL, Mitsuma N, Beales PL, Katsanis N (2006). "The ciliopathies: an emerging class of human genetic disorders". Annu. Rev. Genom. Hum. Genet. 7: 125–48. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. S2CID 40223129. 7. ^ Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N (October 2003). "Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome". Nature. 425 (6958): 628–33. Bibcode:2003Natur.425..628A. doi:10.1038/nature02030. PMID 14520415. S2CID 4310157. 8. ^ Blacque OE, Reardon MJ, Li C, McCarthy J, Mahjoub MR, Ansley SJ, Badano JL, Mah AK, Beales PL, Davidson WS, Johnsen RC, Audeh M, Plasterk RH, Baillie DL, Katsanis N, Quarmby LM, Wicks SR, Leroux MR (2004). "Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport". Genes Dev. 18 (13): 1630–42. doi:10.1101/gad.1194004. PMC 443524. PMID 15231740. 9. ^ Sedmak T, Wolfrum U (April 2010). "Intraflagellar transport molecules in ciliary and nonciliary cells of the retina". J. Cell Biol. 189 (1): 171–86. doi:10.1083/jcb.200911095. PMC 2854383. PMID 20368623. 10. ^ Orozco, JT; Wedaman KP; Signor D; Brown H; Rose L; Scholey JM (1999). "Movement of motor and cargo along cilia". Nature. 398 (6729): 674. Bibcode:1999Natur.398..674O. doi:10.1038/19448. PMID 10227290. S2CID 4414550. 11. ^ a b Hamosh, Ada (2012-11-02). "OMIM entry #209900 Bardet-Biedl Syndrome; BBS". Online Mendelian Inheritance in Man. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine. Archived from the original on 2016-05-17. Retrieved 2013-09-04. 12. ^ synd/3745 at Who Named It? 13. ^ Moore S, Green J, Fan Y, et al. (2005). "Clinical and genetic epidemiology of Bardet–Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study". Am. J. Med. Genet. 132 (4): 352–60. doi:10.1002/ajmg.a.30406. PMC 3295827. PMID 15637713. 14. ^ Hereditary Retinopathies: Progress in Development of Genetic and Molecular Therapies. Springer. 2012. p. 15. ISBN 9781461444992. Retrieved 2013-09-04. ## External links[edit] Classification D * ICD-10: Q87.8 * ICD-9-CM: 759.89 * OMIM: 209900 * MeSH: D020788 * DiseasesDB: 7286 External resources * GeneReviews: Bardet-Biedl Syndrome * Orphanet: 110 * Overview at United States National Library of Medicine * Molecular diagnosis at NCBI * v * t * e Congenital abnormality syndromes Craniofacial * Acrocephalosyndactylia * Apert syndrome * Carpenter syndrome * Pfeiffer syndrome * Saethre–Chotzen syndrome * Sakati–Nyhan–Tisdale syndrome * Bonnet–Dechaume–Blanc syndrome * Other * Baller–Gerold syndrome * Cyclopia * Goldenhar syndrome * Möbius syndrome Short stature * 1q21.1 deletion syndrome * Aarskog–Scott syndrome * Cockayne syndrome * Cornelia de Lange syndrome * Dubowitz syndrome * Noonan syndrome * Robinow syndrome * Silver–Russell syndrome * Seckel syndrome * Smith–Lemli–Opitz syndrome * Snyder–Robinson syndrome * Turner syndrome Limbs * Adducted thumb syndrome * Holt–Oram syndrome * Klippel–Trénaunay–Weber syndrome * Nail–patella syndrome * Rubinstein–Taybi syndrome * Gastrulation/mesoderm: * Caudal regression syndrome * Ectromelia * Sirenomelia * VACTERL association Overgrowth syndromes * Beckwith–Wiedemann syndrome * Proteus syndrome * Perlman syndrome * Sotos syndrome * Weaver syndrome * Klippel–Trénaunay–Weber syndrome * Benign symmetric lipomatosis * Bannayan–Riley–Ruvalcaba syndrome * Neurofibromatosis type I Laurence–Moon–Bardet–Biedl * Bardet–Biedl syndrome * Laurence–Moon syndrome Combined/other, known locus * 2 (Feingold syndrome) * 3 (Zimmermann–Laband syndrome) * 4/13 (Fraser syndrome) * 8 (Branchio-oto-renal syndrome, CHARGE syndrome) * 12 (Keutel syndrome, Timothy syndrome) * 15 (Marfan syndrome) * 19 (Donohue syndrome) * Multiple * Fryns syndrome * v * t * e Diseases of cilia Structural * receptor: Polycystic kidney disease * cargo: Asphyxiating thoracic dysplasia * basal body: Bardet–Biedl syndrome * mitotic spindle: Meckel syndrome * centrosome: Joubert syndrome Signaling * Nephronophthisis Other/ungrouped * Alström syndrome * Primary ciliary dyskinesia * Senior–Løken syndrome * Orofaciodigital syndrome 1 * McKusick–Kaufman syndrome * Autosomal recessive polycystic kidney See also: ciliary proteins * v * t * e Deficiencies of intracellular signaling peptides and proteins GTP-binding protein regulators GTPase-activating protein * Neurofibromatosis type I * Watson syndrome * Tuberous sclerosis Guanine nucleotide exchange factor * Marinesco–Sjögren syndrome * Aarskog–Scott syndrome * Juvenile primary lateral sclerosis * X-Linked mental retardation 1 G protein Heterotrimeic * cAMP/GNAS1: Pseudopseudohypoparathyroidism * Progressive osseous heteroplasia * Pseudohypoparathyroidism * Albright's hereditary osteodystrophy * McCune–Albright syndrome * CGL 2 Monomeric * RAS: HRAS * Costello syndrome * KRAS * Noonan syndrome 3 * KRAS Cardiofaciocutaneous syndrome * RAB: RAB7 * Charcot–Marie–Tooth disease * RAB23 * Carpenter syndrome * RAB27 * Griscelli syndrome type 2 * RHO: RAC2 * Neutrophil immunodeficiency syndrome * ARF: SAR1B * Chylomicron retention disease * ARL13B * Joubert syndrome 8 * ARL6 * Bardet–Biedl syndrome 3 MAP kinase * Cardiofaciocutaneous syndrome Other kinase/phosphatase Tyrosine kinase * BTK * X-linked agammaglobulinemia * ZAP70 * ZAP70 deficiency Serine/threonine kinase * RPS6KA3 * Coffin-Lowry syndrome * CHEK2 * Li-Fraumeni syndrome 2 * IKBKG * Incontinentia pigmenti * STK11 * Peutz–Jeghers syndrome * DMPK * Myotonic dystrophy 1 * ATR * Seckel syndrome 1 * GRK1 * Oguchi disease 2 * WNK4/WNK1 * Pseudohypoaldosteronism 2 Tyrosine phosphatase * PTEN * Bannayan–Riley–Ruvalcaba syndrome * Lhermitte–Duclos disease * Cowden syndrome * Proteus-like syndrome * MTM1 * X-linked myotubular myopathy * PTPN11 * Noonan syndrome 1 * LEOPARD syndrome * Metachondromatosis Signal transducing adaptor proteins * EDARADD * EDARADD Hypohidrotic ectodermal dysplasia * SH3BP2 * Cherubism * LDB3 * Zaspopathy Other * NF2 * Neurofibromatosis type II * NOTCH3 * CADASIL * PRKAR1A * Carney complex * PRKAG2 * Wolff–Parkinson–White syndrome * PRKCSH * PRKCSH Polycystic liver disease * XIAP * XIAP2 See also intracellular signaling peptides and proteins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Bardet–Biedl syndrome	c0752166	6,076	wikipedia	https://en.wikipedia.org/wiki/Bardet%E2%80%93Biedl_syndrome	2021-01-18T18:32:29	{"gard": ["6866"], "mesh": ["D020788"], "umls": ["C0752166"], "icd-9": ["759.89"], "orphanet": ["110"], "wikidata": ["Q1678281"]}
This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (March 2018) (Learn how and when to remove this template message) Porcine enzootic pneumonia, also known as mycoplasmal pneumonia, is a chronic respiratory disease of pigs caused by Mycoplasma hyopneumoniae.[1] It is part of the Porcine Respiratory Disease Complex along with Swine Influenza, PRRS and Porcine circovirus 2, and even though on its own it is quite a mild disease, it predisposes to secondary infections with organisms such as Pasteurella multocida. Clinical signs are most commonly seen in pigs over 8 weeks of age, and the disease occurs worldwide. Transmission is horizontal and vertical from sows. ## Clinical signs and diagnosis[edit] Pigs usually cough and may show more severe respiratory signs if secondary bacteria have invaded. This may lead to signs of pneumonia and systemic involvement. Diagnosis relies on culture and isolation of the bacteria but this can be challenging. PCR, ELISA, fluorescent antibody testing and post-mortem findings all help in making the diagnosis. ## Treatment and control[edit] Tiamulin, chlortetracycline or tilmicosin may be used to treat and prevent the spread of the disease. Vaccination is a very effective method of control, and also has an effect on pig productivity. Eradication of the disease is possible but the organism commonly reinfects herds. ## References[edit] 1. ^ Flanders, Frank; Gillespie, James R. (2015). "Chapter 23 Diseases and parasites of swine. Mycoplasmal pneumonia". Modern Livestock & Poultry Production (9th ed.). Cengage Learning. p. 437. ISBN 9781305483156. "Enzootic Pneumonia - Pigs - WikiVet English". WikiVet. 3 August 2011. Retrieved 2018-03-10. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Porcine enzootic pneumonia	c1258090	6,077	wikipedia	https://en.wikipedia.org/wiki/Porcine_enzootic_pneumonia	2021-01-18T18:57:31	{"mesh": ["D045729"], "wikidata": ["Q1346131"]}
Claude's syndrome SpecialtyNeurology Claude's syndrome is a form of brainstem stroke syndrome characterized by the presence of an ipsilateral oculomotor nerve palsy, contralateral hemiparesis, contralateral ataxia, and contralateral hemiplegia of the lower face, tongue, and shoulder. Claude's syndrome affects oculomotor nerve, red nucleus and brachium conjunctivum.[1] ## Contents * 1 Cause * 1.1 Other causes * 2 Diagnosis * 3 History * 4 See also * 5 References * 6 External links ## Cause[edit] Human brainstem blood supply description. Posterior cerebral artery is #6, and midbrain is behind it. Claude's syndrome is caused by midbrain infarction as a result of occlusion of a branch of the posterior cerebral artery.[2] This lesion is usually a unilateral infarction of the red nucleus and cerebral peduncle, affecting several structures in the midbrain including: Structure damaged Effect dentatorubral tract fibers contralateral ataxia corticospinal tract fibers contralateral hemiparesis corticobulbar tract fibers contralateral hemiplegia of lower facial muscles, tongue, and shoulder oculomotor nerve fibers ipsilateral oculomotor nerve palsy with a drooping eyelid and fixed wide pupil pointed down and out; probable diplopia It is very similar to Benedikt's syndrome. ### Other causes[edit] It has been reported that posterior cerebral artery stenosis can also precipitate Claude's syndrome.[3] ## Diagnosis[edit] ## History[edit] It carries the name of Henri Charles Jules Claude, a French psychiatrist and neurologist, who described the condition in 1912.[4] ## See also[edit] * Wallenberg's syndrome * Moritz Benedikt ## References[edit] 1. ^ Harrison's 2. ^ "Claude's syndrome". GPnotebook. 3. ^ Dhanjal T, Walters M, MacMillan N (2003). "Claude's syndrome in association with posterior cerebral artery stenosis". Scottish Medical Journal. 48 (3): 91–92. doi:10.1177/003693300304800309. PMID 12968516. Archived from the original on 2007-06-12. 4. ^ Claude H, Loyez M (1912). "Ramollissement du noyau rouge". Rev Neurol (Paris). 24: 49–51. ## External links[edit] Classification D * ICD-10: G46.3 * ICD-9-CM: 352.6 * MeSH: D020526 * DiseasesDB: 33869 * 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 * t * e Symptoms, signs and syndromes associated with lesions of the brain and brainstem Brainstem Medulla (CN 8, 9, 10, 12) * Lateral medullary syndrome/Wallenberg * PICA * Medial medullary syndrome/Dejerine * ASA Pons (CN 5, 6, 7, 8) * Upper dorsal pontine syndrome/Raymond-Céstan syndrome * Lateral pontine syndrome (AICA) (lateral) * Medial pontine syndrome/Millard–Gubler syndrome/Foville's syndrome (basilar) * Locked-in syndrome * Internuclear ophthalmoplegia * One and a half syndrome Midbrain (CN 3, 4) * Weber's syndrome * ventral peduncle, PCA * Benedikt syndrome * ventral tegmentum, PCA * Parinaud's syndrome * dorsal, tumor * Claude's syndrome Other * Alternating hemiplegia Cerebellum * Latearl * Dysmetria * Dysdiadochokinesia * Intention tremor) * Medial * Cerebellar ataxia Basal ganglia * Chorea * Dystonia * Parkinson's disease Cortex * ACA syndrome * MCA syndrome * PCA syndrome * Frontal lobe * Expressive aphasia * Abulia * Parietal lobe * Receptive aphasia * Hemispatial neglect * Gerstmann syndrome * Astereognosis * Occipital lobe * Bálint's syndrome * Cortical blindness * Pure alexia * Temporal lobe * Cortical deafness * Prosopagnosia Thalamus * Thalamic syndrome Other * Upper motor neuron lesion * Aphasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Claude's syndrome	c0271373	6,078	wikipedia	https://en.wikipedia.org/wiki/Claude%27s_syndrome	2021-01-18T18:48:29	{"mesh": ["D020526"], "icd-9": ["352.6"], "icd-10": ["G46.3"], "wikidata": ["Q5128655"]}
## Clinical Features Wulfsberg et al. (1993) studied a mother and her 3 affected children from a 4-generation family with apparent autosomal dominant, nonsyndromic, tetramelic, postaxial oligodactyly. The postaxial deficiency ranged from complete absence of the fifth metacarpals, metatarsals, and phalanges to complete absence of the fifth metacarpals and metatarsals with some residual distal fifth phalanges. Ten additional members of the family were reportedly affected, with 2 instances of male-to-male transmission in the first 2 generations. Because of studies in chick and mouse embryos suggesting that 5-prime members of the Hox4 gene cluster (see, e.g., 142984) are responsible for interpreting positional information to effect digit formation, Wulfsberg et al. (1993) suggested that a defect in HOX4 gene patterning of hand and foot formation may be responsible. INHERITANCE \- Autosomal dominant SKELETAL Limbs \- Mild radial bowing \- Normal ulnae Hands \- Single transverse palmar creases \- Postaxial oligodactyly \- Partial-complete absence of 5th phalanges \- Absent 5th metacarpal \- Lunate-triquetral fusion Feet \- Postaxial polydactyly \- Absent 5th phalanges \- Absent 5th metatarsals \- Normal tarsal bones \- Cone-shaped epiphyses (2nd-4th) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	POSTAXIAL OLIGODACTYLY, TETRAMELIC	c1867924	6,079	omim	https://www.omim.org/entry/176240	2019-09-22T16:35:46	{"mesh": ["C566767"], "omim": ["176240"], "orphanet": ["2730"]}
Lujan syndrome is a condition characterized by intellectual disability, behavioral problems, and certain physical features. It occurs almost exclusively in males. The intellectual disability associated with Lujan syndrome is usually mild to moderate. Behavioral problems can include hyperactivity, aggressiveness, extreme shyness, and excessive attention-seeking. Some affected individuals have features of autism or related developmental disorders affecting communication and social interaction. A few have been diagnosed with psychiatric problems such as delusions and hallucinations. Characteristic physical features of Lujan syndrome include a tall, thin body and an unusually large head (macrocephaly). Affected individuals also have a long, thin face with distinctive facial features such as a prominent top of the nose (high nasal root); a short space between the nose and the upper lip (philtrum); a narrow roof of the mouth (palate); crowded teeth; and a small chin (micrognathia). Almost all people with this condition have weak muscle tone (hypotonia). Additional signs and symptoms of Lujan syndrome can include abnormal speech, heart defects, and abnormalities of the genitourinary system. Many affected individuals have long fingers and toes with an unusually large range of joint movement (hyperextensibility). Seizures and abnormalities of the tissue that connects the left and right halves of the brain (corpus callosum) have also been reported in people with this condition. ## Frequency Lujan syndrome appears to be an uncommon condition, but its prevalence is unknown. ## Causes Lujan syndrome is caused by at least one mutation in the MED12 gene. This gene provides instructions for making a protein that helps regulate gene activity; it is involved in many aspects of early development. The MED12 gene mutation that causes Lujan syndrome changes a single protein building block (amino acid) in the MED12 protein. This genetic change alters the structure, and presumably the function, of the MED12 protein. However, it is unclear how the mutation affects development and leads to the cognitive and physical features of Lujan syndrome. ### Learn more about the gene associated with Lujan syndrome * MED12 ## Inheritance Pattern This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Lujan syndrome	c0796022	6,080	medlineplus	https://medlineplus.gov/genetics/condition/lujan-syndrome/	2021-01-27T08:24:52	{"gard": ["3307"], "mesh": ["C537724"], "omim": ["309520"], "synonyms": []}
In 3 generations of a Greek Cypriot family, Middleton et al. (1992) described what appeared to be a new hereditary syndrome characterized by specific and striking facial characteristics and more variable skeletal deformities, as well as neuromuscular abnormalities. The facial appearance consisted of a thickened, ridged, triangular skin fold extending from the glabella to the anterior fontanel, elevation of the medial portion of the eyebrows bilaterally 'giving a Mephistophelian appearance,' hypertelorism, and widow's peak. The variable skeletal features included congenital talipes equinovarus, and dislocation of the hips, as well as kyphoscoliosis. Neurologic and musculoskeletal defects were severe and incapacitating in some. All affected members were of normal intelligence. One member of the family who was thought to have only mild facial manifestations of the disorder was found on examination to have marked kyphoscoliosis, weakness and wasting of arms and legs, and mild sensory changes. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	CYPRUS FACIAL NEUROMUSCULOSKELETAL SYNDROME	c1852396	6,081	omim	https://www.omim.org/entry/123853	2019-09-22T16:42:37	{"mesh": ["C536229"], "omim": ["123853"], "orphanet": ["2674"]}
