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## Description Blount disease is a developmental condition characterized by disordered endochondral ossification of the medial part of the proximal tibial physis resulting in multiplanar deformities of the lower limb (review by Sabharwal, 2009). Clinical Features Blount (1937) distinguished infantile (188700) and adolescent forms. The description by Tobin (1957) of tibia vara beginning at puberty with osteochondritis dissecans of the knees (see 165800) in father and 2 sons suggested that the 2 disorders may be identical. Motzkin et al. (1992) and Tarnok et al. (2003) reported Blount disease in Bardet-Biedl syndrome (209900). Skel \- Osteochondrosis deformans tibiae \- Bowlegs \- Tibia vara Inheritance \- Autosomal recessive vs. multifactorial ▲ 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	BLOUNT DISEASE, ADOLESCENT	c0175756	6,500	omim	https://www.omim.org/entry/259200	2019-09-22T16:23:54	{"doid": ["14798"], "mesh": ["C536237"], "omim": ["259200"], "orphanet": ["2768"], "synonyms": ["Alternative titles", "OSTEOCHONDROSIS DEFORMANS TIBIAE, ADOLESCENT", "TIBIA VARA, ADOLESCENT"]}
Lentigo maligna melanoma SpecialtyOncology, dermatology Lentigo maligna melanoma is a melanoma that has evolved from a lentigo maligna,[1]:695 as seen as a lentigo maligna with melanoma cells invading below the boundaries of the epidermis.[2] They are usually found on chronically sun damaged skin such as the face and the forearms of the elderly. Lentigo maligna is the non-invasive skin growth that some pathologists consider to be a melanoma-in-situ.[3] A few pathologists do not consider lentigo maligna to be a melanoma at all, but a precursor to melanomas. Once a lentigo maligna becomes a lentigo maligna melanoma, it is treated as if it were an invasive melanoma. ## Contents * 1 Presentation * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Presentation[edit] An invasive tumor arising from a classical lentigo maligna. Usually a darkly pigmented raised papule or nodule, arising from a patch of irregularly pigmented flat brown to dark brown lesion of sun exposed skin of the face or arms in an elderly patient. ## Diagnosis[edit] First dilemma in diagnosis is recognition. As lentigo malignas often present on severely sun damaged skin, it is frequently found amongst numerous pigmented lesions – thin seborrheic keratoses, lentigo senilis, lentigines. It is difficult to distinguish these lesions with the naked eye alone, and even with some difficulty using dermatoscopy. As the lentigo maligna is often very large, it often merges with, or encompasses other skin tumors – such as lentigines, melanocytic nevi, and seborrheic keratosis. Second dilemma is the biopsy technique. Even though excisional biopsy (removing the entire lesion) is ideal, and advocated by pathologists, practical reason dictates that this should not be done. These tumors are often large and presenting on the facial area. Excision of such large tumor would be absolutely contraindicated if the lesion's identity is uncertain. The preferred method of diagnosis is by using a shave biopsy because punch biopsies give up to an 80% false negative rate. While one section of the tumor might show benign melanocytic nevus, another section might show features concerning of severe cellular atypia. When cellular atypia is noted, a pathologist might indicate that the entire lesion should be removed. It is at this point that one can comfortably remove the entire lesion, thus confirming the final diagnosis of lentigo maligna. Despite the high false negative rate, punch biopsies are often used and the size of the punch biopsy can vary from 1 mm to 2 mm, but it is preferred to use a punch 1.5 mm or larger. Representative samples of the most atypical part of the nevus should be biopsy, often by the aid of dermatoscopy. ## Treatment[edit] Treatment depends on the thickness of the invasive component of the lentigo maligna. Treatment is essentially identical to other melanomas of the same thickness and stage. ## See also[edit] * Melanoma ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 2. ^ Michael Xiong; Ahmad Charifa; Chih Shan J. Chen. "Cancer, Lentigo Maligna Melanoma". StatPearls, National Center for Biotechnology Information. Last Update: May 18, 2019. 3. ^ McKenna JK, Florell SR, Goldman GD, Bowen GM (April 2006). "Lentigo maligna/lentigo maligna melanoma: current state of diagnosis and treatment". Dermatol Surg. 32 (4): 493–504. doi:10.1111/j.1524-4725.2006.32102.x. PMID 16681656. ## External links[edit] Classification D * ICD-10: C43 (ILDS C43.L40) * ICD-O: M8742/3 * MeSH: D018327 * DiseasesDB: 32059 External resources * eMedicine: med/1278 * v * t * e Skin cancer of nevi and melanomas Melanoma * Mucosal melanoma * Superficial spreading melanoma * Nodular melanoma * lentigo * Lentigo maligna/Lentigo maligna melanoma * Acral lentiginous melanoma * Amelanotic melanoma * Desmoplastic melanoma * Melanoma with features of a Spitz nevus * Melanoma with small nevus-like cells * Polypoid melanoma * Nevoid melanoma * Melanocytic tumors of uncertain malignant potential Nevus/ melanocytic nevus * Nevus of Ito/Nevus of Ota * Spitz nevus * Pigmented spindle cell nevus * Halo nevus * Pseudomelanoma * Blue nevus * of Jadassohn–Tièche * Cellular * Epithelioid * Deep penetrating * Amelanotic * Malignant * Congenital melanocytic nevus (Giant * Medium-sized * Small-sized) * Balloon cell nevus * Dysplastic nevus/Dysplastic nevus syndrome * Acral nevus * Becker's nevus * Benign melanocytic nevus * Nevus spilus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Lentigo maligna melanoma	c2739810	6,501	wikipedia	https://en.wikipedia.org/wiki/Lentigo_maligna_melanoma	2021-01-18T18:59:51	{"gard": ["9962"], "umls": ["C2739810"], "icd-9": ["M8742/3"], "icd-10": ["C43"], "wikidata": ["Q6523346"]}