Focal hyperhidrosis Other namesprimary hyperhidrosis Focal hyperhidrosis, also known as primary hyperhidrosis, is a disease characterized by an excessive sweating localized in certain body regions (particularly palms, feet and underarms). Recent studies have shown that this condition, affecting between 1% and 3% of the general population, seems to have a genetic origin. Focal hyperhidrosis is sometimes referred to as The Silent Handicap,[1] as it has a significant impact on the quality of life, affecting the individual socially, psychologically, emotionally and professionally.[2] Indeed, the disease is accountable for more than 1⁄4 of the cases of social anxiety disorder.[citation needed] Moreover, 20% of the patients suffering from focal hyperhidrosis were not able to pursue the career of their choice, and finally 71% of them endure an important lack of self-confidence (with nearly half of them suffering from depressions).[citation needed] ## Contents * 1 Genetics * 2 Diagnosis * 3 Treatments * 4 References * 5 External links ## Genetics[edit] In 2006, researchers uncovered that primary palmar hyperhidrosis, referring to excess sweating on the palms of the hands and feet, maps to the gene locus 14q11.2-q13.[3] After this discovery, further research was conducted to examine if primary focal hyperhidrosis maps back to the same locus. In addition, researchers wanted to see if other previously unknown genes were responsible for different phenotypes among individuals with hyperhidrosis. Based on previous research using mice and rats, researchers looked towards the role of aquaporin 5 (AQP5), a water channel protein, in human individuals with primary focal hyperhidrosis.[4] AQP5 has been identified as a candidate gene in many hyperhidrosis studies. Using a family that had members with primary focal hyperhidrosis, researchers found that there was no connection between primary focal hyperhidrosis and AQP5. There was also no significant connection between the gene 14q11.2-q13 locus, which was linked to primary palmar hyperhidrosis, and primary focal hyperhidrosis in this family.[5] Due to the inconclusive findings in the study, the question as to what are the genes and proteins that play a significant role in primary focal hyperhidrosis still remains. The expression of the AQP5 protein and AQP5 mRNA was significantly higher in a patient group in comparison to the control group. In 2011, using a control group (individuals without primary focal hyperhidrosis) and a patient group (individuals with primary focal hyperhidrosis) researchers found that there was no difference between the number of sweat coils in the axillary sweat glands. This indicates that there is nothing morphologically different between individuals with and without primary focal hyperhidrosis. The discrepancies between the studies above call on further studies to confirm or deny the role of AQP5, and the role of other proteins, in hyperhidrosis.[6] Beyond looking at the genes and individual proteins that play a role in primary focal hyperhidrosis, researchers have looked at the patterns of heredity for this trait. In a 2003 study, using multiple families, researchers found that primary focal hyperhidrosis was not a sex-linked gene, since male-to-male transmission was seen in multiple families. Instead evidence supported an autosomal dominant pattern of inheritance with an incomplete disease penetrance. 21 patients in this study reported a positive family history of hyperhidrosis (62%). Researchers were able to uncover this by creating pedigrees of all the participants in the study. Not every member of the pedigree exhibited forms of hyperhidrosis, which allowed the researchers to track the patterns of inheritance. The findings in this study indicated that primary focal hyperhidrosis is typically an hereditary disorder.[7] ## Diagnosis[edit] Typical regions of excessive sweating include the hand palms, underarms, the sole of the foot, and sometimes groin, face, and scalp. Indeed, profuse sweating is present mostly in the underarms, followed by the feet, palms and facial region.[8] Sweating patterns of focal hyperhidrosis are typically bilateral or symmetric and rarely occur in just one palm or one underarm. Night sweats or sweating while sleeping is also rare. The onset of focal hyperhidrosis is usually before the age of 25 years. This is in contrast to generalized hyperhidrosis which tends to occur in an older age group. Evidence demonstrates that a positive family history is also present (see the Genetics part).[9] ## Treatments[edit] The Canadian Hyperhidrosis Advisory Committee has published a comprehensive set of guidelines which outlines key aspects of treatment related to this condition. Topical hyperhidrosis gels containing aluminum chloride hexahydrate are usually first choice treatments for this condition.[2] Topical agents for Focal hyperhidrosis therapy include Formaldehyde lotion, topical anticholinergics... These agents reduce perspiration by denaturing keratin, in turn occluding the pores of the sweat glands. They have a short-lasting effect. Contact sensitization is increased, especially with formalin. In addition to topical antiperspirants (whose main active ingredients usually are aluminum or zirconium salts) treatment options include: iontophoresis (hands, feet), onabotulinumtoxinA (Botox) injections (underarms, hands, feet, and other localized areas),[10] electromagnetic/microwave energy thermolysis of underarm sweat glands (miraDry),[11] laser-assisted removal of the sweat glands (underarms),[12] other local procedures such as liposuction and curettage of the sweat glands (underarms), medications of the anticholinergic type that are taken by mouth, and sympathectomy surgery for sweating of the hands or head that can't be controlled by other means.[12] ## References[edit] 1. ^ Swartling, Carl; et al. (2011). "Hyperhidros - det "tysta" handikappet". Läkartidningen (in Swedish). 108 (47): 2428–2432. 2. ^ a b Solish, Nowell; et al. (2007). "A Comprehensive Approach to the Recognition, Diagnosis, and Severity-Based Treatment of Focal Hyperhidrosis: Recommendations of the Canadian Hyperhidrosis Advisory Committee". Dermatologic Surgery. 33 (8): 908–923. doi:10.1111/j.1524-4725.2007.33192.x. PMID 17661933. 3. ^ Higashimoto, Ikuyo; Yoshiura, Koh-Ichiro; Hirakawa, Naomi; Higashimoto, Ken; Soejima, Hidenobu; Totoki, Tadahide; Mukai, Tsunehiro; Niikawa, Norio (2006). "Primary palmar hyperhidrosis locus maps to 14q11.2-q13". American Journal of Medical Genetics Part A. 140A (6): 567–72. doi:10.1002/ajmg.a.31127. PMID 16470694. 4. ^ Gresz, V.; Kwon, T; Gong, H; Agre, P.; Steward, M; King, L; Nielsen, S. (2004). "Immunolocalization of AQP-5 in rat parotid and submandibular salivary glands after stimulation of inhibition of secretion in vivo". American Journal of Physiology. Gastrointestinal and Liver Physiology. 289 (1): 151–161. doi:10.1152/ajpgi.00480.2003. PMID 14988067. 5. ^ Del Sorbo, F.; Brancati, F.; De Joanna, G.; Valente, E.; Lauria, G.; Albanese, A. (2011). "Primary focal hyperhidrosis in a new family not linked to known loci". Dermatology. 223 (4): 335–342. doi:10.1159/000334936. PMID 22237135. 6. ^ Du, G.; Min, M.; Yang, J.; Chen, J.; Tu, Y. (2016). "Overexpression of AQP5 Was Detected in Axillary Sweat Glands of Primary Focal Hyperhidrosis Patients". Dermatology. 232 (2): 150–155. doi:10.1159/000444081. PMID 26930592. 7. ^ Kaufmann, H.; Saadia, D.; Polin, C.; Hague, S.; Singleton, A.; Singleton, A. (2003). "Primary hyperhidrosis--evidence for autosomal dominant inheritance". Clinical Autonomic Research Journal. 13 (2): 96–98. doi:10.1007/s10286-003-0082-x. PMID 12720093. 8. ^ Haider, Aamir & Solish, Nowell (2005). "Focal hyperhidrosis: diagnosis and management". Canadian Medical Association Journal. 172 (1): 69–75. doi:10.1503/cmaj.1040708. PMC 543948. PMID 15632408. 9. ^ Walling, Hobart W. (2011). "Clinical differentiation of primary from secondary hyperhidrosis". Journal of the American Academy of Dermatology. 64 (4): 690–695. doi:10.1016/j.jaad.2010.03.013. PMID 21334095. 10. ^ Stashak, AB; Brewer, JD (29 October 2014). "Management of hyperhidrosis". Clinical, Cosmetic and Investigational Dermatology. 7: 285–99. doi:10.2147/CCID.S53119. PMC 4218921. PMID 25378942. 11. ^ Jacob, C (March 2013). "Treatment of hyperhidrosis with microwave technology". Seminars in Cutaneous Medicine and Surgery. 32 (1): 2–8. PMID 24049923. 12. ^ a b Brown, AL; Gordon, J; Hill, S (August 2014). "Hyperhidrosis: review of recent advances and new therapeutic options for primary hyperhidrosis". Current Opinion in Pediatrics. 26 (4): 460–5. doi:10.1097/mop.0000000000000108. PMID 24905102. ## External links[edit] Classification D * ICD-10: Xxx.x * ICD-9-CM: xxx [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Focal hyperhidrosis	c0476475	6,082	wikipedia	https://en.wikipedia.org/wiki/Focal_hyperhidrosis	2021-01-18T18:47:37	{"icd-10": ["L74.5"], "wikidata": ["Q5463851"]}
"LTBI" redirects here. For the airport, see Eskişehir Airport. Latent tuberculosis Other namesLatent tuberculosis infection SpecialtyInfectious disease Latent tuberculosis (LTB), also called latent tuberculosis infection (LTBI) is when a person is infected with Mycobacterium tuberculosis, but does not have active tuberculosis. Active tuberculosis can be contagious while latent tuberculosis is not, and it is therefore not possible to get TB from someone with latent tuberculosis. The main risk is that approximately 10% of these people (5% in the first two years after infection and 0.1% per year thereafter) will go on to develop active tuberculosis. This is particularly true, and there is added risk, in particular situations such as medication that suppresses the immune system or advancing age. The identification and treatment of people with latent TB is an important part of controlling this disease. Various treatment regimens are in use for latent tuberculosis. They generally need to be taken for several months. ## Contents * 1 Transmission * 1.1 Latent disease * 1.2 Reactivation * 2 Diagnosis * 2.1 Tuberculin skin testing * 2.1.1 Mantoux test * 2.1.2 Heaf test * 2.1.3 Tuberculin conversion * 2.1.4 Boosting * 2.1.5 Interpretation * 2.2 Interferon-γ testing * 2.3 Drug-resistant strains * 3 Treatment * 3.1 Terminology * 3.2 Specific situations * 3.3 Treatment regimens * 3.4 Evidence for treatment effectiveness * 3.5 Treatment efficacy * 4 Epidemiology * 5 Controversy * 6 See also * 7 References * 8 Further reading * 9 External links ## Transmission[edit] ### Latent disease[edit] "TB Bacteria Are Spread Only from a Person with Active TB Disease ... In people who develop active TB of the lungs, also called pulmonary TB, the TB skin test will often be positive. In addition, they will show all the signs and symptoms of TB disease, and can pass the bacteria to others. So, if a person with TB of the lungs sneezes, coughs, talks, sings, or does anything that forces the bacteria into the air, other people nearby may breathe in TB bacteria. Statistics show that approximately one-third of people exposed to pulmonary TB become infected with the bacteria, but only one in ten of these infected people develop active TB disease during their lifetimes."[1] However, exposure to tuberculosis is very unlikely to happen when one is exposed for a few minutes in a store or in a few minutes social contact. "It usually takes prolonged exposure to someone with active TB disease for someone to become infected. After exposure, it usually takes 8 to 10 weeks before the TB test would show if someone had become infected."[2] "Depending on ventilation and other factors, these tiny droplets [from the person who has active tuberculosis] can remain suspended in the air for several hours. Should another person inhale them, he or she may become infected with TB. The probability of transmission will be related to the infectiousness of the person with TB, the environment where the exposure occurred, the duration of the exposure, and the susceptibility of the host."[3] In fact, "it isn't easy to catch TB. You need consistent exposure to the contagious person for a long time. For that reason, you're more likely to catch TB from a relative than a stranger."[4] If a person had latent tuberculosis, they do not have active/contagious tuberculosis. Once exposed, people very often have latent tuberculosis. To convert to active tuberculosis, the bacteria must become active. People have medical privacy or "confidentiality" and do not have to reveal their active tuberculosis case to family, friends, or co-workers; therefore, the person who gets latent tuberculosis may never know who had the active case of tuberculosis that caused the latent tuberculosis diagnosis for them. Only by required testing (required in some jobs) [5] or developing symptoms of active tuberculosis and visiting a medical doctor who does testing will a person know they have been exposed. Because tuberculosis is not common in the United States, doctors may not suspect tuberculosis; therefore, they may not test. If a person has symptoms of tuberculosis, it is wise to be tested.[citation needed] Persons with diabetes may have an 18% chance of converting to active tuberculosis.[6] In fact, death from tuberculosis was greater in diabetic patients.[6] Persons with HIV and latent tuberculosis have a 10% chance of developing active tuberculosis every year. "HIV infection is the greatest known risk factor for the progression of latent M. tuberculosis infection to active TB. In many African countries, 30–60% of all new TB cases occur in people with HIV, and TB is the leading cause of death globally for HIV-infected people."[7] ### Reactivation[edit] Once a person has been diagnosed with Latent Tuberculosis (LTBI) and a medical doctor confirms no active tuberculosis, the person should remain alert to symptoms of active tuberculosis for the remainder of his or her life. Even after completing the full course of medication, there is no guarantee that the tuberculosis bacteria have all been killed.[citation needed]"When a person develops active TB (disease), the symptoms (cough, fever, night sweats, weight loss etc.) may be mild for many months. This can lead to delays in seeking care, and results in transmission of the bacteria to others." [8] Tuberculosis does not always settle in the lungs. If the outbreak of tuberculosis is in the brain, organs, kidneys, joints, or others areas, the patient may have active tuberculosis for an extended period of time before discovering that they are active. "A person with TB disease may feel perfectly healthy or may only have a cough from time to time."[9] However, these symptoms do not guarantee tuberculosis, and they may not exist at all, yet the patient may still have active tuberculosis. A person with symptoms listed may have active tuberculosis, and the person should immediately see a physician so that tuberculosis is not spread. If a person with the above symptoms does not see a physician, ignoring the symptoms can result in lung damage, eye damage, organ damage and eventually death. When tuberculosis settles in other organs (rather than lungs) or other parts of the body (such as the skeletal), symptoms may be different from when it settles in the lungs (such as the symptoms listed above). Thus, without the cough or flu-like symptoms, a person can unwittingly have active tuberculosis. Other symptoms include back pain, flank pain, PID symptoms, confusion, coma, difficulty swallowing, and many other symptoms that would be a part of other diseases.[10] (Please see the reference for more information on symptoms.) Therefore, seeing a physician and asking for a tuberculosis test is absolutely necessary to rule out tuberculosis when a patient has symptoms without a diagnosis of disease. Situations in which tuberculosis may become reactivated are: * if there is onset of a disease affecting the immune system (such as AIDS) or a disease whose treatment affects the immune system (such as chemotherapy in cancer or systemic steroids in asthma or Enbrel, Humira or Orencia in rheumatoid arthritis); * malnutrition (which may be the result of illness or injury affecting the digestive system, or of a prolonged period of not eating, or disturbance in food availability such as famine, residence in refugee camp or concentration camp, or civil war); * degradation of the immune system due to aging.[11] * certain systemic diseases such as diabetes,[12] and "other conditions: debilitating disease (especially haematological and some solid cancers), long-term steroids, end-stage renal disease, silicosis and gastrectomy/jejuno-ileal bypass all confer an increased risk.[13] * "Elderly patients: latent TB may reactivate in elderly patients."[14] * The very young [15] ## Diagnosis[edit] There are two classes of tests commonly used to identify patients with latent tuberculosis: tuberculin skin tests and IFN-γ (Interferon-gamma) tests. The skin tests currently include the following two: * Mantoux test * Heaf test IFN-γ tests include the following three: * T-SPOT.TB * QuantiFERON-TB Gold * QuantiFERON-TB Gold In-Tube ### Tuberculin skin testing[edit] The tuberculin skin test (TST) in its first iteration, the Mantoux Test, was developed in 1908. Conceptually, it's quite simple: tuberculin (also called purified protein derivative or PPD) is a standardised dead extract of cultured TB, injected into the skin to measure the person's immune response to the bacteria. So, if a person has been exposed to the bacteria previously, they should express an immune reaction to the injection, usually a mild swelling or redness around the site. There have been two primary methods of TST: the Mantoux test, and the Heaf test. The Heaf test was discontinued in 2005 because the manufacturer deemed its production to be financially unsustainable, though it was previously preferred in the UK because it was felt to require less training to administer and involved less inter-observer variation in its interpretation than the Mantoux test. The Mantoux test was the preferred test in the US, and is now the most widely used TST globally. #### Mantoux test[edit] See: Mantoux test The Mantoux test is now standardised by the WHO. 0.1 ml of tuberculin (100 units/ml), which delivers a dose of 5 units is given by intradermal injection into the surface of the lower forearm (subcutaneous injection results in false negatives). A waterproof ink mark is drawn around the injection site so as to avoid difficulty finding it later if the level of reaction is small. The test is read 48 to 72 hours later.[16] The area of induration (NOT of erythema) is measured transversely across the forearm (left to right, not up and down) and recorded to the nearest millimetre.[17] #### Heaf test[edit] See:Heaf test The Heaf test was first described in 1951.[18] The test uses a Heaf gun with disposable single-use heads; each head has six needles arranged in a circle. There are standard heads and pediatric heads: the standard head is used on all patients aged 2 years and older; the pediatric head is for infants under the age of 2. For the standard head, the needles protrude 2 mm when the gun is actuated; for the pediatric heads, the needles protrude 1 mm. Skin is cleaned with alcohol, then tuberculin (100,000 units/ml) is evenly smeared on the skin (about 0.1 ml); the gun is then applied to the skin and fired. The excess solution is then wiped off and a waterproof ink mark is drawn around the injection site. The test is read 2 to 7 days later. * Grade 0: no reaction, or induration of 3 or less puncture points; * Grade 1: induration of four or more puncture points; * Grade 2: induration of the six puncture points coalesce to form a circle; * Grade 3: induration of 5 mm; or more * Grade 4: induration of 10 mm or more, or ulceration The results of both tests are roughly equivalent as follows: * Heaf grade 0 & 1 ~ Mantoux less than 5 mm; * Heaf grade 2 ~ Mantoux 5–14 mm; * Heaf grade 3 & 4 ~ Mantoux 15 or greater #### Tuberculin conversion[edit] Tuberculin conversion is said to occur if a patient who has previously had a negative tuberculin skin test develops a positive tuberculin skin test at a later test. It indicates a change from negative to positive, and usually signifies a new infection. #### Boosting[edit] The phenomenon of boosting is one way of obtaining a false positive test result. Theoretically, a person's ability to develop a reaction to the TST may decrease over time – for example, a person is infected with latent TB as a child, and is administered a TST as an adult. Because there has been such a long time since the immune responses to TB has been necessary, that person might give a negative test result. If so, there is a fairly reasonable chance that the TST triggers a hypersensitivity in the person's immune system – in other words, the TST reminds the person's immune system about TB, and the body overreacts to what it perceives as a reinfection. In this case, when that subject is given the test again (as is standard procedure, see above) they may have a significantly greater reaction to the test, giving a very strong positive; this can be commonly misdiagnosed as Tuberculin Conversion. This can also be triggered by receiving the BCG vaccine, as opposed to a proper infection. Although boosting can occur in any age group, the likelihood of the reaction increases with age.[19] Boosting is only likely to be relevant if an individual is beginning to undergo periodic TSTs (health care workers, for example). In this case the standard procedure is called two-step testing. The individual is given their first test and in the event of a negative, given a second test in 1 to 3 weeks. This is done to combat boosting in situations where, had that person waited up to a year to get their next TST, they might still have a boosted reaction, and be misdiagnosed as a new infection.[20] Here there is a difference in US and UK guidelines; in the US testers are told to ignore the possibility of false positive due to the BCG vaccine, as the BCG is seen as having waning efficacy over time. Therefore, the CDC urges that individuals be treated based on risk stratification regardless of BCG vaccination history, and if an individual receives a negative and then a positive TST they will be assessed for full TB treatment beginning with X-ray to confirm TB is not active and proceeding from there.[21] Conversely, the UK guidelines acknowledge the potential effect of the BCG vaccination, as it is mandatory and therefore a prevalent concern – though the UK shares the procedure of administering two tests, one week apart, and accepting the second one as the accurate result, they also assume that a second positive is indicative of an old infection (and therefore certainly LTBI) or the BCG itself. In the case of BCG vaccinations confusing the results, Interferon-γ (IFN-γ) tests may be used as they will not be affected by the BCG. #### Interpretation[edit] According to the U.S. guidelines, there are multiple size thresholds for declaring a positive result of latent tuberculosis from the Mantoux test: For testees from high-risk groups, such as those who are HIV positive, the cutoff is 5 mm of induration; for medium risk groups, 10 mm; for low-risk groups, 15 mm. The U.S. guidelines recommend that a history of previous BCG vaccination should be ignored. For details of tuberculin skin test interpretation, please refer to the CDC guidelines (reference given below). The UK guidelines are formulated according to the Heaf test: In patients who have had BCG previously, latent TB is diagnosed if the Heaf test is grade 3 or 4 and have no signs or symptoms of active TB; if the Heaf test is grade 0 or 1, then the test is repeated. In patients who have not had BCG previously, latent TB is diagnosed if the Heaf test is grade 2, 3 or 4, and have no signs or symptoms of active TB. Repeat Heaf testing is not done in patients who have had BCG (because of the phenomenon of boosting). For details of tuberculin skin test interpretation, please refer to the BTS guidelines (references given below). Given that the US recommendation is that prior BCG vaccination be ignored in the interpretation of tuberculin skin tests, false positives with the Mantoux test are possible as a result of: (1) having previously had a BCG (even many years ago), and/or (2) periodical testing with tuberculin skin tests. Having regular TSTs boosts the immunological response in those people who have previously had BCG, so these people will falsely appear to be tuberculin conversions. This may lead to treating more people than necessary, with the possible risk of those patients suffering adverse drug reactions. However, as Bacille Calmette-Guérin vaccine is not 100% effective, and is less protective in adults than pediatric patients, not treating these patients could lead to a possible infection. The current US policy seems to reflect a desire to err on the side of safety. The U.S. guidelines also allow for tuberculin skin testing in immunosuppressed patients (those with HIV, or who are on immunosuppressive drugs), whereas the UK guidelines recommend that tuberculin skin tests should not be used for such patients because it is unreliable. ### Interferon-γ testing[edit] The role of IFN-γ tests is undergoing constant review and various guidelines have been published with the option for revision as new data becomes available.CDC:MMWR Health Protection Agency:UK There are currently two commercially available interferon-γ release assays (IGRAs): QuantiFERON-TB Gold and T-SPOT.TB.[22] These tests are not affected by prior BCG vaccination, and look for the body's response to specific TB antigens not present in other forms of mycobacteria and BCG (ESAT-6). Whilst these tests are new they are now becoming available globally. CDC: > CDC recommends that QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control (e.g., those for health-care workers). HPA Interim Guidance: > The HPA recommends the use of IGRA testing in health care workers, if available, in view of the importance of detecting latently infected staff who may go on to develop active disease and come into contact with immunocompromised patients and the logistical simplicity of IGRA testing. ### Drug-resistant strains[edit] It is usually assumed by most medical practitioners in the early stages of a diagnosis that a case of latent tuberculosis is the normal or regular strain of tuberculosis. It will therefore be most commonly treated with Isoniazid (the most used treatment for latent tuberculosis.) Only if the tuberculosis bacteria does not respond to the treatment will the medical practitioner begin to consider more virulent strains, requiring significantly longer and more thorough treatment regimens. There are 4 types of tuberculosis recognized in the world today: * Tuberculosis (TB) * Multi-drug-resistant tuberculosis (MDR TB)[23] * Extensively drug-resistant tuberculosis (XDR TB)[24] * Totally drug-resistant tuberculosis (TDR TB)[25] ## Treatment[edit] Main article: Tuberculosis treatment The treatment of latent tuberculosis infection (LTBI) is essential to controlling and eliminating TB by reducing the risk that TB infection will progress to disease. Latent tuberculosis will convert to active tuberculosis in 10% of cases (or more in cases of immune compromised patients). Taking medication for latent tuberculosis is recommended by many doctors.[26] In the U.S., the standard treatment is nine months of isoniazid, but this regimen is not widely used outside of the US. ### Terminology[edit] There is no agreement regarding terminology: the terms preventive therapy and chemoprophylaxis have been used for decades, and are preferred in the UK because it involves giving medication to people who have no disease and are currently well: the reason for giving medication is primarily to prevent people from becoming unwell. In the U.S., physicians talk about latent tuberculosis treatment because the medication does not actually prevent infection: the person is already infected and the medication is intended to prevent existing silent infection from becoming active disease. There are no convincing reasons to prefer one term over the other. ### Specific situations[edit] Main article: tuberculosis treatment "Populations at increased risk of progressing to active infection once exposed: * Persons with recent TB infection [those infected within the previous two years] * Congenital or acquired immunosuppressed patients (in particular, HIV-positive patients) * Illicit intravenous drug users; alcohol and other chronic substance users * Children (particularly those younger than 4 years old) * Persons with comorbid conditions (ie, chronic kidney failure, diabetes, malignancy, hematologic cancers, body weight of at least 10% less than ideal, silicosis, gastrectomy, jejunoileal bypass, asthma, or other disorders requiring long-term use of corticosteroids or other immunosuppressants)."[27] ### Treatment regimens[edit] It is essential that assessment to rule out active TB be carried out before treatment for LTBI is started. To give treatment for latent tuberculosis to someone with active tuberculosis is a serious error: the tuberculosis will not be adequately treated and there is a serious risk of developing drug-resistant strains of TB. There are several treatment regimens currently in use: * 9H — isoniazid for 9 months is the gold standard (93% effective, in patients with positive test results and fibrotic pulmonary lesions compatible with tuberculosis[28]). * 6H — Isoniazid for 6 months might be adopted by a local TB program based on cost-effectiveness and patient compliance. This is the regimen currently recommended in the UK for routine use. The U.S. guidance excludes this regimen from use in children or persons with radiographic evidence of prior tuberculosis (old fibrotic lesions) (69% effective). * 6 to 9H2 — An intermittent twice-weekly regimen for the above 2 treatment regimens is an alternative if administered under Directly observed therapy (DOT). * 4R — rifampicin for 4-months is an alternative for those who are unable to take isoniazid or who have had known exposure to isoniazid-resistant TB. * 3HR — Isoniazid and rifampin may be given daily for three months. * 2RZ — The two-month regimen of rifampin and pyrazinamide is no longer recommended for treatment of LTBI because of the greatly increased risk of drug-induced hepatitis and death.[29] * 3HP – three-month (12-dose) regimen of weekly rifapentine and isoniazid.[30][31] The 3HP regimen has to be administered under DOT. A self-administered therapy (SAT) of 3HP is investigated in a large international study.[32] ### Evidence for treatment effectiveness[edit] A 2000 Cochrane review containing 11 double-blinded, randomized control trials and 73,375 patients examined six and 12 month courses of isoniazid (INH) for treatment of latent tuberculosis. HIV positive and patients currently or previously treated for tuberculosis were excluded. The main result was a relative risk (RR) of 0.40 (95% confidence interval (CI) 0.31 to 0.52) for development of active tuberculosis over two years or longer for patients treated with INH, with no significant difference between treatment courses of six or 12 months (RR 0.44, 95% CI 0.27 to 0.73 for six months, and 0.38, 95% CI 0.28 to 0.50 for 12 months).[33] A Cochrane systematic review published in 2013 evaluated four different alternatives regimens to INH monotherapy for preventing active TB in HIV-negative people with latent tuberculosis infection. The evidence from this review found no difference between shorter regimens of Rifampicin or weekly, directly observed Rifapentine plus INH compare to INH monotherapy in preventing active TB in HIV-negative people at risk of developing it . However the review found that the shorter Rifampicin regimen for four months and weekly directly observed Rifapentine plus INH for three months “may have additional advantages of higher treatment completion and improved safety." However the overall quality of evidence was low to moderate (as per GRADE criteria )and none of the included trials were conducted in LMIC nations with high TB transmission and hence might not be applicable to nations with high TB transmission.[34] ### Treatment efficacy[edit] There is no guaranteed "cure" for latent tuberculosis. "People infected with TB bacteria have a lifetime risk of falling ill with TB..." [8] with those who have compromised immune systems, those with diabetes and those who use tobacco at greater risk.[8] A person who has taken the complete course of Isoniazid (or other full course prescription for tuberculosis) on a regular, timely schedule may have been cured. "Current standard therapy is isoniazid (INH) which reduce the risk of active TB by as much as 90 per cent (in patients with positive LTBI test results and fibrotic pulmonary lesions compatible with tuberculosis[35]) if taken daily for 9 months." [Emphasis added][33] However, if a person has not completed the medication exactly as prescribed, the "cure" is less likely, and the "cure" rate is directly proportional to following the prescribed treatment specifically as recommended. Furthermore, "[I]f you don't take the medicine correctly and you become sick with TB a second time, the TB may be harder to treat if it has become drug resistant."[9] If a patient were to be cured in the strictest definition of the word, it would mean that every single bacterium in the system is removed or dead, and that person cannot get tuberculosis (unless re-infected). However, there is no test to assure that every single bacterium has been killed in a patient's system. As such, a person diagnosed with latent TB can safely assume that, even after treatment, they will carry the bacteria – likely for the rest of their lives. Furthermore, " It has been estimated that up to one-third of the world's population is infected with M. tuberculosis, and this population is an important reservoir for disease reactivation."[34] This means that in areas where TB is endemic treatment may be even less certain to "cure" TB, as reinfection could trigger activation of latent TB already present even in cases where treatment was followed completely. ## Epidemiology[edit] Tuberculosis exists in all countries in the world. Some countries have a larger number of people infected with tuberculosis than others. For each 100,000 people, Swaziland has the greatest number (627) of tuberculosis cases in the world. Second is Cambodia (560), followed in third position by Zambia (445), fourth is Djibouti (382), fifth is Indonesia (321), sixth is Mali (295), seventh is Zimbabwe (291), eighth is Kenya (291), ninth is Papua New Guinea (283) and tenth is Gambia (283).[36] The United States, Sweden and Iceland have one of the lowest populations of tuberculosis at 2 per 100,000.[36] with Canada, Netherlands, Jamaica, Norway, Malta, Granada and Antigua and Barbuda with 3 per 100,000. In North America, countries over 10:100,000 are Mexico (14), Belize (18), Bahamas (19), Panama (28), El Salvador (36), Nicaragua (35), Honduras (46), Guatemala (48), and the worst is the Dominican Republic (88).[36] Most Western European countries have less than 10 per 100,000 except Spain (14), Portugal (16), Estonia (27), Latvia (43), Lithuania (48), while Eastern and Southern European countries have a greater number with Romania (94) being the highest.[36] In South America, the greatest number of cases of tuberculosis are in Bolivia (30) with Guyana (18) and Honduras (15) following with the remaining countries having less than 10:100,000.[37] "One-third of the world’s burden of tuberculosis (TB), or about 4.9 million prevalent cases, is found in the World Health Organization (WHO) South-East Asia Region."[38] "About one-third of the world's population has latent TB, which means people have been infected by TB bacteria but are not (yet) ill with disease and cannot transmit the disease,"[8] and most of those cases are in developing countries.[7] "In the US, over half of all active TB cases occur in immigrants. The reported cases of active TB in foreign-born persons has remained at 7000–8000 per year, while the number of cases in US-born people has dropped from 17,000 in 1993 to 6,500 in 2005. As a result, the percentage of active TB cases in immigrants has increased steadily (from 29% of all cases in 1993 to 54% in 2005)."[8] and most of those cases are in developing countries.[7] ## Controversy[edit] There is controversy over whether people who test positive long after infection have a significant risk of developing the disease (without re-infection). Some researchers and public health officials have warned that this test-positive population is a "source of future TB cases" even in the US and other wealthy countries, and that this "ticking time bomb" should be a focus of attention and resources.[39] On the other hand, Marcel Behr, Paul Edelstein, and Lalita Ramakrishnan reviewed studies concerning the concept of latent tuberculosis in order to determine whether tuberculosis-infected persons have life-long infection capable of causing disease at any future time. These studies, both published in the British Medical Journal (BMJ) in 2018 and 2019, show that the incubation period of tuberculosis is short, usually within months after infection, and very rarely more than 2 years after infection.[40] They also show that more than 90% of people infected with M. tuberculosis for more than two years never develop tuberculosis even if their immune system is severely suppressed.[41] Immunologic tests for tuberculosis infection such as the tuberculin skin test and interferon gamma release assays (IGRA) only indicate past infection, with the majority of previously infected persons no longer capable of developing tuberculosis. Ramakrishnan told the New York Times that researchers "have spent hundreds of millions of dollars chasing after latency, but the whole idea that a quarter of the world is infected with TB is based on a fundamental misunderstanding."[42] The first BMJ article about latency was accompanied by an editorial written by Dr. Soumya Swaminathan, Deputy Director-General of the World Health Organization, who endorsed the findings and called for more funding of TB research directed at the most heavily afflicted parts of the world, rather than disproportionate attention to a relatively minor problem that affects just the wealthy countries.[42] ## See also[edit] * Silent disease ## References[edit] 1. ^ "Detailed Explanation of Tuberculosis (TB)". Niaid.nih.gov. 2009-03-06. Retrieved 2015-10-05. 2. ^ "CDC issues Important info about TB exposure, explains tests here". Democratic Underground. Retrieved 2015-10-05. 3. ^ Chapter 3—The Facts About Tuberculosis – The Tuberculosis Epidemic – NCBI Bookshelf. Ncbi.nlm.nih.gov. 1995. Retrieved 2015-10-05. 4. ^ "Tuberculosis \| University of Maryland Medical Center". Umm.edu. 2015-03-24. Retrieved 2015-10-05. 5. ^ {{For example, if you work in the Retirement Home industry in Ontario, Canada you are required by law to have a TB test to confirm that you do not have active TB cite - Ontario Regulation 166/11 s. 27 (8) (b) 6. ^ a b Kelly E. Dooley; Tania Tang; Jonathan E. Golub; Susan E. Dorman; Wendy Cronin (2009). "Impact of diabetes mellitus on treatment outcomes of patients with active tuberculosis". American Journal of Tropical Medicine and Hygiene. 80 (4): 634–639. doi:10.4269/ajtmh.2009.80.634. PMC 2750857. PMID 19346391. 7. ^ a b c "Latent TB: FAQ's — EthnoMed". Ethnomed.org. Retrieved 2015-10-05. 8. ^ a b c d e "WHO \| Tuberculosis". Who.int. 2015-03-09. Retrieved 2015-10-05. 9. ^ a b "Tuberculosis Symptoms, Causes & Risk Factors". American Lung Association. Retrieved 2015-10-05. 10. ^ Tuberculosis at eMedicine 11. ^ Comstock, George W; Livesay, Verna T; Woolpert, Shirley F (1974). "The prognosis of a positive tuberculin reaction in childhood and adolescence". American Journal of Epidemiology. 99 (2): 131–8. doi:10.1093/oxfordjournals.aje.a121593. PMID 4810628. 12. ^ "Diabetes and tuberculosis". idf.org. International Diabetes Federation. Retrieved September 5, 2013. 13. ^ "Risk Factors". The Mayo Clinic. July 12, 2013. 14. ^ "Tuberculosis \| Doctor". Patient. 2014-05-21. Retrieved 2015-10-05. 15. ^ "Tuberculosis". Mayo Clinic. 2014-08-01. Retrieved 2015-10-05. 