This syndrome is characterised by the association of toe syndactyly, facial dysmorphism including telecanthus (abnormal distance between the eyes) and a broad nasal tip, urogenital malformations and anal atresia. ## Epidemiology Around ten cases have been reported so far. ## Etiology The syndrome is caused by mutations in the FAM58A gene (located on the X chromosome) encoding a protein of unknown function. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Syndactyly-telecanthus-anogenital and renal malformations syndrome	c2678045	6,502	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=140952	2021-01-23T16:56:40	{"gard": ["10295"], "mesh": ["C567475"], "omim": ["300707"], "umls": ["C2678045"], "icd-10": ["Q87.8"], "synonyms": ["STAR syndrome"]}
Isolated polycystic liver disease (PCLD) is a genetic disorder characterized by the appearance of numerous cysts spread throughout the liver and that in most cases is described as autosomal dominant polycystic liver disease (ADPCLD). ## Epidemiology The prevalence of ADPCLD is 1/100, 000. ## Clinical description Women are predominantly affected and have a larger number of cysts than affected males. Cysts are undetectable early in life and usually appear after the age of 40 years. Their number and size increases with age. Symptoms depend on the mass (compression effect) and can include abdominal distension, gastro-esophageal reflux, early satiety, dyspnea, decreased mobility and back pain due to hepatomegaly. Some patients are asymptomatic. Other complications (intracystic hemorrhage or infection, torsion or rupture of cysts) can cause acute abdominal pain. Liver function is usually normal. There is no portal hypertension. Extrahepatic manifestations are very rare and may include intracranial aneurysms (usually small sized and at a low risk of rupture) and mitral leaflet abnormalities. In rare cases hepatomegaly can lead to malnutrition which can be lethal. ## Etiology Liver cysts result from overgrowth of biliary epithelium or from dilatation of peribiliary glands. Some cases occur sporadically, but most are inherited as an autosomal dominant trait (ADPCLD). ADPCLD is caused in 1/3-1/2 of cases by mutations in the PRKCSH or SEC63 genes. As not all cases of PCLD have a mutation in one of these genes, other not yet discovered genes and modes of transmission may exist. ## Diagnostic methods Ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) is used for diagnosis. Among patients at risk (belonging to a family known to be affected), diagnostic criteria include more than one cyst in patients below the age of 40 years, and more than three cysts in those over 40. For patients with no known affected relatives, the usual criterion is more than 20 cysts. ## Differential diagnosis Differential diagnoses include multiple liver cysts, found in association with autosomal dominant polycystic kidney disease (ADPKD; see this term), but PCLD is genetically distinct from ADPKD with liver cysts. Simple liver cysts are also a differential diagnosis. Caroli disease (see this term), characterized by cysts communicating with the biliary tract, is differentiated by using imaging with contrast agents specifically excreted into the bile. ## Management and treatment Most patients are asymptomatic and do not require treatment. For those with symptoms, management depends on the extent, distribution, and anatomy of the cysts and may include percutaneous cyst aspiration, alcohol sclerosis, cyst fenestration, partial hepatectomy, and even liver transplantation (in rare cases where the massively enlarged liver considerably alters the quality of life). Any form of estrogen therapy should be stopped immediately. Recently, lanreotide and long acting octreotide (somatostatin analogues) have been shown to be safe and effective treatments for PCLD that reduce moderate polycystic liver volume and prevent its growth. ## Prognosis Most patients with PCLD have good prognosis and do not require 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	Isolated polycystic liver disease	c0158683	6,503	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2924	2021-01-23T18:21:24	{"gard": ["9457"], "mesh": ["C536330"], "omim": ["174050", "617004"], "umls": ["C0158683"], "icd-10": ["Q44.6"], "synonyms": ["ADPCLD", "Autosomal dominant polycystic liver disease", "PCLD"]}
A number sign (#) is used with this entry because familial hypertrophic cardiomyopathy-14 is caused by mutation in the MYH6 gene (160710). For a phenotypic description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600). Molecular Genetics In a study of late-onset hypertrophic cardiomyopathy (CMH), Niimura et al. (2002) reported a 75-year-old woman in whom they identified a heterozygous mutation in the MYH6 gene (R795Q; 160710.0002). The patient, who became symptomatic at age 74 years, had a maximum left ventricular wall thickness of 19 mm. Carniel et al. (2005) analyzed the MYH6 gene in 21 CMH families, including 29 affected and 30 unaffected individuals, and identified a heterozygous mutation (Q1065H; 160710.0004) in 1 Caucasian proband that was not found in 150 ethnically similar controls. The patient was diagnosed with CMH at 27 years of age, at which time the maximal wall thickness was 23 mm, and died of refractory congestive heart failure while awaiting heart transplantation at age 45 years. Family history was significant for sudden death of the proband's mother at age 47 years; the proband's 2 offspring were clinically unaffected and did not carry the mutation. Mutations in 3 known CMH-causing genes (MYH7, 160760; TNNT2, 191045; and MYBPC3, 600958) were excluded in the patient. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Increased left ventricular wall thickness \- Decreased left ventricular fractional shortening \- Decreased left ventricular ejection fraction \- Ventricular outflow obstruction \- Progression to cardiac dilation \- Refractory heart failure MISCELLANEOUS \- Variable age of onset from third to eighth decade of life MOLECULAR BASIS \- Caused by mutation in the alpha cardiac muscle heavy chain 6 myosin gene (MYH6, 160710.0002 ) ▲ 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	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 14	c2750467	6,504	omim	https://www.omim.org/entry/613251	2019-09-22T15:59:09	{"mesh": ["C567684"], "omim": ["613251"]}