16. ^ "CDC \| TB \| Testing & Diagnosis". Cdc.gov. Retrieved 2015-10-05. 17. ^ [1] Archived October 21, 2013, at the Wayback Machine 18. ^ Heaf 1951, pp. 151–3. sfn error: no target: CITEREFHeaf1951 (help) 19. ^ "Booster Phenomenon". Mass.gov. Retrieved 2015-10-05. 20. ^ "CDC \| TB \| Fact Sheets – Tuberculin Skin Testing for TB". Cdc.gov. 2012-09-01. Retrieved 2015-10-05. 21. ^ "CDC \| TB \| LTBI – Diagnosis of Latent TB Infection". Cdc.gov. Retrieved 2015-10-05. 22. ^ "How the T-SPOT.TB Test Works". 23. ^ "CDC \| TB \| Fact Sheets \| Multidrug-Resistant Tuberculosis (MDR TB)". Cdc.gov. Retrieved 2015-10-05. 24. ^ "CDC \| TB \| Fact sheets \| Extensively Drug-Resistant Tuberculosis (XDR TB)". Cdc.gov. 2013-01-18. Retrieved 2015-10-05. 25. ^ "Doctors Report Tuberculosis Now 'Virtually Untreatable' \| Incurable TB Antibiotics". Livescience.com. 2013-02-12. Retrieved 2015-10-05. 26. ^ "Does Latent TB Need Treatment? – Ask Dr. Weil". Drweil.com. 2011-08-16. Retrieved 2015-10-05. 27. ^ "Tuberculosis". December 9, 2011. 28. ^ Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. International Union Against Tuberculosis Committee on Prophylaxis. Bull World Health Organ. 1982;60(4):555-64. 29. ^ Schechter M, Zajdenverg R, Falco G, Barnes G, Faulhaber J, Coberly J, Moore R, Chaisson R (2006). "Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts". Am J Respir Crit Care Med. 173 (8): 922–6. doi:10.1164/rccm.200512-1953OC. PMC 2662911. PMID 16474028. 30. ^ Timothy R. Sterling; M. Elsa Villarino; Andrey S. Borisov; Nong Shang; Fred Gordin; Erin Bliven-Sizemore; Judith Hackman; Carol Dukes Hamilton; Dick Menzies; Amy Kerrigan; Stephen E. Weis; Marc Weiner; Diane Wing; Marcus B. Conde; Lorna Bozeman; C. Robert Horsburgh, Jr.; Richard E. Chaisson (2011). "Three months of rifapentine and isoniazid for latent tuberculosis infection". New England Journal of Medicine. 365 (23): 2155–2166. doi:10.1056/NEJMoa1104875. PMID 22150035. 31. ^ Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection. cdc.gov. updated November 22, 2013. 32. ^ Clinical trial number NCT01582711 for "Study 33: Adherence to Latent Tuberculosis Infection Treatment 3HP SAT Versus 3HP DOT (iAdhere)" at ClinicalTrials.gov 33. ^ a b Menzies, Dick; Al Jahdali, Hamdan; Al Otaibi, Badriah (2011). "Recent developments in treatment of latent tuberculosis infection". The Indian Journal of Medical Research. 133: 257–66. PMC 3103149. PMID 21441678. 34. ^ a b Flynn, J. L.; Chan, J. (2001). "Tuberculosis: Latency and Reactivation". Infection and Immunity. 69 (7): 4195–201. doi:10.1128/IAI.69.7.4195-4201.2001. PMC 98451. PMID 11401954. 35. ^ Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. International Union Against Tuberculosis Committee on Prophylaxis. Bull World Health Organ. 1982;60(4):555-64. 36. ^ a b c d "Countries Compared by Health > Tuberculosis cases > Per 100,000. International Statistics at". Nationmaster.com. Retrieved 2015-10-05. 37. ^ "Tuberculosis South America Cause Of Death". Worldlifeexpectancy.com. Retrieved 2015-10-05. 38. ^ Dewan, Puneet K.; Lal, S. S.; Lonnroth, Knut; Wares, Fraser; Uplekar, Mukund; Sahu, Suvanand; Granich, Reuben; Chauhan, Lakhbir Singh (2006). "WHO \| Tuberculosis in the WHO South-East Asia Region". BMJ. 332 (7541): 574–578. doi:10.1136/bmj.38738.473252.7C. PMC 1397734. PMID 16467347. Retrieved 2015-10-05. 39. ^ Maugh II, Thomas H. (2011-05-17). "Shorter treatment found for latent tuberculosis". Los Angeles Times. "Although TB control measures in the United States have brought the incidence of the disease to an all-time low of 11,181 cases in 2010, it is estimated that at least 11 million Americans have latent TB. 'The 11 million Americans with latent TB represent a ticking time bomb,' Dr. Kenneth Castro, director of the Centers for Disease Control and Prevention’s division of tuberculosis elimination, said at a news conference Monday. 'They're the source of future TB cases.'" 40. ^ Behr, Marcel A.; Edelstein, Paul H.; Ramakrishnan, Lalita (August 23, 2018). "Revisiting the timetable of tuberculosis". BMJ (Clinical Research Ed.). 362: k2738. doi:10.1136/bmj.k2738. ISSN 1756-1833. PMC 6105930. PMID 30139910. 41. ^ Behr, Marcel A.; Edelstein, Paul H.; Ramakrishnan, Lalita (2019-10-24). "Is Mycobacterium tuberculosis infection life long?". BMJ. 367: l5770. doi:10.1136/bmj.l5770. ISSN 0959-8138. PMC 6812595. PMID 31649096. 42. ^ a b McNeil, Donald G. Jr. (20 September 2018). "'Latent' tuberculosis? It's not that common, experts find". The New York Times. This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention. ## Further reading[edit] * Jasmer, R. M.; Nahid, P.; Hopewell, P. C. (2002). "Latent tuberculosis infection". New England Journal of Medicine. 347 (23): 1860–1866. doi:10.1056/NEJMcp021045. PMID 12466511. * Mazurek, G. H.; Villarino, M. E. (2003). "Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection". Morbidity and Mortality Weekly Report. 52 (RR–2): 15–18. * Ormerod, P.; Skinner, C.; Moore-Gillon, J.; Davies, P.; Connolly, M. (2000). "BTS Guidelines: control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000". Thorax. 55 (11): 887–901. doi:10.1136/thorax.55.11.887. PMC 1745632. PMID 11050256. ## External links[edit] Classification D * ICD-10: R76.1 * MeSH: D055985 * v * t * e Blood film findings Red blood cells Size * Anisocytosis * Macrocytosis * Microcytosis Shape * Poikilocytosis * Membrane abnormalities * Acanthocyte * Codocyte * Elliptocyte * Hereditary elliptocytosis * Spherocyte * Hereditary spherocytosis * Dacrocyte * Echinocyte * Schistocyte * Degmacyte * Sickle cell/drepanocyte * Sickle cell disease * Stomatocyte * Hereditary stomatocytosis Colour * Anisochromia * Hypochromic anemia * Polychromasia Inclusion bodies * Developmental * Howell–Jolly body * Basophilic stippling * Pappenheimer bodies * Cabot rings * Hemoglobin precipitation * Heinz body Other * Red cell agglutination * Rouleaux White blood cells Lymphocytes * Reactive lymphocyte * Smudge cell * Russell bodies Granulocytes * Hypersegmented neutrophil * Arneth count * Pelger–Huët anomaly * Döhle bodies * Toxic granulation * Toxic vacuolation * Critical green inclusion * Alder–Reilly anomaly * Jordans' anomaly * Birbeck granules * Left shift Other * Auer rod * v * t * e Tuberculosis Symptoms, signs and associated conditions * Caseous necrosis * Ghon focus / Ghon's complex * Giant multinucleated cell * Pott disease * Canga's bead symptom * Prosector's wart * Latent tuberculosis * Paronychia * Lupus vulgaris * Tuberculous lymphadenitis * Tuberculous meningitis * Miliary tuberculosis Mycobacterium species * Mycobacterium africanum * Mycobacterium bovis * Mycobacterium caprae * Mycobacterium tuberculosis Tuberculosis diagnosis * Ziehl–Neelsen stain * Auramine phenol stain * Culture on Löwenstein–Jensen medium and/or MGIT * Chest photofluorography * GeneXpert MTB/RIF * Interferon gamma release assay * QuantiFERON * T-SPOT.TB * Microscopic Observation Drug Susceptibility assay * Tuberculin * Heaf test * Mantoux test * Tine test Management * ATC code J04 * Isoniazid * 4-Aminosalicylic acid * Ethambutol * Capreomycin * Cycloserine * Rifampicin * Thioacetazone * Streptomycin * Bedaquiline * RBCG30 * Pyrazinamide * MVA85A * Rifater * vaccines * BCG vaccine Resistance * Multi-drug-resistant tuberculosis * Extensively drug-resistant tuberculosis * Totally drug-resistant tuberculosis History of tuberculosis * Manuel de Abreu * Hermann Brehmer * Albert Calmette * Christopher Dye * Marcos Espinal * Friedrich Franz Friedmann * Max Gerson * Philip D'Arcy Hart * F. R. G. Heaf * George M. Heath * Robert Koch * Charles Mantoux * Richard Morton * Mario Raviglione * Carl Rüedi * Lucius Rüedi * Madonna Swan * Edward Livingston Trudeau Organizations * Adirondack Cottage Sanitarium * Campaign for Access to Essential Medicines * Center for Infectious Disease Research * Cure Cottages of Saranac Lake * Glen Lake Children's Camp * Glen Lake Sanatorium * Glenn Dale Hospital * The Global Fund to Fight AIDS, Tuberculosis and Malaria * Global Plan to Stop Tuberculosis * International Congress on Tuberculosis * International Union Against Tuberculosis and Lung Disease * Millennium Foundation * Mycobacterium Tuberculosis Structural Genomics Consortium * National Jewish Health * Phipps Institute for the Study, Treatment and Prevention of Tuberculosis * Stop TB Partnership * TB Alliance * Unitaid Other * 2007 tuberculosis scare * 72F fusion protein vaccine * Baumgarten-Tangl law * CFP-10 * ESAT-6 * Iowa Cow War * List of tuberculosis cases * Plombage * Preventorium * Sanatorium * Sunshine Way * Tuberculosis classification * Tuberculosis in China * Tuberculosis in popular culture * Tuberculosis radiology * Tygerberg score * World Tuberculosis Day [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Latent tuberculosis	c1609538	6,083	wikipedia	https://en.wikipedia.org/wiki/Latent_tuberculosis	2021-01-18T18:39:10	{"mesh": ["D055985"], "icd-9": ["795.5"], "icd-10": ["R76.1"], "wikidata": ["Q4254929"]}
A number sign (#) is used with this entry because of evidence that odontoonychodermal dysplasia (OODD) is caused by homozygous or compound heterozygous mutation in the WNT10A gene (606268) on chromosome on chromosome 2q35. Clinical Features In 3 consanguineous Lebanese Muslim Shiite sibships, Fadhil et al. (1983) described an apparently 'new' form of ectodermal dysplasia with dystrophic nails, misshapen teeth, including peg-shaped incisors, and erythematous lesions of face and thickening of the palms and soles which showed hyperhidrosis. The hair was unaffected in some but was described as dry and sparse with thinning of the eyebrows in others. The 3 sibships contained 24 children of whom 7 were affected. Arnold et al. (1995) described a sporadic case. The 31-year-old man was born of nonconsanguineous parents. He complained of progressive thickening of the palmar skin with painful chaffing and increased sweating. Hypodontia with persistence of deciduous teeth was found. There was mild mental deficiency. Zirbel et al. (1995) described an 11-month-old male infant of nonconsanguineous parents who had atrophic malar plaques that reddened with heat, nail dystrophy, sparse hair, lingual concavity of the incisors, a bifid maxillary incisor, a 5-cusped molar, and hyperhidrosis of the palms and soles. In addition, he had chronic tearing, photophobia, blepharitis, and a mild keratitis. Zirbel et al. (1995) concluded that the child most resembled patients with odontoonychodermal dysplasia, although his eye findings were unique. Megarbane et al. (2004) reported 3 patients, 2 Lebanese Muslim Shiite brothers and their maternal cousin, who presented with dry hair, pilar keratosis, severe hypodontia, smooth tongue, onychodysplasia, and keratoderma and hyperhidrosis of palms and soles. Molecular analysis excluded X-linkage, suggesting instead autosomal recessive inheritance. The parents denied direct consanguinity but all members of the family originated from the same village. Bohring et al. (2009) reported 12 patients from 11 unrelated families of German and Turkish origin with ectodermal dysplasia due to confirmed WNT10A mutations. A brother and sister from 1 family had oligodontia and sparse body hair and eyebrows as their only manifestations, and a female proband from another family had cysts of the eyelids in addition to hypodontia, hypotrichosis, palmoplantar keratosis, and dystrophic nails (Schopf-Schulz-Passarge syndrome; 224750). Three patients had photophobia, which was previously described in a patient with OODD by Zirbel et al. (1995). The proband with SSPS was also diagnosed with a porocarcinoma of the left heel. Bohring et al. (2009) suggested that patients with OODD might also be at increased risk for skin tumors. The most consistent finding in all cases and the most specific diagnostic criterion was severe oligodontia of the permanent teeth with normal or less-affected deciduous dentition, involving conical front teeth or agenesis of the upper lateral or central incisors. The authors noted that this pattern of tooth anomalies was similar to that seen in selective tooth agenesis-4 (STHAG4; 150400) and anodontia of permanent teeth (206780), dominant and recessive dental traits, respectively. Despite the high degree of variability in phenotypic expression, Bohring et al. (2009) stated that there was no recognizable genotype/phenotype correlation. Mapping Adaimy et al. (2007) studied 3 consanguineous Lebanese Muslim Shiite families that included 6 individuals affected with odontoonychodermal dysplasia. Using a homozygosity mapping strategy, they assigned the disease locus to a region of approximately 9 cM at 2q35-q36.2, with a maximum multipoint lod score of 5.7. Molecular Genetics In affected members of 3 consanguineous Lebanese Muslim Shiite families with odontoonychodermal dysplasia, Adaimy et al. (2007) found homozygosity for the same nonsense mutation in the WNT10A gene (E233X; 606268.0001). The mutation was predicted to result in a prematurely terminated protein of 232 amino acids instead of 417 amino acids. One of the families had been reported by Megarbane et al. (2004), and another was a branch of one of the families described by Fadhil et al. (1983). The authors stated that this was the first report of a phenotype related to a mutation in WNT10A and the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, thus expanding the list of WNT-related diseases. In 12 patients from 11 unrelated families of German and Turkish origin with ectodermal dysplasia, who were known to be negative for mutation in the ectodysplasin-A gene (EDA; 300451), Bohring et al. (2009) identified homozygosity or compound heterozygosity for 5 missense and nonsense mutations in the WNT10A gene (606268.0002-606268.0006). Approximately half of heterozygotes had minor manifestations, and none of the wildtype homozygotes had any symptoms. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Sparse eyebrows Mouth \- Smooth tongue \- Reduced fungiform papillae \- Reduced filiform papillae Teeth \- Severe hypodontia SKIN, NAILS, & HAIR Skin \- Palmar erythema \- Keratosis pilaris \- Keratoderma (palms and soles) \- Hyperhidrosis (palms and soles) \- Hyperkeratosis Skin Histology \- Orthokeratosis in epidermis \- Hyperkeratosis in epidermis \- Hypergranulosis in epidermis \- Acanthosis, mild, in epidermis Nails \- Dystrophic fingernails (onychodysplasia) \- Dystrophic toenails \- Congenital absence of nails (anonychia) Hair \- Hair is absent at birth \- Dry hair \- Thin hair \- Sparse eyebrows \- Longitudinal depressions on microscopic examination MOLECULAR BASIS \- Caused by mutation in the wingless-type MMTV integration site family, member 10A gene (WNT10A, 606268.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	ODONTOONYCHODERMAL DYSPLASIA	c1275074	6,084	omim	https://www.omim.org/entry/257980	2019-09-22T16:24:09	{"omim": ["257980"], "orphanet": ["2721"]}
Baboon M7 xenotropic (type C) virus infects human cells but not Chinese hamster cells. By human-hamster cell hybrids, Brown et al. (1978) showed that this behavior of human cells requires chromosome 19. Thus, several virus susceptibilities have been related to chromosome 19; see poliovirus sensitivity (173850) and Echo 11 sensitivity (129150). Contradictory findings were reported by Lemons et al. (1977), who assigned the locus to chromosome 6. Lemons et al. (1977) referred to the locus as 'Bevi' for 'baboon endogenous virus infection', but it can equally well stand for 'baboon endogenous virus integration' because Lemons et al. (1978) presented evidence that 'Bevi' is the preferred proviral integration site in the human genome. It was the conclusion of the fifth Human Gene Mapping Workshop in Edinburgh (1979) that BEVI is on chromosome 6, but that chromosome 19 carries a locus, symbolized M7V1, which is essential to replication of the baboon virus (see 109190). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	BABOON M7 VIRUS INTEGRATION SITE	c1412786	6,085	omim	https://www.omim.org/entry/109180	2019-09-22T16:44:34	{"omim": ["109180"]}
Shprintzen-Goldberg syndrome (SGS) is a very rare genetic disorder characterized by craniosynostosis, craniofacial and skeletal abnormalities, marfanoid habitus, cardiac anomalies, neurological abnormalities, and intellectual disability. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Shprintzen-Goldberg syndrome	c1321551	6,086	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2462	2021-01-23T18:08:01	{"gard": ["4861"], "mesh": ["C537328"], "omim": ["182212"], "umls": ["C1321551"], "icd-10": ["Q87.8"], "synonyms": ["Marfanoid craniosynostosis syndrome", "SGS"]}
Suppression of an eye is a subconscious adaptation by a person's brain to eliminate the symptoms of disorders of binocular vision such as strabismus, convergence insufficiency and aniseikonia. The brain can eliminate double vision by ignoring all or part of the image of one of the eyes. The area of a person's visual field that is suppressed is called the suppression scotoma (with a scotoma meaning, more generally, an area of partial alteration in the visual field). Suppression can lead to amblyopia. ## Contents * 1 Effect * 2 Measurement * 3 Anti-suppression therapy * 4 Age factors * 5 See also * 6 References ## Effect[edit] Nobel-prize winner David H. Hubel described suppression in simple terms as follows: "Suppression is familiar to anyone who has trained himself to look through a monocular microscope, sight a gun, or do any other strictly one-eye task, with the other eye open. The scene simply disappears for the suppressed eye."[1] Suppression is frequent in children with anisometropia or strabismus or both. For instance, children with infantile esotropia may alternate with which eye they look, each time suppressing vision in the other eye. ## Measurement[edit] During an eye examination, the presence of suppression and the size and location of the suppression scotoma may be the Worth 4 dot test (a subjective test that is considered to be the most precise suppression test), or with other subjective tests such as the Bagolini striated lens test, or with objective tests such as the 4 prism base out test.[2][3] ## Anti-suppression therapy[edit] Suppression may treated with vision therapy, though there is a wide range of opinions on long-term effectiveness between eye care professionals. ## Age factors[edit] Young children with strabismus normally suppress the visual field of one eye (or part of it), whereas adults who develop strabismus normally do not suppress and therefore suffer from double vision (diplopia). This also means that adults (and older children) have a higher risk of post-operative diplopia after undergoing strabismus surgery than young children. Patients who have undergone strabismus surgery at a young age often have monofixation syndrome (with peripheral binocular fusion and a central suppression scotoma). ## See also[edit] * Amblyopia * Bagolini Striated Glasses Test * Diplopia * Infantile esotropia ## References[edit] 1. ^ David H. Hubel: Eye, Brain, and Vision, Chapter 9 "Deprivation and development", section "Strabismus". Published online by Harvard Medical School (downloaded 30 September 2014) 2. ^ Mitchell Scheiman; Bruce Wick (2008). Clinical Management of Binocular Vision: Heterophoric, Accommodative, and Eye Movement Disorders. Lippincott Williams & Wilkins. p. 16. ISBN 978-0-7817-7784-1. 3. ^ Namrata Sharma; Rasik B. Vajpayee; Laurence Sullivan (12 August 2005). "Refractive surgery and strabismus". Step by Step LASIK Surgery. CRC Press. pp. 100–107. ISBN 978-1-84184-469-5. * Carlson, NB, et al. Clinical Procedures for Ocular Examination. Second Ed. Mc Graw-Hill. New York 1996. This article about the eye is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Suppression (eye)	c0750903	6,087	wikipedia	https://en.wikipedia.org/wiki/Suppression_(eye)	2021-01-18T18:38:43	{"mesh": ["D000550"], "umls": ["C0750903"], "wikidata": ["Q7644639"]}