Acrocallosal syndrome Polydactyly and hallux duplication in a 1 day old infant due to acrocallosal syndrome. SpecialtyMedical genetics Acrocallosal syndrome (also known as ACLS) is a rare autosomal recessive syndrome characterized by corpus callosum agenesis, polydactyly, multiple dysmorphic features, motor and intellectual disabilities, and other symptoms.[1] The syndrome was first described by Albert Schinzel in 1979.[2] It is associated with GLI3.[3] ## Contents * 1 Signs and symptoms * 2 Pathology * 3 Mechanism * 4 Diagnosis * 5 Treatment * 6 References * 7 External links ## Signs and symptoms[edit] Acrocallosal syndrome (ACLS, ACS, Schinzel-Type, Hallux-duplication) is a rare, heterogeneous[3] autosomal recessive disorder first discovered by Albert Schinzel (1979) in a 3-year-old boy.[2] To inherit ACLS, one gene copy from each parent must contain a mutation somewhere in the KIF7 gene and be passed on to the child . Characteristics of this syndrome include absence or poor development of the area connecting the left and right parts of the brain, an abnormally large head, increased distance between facial features (eyes), poor motor skills, mental retardation, extra fingers and toes, many facial deformities,[3] and cleft palate . This is considered a rare disorder and is placed on the NIH Office of Rare Diseases (fewer than 200,000 cases) rare disease list. Lifespan may range from stillbirth to normal expectancy depending on pregnancy complications and severity of the disorder.[2] In mild cases, the subjects have been shown to live relatively normal lives, but with developmental delays.[2] ## Pathology[edit] This disease is autosomal recessive. Acrocallosal syndrome (ACLS, ACS, Schinzel-Type) is a rare, heterogeneous, autosomal recessive disorder.[3] The heterogeneity of this condition refers to the multiple genes that may function to contribute to varying degrees of this syndrome[3] and is often linked to consanguinity.[2] Characteristics of this syndrome include agenesis of the corpus, macrocephaly, hypertelorism, polydactyly, mental and motor retardation,[2] craniofacial dysmorphism, hallux duplication,[3] and sometimes palatal clefting. It has also been reported that there are many similar signs and symptoms between ACLS, Greig cephalopolysyndactyly, and hydrolethalus syndrome (HLS), although there is little evidence to support common genetic causation at this point.[3] ## Mechanism[edit] Recent studies by, have indicated that the mutations responsible for ACLS are located in the KIF7 protein. KIF7 is a 1343 amino acid protein with a kinesin motor, coiled coil, and Gli-binding domains. Its functions are largely associated with ciliary motor function,[3] and is a key factor in the Sonic Hedgehog (Shh) transduction pathways that are crucial during embryogenesis . Therefore, mutations in Hedgehog signaling components (KIF7) may lead to cilia based pathologies and ultimately defects in the brain and other areas associated with ACLS and related disorders . More specifically, mutations observed by, in the GLI3 gene have yielded similar characteristics to ACLS, but further evidence is needed since the corpus callosum is usually present in these cases. Other studies have also indicated that KIF7 interacts with Gli transcription factors, so mutations in the KIF7 gene may be upstream effectors of GLI3. Further understanding about the functionality of ACLS and its underlying mechanisms opens new doors to pharmacological manipulation and other forms of molecular therapy.[4] ## Diagnosis[edit] This section is empty. You can help by adding to it. (July 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (July 2017) ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): Acrocallosal syndrome; ACLS - 200990 2. ^ a b c d e f Schinzel, Albert (May 1979). "Postaxial polydactyly, hallux duplication, absence of the corpus callosum, macroencephaly and severe mental retardation: a new syndrome?". Helvetica Paediatrica Acta. 34 (2): 141–6. PMID 457430. 3. ^ a b c d e f g h Elson E, Perveen R, Donnai D, Wall S, Black GC (November 2002). "De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models". J. Med. Genet. 39 (11): 804–6. doi:10.1136/jmg.39.11.804. PMC 1735022. PMID 12414818. 4. ^ Putoux, Audrey; Thomas, Sophie; Coene, Karlien L M; Davis, Erica E; Alanay, Yasemin; Ogur, Gönül; Uz, Elif; Buzas, Daniela; Gomes, Céline (2013-06-06). "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes". Nature Genetics. 43 (6): 601–606. doi:10.1038/ng.826. ISSN 1061-4036. PMC 3674836. PMID 21552264. * Koenig R.; Bach A.; Ulrike W.; Grzeschik K-H; Fuchs S. (2002). "Spectrum of the acrocallosal syndrome". American Journal of Medical Genetics. 108 (1): 7–11. doi:10.1002/ajmg.10236. PMID 11857542. * Walsh D.; Shalev S.; Simpson M.; Morgan N.; Gelman-Kohan Z.; Chemke J.; Trembath R.; Maher E. (2013). "Acrocallosal syndrome: Identification of a novel KIF7 mutation and evidence for oligogenic inheritance". European Journal of Medical Genetics. 56 (1): 39–42. doi:10.1016/j.ejmg.2012.10.004. PMID 23142271. * Putoux A.; Nampoothiri S.; Laurent N.; Cormier-Daire V.; Beales P.; et al. (2012). "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal sndrome". Journal of Medical Genetics. 49 (11): 713–720. doi:10.1136/jmedgenet-2012-101016. PMID 23125460. * Putoux A.; Thomas S.; Coene K. L. M.; Davis E. E.; Alanay Y.; Ogur G.; et al. (2011). "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes". Nature Genetics. 43 (6): 601–606. doi:10.1038/ng.826. PMC 3674836. PMID 21552264. * Elson E.; Perveen R.; Donnai D.; Wall S.; Black G.C.M. (2002). "De novo GLI3 mutation in acrocallosal syndrome:broadening the phenotypic spectrum of GLI3 defects and overlap with murine models". Journal of Medical Genetics. 39 (11): 804–806. doi:10.1136/jmg.39.11.804. PMC 1735022. PMID 12414818. * Klejnot M.; Kozielski F. (2011). "Structural insights into human Kif7, a kinesin involved in Hedgehog signaling". Acta Crystallographica Section D. 68 (2): 154–159. doi:10.1107/S0907444911053042. PMC 3266853. PMID 22281744. * NIH Office of Rare Diseases Research. (n.d.). Acrocallosal syndrome, Schinzel type. Bethesda, MD. Retrieved on 2/4/14 from: http://rarediseases.info.nih.gov/gard/5721/acrocallosal-syndrome-schinzel-type/resources/1 ## External links[edit] Classification D * ICD-10: Q04.0 * OMIM: 200990 * MeSH: D055673 External resources * Orphanet: 36 * Acrocallosal syndrome, Schinzel type at NIH's Office of Rare Diseases * v * t * e Congenital malformations and deformations of nervous system Brain Neural tube defect * Anencephaly * Acephaly * Acrania * Acalvaria * Iniencephaly * Encephalocele * Chiari malformation Other * Microcephaly * Congenital hydrocephalus * Dandy–Walker syndrome * other reduction deformities * Holoprosencephaly * Lissencephaly * Microlissencephaly * Pachygyria * Hydranencephaly * Septo-optic dysplasia * Megalencephaly * Hemimegalencephaly * CNS cyst * Porencephaly * Schizencephaly * Polymicrogyria * Bilateral frontoparietal polymicrogyria Spinal cord Neural tube defect * Spina bifida * Rachischisis Other * Currarino syndrome * Diastomatomyelia * Syringomyelia * v * t * e Genetic disorders relating to deficiencies of transcription factor or coregulators (1) Basic domains 1.2 * Feingold syndrome * Saethre–Chotzen syndrome 1.3 * Tietz syndrome (2) Zinc finger DNA-binding domains 2.1 * (Intracellular receptor): Thyroid hormone resistance * Androgen insensitivity syndrome * PAIS * MAIS * CAIS * Kennedy's disease * PHA1AD pseudohypoaldosteronism * Estrogen insensitivity syndrome * X-linked adrenal hypoplasia congenita * MODY 1 * Familial partial lipodystrophy 3 * SF1 XY gonadal dysgenesis 2.2 * Barakat syndrome * Tricho–rhino–phalangeal syndrome 2.3 * Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome * Denys–Drash syndrome * Duane-radial ray syndrome * MODY 7 * MRX 89 * Townes–Brocks syndrome * Acrocallosal syndrome * Myotonic dystrophy 2 2.5 * Autoimmune polyendocrine syndrome type 1 (3) Helix-turn-helix domains 3.1 * ARX * Ohtahara syndrome * Lissencephaly X2 * MNX1 * Currarino syndrome * HOXD13 * SPD1 synpolydactyly * PDX1 * MODY 4 * LMX1B * Nail–patella syndrome * MSX1 * Tooth and nail syndrome * OFC5 * PITX2 * Axenfeld syndrome 1 * POU4F3 * DFNA15 * POU3F4 * DFNX2 * ZEB1 * Posterior polymorphous corneal dystrophy * Fuchs' dystrophy 3 * ZEB2 * Mowat–Wilson syndrome 3.2 * PAX2 * Papillorenal syndrome * PAX3 * Waardenburg syndrome 1&3 * PAX4 * MODY 9 * PAX6 * Gillespie syndrome * Coloboma of optic nerve * PAX8 * Congenital hypothyroidism 2 * PAX9 * STHAG3 3.3 * FOXC1 * Axenfeld syndrome 3 * Iridogoniodysgenesis, dominant type * FOXC2 * Lymphedema–distichiasis syndrome * FOXE1 * Bamforth–Lazarus syndrome * FOXE3 * Anterior segment mesenchymal dysgenesis * FOXF1 * ACD/MPV * FOXI1 * Enlarged vestibular aqueduct * FOXL2 * Premature ovarian failure 3 * FOXP3 * IPEX 3.5 * IRF6 * Van der Woude syndrome * Popliteal pterygium syndrome (4) β-Scaffold factors with minor groove contacts 4.2 * Hyperimmunoglobulin E syndrome 4.3 * Holt–Oram syndrome * Li–Fraumeni syndrome * Ulnar–mammary syndrome 4.7 * Campomelic dysplasia * MODY 3 * MODY 5 * SF1 * SRY XY gonadal dysgenesis * Premature ovarian failure 7 * SOX10 * Waardenburg syndrome 4c * Yemenite deaf-blind hypopigmentation syndrome 4.11 * Cleidocranial dysostosis (0) Other transcription factors 0.6 * Kabuki syndrome Ungrouped * TCF4 * Pitt–Hopkins syndrome * ZFP57 * TNDM1 * TP63 * Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8 Transcription coregulators Coactivator: * CREBBP * Rubinstein–Taybi syndrome Corepressor: * HR (Atrichia with papular lesions) symptoms of vibes [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Acrocallosal syndrome	c3277723	6,505	wikipedia	https://en.wikipedia.org/wiki/Acrocallosal_syndrome	2021-01-18T18:54:41	{"gard": ["5721"], "mesh": ["D055673"], "umls": ["C3277723", "C2931760"], "icd-10": ["Q04.0"], "orphanet": ["36"], "wikidata": ["Q4675304"]}
In an Iranian family, Passwell et al. (1975) described a combination of congenital ichthyosis, mental retardation, dwarfism, and renal impairment. Two sisters and a brother were affected as well as a female who was a half sister of both parents (the offspring of the mother of the mother by the father of the father). GU \- Nephropathy Neuro \- Mental retardation Inheritance \- Autosomal recessive Lab \- Elevated BUN \- Elevated creatinine \- Reduced creatinine clearance Growth \- Dwarfism Skin \- Congenital non-bullous ichthyosis ▲ 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	ICHTHYOSIS, MENTAL RETARDATION, DWARFISM, AND RENAL IMPAIRMENT	c1855787	6,506	omim	https://www.omim.org/entry/242530	2019-09-22T16:26:31	{"mesh": ["C536274"], "omim": ["242530"], "orphanet": ["2278"]}
Post-traumatic amnesia SpecialtyPsychiatry, neurology, neuropsychology Post-traumatic amnesia (PTA) is a state of confusion that occurs immediately following a traumatic brain injury (TBI) in which the injured person is disoriented and unable to remember events that occur after the injury.[1] The person may be unable to state their name, where they are, and what time it is.[1] When continuous memory returns, PTA is considered to have resolved.[2] While PTA lasts, new events cannot be stored in the memory.[3] About a third of patients with mild head injury are reported to have "islands of memory", in which the patient can recall only some events.[3] During PTA, the patient's consciousness is "clouded".[4] Because PTA involves confusion in addition to the memory loss typical of amnesia, the term "post-traumatic confusional state" has been proposed as an alternative.[4] There are two types of amnesia: retrograde amnesia (loss of memories that were formed shortly before the injury) and anterograde amnesia (problems with creating new memories after the injury has taken place).[5] PTA may refer to only anterograde forms, or to both retrograde and anterograde forms.[6][7] A common example in sports concussion is the quarterback who was able to conduct the complicated mental tasks of leading a football team after a concussion, but has no recollection the next day of the part of the game that took place after the injury. Retrograde amnesia sufferers may partially regain memory later, but memories are not regained with anterograde amnesia because they were not encoded properly.[8] The term "post-traumatic amnesia" was first used in 1940 in a paper by Symonds to refer to the period between the injury and the return of full, continuous memory, including any time during which the patient was unconscious.