Alagille syndrome is a genetic disorder that can affect the liver, heart, and other parts of the body. One of the major features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts. These ducts carry bile (which helps to digest fats) from the liver to the gallbladder and small intestine. In Alagille syndrome, the bile ducts may be narrow, malformed, and reduced in number (bile duct paucity). As a result, bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream. Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the skin and the whites of the eyes (jaundice), itchy skin, and deposits of cholesterol in the skin (xanthomas). Alagille syndrome is also associated with several heart problems, including impaired blood flow from the heart into the lungs (pulmonic stenosis). Pulmonic stenosis may occur along with a hole between the two lower chambers of the heart (ventricular septal defect) and other heart abnormalities. This combination of heart defects is called tetralogy of Fallot. People with Alagille syndrome may have distinctive facial features including a broad, prominent forehead; deep-set eyes; and a small, pointed chin. The disorder may also affect the blood vessels within the brain and spinal cord (central nervous system) and the kidneys. Affected individuals may have an unusual butterfly shape of the bones of the spinal column (vertebrae) that can be seen in an x-ray. Problems associated with Alagille syndrome generally become evident in infancy or early childhood. The severity of the disorder varies among affected individuals, even within the same family. Symptoms range from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation. Some people with Alagille syndrome may have isolated signs of the disorder, such as a heart defect like tetralogy of Fallot, or a characteristic facial appearance. These individuals do not have liver disease or other features typical of the disorder. ## Frequency The estimated prevalence of Alagille syndrome is 1 in 70,000 newborns. This figure is based on diagnoses of liver disease in infants, and may be an underestimation because some people with Alagille syndrome do not develop liver disease during infancy. ## Causes In more than 90 percent of cases, mutations in the JAG1 gene cause Alagille syndrome. Another 7 percent of individuals with Alagille syndrome have small deletions of genetic material on chromosome 20 that include the JAG1 gene. A few people with Alagille syndrome have mutations in a different gene, called NOTCH2. The JAG1 and NOTCH2 genes provide instructions for making proteins that fit together to trigger interactions called Notch signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Changes in either the JAG1 gene or NOTCH2 gene probably disrupt the Notch signaling pathway. As a result, errors may occur during development, especially affecting the bile ducts, heart, spinal column, and certain facial features. ### Learn more about the genes and chromosome associated with Alagille syndrome * JAG1 * NOTCH2 * chromosome 20 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered or deleted gene in each cell is sufficient to cause the disorder. In approximately 30 to 50 percent of cases, an affected person inherits the mutation or deletion from one affected parent. Other cases result from new mutations in the gene or new deletions of genetic material on chromosome 20 that occur as random events during the formation of reproductive cells (eggs or sperm) or in early fetal development. These cases occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Alagille syndrome	c1956125	6,088	medlineplus	https://medlineplus.gov/genetics/condition/alagille-syndrome/	2021-01-27T08:25:10	{"gard": ["804"], "mesh": ["D016738"], "omim": ["118450", "610205"], "synonyms": []}
A number sign (#) is used with this entry because resistance to melioidosis is associated with a nonsense polymorphism in the gene encoding Toll-like receptor-5 (TLR5; 603031) on chromosome 1q41. Description Melioidosis is infection caused by the gram-negative, flagellated soil saprophyte Burkholderia pseudomallei, which is endemic in parts of southeast Asia and northern Australia. Sepsis is a common clinical presentation of disease, and lung is the organ most commonly involved. In northern Thailand, where B. pseudomallei is the most common bloodstream isolate, the overall melioidosis mortality rate exceeds 40%, and pneumonia confers more than 2-fold increased risk of death (summary by West et al., 2013). Molecular Genetics West et al. (2013) found that B. pseudomallei induced NFKB (see 164011) signaling in human embryonic kidney cells transfected with full-length TLR5 (603031), but not those transfected with TLR5 containing a nonsense polymorphism, arg392 to ter (R392X; 603031.0001). By studying 600 Thai patients with melioidosis, they found that, in a dominant model, TLR5 with R392X was associated with protection against in-hospital death (adjusted odds ratio (OR) = 0.20; 95% confidence interval (CI) = 0.08-0.50; p = 0.001) and organ failure (adjusted OR = 0.37; 95% CI = 0.19-0.71; p = 0.003). Stimulation of whole blood cells with flagellin or heat-killed B. pseudomallei and normalizing for monocyte count showed that there were lower levels of proinflammatory cytokines, notably IL10 (124092), and chemokines in healthy individuals with full-length TLR5 compared with R392X. West et al. (2013) concluded that the hypofunctional TLR5 variant R392X is associated with reduced organ failure and improved survival in melioidosis, possibly due to the absence of immunoregulatory effects mediated by IL10. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	MELIOIDOSIS, SUSCEPTIBILITY TO	c0025229	6,089	omim	https://www.omim.org/entry/615557	2019-09-22T15:51:37	{"mesh": ["D008554"], "omim": ["615557"], "orphanet": ["31202"]}
A rare developmental defect during embryogenesis that is characterized by growth dysregulation with overgrowth of the brain and multiple somatic tissues, with capillary skin malformations, megalencephaly (MEG) or hemimegalencephaly (HMEG), cortical brain abnormalities (in particular polymicrogyria), typical facial dysmorphisms, abnormalities of somatic growth with asymmetry of the body and brain, developmental delay and digital anomalies. ## Epidemiology Over 200 patients have been reported without sex predominance. ## Clinical description Symptoms are usually recognizable at birth. Their severity varies widely among patients. Megalencephaly is a major clinical feature (MEG: occipitofrontal circumference [OFC] greater than or equal to 3 SD above the mean), which sometimes progresses to hydrocephaly, malformations of cortical development with polymicrogyria and Chiari malformation. Cutaneous capillary anomalies are often scattered over the limbs, palms, soles and trunk, are frequently pink/red and are aggravated by crying and emotions. Facial dysmorphism is observed with frontal bossing, full cheeks, prominent lips and nevus flammeus of the nose and/or philtrum and upper lip. There is a delay in speech and motor skills. Patients may present neurological symptoms, mainly neonatal hypotonia, and, less frequently, seizures. Additional clinical manifestations include prenatal overgrowth, limb asymmetry, joint laxity, soft skin and thick, ''doughy'' subcutaneous tissue, postaxial polydactyly and/or syndactyly of toes 2-3 or fingers 3-4. Some patients develop neoplasias (risk of tumor development estimated at 2-3%). There is a slight increased risk for congenital heart defects and/or cardiac rhythm abnormalities. Adult OFCs range from +2 to +10 SDs above the mean. ## Etiology Somatic mutations of the PIK3CA gene (3q26), with evidence of postzygotic mosaicism, were found in several patients. Two individuals had a de novo germline pathogenic variant in PIK3CA. The gene PIK3CA encodes the alpha catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase. PIK3CA mutations are found in several benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS). The mutational spectrum in children with the disorder is broader than other PIK3CA-related overgrowth disorders. ## Diagnostic methods The disorder can be diagnosed based on clinical findings in individuals with classic features of MEG or HMEG (major finding 1) associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability and characteristic capillary malformations (major finding 2) with focal or generalized somatic overgrowth.. Mosaic mutations of the PIK3CA gene were mainly identified with the advent of massively parallel or next-generation sequencing (NGS) methods. that facilitate detection of low-frequency variation. The level of mosaicism is often lowest in blood‐derived DNA, and higher in saliva and fibroblast‐derived DNA: multiple tissue samples should be tested, prioritizing samples other than blood. ## Differential diagnosis Differential diagnoses include Hemimegalencephaly (HMEG), Megalencephaly - polymicrogyria - post-axial polydactyly - hydrocephalus (MPPH), Klippel-Trénaunay syndrome (KTS), Beckwith-Wiedemann syndrome (BWS), PTEN-related overgrowth disorders. ## Antenatal diagnosis Findings of prenatal ultrasound include marked fetal overgrowth and progressive macrocephaly in the absence of maternal hyperglycemia or fetal hyperinsulinemia, ventriculomegaly, hydrocephalus, frontal bossing, polydactyly, limb asymmetry, polyhydramnios, hydrops fetalis and pleural effusions. ## Genetic counseling The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in PIK3CA would be expected to be the same as in the general population. However, low-level germline mosaicism may theoretically be present in a parent of a very rare child with a germline PIK3CA pathogenic variant. ## Management and treatment Management requires a multidisciplinary approach (involving pediatrician, neurologist, ophthalmologist, cardiologist, orthopedist, physiatrist, ENT, and dermatologist). Neurologic complications (obstructive hydrocephalus, increased intracranial pressure, cerebellar tonsillar ectopia or Chiari malformation; epilepsy in those with HMEG) may warrant neurosurgical intervention. Regular surveillance is recommended (brain MRI in the first 8 years of life, kidney ultrasound for Wilms tumor screening in the first 8 years of life). However, tumor risk in the disorder appears to be lower than in BWS. ## Prognosis Prognosis depends on the severity of symptoms. Early death, due to complex cardiac heart disease and arrhythmia, has been reported in rare occasions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Megalencephaly-capillary malformation-polymicrogyria syndrome	c1865285	6,090	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=60040	2021-01-23T18:28:34	{"gard": ["6950"], "mesh": ["C536142"], "omim": ["602501"], "umls": ["C1865285"], "icd-10": ["Q87.3"], "synonyms": ["MCAP", "MCM", "MCMTC", "Macrocephaly-capillary malformation syndrome", "Macrocephaly-cutis marmorata telangiectatica congenita syndrome", "Megalencephaly-capillary malformation syndrome", "Megalencephaly-cutis marmorata telangiectatica congenita syndrome"]}
Foodborne illness Ciguatera fish poisoning Other namesCiguatera, ciguatera food poisoning Chemical structure of ciguatoxin SpecialtyInfectious disease SymptomsDiarrhea, vomiting, numbness, itchiness, sensitivity to hot and cold, dizziness, weakness[1][2] Usual onset30 min to 2 days[3] DurationFew weeks to months[3] CausesCiguatoxin and maitotoxin within certain reef fish[2] Risk factorsBarracuda, grouper, moray eel, amberjack, sea bass, surgeon fish.[2] Diagnostic methodBased on symptoms and recently eating fish[1] Differential diagnosisParalytic shellfish poisoning, neurotoxic shellfish poisoning, scombroid food poisoning, pufferfish poisoning[1] TreatmentMannitol, gabapentin, amitriptyline[1][2] PrognosisRisk of death < 0.1%[2] Frequency≈50,000 per year[2] Ciguatera fish poisoning (CFP), also known simply as ciguatera, is a foodborne illness caused by eating reef fish whose flesh is contaminated with certain toxins.[2] Such individual fish are said to be ciguatoxic. Symptoms may include diarrhea, vomiting, numbness, itchiness, sensitivity to hot and cold, dizziness, and weakness.[1][2] The onset of symptoms varies with the amount of toxin eaten from half an hour to up to two days.[3] The diarrhea may last for up to four days.[1] Some symptoms typically remain for a few weeks to months.[3] Heart difficulties such as slow heart rate and low blood pressure may also occur.[2] The specific toxins involved are ciguatoxin and maitotoxin.[2] They are originally made by a small marine organism, Gambierdiscus toxicus, that grows on and around coral reefs in tropical and subtropical waters.[2] These are eaten by herbivorous fish which in turn are eaten by larger carnivorous fish.[2] The toxins become more concentrated as they move up the food chain.[3] The fish most often implicated include barracuda, grouper, moray eel, amberjack, sea bass, and sturgeon.[2] Diagnosis is based on a person's symptoms together with having recently eaten fish.[1] If a number of those who eat the same fish develop symptoms the diagnosis becomes more likely.[1] If some of the fish they had previously eaten is available this can also be tested to confirm the diagnosis.[1] Preventive efforts include not eating reef fish, not eating high-risk fish such as barracuda, and not eating fish liver, roe, or fish heads.[2] Ciguatoxin has no taste or smell, and cannot be destroyed by conventional cooking.[2] There is no specific treatment for ciguatera fish poisoning once it occurs.[2] Mannitol may be considered, but the evidence supporting its use is not very strong.[1] Gabapentin or amitriptyline may be used to treat some of the symptoms.[2] The Centers for Disease Control estimates that around 50,000 cases occur globally each year.[2] Other estimates suggest up to 500,000 cases per year.[1] It is the most frequent seafood poisoning.[3] It occurs most commonly in the Pacific Ocean, Indian Ocean, and the Caribbean Sea between the latitudes of 35°N and 35°S.[2] The risk of the condition appears to be increasing due to coral reef deterioration and increasing trade in seafood.[2] The risk of death from poisoning is less than 1 in 1,000.[2] Descriptions of the condition date back to at least 1511.[3] The current name came into use in 1787.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 4.1 Mannitol * 5 Epidemiology * 5.1 20th and 21st centuries * 6 History * 6.1 Folk tales * 6.2 Folk remedies * 7 See also * 8 Footnotes * 9 References ## Signs and symptoms[edit] Hallmark symptoms of ciguatera in humans include gastrointestinal, cardiovascular, and neurological effects.[4][5] Gastrointestinal symptoms include nausea, vomiting, and diarrhea, usually followed by neurological symptoms such as headaches, muscle aches, paresthesia, numbness of extremities, mouth and lips, reversal of hot and cold sensation,[6][7] ataxia, vertigo, and hallucinations.[8][5] Severe cases of ciguatera can also result in cold allodynia, which is a burning sensation on contact with cold.[4] Neurological symptoms can persist and ciguatera poisoning is occasionally misdiagnosed as multiple sclerosis.[9] Cardiovascular symptoms include bradycardia, tachycardia, hypotension, hypertension, orthostatic tachycardia, exercise intolerance, and rhythm disorders.[10] Death from the condition can occur, but is very rare.[11] Dyspareunia and other ciguatera symptoms have developed in otherwise healthy males and females following sexual intercourse with partners suffering ciguatera poisoning, signifying that the toxin may be sexually transmitted.[12] Diarrhea and facial rashes have been reported in breastfed infants of poisoned mothers, suggesting that ciguatera toxins migrate into breast milk.[13] The symptoms can last from weeks to years, and in extreme cases as long as 20 years, often leading to long-term disability.[14] Most people do recover slowly over time.[15] ## Cause[edit] Gambierdiscus toxicus is the primary dinoflagellate responsible for the production of a number of similar polyether toxins, including ciguatoxin, maitotoxin, gambieric acid and scaritoxin, as well as the long-chain alcohol palytoxin.[16][17] Other dinoflagellates that may cause ciguatera include Prorocentrum spp., Ostreopsis spp., Coolia monotis, Thecadinium spp. and Amphidinium carterae.[18] ## Diagnosis[edit] Diagnosis is based on a person's symptoms together with having recently eaten fish.[1] If a number of those who eat the same fish have symptoms the diagnosis becomes more likely.[1] If some of the fish they had previously eaten is available this can also be tested to confirm the diagnosis.[1] Other potential causes such as paralytic shellfish poisoning (PSP), neurotoxic shellfish poisoning (NSP), scombrotoxin fish poisoning, and pufferfish poisoning should be excluded.[1] The reversal of hot and cold sensations is an occasional symptom of CFP that may help differentiate it from intestinal "flu".[19] ## Treatment[edit] There is no effective treatment or antidote for ciguatera poisoning. The mainstay of treatment is supportive care. There is some evidence that calcium channel blockers like nifedipine and verapamil are effective in treating some of the symptoms that remain after the initial sickness passes, such as poor circulation and shooting pains through the chest. These symptoms are due to vasoconstriction caused by maitotoxin.[5][20][21][22] Ciguatoxin lowers the threshold for opening voltage-gated sodium channels in synapses of the nervous system. Opening a sodium channel causes depolarization, which could sequentially cause paralysis, heart contraction, and changing the senses of hot and cold. Some medications such as amitriptyline may reduce some symptoms, such as fatigue and paresthesia,[23] although benefit does not occur in every case.[24] ### Mannitol[edit] Mannitol was once used for poisoning after one study reported symptom reversal.[5][25] Follow-up studies in animals[26] and case reports in humans[27] also found benefit from mannitol. However, a randomized, double-blind clinical trial found no difference between mannitol and normal saline.[28] Despite this its use may still be considered.[1] ## Epidemiology[edit] The current estimated global incidence annually is 20,000 to 50,000 people, though a large number of cases are believed to go unreported.[29] Due to the limited habitats of ciguatoxin-producing microorganisms, ciguatera is common only in subtropical and tropical waters, particularly the Pacific and Caribbean, and usually is associated with fish caught in tropical reef waters.[4] Exportation of reef fish, as well as tourism, often account for cases that develop in other regions.[29] Ciguatoxin is found in over 400 species of reef fish. Avoiding consumption of all reef fish is the only sure way to avoid exposure.[30] Imported fish served in restaurants may contain the toxin and produce illness which often goes unexplained by physicians unfamiliar with the symptoms of a tropical toxin.[30][31] Ciguatoxin can also occur in farm-raised salmon.[32] Furthermore, species substitution, labeling a reef fish as a non-reef fish at restaurants and retail, can complicate efforts by consumers to avoid ciguatera. ### 20th and 21st centuries[edit] * In 1994, Nobel Prize winning novelist Saul Bellow nearly died from Ciguatera after eating red snapper on vacation in St. Martin, fictionalized in his last novel Ravelstein.[33] * In 2007, ten people in St. Louis, Missouri developed the disease after eating imported fish.[34] * In February 2008, the U.S. Food and Drug Administration (FDA) traced several outbreaks to the Flower Garden Banks National Marine Sanctuary in the northern Gulf of Mexico, near the Texas–Louisiana shoreline. The FDA advised seafood processors that ciguatera poisoning was reasonably likely to occur from eating several species of fish caught as far as 50 miles (80 km) from the sanctuary.[35] * From August 2010 to July 2011, there were eight outbreaks of Ciguatera fish poisoning in New York City. Outbreaks were linked to barracuda and grouper purchased at a fish market in Queens, New York.[36] * In the first quarter of 2012, two restaurants in Lanzarote, Canary Islands are thought to have been the source of ciguatera poisoning, leading to new fishing regulations issued 18 April 2012. The first outbreak was reported in February 2012. Diners suffered with vomiting, diarrhoea and abdominal pain several hours after eating amberjack. The second case was in early April affecting six people who live in Lanzarote and had all eaten amberjack at a local restaurant.[37] * In March 2014, nine people were hospitalised near Macksville, New South Wales, Australia after a recreational fisherman caught a 55 lb Spanish Mackerel (Scomberomorus commerson) off Scott's Head (NSW) and then shared it among his friends and family.[38] * In April 2015, fourteen crew members of a potash ship were hospitalized in Saint John, New Brunswick, Canada after consuming tropical fish obtained from international waters.[39] After the incident, Marine Catering Services issued a reminder to seafarers that the UK Food Act makes it illegal for crews to fish for food from their vessels.[40] * In September 2016, a British holidaymaker died while on honeymoon in Mexico after consuming fish contaminated with the algae that causes ciguatera poisoning.[11] During October 2016, more than 100 people suffered from ciguatera poisoning after eating fish heads supplied by an export firm in Mangalore, India.[41] ## History[edit] Ciguatera was first described by one of the surgeon's mates, William Anderson, on the crew of HMS Resolution in 1774.[42] Researchers suggest that ciguatera outbreaks caused by warm climatic conditions in part propelled the migratory voyages of Polynesians between 1000 and 1400AD.[43][44] ### Folk tales[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (October 2014) (Learn how and when to remove this template message) In Northern Australia, where ciguatera is a common problem, two different folk science methods are widely believed to detect whether fish harbor significant ciguatoxin. The first method is that flies are supposed not to land on contaminated fish. The second is that cats will either refuse to eat or vomit/display symptoms after eating contaminated fish. A third, less common testing method involves putting a silver coin under the scales of the suspect fish. If the coin turns black, according to the theory, it is contaminated. On Grand Cayman and other islands the locals will test barracuda by placing a piece of the fish on the ground and allowing ants to crawl on it. If the ants do not avoid the flesh and will eat it, then the fish is deemed safe.[citation needed] In Dominican Republic, another common belief is that during months whose names do not include the letter "R" (May through August), it is not recommended to eat certain kinds of fish, because they are more likely to be infected by the ciguatera toxin. The validity of many of these tests has been scientifically rejected.[45] ### Folk remedies[edit] Leaves of Heliotropium foertherianum (Boraginaceae) – also known as octopus bush – are used in many Pacific islands as a traditional medicine to treat ciguatera fish poisoning. Senescent octopus bush leaves contain rosmarinic acid and derivatives, which are known for their antiviral, antibacterial, antioxidant, and anti-inflammatory properties.[46] Rosmarinic acid may remove the ciguatoxins from their sites of action, as well as being an anti-inflammatory. An account of ciguatera poisoning from a linguistics researcher living on Malakula island, Vanuatu, indicates the local treatment: "We had to go with what local people told us: avoid salt and any seafood. Eat sugary foods. And they gave us a tea made from the roots of ferns growing on tree trunks. I don't know if any of that helped, but after a few weeks, the symptoms faded away".[47] Various Caribbean folk and ritualistic treatments originated in Cuba and nearby islands. The most common old-time remedy involves bed rest subsequent to a guanabana juice enema.[citation needed] In Puerto Rico, natives drink a tea made from mangrove buttons, purportedly high in B vitamins, to flush the toxic symptoms from the system.[citation needed] There has never been a funded study of these treatments. Other folk treatments range from directly porting and bleeding the gastrointestinal tract to "cleansing" the diseased with a dove during a Santería ritual.[citation needed] ## See also[edit] * Algal bloom * Gambierdiscus toxicus * Red tide * Yessotoxin ## Footnotes[edit] 1. ^ a b c d e f g h i j k l m n o p Friedman, MA; Fernandez, M; Backer, LC; Dickey, RW; Bernstein, J; Schrank, K; Kibler, S; Stephan, W; Gribble, MO; Bienfang, P; Bowen, RE; Degrasse, S; Flores Quintana, HA; Loeffler, CR; Weisman, R; Blythe, D; Berdalet, E; Ayyar, R; Clarkson-Townsend, D; Swajian, K; Benner, R; Brewer, T; Fleming, LE (14 March 2017). "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management". Marine Drugs. 15 (3): 72. doi:10.3390/md15030072. PMC 5367029. PMID 28335428. 2. ^ a b c d e f g h i j k l m n o p q r s t u "Food Poisoning from Marine Toxins - Chapter 2 - 2018 Yellow Book". CDC. 2017. Retrieved 1 June 2018. This article incorporates text from this source, which is in the public domain. 3. ^ a b c d e f g h "Ciguatera Fish Poisoning (CFP)". Marine biotoxins. Food and Agriculture Organization. 2004. p. Chapter 7. ISBN 978-92-5-105129-0. 4. ^ a b c Isbister G, Kiernan M (2005). "Neurotoxic marine poisoning". The Lancet Neurology. 4 (4): 219–28. doi:10.1016/S1474-4422(05)70041-7. PMID 15778101. 5. ^ a b c d Clark RF, Williams SR, Nordt SP, Manoguerra AS (1999). "A review of selected seafood poisonings". Undersea Hyperb Med. 26 (3): 175–84. PMID 10485519. Archived from the original on 2011-08-11. Retrieved 2008-08-12. 6. ^ Patel, Ryan; Brice, Nicola L.; Lewis, Richard J.; Dickenson, Anthony H. (December 2015). "Ionic mechanisms of spinal neuronal cold hypersensitivity in ciguatera". The European Journal of Neuroscience. 42 (11): 3004–3011. doi:10.1111/ejn.13098. ISSN 0953-816X. PMC 4744673. PMID 26454262. 7. ^ Vetter, Irina; Touska, Filip; Hess, Andreas; Hinsbey, Rachel; Sattler, Simon; Lampert, Angelika; Sergejeva, Marina; Sharov, Anastasia; Collins, Lindon S (2012-10-03). "Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling". The EMBO Journal. 31 (19): 3795–3808. doi:10.1038/emboj.2012.207. ISSN 0261-4189. PMC 3463840. PMID 22850668. 8. ^ Swift A, Swift T (1993). "Ciguatera". J. Toxicol. Clin. Toxicol. 31 (1): 1–29. doi:10.3109/15563659309000371. PMID 8433404. 9. ^ Ting J, Brown A (2001). "Ciguatera poisoning: a global issue with common management problems" (PDF). Eur. J. Emerg. Med. 8 (4): 295–300. doi:10.1097/00063110-200112000-00009. PMID 11785597. 10. ^ Hokama, Y. (1988-01-01). "Ciguatera fish poisoning". Journal of Clinical Laboratory Analysis. 2 (1): 44–50. doi:10.1002/jcla.1860020110. ISSN 1098-2825. 11. ^ a b "Newlywed bride dies 10 days after wedding from heart attack believed to have been caused by 'contaminated fish'". The Daily Telegraph. Telegraph Media Group. 13 October 2016. Retrieved 14 October 2016. 12. ^ Lange W, Lipkin K, Yang G (1989). "Can ciguatera be a sexually transmitted disease?". J. Toxicol. Clin. Toxicol. 27 (3): 193–7. doi:10.3109/15563658909038583. PMID 2810444. 13. ^ Blythe D, de Sylva D (1990). "Mother's milk turns toxic following fish feast". JAMA. 264 (16): 2074. doi:10.1001/jama.264.16.2074b. PMID 2214071. 14. ^ Gillespie N, Lewis R, Pearn J, Bourke A, Holmes M, Bourke J, Shields W (1986). "Ciguatera in Australia. Occurrence, clinical features, pathophysiology and management". Med. J. Aust. 145 (11–12): 584–90. PMID 2432386. 15. ^ Pearn J (2001). "Neurology of ciguatera". J. Neurol. Neurosurg. Psychiatry. 70 (1): 4–8. doi:10.1136/jnnp.70.1.4. PMC 1763481. PMID 11118239. 16. ^ Faust, MA and Gulledge RA. Identifying Harmful Marine Dynoflagellates. Smithsonian Institution, Contributions from the United States National Herbarium. Volume 42:1-144. 2002. 17. ^ National Office for Harmful Algal Blooms, Ciguatera Fish Poisoning. Woods Hole Oceanographic Institution. 18. ^ National Office for Harmful Algal Blooms, Ciguatera Fish Poisoning: Causative organisms:. Woods Hole Oceanographic Institution. 19. ^ Lehane, Leigh; Lewis, Richard J (November 2000). "Ciguatera: recent advances but the risk remains". International Journal of Food Microbiology. 61 (2–3): 91–125. doi:10.1016/S0168-1605(00)00382-2. PMID 11078162. 20. ^ Attaway D, Zaborsky O (1993). Marine Biotechnology. p. 8. 21. ^ Fleming L. "Ciguatera Fish Poisoning". Woods Hole Oceanographic Institution. 22. ^ Schlossberg D (1999). Infections of leisure. p. 13. ISBN 978-3-540-94069-2. 23. ^ Davis R, Villar L (1986). "Symptomatic improvement with amitriptyline in ciguatera fish poisoning". N. Engl. J. Med. 315 (1): 65. doi:10.1056/NEJM198607033150115. PMID 3713788. 24. ^ Hampton M, Hampton A (1989). "Ciguatera fish poisoning". J. Am. Acad. Dermatol. 20 (3): 510–1. doi:10.1016/S0190-9622(89)80094-5. PMID 2918120. 25. ^ Palafox N, Jain L, Pinano A, Gulick T, Williams R, Schatz I (1988). "Successful treatment of ciguatera fish poisoning with intravenous mannitol". JAMA. 259 (18): 2740–2. doi:10.1001/jama.259.18.2740. PMID 3128666. 26. ^ Mattei C, Molgó J, Marquais M, Vernoux J, Benoit E (1999). "Hyperosmolar D-mannitol reverses the increased membrane excitability and the nodal swelling caused by Caribbean ciguatoxin-1 in single frog myelinated axons". Brain Res. 847 (1): 50–8. doi:10.1016/S0006-8993(99)02032-6. PMID 10564735. 27. ^ Williamson J (1990). "Ciguatera and mannitol: a successful treatment". Med. J. Aust. 153 (5): 306–7. PMID 2118229. 28. ^ Schnorf H, Taurarii M, Cundy T (2002). "Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy". Neurology. 58 (6): 873–80. doi:10.1212/WNL.58.6.873. PMID 11914401. 29. ^ a b Marcus, Erin N., Ciguatera fish poisoning, retrieved 6 April 2015 30. ^ a b Schep LJ, Slaughter RJ, Temple WA, Beasley DM (2010). "Ciguatera poisoning: an increasing occurrence in New Zealand". N. Z. Med. J. 123 (1308): 100–102. PMID 20173810. 31. ^ Geller R, Olson K, Senécal P (1991). "Ciguatera fish poisoning in San Francisco, California, caused by imported barracuda". West. J. Med. 155 (6): 639–642. PMC 1003121. PMID 1812639. 32. ^ DiNubile M, Hokama Y (1995). "The ciguatera poisoning syndrome from farm-raised salmon". Annals of Internal Medicine. 122 (2): 113–114. doi:10.7326/0003-4819-122-2-199501150-00006. PMID 7992985. 33. ^ Leader, Zachary, The Life of Saul Bellow: Love and Strife 1965-2005, p. 528. 34. ^ "Bizarre fish poisoning sparks alarm". NBC News. 2019-05-01. Retrieved 2019-05-07. 35. ^ "FDA Advises Seafood Processors About Ciguatera Fish Poisoning in the Northern Gulf of Mexico Near the Flower Garden Banks National Marine Sanctuary" (Press release). U.S. Food and Drug Administration. 2008-02-05. Retrieved 2008-02-07. 36. ^ Centers for Disease Control and Prevention (CDC) (2013). "Ciguatera fish poisoning - New York City, 2010-2011". MMWR. Morbidity and Mortality Weekly Report. 62 (4): 61–5. PMC 4604878. PMID 23364271. 37. ^ Cliffe-Jones, Mike Jules (April 17, 2012). "Isolated Cases of Ciguatera Poisoning in Lanzarote". Information Lanzarote. Information Lanzarote. Archived from the original on 5 March 2016. Retrieved 31 October 2015. 38. ^ "Ciguatera poisoning from Spanish Mackerel caught off Scotts Head". ABC News. 2014-03-04. Retrieved 2017-10-16. 39. ^ "Balsa 85 ID'd as ship in Saint John whose crew was hit by food poisoning". CBC New Brunswick. CBC. CBC. 13 April 2015. Retrieved 31 October 2015. 40. ^ "Seafarers told no fishing!". The Sea (236). Mission to Seafarers Limited. Jul–Aug 2015. 41. ^ "Love your fish? Then know about seafood poisoning too". Times of India. 4 October 2016. Retrieved 14 October 2016. 42. ^ Sanders, Lisa (April 5, 2010). "Fish Tale". The New York Times. Retrieved 2010-04-10. "The illness was first described in 1774 by a surgeon's mate on the crew of Captain Cook's South Pacific exploration aboard HMS Resolution. The crewman, John Anderson, documented the symptoms described by several shipmates who had eaten a large fish caught in the tropical waters." (The New York Times incorrectly gives William Anderson's first name as John.) 43. ^ Rongo, Teina; Bush, Mark; Van Woesik, Robert (2009). "Did ciguatera prompt the late Holocene Polynesian voyages of discovery?". Journal of Biogeography. 36 (8): 1423–32. doi:10.1111/j.1365-2699.2009.02139.x. 44. ^ "Did fish poisoning drive Polynesian colonization of the Pacific?". news.mongabay.com. 7 July 2009. Retrieved 1 June 2018. 45. ^ Park, D. L. (1994). "Evaluation of methods for assessing ciguatera toxins in fish". Reviews of Environmental Contamination and Toxicology. 136: 1–20. PMID 8029489. 46. ^ Rossi, Fanny; Jullian, Valérie; Pawlowiez, Ralph; Kumar-Roiné, Shilpa; Haddad, Mohamed; Darius, H. Taiana; Gaertner-Mazouni, Nabila; Chinain, Mireille; Laurent, Dominique (2012). "Protective effect of Heliotropium foertherianum (Boraginaceae) folk remedy and its active compound, rosmarinic acid, against a Pacific ciguatoxin". Journal of Ethnopharmacology. 143 (1): 33–40. doi:10.1016/j.jep.2012.05.045. PMID 22706150. 47. ^ Dimock, Laura (June 2010). "Rescue mission for fading tongue". New Zealand Education Review. Archived from the original on 2014-01-04. Retrieved 2014-01-04. ## References[edit] * Ciguatera fish poisoning CDC * Friedman, M. A.; Fernandez, M.; Backer, L. C.; Dickey, R. W.; Bernstein, J.; Schrank, K.; Kibler, S.; Stephan, W.; Gribble, M. O.; Bienfang, P.; Bowen, R. E.; Degrasse, S.; Flores Quintana, H. A.; Loeffler, C. R.; Weisman, R.; Blythe, D.; Berdalet, E.; Ayyar, R.; Clarkson-Townsend, D.; Swajian, K.; Benner, R.; Brewer, T.; Fleming, L. E. (2017). "An Updated Review of Ciguatera Fish Poisoning: Clinical, Epidemiological, Environmental, and Public Health Management". Marine Drugs. 15 (3): 72. doi:10.3390/md15030072. PMC 5367029. PMID 28335428. * v * t * e Plankton About plankton * Algal bloom * CLAW hypothesis * High lipid content microalgae * Holoplankton * Marine microorganisms * Meroplankton * Mycoplankton * Milky seas effect * Paradox of the plankton * Planktivore * Planktology * Red tide * Spring bloom * Thin layers * More... 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Lujan–Fryns syndrome Other namesX-linked mental retardation with Marfanoid habitus, Lujan syndrome[1][2][3] Lujan–Fryns syndrome in a young adult male, with features that include a long, narrow face and recessed chin. SpecialtyMedical genetics Lujan–Fryns syndrome (LFS) is an X-linked genetic disorder that causes mild to moderate intellectual disability and features described as Marfanoid habitus, referring to a group of physical characteristics similar to those found in Marfan syndrome.[4][5] These features include a tall, thin stature and long, slender limbs.[5] LFS is also associated with psychopathology and behavioral abnormalities, and it exhibits a number of malformations affecting the brain and heart.[6][7][8] The disorder is inherited in an X-linked dominant manner, and is attributed to a missense mutation in the MED12 gene.[3] There is currently no treatment or therapy for the underlying MED12 malfunction, and the exact cause of the disorder remains unclear.[9] ## Contents * 1 Signs and symptoms * 1.1 Psychiatric * 1.2 Marfanoid habitus * 1.3 Head and face * 1.4 Heart * 2 Cause * 3 Pathophysiology * 3.1 Genetics * 3.2 Similarities to other genetic diseases * 4 Diagnosis * 4.1 Differential diagnosis * 5 Treatment * 6 Epidemiology * 7 History * 8 See also * 9 References * 10 Further reading * 11 External links ## Signs and symptoms[edit] Intellectual disability in LFS usually ranges from mild to moderate, but severe cases have also been reported.[10][11] A relatively common brain anomaly seen with LFS is agenesis of the corpus callosum, an error of embryonic development in which the corpus callosum (a structure of the mammalian brain composed of nerves that allows communication between the left and right cerebral hemispheres) is not present.[7][12] Among a number of adverse neurological effects sometimes found with an absence of the corpus callosum, intellectual disability has been shown to occur at a rate of approximately 73 percent.[12] A correlation between agenesis of the corpus callosum and intellectual disability in LFS, however, has not been suggested.[13] ### Psychiatric[edit] Psychopathology and related behavioral abnormalities are typically seen in LFS, and they may be considered in the diagnosis of the disorder.[7] The most common of these in LFS is an autism-like spectrum disorder, and LFS is considered as one of a number of genetic disorders associated with autism.[7][14] Additional alterations of psychopathology with behavioral manifestations that have been observed in LFS include: psychotic behavior,[15] schizophrenia,[16] hyperactivity and attention-deficit hyperactivity disorder,[13][17] aggression,[17] oppositional defiant disorder,[13][18] obsessive compulsive disorder,[13] extreme shyness,[17] learning disability,[13] cognitive impairment,[13] short-term memory deficit,[13] low frustration tolerance,[13] social dysfunction,[13] lack of impulse control,[13] eating disorder and associated malnutrition, attributed to psychogenic loss of appetite;[6] and pyromania.[7][13][18] While psychiatric conditions like these are to be expected with LFS, there have also been cases of the disorder with some preservation of mental and behavioral abilities, such as problem solving, reasoning and normal intelligence.[19] The psychopathology of LFS usually exhibits schizophrenia.