[9] ## Contents * 1 Symptoms * 1.1 Attention * 1.2 Communication skills * 2 Pathophysiology * 2.1 Neurological mechanisms * 2.2 Diaschisis * 2.3 Brain-imaging studies * 2.3.1 Accelerated forgetting * 3 Diagnosis * 3.1 Measure of traumatic brain injury severity * 3.2 Assessment * 3.3 Testing * 3.3.1 GOAT * 3.3.2 WPTAS and AWPTAS * 3.3.2.1 Drawbacks * 3.4 Severity * 4 Treatment * 4.1 Vasopressin * 4.1.1 Animal research * 4.1.2 Human studies * 4.2 Norepinephrine agonists * 5 Research * 5.1 The North Star Project * 5.1.1 Findings * 6 History * 6.1 C.P. Symonds * 6.2 In WWI soldiers * 7 Other psychological disorders * 8 Aging * 9 Controversies * 10 References ## Symptoms[edit] A common symptom of PTA is confusion. The most prominent symptom of post-traumatic amnesia (PTA) is a loss of memory of the present time.[10] As a result, patients are often unaware of their condition and may behave as if they are going about their regular lives. This can cause complications if patients are confined to a hospital and may lead to agitation, distress and anxiety.[10] Many patients report feeling as though they were being "held prisoner" and being prevented from carrying on with their daily lives.[10] Other symptoms include agitation, confusion, disorientation, and restlessness.[11] Patients also often display behavioral disturbances. Patients may shout, swear and behave in a disinhibited fashion.[10] There have been cases in which patients who do not recognize anyone will ask for family members or acquaintances that they have not seen in years.[10] Some patients exhibit childlike behavior.[10] Other patients show uncharacteristically quiet, friendly and loving behavior. Although this behavior may seem less threatening because of its lack of aggressiveness, it may be equally worrisome.[10] PTA patients are often unaware of their surroundings and will ask questions repeatedly.[10] Patients may also have a tendency to wander off, which can be a major concern in those who have suffered additional injuries at the time of trauma, such as injured limbs, as it may lead to the worsening of these secondary injuries.[10] ### Attention[edit] Attention is a cognitive resource that contributes to many mental functions. The ability to engage attention requires a certain level of conscious awareness, arousal and concentration, all mechanisms that are generally impaired by traumatic brain injury.[12] The involvement of attention in such a vast array of cognitive processes has led to the suggestion that attentional deficit may act as an underlying factor in the range of cognitive deficits observed in patients experiencing post-traumatic amnesia (PTA). Attention has been regarded as an important factor in the healthy functioning of encoding, verbal comprehension and new learning.[12] Automatic attention processes (such as counting forwards) are recovered before simple memory skills (such as a recognition test of verbal material) in individuals with mild to moderate brain injury.[12] This implies that the recovery of attentional ability precedes the progression of memory recovery after injury, helping to pave the way to regain ability for new learning. In terms of more severe brain injuries, this automatic attention task performance recovers before disorientation completely resolves.[12] One of the weaknesses of the method most often used in assessing PTA, the Galveston Orientation and Amnesia Test (GOAT), is that it does not include any assessment of attention, which could help give a better indication of potential for recovery. By omitting attention, the test is omitting some crucial aspects of a person's cognitive capabilities. In addition, assessing attention during the period of PTA may help determine whether the patient is still in a state of PTA or if they are suffering from a more permanent form of memory deficit.[12] In patients with mild TBI, the damage consists primarily of diffuse axonal injury (widespread damage to white matter) without any focal damage (damage to specific areas). Sometimes, injury of the brainstem was also observed. In these cases, there is likely the presence of an attentional deficit without a true amnesiac state. In more severely brain-damaged individuals, the damage to the temporal lobes and the frontal lobes serves as good indication that amnesia will result.[13] Patients suffering from more chronic forms of memory impairment showed poor performance when tested with PTA scales, making differentiation between the two types of memory impairment very difficult. PTA patients exhibit poor simple reaction time, reduced information processing speed and reduced verbal fluency, which are all attentional deficits that could be used to distinguish these patients from those suffering from more severe and permanent memory problems.[12] ### Communication skills[edit] The effects of PTA on communication skills were studied using the Revised Edinburgh Functional Communication Profile (REFCP), which measures both linguistic elements (related to speech) and pragmatic elements (related to body language and other non-verbal communication skills).[14] PTA has effects on memory, perception and attention, which are all important for communication. Patients showed mild deficits in verbal communication skills, and moderate to severe deficits in nonverbal communication skills such as maintaining eye contact, initiating greetings, and responding appropriately.[14] Also, a negative correlation was found between the duration of a patient's episode of PTA and his REFCP score; the longer the PTA episode, the more severe the deficit in non-linguistic pragmatic skills. However, the small sample size of this study (only 10 males) means that the results must be interpreted with caution, as they may not generalize to larger samples or to the population at large. ## Pathophysiology[edit] Currently, the pathophysiological mechanisms which produce post-traumatic amnesia are not completely known. The most common research strategy to clarify these mechanisms is the examination of the impaired functional capabilities of people with post-traumatic amnesia (PTA) after a traumatic brain injury.