[16] When schizophrenia is diagnosed in an individual known to be affected by intellectual disability, LFS may be considered in the differential diagnosis of schizophrenia, with confirmation of cause through appropriate psychiatric and genetic evaluation methods.[16] ### Marfanoid habitus[edit] LFS is clinically distinguished from other X-linked forms of intellectual disability by the accompanying presence of marfanoid habitus.[10] Marfanoid habitus describes a group of physical features common to Marfan syndrome.[5] Including Marfan syndrome and LFS, marfanoid features of this type have also been observed with several other disorders, one of which is multiple endocrine neoplasia type 2.[20] In LFS, specific features identified as marfanoid include: a long, narrow face;[5][9] tall, thin stature;[3][9] long, slender limbs, fingers and toes (not unlike arachnodactyly)[3][21][22] with joint hyperextensibility,[17] shortened halluces (the big toes) and long second toes.[9] The diagnosis of marfanoid habitus in LFS is often delayed because many of the physical features and characteristics associated with it are usually not evident until adolescence.[2] ### Head and face[edit] Craniofacial and other features of LFS include: maxillary hypoplasia (underdevelopment of the upper jaw bone),[9] a small mandible (lower jaw bone) and receding chin,[3][17] a high-arched palate (the roof of the mouth), with crowding and misalignment of the upper teeth;[5][7] macrocephaly (enlarged skull) with a prominent forehead,[3][9] hypernasal speech (voice),[5][7] a long nose with a high, narrow nasal bridge;[9] a deep, short philtrum (the indentation in the upper lip, beneath the nose),[9] low-set ears with some apparent retroversion,[9] hypotonia (decreased muscle tone),[3] pectus excavatum (a malformity of the chest),[9] slightly enlarged to normal testicular size in males,[9][17] and seizures.[9] Hypernasal speech, or "hypernasality", is primarily the result of velopharyngeal insufficiency, a sometimes congenital aberration in which the velopharyngeal sphincter allows too much air into the nasal cavity during speech.[23][24] In LFS, hypernasality may also be caused by failure of the soft palate and uvula to reach the back wall of the pharynx (the interior cavity of the throat where swallowing generally occurs) during speech, a condition that can be associated with a submucosal cleft palate.[13][25] ### Heart[edit] A number of features involving the heart have been noted in several LFS cases, the most significant being dilation of the aortic root, a section of the ascending aorta.[8] Aortic root dilation (enlargement) is associated with a greatly increased risk of dissection of the aortic wall, resulting in aortic aneurysm.[26] As this presents a possible life-threatening consequence of LFS, routine cardiac evaluation methods such as echocardiogram are implemented when the disorder is first diagnosed, along with MRI scans of the brain to screen for suspected agenesis of the corpus callosum.[7] Additional effects on the heart that have been reported with LFS are ventricular and atrial septal defect.[8][17] ## Cause[edit] A missense mutation in the MED12 gene, located on the human X chromosome, has been established as the cause of LFS.[3][27] Missense mutations are genetic point mutations in which a single nucleotide in the genetic sequence is exchanged with another one. This leads to an erroneously substitution of a particular amino acid in the protein sequence during translation. The missense mutation in the MED12 gene, that causes LFS, is identified as p.N1007S.[3] This indicates that the amino acid asparagine, normally located at position 1007 along the MED12 sequence, has been mistakenly replaced by serine.[27] This mutation in MED12 causes incorrect expression and activity of the protein it encodes, resulting in the disorder.[3][9] ## Pathophysiology[edit] Known genes and mutations found on the human X chromosome. The MED12 gene is found at location q13, highlighted in green. MED12, or mediator of RNA polymerase II transcription, subunit 12 homolog of S. cerevisiae, is one of several subunits in the mammalian mediator complex, which regulates RNA polymerase II during mRNA transcription.[28][29] The Mediator complex is required for polymerase II transcription and acts as a bridge between the polymerase II enzyme and different gene-specific transcription factors. Mediator can contain up to 30 subunits, but some of the subunits are only required for regulation of transcription in particular tissues or cells.[30] Currently, the exact mechanism by which dysfunction of MED12 results in LFS and its associated neuropsychopathic and physical characteristics is unclear. Marfanoid habitus, a highly arched palate and several other features of LFS can be found with Marfan syndrome, a connective tissue disorder.[4] The finding of aortic root dilation in both disorders suggests that a mutation in an unspecified connective tissue regulating gene may contribute to the etiology of LFS.[1][5][8][13] A number of interesting experimental results have been obtained by studying MED12 mutations in the zebrafish, an animal model representing vertebrates.[31][32][33] In zebrafish, a mutation in MED12 was found to be responsible for the mutant motionless (mot). Zebrafish with the mot mutation have neuronal and cardiovascular defects, although not all types of neurons are affected. Introduction of human MED12 mRNA into the zebrafish restores normal development.[34] MED12 is also a critical coactivator for the gene SOX9, which is involved in the developmental regulation of neurons, cartilage and bone. In the zebrafish, MED12 defects cause maldevelopment of vertebrate embryonic structures such as the neural crest, which would alter function of the autonomic and peripheral nervous systems; and they also cause malformations of cell types serving as precursors to cartilage and bone, such as osteocytes.[34][35][36] Some features found in LFS, like agenesis of the corpus callosum and cartilage-related craniofacial anomalies, are similar to defects found in zebrafish with MED12 and associated mutations.[3] ### Genetics[edit] This condition is inherited in an X-linked dominant manner. Lujan–Fryns syndrome is inherited in an X-linked dominant manner.[9][13][37] This means the defective gene responsible for the disorder (MED12) is located on the X chromosome, and only one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who has the disorder. Males are normally hemizygous for the X chromosome, having only one copy. As a result, X-linked dominant disorders usually show higher expressivity in males than females. This phenomenon is thought to occur with LFS.[13][37] As the X chromosome is one of the sex chromosomes (the other being the Y chromosome), X-linked inheritance is determined by the gender of the parent carrying a specific gene and can often seem complex. This is because, typically, females have two copies of the X-chromosome, while males have only one copy. The difference between dominant and recessive inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage. In LFS, X-linked dominant inheritance was suspected, as boy and girl siblings in one family both exhibited the disorder.[13][37] A scenario such as this would also be possible with X-linked recessive inheritance, but in this particular case report, the girl was believed to be a manifesting heterozygote[13][37] carrying one copy of the mutated gene. Sporadic cases of LFS, where the disorder is present in an individual with no prior family history of it, have also been reported in a small number of affected males.[13][15][38] ### Similarities to other genetic diseases[edit] An individual exhibiting intellectual disability and other symptoms similar to LFS was found to have a terminal deletion of the subtelomeric region in the short arm of chromosome 5.[25] Deletion of this area of chromosome 5 is associated with intellectual disability, psychotic behavior, autism, macrocephaly and hypernasal-like speech, as well as the disorder Cri du chat syndrome.[25][39] Fryns (2006) suggests a detailed examination of chromosome 5 with FISH should be performed as part of the differential diagnosis of LFS.[9] Mutations in the UPF3B gene, also found on the X chromosome, are another cause of X-linked intellectual disability.[40] UPF3B is part of the nonsense-mediated mRNA decay (NMD) complex, which performs mRNA surveillance, detecting mRNA sequences that have been erroneously truncated (shortened) by the presence of nonsense mutations.[41] Mutations in UPF3B alter and prevent normal function of the NMD pathway, resulting in translation and expression of truncated mRNA sequences into malfunctioning proteins that can be associated with developmental errors and intellectual disability.[41][42] Individuals from two families diagnosed with LFS and one family with FGS were found to have mutations in UPF3B, confirming that the clinical presentations of the different mutations can overlap.[42] ## Diagnosis[edit] Although LFS is usually suspected when intellectual disability and marfanoid habitus are observed together in a patient, the diagnosis of LFS can be confirmed by the presence of the p.N1007S missense mutation in the MED12 gene.[3][9][10] ### Differential diagnosis[edit] In the differential diagnosis of LFS, another disorder that exhibits some features and symptoms of LFS and is also associated with a missense mutation of MED12 is Opitz-Kaveggia syndrome (FGS).[3][43] Common features shared by both LFS and FGS include X-linked intellectual disability, hyperactivity, macrocephaly, corpus callosum agenesis and hypotonia.[3] Notable features of FGS that have not been reported with LFS include excessive talkativness, consistent strength in socialization skills, imperforate anus (occlusion of the anus) and ocular hypertelorism (extremely wide-set eyes).[44][45] Whereas LFS is associated with missense mutation p.N1007S, FGS is associated with missense mutation p.R961W.[3][46] As both disorders originate from an identical type of mutation in the same gene, while exhibiting similar, yet distinct characteristics; LFS and FGS are considered to be allelic.[3][9][13][43] In the context of MED12, this suggests that the phenotype of each disorder is related to the way in which their respective mutations alter the MED12 sequence and its function.[3][27][43] ## Treatment[edit] While there is no specific treatment for the underlying genetic cause of LFS, corrective procedures, preventive intervention measures, and therapies may be considered in the treatment and management of the many craniofacial, orthopedic, and psychiatric problems associated with the disorder. More pressing issues such as cardiac involvement or epileptic seizures should be routinely examined and monitored. Close attention and specialized follow-up care, including neuropshycological evaluation methods and therapies, and special education, should be given to diagnose and prevent psychiatric disorders and related behavioral problems such as psychosis and outbursts of aggression.[9] ## Epidemiology[edit] Lujan–Fryns syndrome is a rare X-linked dominant syndrome and is more common in males than females. Its prevalence within the general population has not yet been determined.[9] ## History[edit] Lujan–Fryns syndrome is named after physicians J. Enrique Lujan and Jean-Pierre Fryns.[21] The initial observation of suspected X-linked intellectual disability with Marfanoid features and craniofacial effects such as a high-arched palate was described by Lujan et al. in 1984.[17] In the report, four affected male members of a large kindred (consanguinous family) were noted.[3][13][17] Additional investigations of combined X-linked intellectual disability and Marfanoid habitus in other families, including two brothers, were reported by Fryns et al., beginning in 1987.[5] The disorder soon became known as Lujan–Fryns syndrome.[37] ## See also[edit] * Fragile X syndrome * Aarskog syndrome * Coffin–Lowry syndrome * FG syndrome ## References[edit] 1. ^ a b Lacombe, D.; Bonneau, D.; Verloes, A.; Couet, D.; Koulischer, L.; Battin, J. (1993). "Lujan-Fryns syndrome (X-linked mental retardation with marfanoid habitus): report of three cases and review". Genetic Counseling (Geneva, Switzerland). 4 (3): 193–198. ISSN 1015-8146. PMID 8267926. 2. ^ a b Fryns, J. P.; Van Den Berghe, H. (1991). "X-linked mental retardation with Marfanoid habitus: a changing phenotype with age?". Genetic Counseling (Geneva, Switzerland). 2 (4): 241–244. ISSN 1015-8146. PMID 1799424. 3. ^ a b c d e f g h i j k l m n o p q r Schwartz, C. E.; Tarpey, P. S.; Lubs, H. A.; Verloes, A.; May, M. M.; Risheg, H.; Friez, M. J.; Futreal, P. A.; Edkins, S.; Teague, J.; Briault, S.; Skinner, C.; Bauer-Carlin, A.; Simensen, R. J.; Joseph, S. M.; Jones, J. R.; Gecz, J.; Stratton, M. R.; Raymond, F. L.; Stevenson, R. E. (July 2007). "The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene". Journal of Medical Genetics. 44 (7): 472–477. doi:10.1136/jmg.2006.048637. ISSN 0022-2593. PMC 2597996. PMID 17369503. 4. ^ a b Online Mendelian Inheritance in Man (OMIM): 154700 5. ^ a b c d e f g h Fryns, J. P.; Buttiens, M.; Opitz, J. M.; Reynolds, J. F. (Oct 1987). "X-linked mental retardation with marfanoid habitus". American Journal of Medical Genetics. 28 (2): 267–274. doi:10.1002/ajmg.1320280202. ISSN 0148-7299. PMID 3322000. 6. ^ a b Alonso, P.; Pintos, G.; Almazan, F.; Hernández, L.; Loran, E.; Menchon, J. M.; Vallejo, J. (July 2006). "Eating disorder in a patient with phenotypical features of Lujan-Fryns syndrome". Clinical Dysmorphology. 15 (3): 181–184. doi:10.1097/01.mcd.0000220610.24908.a4. ISSN 0962-8827. PMID 16760741. 7. ^ a b c d e f g h Lerma‐Carrillo, I.; Molina, J. D.; Cuevas-Duran, T.; Julve-Correcher, C.; Espejo-Saavedra, J. M.; Andrade-Rosa, C.; Lopez-Muñoz, F. (December 2006). "Psychopathology in the Lujan-Fryns syndrome: report of two patients and review". American Journal of Medical Genetics Part A. 140 (24): 2807–2811. doi:10.1002/ajmg.a.31503. ISSN 1552-4825. PMID 17036352. 8. ^ a b c d Wittine, L. M.; Josephson, K. D.; Williams, M. S. (Oct 1999). "Aortic root dilation in apparent Lujan-Fryns syndrome". American Journal of Medical Genetics. 86 (5): 405–409. doi:10.1002/(SICI)1096-8628(19991029)86:5<405::AID-AJMG2>3.0.CO;2-1. ISSN 0148-7299. PMID 10508979. 9. ^ a b c d e f g h i j k l m n o p q r s Buggenhout, G. V.; Fryns, J. -P. (July 2006). "Lujan-Fryns syndrome (mental retardation, X-linked, marfanoid habitus)". Orphanet Journal of Rare Diseases (Free full text). 1: 26. doi:10.1186/1750-1172-1-26. PMC 1538574. PMID 16831221. 10. ^ a b c Fryns, J. P.; Buttiens, M.; Van Den Berghe, H. (Jan 1988). "Chromosome X-linked mental retardation and marfanoid syndrome". Journal de Génétique Humaine. 36 (1–2): 123–128. ISSN 0021-7743. PMID 3379374. 11. ^ Mégarbané A, C. C.; Chammas, C. (1997). "Severe mental retardation with marfanoid habitus in a young Lebanese male. A diagnostic challenge". Genetic Counseling (Geneva, Switzerland). 8 (3): 195–200. ISSN 1015-8146. PMID 9327261. 12. ^ a b Jeret, J. S.; Serur, D.; Wisniewski, K. E.; Lubin, R. A. (1987). "Clinicopathological findings associated with agenesis of the corpus callosum". Brain & Development. 9 (3): 255–264. doi:10.1016/s0387-7604(87)80042-6. ISSN 0387-7604. PMID 3310713. 13. ^ a b c d e f g h i j k l m n o p q r s t Online Mendelian Inheritance in Man (OMIM): 309520 14. ^ Artigas-Pallarés, J.; Gabau-Vila, E.; Guitart-Feliubadaló, M. (Jan 2005). "Syndromic autism: II. Genetic syndromes associated with autism". Revista de Neurología. 40 Suppl 1: S151–S162. ISSN 0210-0010. PMID 15736079. 15. ^ a b Lalatta, F.; Livini, E.; Selicorni, A.; Briscioli, V.; Vita, A.; Lugo, F.; Zollino, M.; Gurrieri, F.; Neri, G. (Feb 1991). "X-linked mental retardation with marfanoid habitus: first report of four Italian patients". American Journal of Medical Genetics. 38 (2–3): 228–232. doi:10.1002/ajmg.1320380211. ISSN 0148-7299. PMID 2018063. 16. ^ a b c De Hert, M.; Steemans, D.; Theys, P.; Fryns, J. P.; Peuskens, J. (Apr 1996). "Lujan-Fryns syndrome in the differential diagnosis of schizophrenia". American Journal of Medical Genetics. 67 (2): 212–213. doi:10.1002/(SICI)1096-8628(19960409)67:2<212::AID-AJMG13>3.0.CO;2-M. PMID 8723050. 17. ^ a b c d e f g h i Lujan, J. E.; Carlin, M. E.; Lubs, H. A.; Opitz, J. M. (Jan 1984). "A form of X-linked mental retardation with marfanoid habitus". American Journal of Medical Genetics. 17 (1): 311–322. doi:10.1002/ajmg.1320170124. ISSN 0148-7299. PMID 6711603. 18. ^ a b Williams, M. S. (Dec 2006). "Neuropsychological evaluation in Lujan-Fryns syndrome: commentary and clinical report". American Journal of Medical Genetics Part A. 140 (24): 2812–2815. doi:10.1002/ajmg.a.31501. ISSN 1552-4825. PMID 17103446. 19. ^ Donders, J.; Toriello, H.; Van Doornik, S. (Jan 2002). "Preserved neurobehavioral abilities in Lujan-Fryns syndrome". American Journal of Medical Genetics. 107 (3): 243–246. doi:10.1002/ajmg.10144. ISSN 0148-7299. PMID 11807907. 20. ^ Prabhu, M.; Khouzam, R. N.; Insel, J. (Nov 2004). "Multiple endocrine neoplasia type 2 syndrome presenting with bowel obstruction caused by intestinal neuroma: case report". Southern Medical Journal. 97 (11): 1130–1132. doi:10.1097/01.SMJ.0000140873.29381.12. ISSN 0038-4348. PMID 15586612. 21. ^ a b synd/3838 at Who Named It? 22. ^ Buntinx, I. M.; Willems, P. J.; Spitaels, S. E.; Van Reempst, P. J.; De Paepe, A. M.; Dumon, J. E. (April 1991). "Neonatal Marfan syndrome with congenital arachnodactyly, flexion contractures, and severe cardiac valve insufficiency". Journal of Medical Genetics. 28 (4): 267–273. doi:10.1136/jmg.28.4.267. ISSN 0022-2593. PMC 1016831. PMID 1856834. 23. ^ Willging, J. P. (Oct 1999). "Velopharyngeal insufficiency". International Journal of Pediatric Otorhinolaryngology. 49 Suppl 1: S307–S309. doi:10.1016/S0165-5876(99)00182-2. ISSN 0165-5876. PMID 10577827. 24. ^ Warren, D. W.; Dalston, R. M.; Mayo, R. (Jul 1994). "Hypernasality and velopharyngeal impairment". 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J.; Fischer, S.; Neumann, C. J. (Aug 2006). "Zebrafish Trap230/Med12 is required as a coactivator for Sox9-dependent neural crest, cartilage and ear development". Developmental Biology. 296 (1): 83–93. doi:10.1016/j.ydbio.2006.04.437. ISSN 0012-1606. PMID 16712834. 36. ^ Hong, S. -K.; Haldin, C. E.; Lawson, N. D.; Weinstein, B. M.; Dawid, I. B.; Hukriede, N. A. (December 2005). "The zebrafish kohtalo/trap230 gene is required for the development of the brain, neural crest, and pronephric kidney". Proceedings of the National Academy of Sciences of the United States of America. 102 (51): 18473–18478. Bibcode:2005PNAS..10218473H. doi:10.1073/pnas.0509457102. ISSN 0027-8424. PMC 1311743. PMID 16344459. 37. ^ a b c d e Gurrieri, F.; Neri, G. (Feb 1991). "A girl with the Lujan-Fryns syndrome". American Journal of Medical Genetics. 38 (2–3): 290–291. doi:10.1002/ajmg.1320380225. ISSN 0148-7299. PMID 2018074. 38. ^ Fryns, J. P. (Feb 1991). "X-linked mental retardation with marfanoid habitus". American Journal of Medical Genetics. 38 (2–3): 233. doi:10.1002/ajmg.1320380212. ISSN 0148-7299. PMID 2018064. 