[15] ### Neurological mechanisms[edit] Hippocampus (animation) Research on the effect of emotional trauma on memory retention and amnesic symptoms has shown that exposure to prolonged levels of extreme stress has a direct effect on the hippocampus. Elevated stress levels can lead to an increase in the production of enkephalins and corticosteroids, which can produce abnormal neural activity and disrupt long-term potentiation (a neural mechanism associated with learning) in the hippocampus.[16] Individuals who have been subjected to repeated sexual abuse during childhood or who have experienced combat show significant impairment and atrophy of the hippocampal region of the brain.[16] The amygdala, an area of the brain involved in emotional regulation, may be involved in producing remembrance for some aspects of the trauma.[17] Even though the trace of a memory for trauma may be lost from the hippocampus, it may remain partially encoded in the form of an emotional memory in the amygdala where it can be subsequently recalled in the form of a flashback or partially recovered memory. ### Diaschisis[edit] Diaschisis refers to the sudden dysfunction of portions of the brain due to lesions in distant but connected neurons. Diaschisis is implicated as playing an important role in PTA, more particularly in the declarative memory impairments observed in patients experiencing an episode of PTA. The loss of function observed after traumatic brain injuries, as well as the resulting loss of consciousness, was thought to be mediated by the 'neural shock' associated with diaschisis.[18] Diaschisis was originally believed to be a result of disruption to neural tissue, but more recent evidence implicates increased activity levels of choline acetyltransferase, the enzyme responsible for the production of acetylcholine, as a major cause. Based on these findings, diaschisis could be helped through the use of drugs that would reduce cholinergic (acetylcholine) activity, and reduce the levels of acetylcholine in the brain.[19] This idea is supported by the fact that there is an increase in acetylcholine concentrations in the brain after head injury. Animal studies have shown that concussive injuries in rats lead to changes in the central nervous system's cholinergic system. This increase in acetylcholine levels has also been tied to behavioral suppression and unconsciousness, both symptoms of PTA. In long-term recovery, acetylcholine levels associated with diaschisis may continue to play a role in maintaining memory deficits.[15] ### Brain-imaging studies[edit] Brain imaging techniques are useful for examining the changes in the brain that occur as a result of damage. Metting et al. (2001) used CT scans to examine the pathophyiological damage in patients currently experiencing an episode of PTA, patients with resolved PTA, and a control group that had not experienced PTA. Bloodflow to the occipital lobe, the caudate nucleus, and the grey matter of the frontal lobe was significantly reduced in patients who were scanned during the episode of PTA. No differences were seen between patients with resolved PTA and the control group.[11] This encouraging finding points to the positive long term prognosis of PTA; most patients return to normal levels of functioning.[11] The frontal lobes are associated with explicit memory retrieval, and deficits on explicit memory tasks are often found with patients experiencing PTA. Working memory deficits are a common symptom in patients with PTA. The duration of an episode of PTA was correlated with reduced bloodflow to the right hemisphere, a finding which was consistent with functional MRI studies that link working memory with right frontal activity.[11] The prefrontal cortex, which plays an important role in explicit memory retrieval, was also found to have decreased neural activation in patients scanned during the episode of PTA.[11] Researchers noted that the damage was related to vascularization and neural functionality, but not to structural injury, suggesting that the resolution of PTA is dependent on functional changes.[11] Memory and new learning involve the cerebral cortex, the subcortical projections, the hippocampus, the diencephalon and the thalamus, areas that often suffer damage as a result of TBI. Frontal lobe lesions may also play a role in PTA, as damage to these areas is associated with changes in behavior, including irritability, aggressiveness, disinhibition, and a loss of judgment.[20] Damage to this area may account for the uncharacteristic behavior often exhibited in PTA patients. #### Accelerated forgetting[edit] Researchers have also found that individuals experiencing PTA show accelerated forgetting. This contrasts with the normal forgetting observed by patients with normal amnesia related to brain damage. The temporal lobes are often the most vulnerable to the diffuse (widely distributed) and focal (more specifically localized) effects of TBI and it is possible that temporal lobe lesions may account for the accelerated forgetting observed in patients with PTA. These predictions were supported by the finding that most of the patients who showed rapid forgetting also had lesions to the temporal lobe.[21] Bilateral damage to the temporal lobes also causes severe anterograde amnesia, making it likely that lesions to this area would be involved in PTA. Patients exhibit a temporal gradient with memory loss, meaning that older memories are preserved at the expense of newer memories. Temporal lobe damage has been linked to a temporal gradient of this sort, because older memories are less dependent on the hippocampus and thus are less influenced by its damage.[15] There is a significant link between individuals currently suffering from PTA and their performance on the Wechsler Adult Intelligence Scale (WAIS). The scores of those currently experiencing an episode of PTA were compared to individuals who had previously suffered a traumatic brain injury resulting in PTA. Those still suffering from PTA performed significantly worse on both the performance and the verbal subscales of the WAIS.