39. ^ Fang, J. S.; Lee, K. F.; Huang, C. T.; Syu, C. L.; Yang, K. J.; Wang, L. H.; Liao, D. L.; Chen, C. H. (Jun 2008). "Cytogenetic and molecular characterization of a three-generation family with chromosome 5p terminal deletion". Clinical Genetics. 73 (6): 585–590. doi:10.1111/j.1399-0004.2008.00995.x. ISSN 0009-9163. PMID 18400035. 40. ^ Online Mendelian Inheritance in Man (OMIM): 300298 41. ^ a b Chang, Y. F.; Imam, J. S.; Wilkinson, M. F. (2007). "The nonsense-mediated decay RNA surveillance pathway". Annual Review of Biochemistry. 76: 51–74. doi:10.1146/annurev.biochem.76.050106.093909. ISSN 0066-4154. PMID 17352659. 42. ^ a b Tarpey, P. S.; Raymond, F. L.; Nguyen, L. S.; Rodriguez, J.; Hackett, A.; Vandeleur, L.; Smith, R.; Shoubridge, C.; Edkins, S.; Stevens, C.; O'Meara, S.; Tofts, C.; Barthorpe, S.; Buck, G.; Cole, J.; Halliday, K.; Hills, K.; Jones, D.; Mironenko, T.; Perry, J.; Varian, J.; West, S.; Widaa, S.; Teague, J.; Dicks, E.; Butler, A.; Menzies, A.; Richardson, D.; Jenkinson, A.; Shepherd, R. (September 2007). "Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation". Nature Genetics (Free full text). 39 (9): 1127–1133. doi:10.1038/ng2100. ISSN 1061-4036. PMC 2872770. PMID 17704778. 43. ^ a b c Online Mendelian Inheritance in Man (OMIM): 305450 44. ^ Graham, J. M.; Superneau, D.; Rogers, R. C.; Corning, K.; Schwartz, C. E.; Dykens, E. M. (1999). "Clinical and behavioral characteristics in FG syndrome". American Journal of Medical Genetics. 85 (5): 470–475. doi:10.1002/(SICI)1096-8628(19990827)85:5<470::AID-AJMG7>3.0.CO;2-S. PMID 10405444. 45. ^ Jr, G.; Visootsak, M.; Dykens, J.; Huddleston, E.; Clark, L.; Jones, R. D.; Moeschler, K. L.; Opitz, J. B.; Morford, J. M.; Simensen, R.; Rogers, R. C.; Schwartz, C. E.; Friez, M. J.; Stevenson, R. E. (December 2008). "Behavior of 10 patients with FG Syndrome (Opitz-Kaveggia Syndrome) and the p.R961W Mutation in the MED12 Gene". American Journal of Medical Genetics Part A. 146A (23): 3011–3017. doi:10.1002/ajmg.a.32553. ISSN 1552-4825. PMC 3092600. PMID 18973276. 46. ^ Risheg, H.; Graham Jr, J. M.; Clark, R. D.; Rogers, R. C.; Opitz, J. M.; Moeschler, J. B.; Peiffer, A. P.; May, M.; Joseph, S. M.; Jones, J. R.; Stevenson, R. E.; Schwartz, C. E.; Friez, M. J. (April 2007). "A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome". Nature Genetics. 39 (4): 451–453. doi:10.1038/ng1992. ISSN 1061-4036. PMID 17334363. ## Further reading[edit] * GeneReview/NIH/UW entry on MED12-Related Disorders * Van Buggenhout, G. J. C. M.; Trommelen, J. C. M.; Brunner, H. G.; Hamel, B. C. J.; Fryns, J. P. (Jan 2001). "The clinical phenotype in institutionalised adult males with X-linked mental retardation (XLMR)". Annales de Génétique. 44 (1): 47–55. doi:10.1016/S0003-3995(01)01038-3. ISSN 0003-3995. PMID 11334618. ## External links[edit] Classification D * ICD-10: F70.1 * ICD-9-CM: 317 * OMIM: 309520 * MeSH: C537724 * DiseasesDB: 32654 External resources * GeneReviews: MED12-Related Disorders * v * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy * v * t * e X-linked disorders X-linked recessive Immune * Chronic granulomatous disease (CYBB) * Wiskott–Aldrich syndrome * X-linked severe combined immunodeficiency * X-linked agammaglobulinemia * Hyper-IgM syndrome type 1 * IPEX * X-linked lymphoproliferative disease * Properdin deficiency Hematologic * Haemophilia A * Haemophilia B * X-linked sideroblastic anemia Endocrine * Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy * KAL1 Kallmann syndrome * X-linked adrenal hypoplasia congenita Metabolic * Amino acid: Ornithine transcarbamylase deficiency * Oculocerebrorenal syndrome * Dyslipidemia: Adrenoleukodystrophy * Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency * Pyruvate dehydrogenase deficiency * Danon disease/glycogen storage disease Type IIb * Lipid storage disorder: Fabry's disease * Mucopolysaccharidosis: Hunter syndrome * Purine–pyrimidine metabolism: Lesch–Nyhan syndrome * Mineral: Menkes disease/Occipital horn syndrome Nervous system * X-linked intellectual disability: Coffin–Lowry syndrome * MASA syndrome * Alpha-thalassemia mental retardation syndrome * Siderius X-linked mental retardation syndrome * Eye disorders: Color blindness (red and green, but not blue) * Ocular albinism (1) * Norrie disease * Choroideremia * Other: Charcot–Marie–Tooth disease (CMTX2-3) * Pelizaeus–Merzbacher disease * SMAX2 Skin and related tissue * Dyskeratosis congenita * Hypohidrotic ectodermal dysplasia (EDA) * X-linked ichthyosis * X-linked endothelial corneal dystrophy Neuromuscular * Becker's muscular dystrophy/Duchenne * Centronuclear myopathy (MTM1) * Conradi–Hünermann syndrome * Emery–Dreifuss muscular dystrophy 1 Urologic * Alport syndrome * Dent's disease * X-linked nephrogenic diabetes insipidus Bone/tooth * AMELX Amelogenesis imperfecta No primary system * Barth syndrome * McLeod syndrome * Smith–Fineman–Myers syndrome * Simpson–Golabi–Behmel syndrome * Mohr–Tranebjærg syndrome * Nasodigitoacoustic syndrome X-linked dominant * X-linked hypophosphatemia * Focal dermal hypoplasia * Fragile X syndrome * Aicardi syndrome * Incontinentia pigmenti * Rett syndrome * CHILD syndrome * Lujan–Fryns syndrome * Orofaciodigital syndrome 1 * Craniofrontonasal dysplasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Lujan–Fryns syndrome	c0796022	6,092	wikipedia	https://en.wikipedia.org/wiki/Lujan%E2%80%93Fryns_syndrome	2021-01-18T18:56:40	{"gard": ["3307"], "mesh": ["C537724"], "umls": ["C0796022"], "icd-9": ["317"], "icd-10": ["F70.1"], "wikidata": ["Q640836"]}
Cholangiocarcinoma is a group of cancers that begin in the bile ducts. Bile ducts are branched tubes that connect the liver and gallbladder to the small intestine. They carry bile, which is a fluid that helps the body digest fats that are in food. Bile is made in the liver and stored in the gallbladder before being released in the small intestine after a person eats. Cholangiocarcinoma is classified by its location in relation to the liver. Intrahepatic cholangiocarcinoma begins in the small bile ducts within the liver. This is the least common form of the disease, accounting for less than 10 percent of all cases. Perihilar cholangiocarcinoma (also known as a Klatskin tumor) begins in an area called the hilum, where the right and left major bile ducts join and leave the liver. It is the most common form of the disease, accounting for more than half of all cases. The remaining cases are classified as distal cholangiocarcinomas, which begin in bile ducts outside the liver. The perihilar and distal forms of the disease, which both occur outside the liver, are sometimes grouped together and called extrahepatic cholangiocarcinoma. The three types of cholangiocarcinoma do not usually cause any symptoms in their early stages, and this cancer is usually not diagnosed until it has already spread beyond the bile ducts to other tissues. Symptoms often result when bile ducts become blocked by the tumor. The most common symptom is jaundice, in which the skin and whites of the eyes turn yellow. Other symptoms can include extreme tiredness (fatigue), itching, dark-colored urine, loss of appetite, unintentional weight loss, abdominal pain, and light-colored and greasy stools. These symptoms are described as "nonspecific" because they can be features of many different diseases. Most people who develop cholangiocarcinoma are older than 65. Because this cancer is often not discovered until it has already spread, it can be challenging to treat effectively. Affected individuals can survive for several months to several years after diagnosis, depending on the location of the cancer and how advanced it is. ## Frequency Cholangiocarcinoma affects 8,000 people each year in the United States. This type of cancer occurs much more frequently in Southeast Asian countries such as Thailand, where it is related to infection with a parasite that is common there. For unknown reasons, cholangiocarcinoma occurs slightly more often in men than in women. ## Causes Cancers occur when a buildup of mutations in critical genes—those that control cell division, for example—allow cells to grow and divide uncontrollably to form a tumor. In most cases of cholangiocarcinoma, these genetic changes are acquired during a person's lifetime and are present only in the bile duct cells that give rise to the tumor. The genetic changes, which are called somatic mutations, are not inherited. Somatic mutations in many different genes have been found in cholangiocarcinoma. Some of these genes act as tumor suppressors, which means they help keep the growth and division of cells tightly regulated. Mutations in or deletions of tumor suppressor genes can allow cells to grow and divide without control or order, which is a hallmark of cancer. Other genes associated with cholangiocarcinoma are oncogenes; when they are turned on (activated) abnormally, these genes have the potential to cause normal cells to become cancerous. Identifying somatic mutations in cholangiocarcinoma may provide clues to how quickly the cancer will grow and spread, and which treatments might be most effective. Researchers have also investigated inherited variations in several genes as possible risk factors for cholangiocarcinoma. These genetic changes, which are classified as germline mutations, are present in essentially all of the body's cells. However, no specific inherited changes have been found to be major risk factors for this disease. Several non-genetic risk factors for cholangiocarcinoma have been identified. These include a bile duct disease called primary sclerosing cholangitis, bile duct stones or cysts, and exposure to certain chemical toxins used in manufacturing. In Southeast Asia, infection with parasitic worms that live in the human bile ducts greatly increase the risk of developing cholangiocarcinoma. Other risk factors that have been studied include long-term infection with viral hepatitis B or C, scarring of the liver (cirrhosis), and chronic diseases such as inflammatory bowel disease and diabetes. Researchers suspect that certain lifestyle factors, including smoking, alcohol use, and obesity, may also contribute to the risk of developing cholangiocarcinoma. Studies suggest that a combination of genetic, environmental, and lifestyle factors influence whether a person will develop cholangiocarcinoma. However, most people who develop the disease do not have any of the identified risk factors. ### Learn more about the genes associated with Cholangiocarcinoma * ARID1A * BAP1 * BRAF * BRCA1 * BRCA2 * EGFR * FGFR2 * GNAS * IDH1 * IDH2 * KRAS * LAMA2 * NF1 * NRAS * PIK3CA * PTEN * RB1 * SMAD4 * TERT * TP53 * TSC1 Additional Information from NCBI Gene: * ARAF * CDK6 * ERBB3 * KMT2C * MET * NDC80 * PBRM1 * PCDHA13 * PEG3 * PTPN3 * RADIL * RNF43 * ROBO2 ## Inheritance Pattern Cholangiocarcinoma is not inherited. Studies suggest that blood relatives of a person with cholangiocarcinoma may have an increased risk of developing this cancer compared with the general population. However, most people with cholangiocarcinoma do not have a family history of the disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Cholangiocarcinoma	c3810156	6,093	medlineplus	https://medlineplus.gov/genetics/condition/cholangiocarcinoma/	2021-01-27T08:25:36	{"gard": ["6042"], "omim": ["615619"], "synonyms": []}
Leishmaniasis is a parasitic disease spread by the bite of infected sand flies. There are several different forms of leishmaniasis. The most common are cutaneous and visceral. The cutaneous type causes skin sores. The visceral type affects internal organs such as the spleen, liver and bone marrow. People with this form usually have fever, weight loss, and an enlarged spleen and liver. Visceral disease can be deadly without proper treatment. Leishmaniasis is found in parts of the Middle East, Central America, South American, Asia, Africa, and southern Europe. Most of these countries are in the tropics and subtropics. It is possible but very unlikely to get this disease in the United States. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Leishmaniasis	c0023281	6,094	gard	https://rarediseases.info.nih.gov/diseases/6881/leishmaniasis	2021-01-18T17:59:28	{"mesh": ["D007896"], "omim": ["608207"], "orphanet": ["507"], "synonyms": ["Kala-azar", "Visceral leishmaniasis (subtype)", "Cutaneous leishmaniasis (subtype)"]}
Hyper-IgM syndrome with susceptibility to opportunistic infections is a rare, genetic, non-severe combined immunodeficiency disorder characterized by normal or elevated IgM serum levels with low or absent IgG, IgA and IgE serum concentrations, which manifests with recurrent or severe bacterial infections and increased susceptibility to opportunistic infections (in particular, pneumonia due to P. jiroveci, but also chronic cryptosporidial, cryptococcal, cytomegalovirus and toxoplasma infections). Hematologic disorders (neutropenia, anemia, thrombocytopenia) are frequently associated. Immunologic findings reveal decreased numbers of CD27+ memory B cells and lack of germinal center formation. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Hyper-IgM syndrome with susceptibility to opportunistic infections	c0398689	6,095	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=183663	2021-01-23T17:40:29	{"mesh": ["D053307"], "omim": ["308230", "606843"], "icd-10": ["D80.5"], "synonyms": ["HIGM with susceptibility to opportunistic infections"]}
A recessive distal myopathy characterized by weakness in the distal lower extremity posterior compartment (gastrocnemius and soleus muscles) and associated with difficulties in standing on tip toes. ## Epidemiology Miyoshi myopathy (MM) is the most common form of recessive distal myopathy in populations with founder mutations such as Libyan and Israeli Jewish population, Italian and Spanish populations. ## Clinical description The typical age of onset of MM lies between 15 and 30 years (median 19 years) and the disease is characterized by muscle atrophy usually symmetric especially of the calf muscles (soleus and gastrocnemius). Onset in the anterior tibial muscles has been rarely reported. Ankle muscle stretch reflexes are lost and difficulties for toe walking or climbing stairs are encountered. Exercise-induced myalgia and aching discomfort in the calves can be an early symptom. Anterior compartment muscles of the distal lower extremities eventually become weak as well. As the disease progresses, patients will develop proximal leg and arm weakness to varying degrees. Decrease in respiratory functions have been reported only in few patients with moderate to severe disease. Bulbar or symptoms have not been reported. ## Etiology MM is caused by mutations in the DYSF gene (2p13), which encodes dysferlin. The latter orchestrates skeletal muscle membrane repair and has also been associated with myogenesis, angiogenesis and microtubule dynamics. ## Diagnostic methods Diagnosis of MM relies on laboratory findings showing an elevated serum creatine kinase level (20 to 150 times the normal), muscle biopsy routine reveals dystrophic features. Western blotting may help in cases with uncertain immunohistochemistry findings. Magnetic resonance imaging (MRI) of calf muscles show typical fatty replacement. EMG reveals 'myopathic' motor units and recruitment patterns. Diagnosis is confirmed by the genetic screening of DYSF. ## Differential diagnosis Differential diagnosis includes autosomal recessive limb-girdle muscular dystrophy type 2L (LGMD2L), LGMD2B and qualitative or quantitative defects of caveolin-3. ## Genetic counseling Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child. ## Management and treatment No definitive treatments for MM exist and management is mainly supportive. To prolong survival and improve quality of life, weight control to avoid obesity, physical therapy and stretching exercises to promote mobility and use of mechanical aids to help ambulation and mobility are recommended. ## Prognosis Progression is variable with some patients remaining fairly stable with distal weakness, while others can have a more aggressive pattern involving both proximal and distal muscles. Patients may become wheelchair bound 10-30 years after onset of symptoms. Disease progression is usually related to disease duration rather than age of onset of symptoms. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Miyoshi myopathy	c1850808	6,096	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=45448	2021-01-23T17:16:44	{"gard": ["9676"], "mesh": ["C537480"], "omim": ["254130", "613318"], "umls": ["C1850808"], "icd-10": ["G71.0"]}
Virchow (1912) found a whorl in the hair of the left eyebrow near the nose in 8 members of 2 generations. The progenitor in the previous generation may have shown it also. Hair \- Whorl in eyebrow Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	EYEBROW, WHORL IN	c1851401	6,097	omim	https://www.omim.org/entry/133800	2019-09-22T16:41:16	{"omim": ["133800"]}
Singh et al. (2003) described sisters who presented in their early teenage years with bilateral ankle, knee, and later, wrist pain. Radiologic examination revealed bilateral osteolysis of tali, scaphoids, and patella. Bone loss, sclerosis, and irregularity were seen in the affected areas. Short fourth metacarpals were also found. Synovial ankle biopsies in both sisters showed evidence of chronic inflammatory changes with infiltration of plasma cells and lymphocytes consistent with chronic synovitis. There was no renal involvement, and excretion of amino acids, mucopolysaccharides, and oligosaccharides was normal. Both parents and a younger brother had no clinical or radiologic evidence of the disease. There was no history of consanguinity. Singh et al. (2003) suggested autosomal recessive inheritance. INHERITANCE \- Autosomal recessive GENITOURINARY Kidneys \- Normal kidneys SKELETAL Limbs \- Osteolysis of patellae (bone loss of posterior patella) Hands \- Osteolysis of scaphoids (bone loss and fragmentation of scaphoid) \- Short fourth metacarpals Feet \- Osteolysis of tali (bone loss and fragmentation of posterior talus) MISCELLANEOUS \- Onset 13-15 years ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	TALO-PATELLO-SCAPHOID OSTEOLYSIS, SYNOVITIS, AND SHORT FOURTH METACARPALS	c1864784	6,098	omim	https://www.omim.org/entry/609655	2019-09-22T16:05:42	{"mesh": ["C536894"], "omim": ["609655"], "orphanet": ["50809"]}
Intraneural perineurioma is a rare tumor of cranial and spinal nerves arising from peripheral nerve sheet and composed exclusively or predominantly of cells showing perineurial differentiation. It presents as a localized, tubular or fusiform enlargement of a nerve or nerve segment, usually in the extremities or the trunk, associated with a motor-predominant mononeuropathy including slow, painless, gradual loss of motor function in the involved nerve trunk with muscle weakness and atrophy and, rarely, sensory dysfunction. Cranial nerve involvement is rare. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Intraneural perineurioma	c1370658	6,099	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100003	2021-01-23T17:33:49	{"gard": ["10921"], "umls": ["C1370658"]}

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