[22] Also, people in early stages of PTA have substantial impairment to anterograde memory function. For example, in the case report of a patient referred to as "JL", Demery et al. noted that his memory impairments were so severe following his injury that he had forgotten that he had attended a Major League Baseball game less than 30 minutes after returning to the center where he was being treated.[23] The majority of neuropsychological studies available have suggested that the medial temporal lobes are the most important system in the pathophysiology of PTA. However, there is little research done on this topic, and as new research is done, more information should come forth concerning functionality in these areas in PTA patients. One MRI study showed that a long duration of PTA was correlated with damage in the hemispheric and central areas, regardless of whether the duration of the coma was relatively short. In patients who had a longer coma duration, deeper lesions in the central area were observed without extensive damage to the hemispheric area.[15] ## Diagnosis[edit] ### Measure of traumatic brain injury severity[edit] Levels of TBI severity[24] GCS PTA LOC Mild 13–15 < 1 hour < 30 minutes Moderate 9–12 30 minutes– 24 hours 1–24 hours Severe 3–8 > 1 day > 24 hours TBI severity using PTA alone[25] Severity PTA Very mild < 5 minutes Mild 5–60 minutes Moderate 1–24 hours Severe 1–7 days Very severe 1–4 weeks Extremely severe > 4 weeks PTA has been proposed to be the best measure of head trauma severity,[8] but it may not be a reliable indicator of outcome.[3] However, PTA duration may be linked to the likelihood that psychiatric and behavioral problems will occur as consequences of TBI.[4] Classification systems for determining the severity of TBI may use duration of PTA alone or with other factors such as Glasgow Coma Scale (GCS) score and duration of loss of consciousness (LOC) to divide TBI into categories of mild, moderate, and severe. One common system using all three factors and one using PTA alone are shown in the tables at right. Duration of PTA usually correlates well with GCS and usually lasts about four times longer than unconsciousness.[25] PTA is considered a hallmark of concussion,[8] and is used as a measure of predicting its severity, for example in concussion grading scales. It may be more reliable for determining severity of concussion than GCS because the latter may not be sensitive enough; concussion sufferers often quickly regain a GCS score of 15.[3] Longer periods of amnesia or loss of consciousness immediately after the injury may indicate longer recovery times from residual symptoms from concussion.[26] Increased duration of PTA is associated with a heightened risk for TBI complications such as post-traumatic epilepsy.[27] ### Assessment[edit] Duration of PTA may be difficult to gauge accurately; it may be overestimated (for example, if the patient is asleep or under the influence of drugs or alcohol for part of the time) or underestimated (for example, if some memories come back before continuous memory is regained).[3] The Galveston Orientation and Amnesia Test (GOAT) exists to determine how oriented a patient is and how much material they are able to recall.[28] The GOAT is the most widely used standardized scale for the prospective assessment of PTA in the United States and Canada. The test is made up of 10 items that assess orientation and recollection of the events before and after the injury. It can be used to assess the duration of PTA; this particular GOAT assessment has been found to strongly predict functional outcome as measured by the Glasgow Outcome Scale, return to productivity, psychosocial function and distress.[29] An alternative to the GOAT is the Westmead Post-Traumatic Amnesia Scale (WPTAS)[30][31] which examines not only orientation to person, place and time, but also crucially the ability to consistently remember new information from one day to the next. It consists of twelve questions (seven orientation questions, and five memory items) and is administered once daily, each and every day, until the patient scores a perfect score of 12/12 on three consecutive days. It is suitable for patients with moderate to severe traumatic brain injury. The WPTAS is the most common post-traumatic amnesia scale used in Australia and New Zealand.[32] An abbreviated version has been developed to assess patients with mild traumatic brain injury, the Abbreviated Westmead PTA Scale (AWPTAS).[33] ### Testing[edit] Before the development of the current tests for the assessment of post-traumatic amnesia (PTA), a retrospective method was used to determine the patient's condition, consisting of one or more interviews with the patient after the episode of PTA was judged to be over. The retrospective method, however, fails to account for the apparent lucidity of patients who are still experiencing substantial disorientation, or the finding that the recovery from post-traumatic amnesia is often characterized by the presence of "islands of memory" (short periods of clarity).[15] A failure to take these facts into consideration may have biased retrospective methods towards underestimating the length and severity of an episode of PTA.[15] Also, the retrospective method relies on retrospective memory, one's memory for past events, which is not very reliable in healthy individuals, and even less so in patients who have recently experienced a traumatic brain injury (TBI). Patients may also unconsciously or consciously bias their answers because they want to appear more healthy or more ill than they truly were, or because of poor insight.[15] The retrospective method is also flawed because there is no standard measurement procedure.[15] Although the retrospective method may provide useful subjective data, it is not a useful tool for measurement or categorization. #### GOAT[edit] The Galveston Orientation and Amnesia Test (GOAT) is the most frequently used test for assessing PTA in the United States and Canada. The test consists of 10 items that involve the recall of events that occurred right before and after the injury, as well as questions about disorientation. Scores of 75 or more on this scale (out of a total possible score of 100) correspond to the termination of the PTA episode. The GOAT typically classifies orientation into three categories: orientation to the person, orientation to the place, and orientation to the time. The idea behind these questions is that each of these classifications places a large demand on the patient's memory and learning abilities.[15] #### WPTAS and AWPTAS[edit] The Westmead Post-Traumatic Amnesia Scale (WPTAS)[30][31] is commonly used in Australia and New Zealand.[32] It questions twelve questions that examine orientation to person, place and time, in addition to the ability to consistently remember new information from one day to the next. The scale is administered once each day, until the patient scores 12/12 on three consecutive days. The WPTAS is suitable for patients with moderate-to-severe traumatic brain injury. An abbreviated version of the WPTAS, the Abbreviated Westmead PTA Scale (AWPTAS) assesses patients with mild traumatic brain injury.[33] ##### Drawbacks[edit] Although the GOAT has proved useful in acute care, recent research has called attention to some of its drawbacks. The GOAT's assessment of orientation may put too much of a focus on memory as the main mechanism behind orientation. The range of cognitive and behavioral symptoms associated with PTA seems to indicate that the patient's disorientation is more than just a memory deficit. Consequently, it may be beneficial to incorporate tests of other cognitive functions, such as attention, which relate to both memory and orientation.[12] Another recent study compared the success of the GOAT and the Orientation Log (O-Log) in predicting rehabilitation outcomes, and found that, while the O-Log and the GOAT perform similarly as measures of PTA severity and duration, the O-Log provides a more accurate picture of rehabilitation.[34] While the GOAT is a useful tool, these results suggest that using alternative methods of assessing PTA may increase the amount of information available to physicians and may help in predicting rehabilitative success. The international cognitive (INCOG) expert panel has recommended the use of a validated PTA scale such as the GOAT or WPTAS for assessing PTA duration in patients with moderate-to-severe traumatic brain injury on a daily basis.[35] ### Severity[edit] The severity of post-traumatic amnesia (PTA) is directly related to its duration, although a longer duration does not necessarily indicate more severe symptoms.[15] The duration of PTA in brain-injured patients is a useful predictor of the expected long-term effects of the injury,[36] along with the duration of loss of consciousness(LOC), and scores on the Glasgow Coma Scale (GCS), which measures degrees of consciousness, with higher scores indicating higher levels of functioning. A score of three indicates complete unconsciousness, and a score of 15 indicates normal functioning.[15] Levels of TBI severity[37] GCS score duration of PTA duration of LOC Mild 13–15 < 1 hour < 30 minutes Moderate 9–12 30 minutes – 24 hours 1–2 24 hours Severe 3–8 > 1 day > 24 hours In patients experiencing PTA for the duration of: Up to one hour – the injury is very mild in severity and full recovery is expected. The patient may experience a few minor post-concussive symptoms (e.g. headaches, dizziness). 1–24 hours – the injury is moderate in severity and full recovery is expected. The patient may experience some minor post-concussive symptoms (e.g. headaches, dizziness). 1–7 days – the injury is severe, and recovery may take weeks to months. The patient may be able to return to work, but may be less capable than before the injury. 1–2 weeks – the injury is very severe, and recovery is likely to take many months. The patient is likely to experience long-lasting cognitive effects such as decreased verbal and nonverbal intelligence as well as decreased performance on visual tests. Patients should, however, still be able to return to work. 2–12 weeks – the injury is very severe, and recovery is likely to take a year or more. The patient is likely to exhibit permanent deficits in memory and cognitive function, and the patient is unlikely to be able to return to work. 12+ weeks – injury is very severe and accompanied by significant disabilities that will require long-term rehabilitation and management. The patient is unlikely to be able to return to work.[10] Note: return to work is meant to indicate a return to a reasonable level of functionality, both in professional and personal arenas.[10] The long-term prognosis of PTA is generally positive. Many patients do recover a great deal of cognitive function, although they may not return to their pre-injury state.[10] ## Treatment[edit] A Vasopressin molecule ### Vasopressin[edit] #### Animal research[edit] Early research pointed to vasopressin as a potential treatment for improving the memory of patients living with post-traumatic amnesia (PTA). Lysine vasopressin, a modified form of the vasopressin molecule, had positive effects on memory when administered by injection to patients with amnesia resulting from traumatic brain injury and Korsakoff's syndrome.[38] Subsequent animal studies with rats found similar results, particularly in aversion and avoidance learning tasks. Rats lacking adequate vasopressin, either due to genetic defect or hypophysectomy (surgical removal of the pituitary gland), exhibited significant improvements in memory and learning functions when exogenous vasopressin was administered.[39] Particularly encouraging was the finding that a short treatment period produced long-lasting improvements, in both humans and rats.[39] However, the animal models of PTA are highly limited, as the dimension of self-awareness and orientation is almost impossible to model adequately. PTA in animals, especially rats, is often observed post-trauma (commonly post-surgery), but it is often only measured in terms of impaired learning or unusual behavior.[39] #### Human studies[edit] One subsequent human study found no effects of vasopressin on memory.[40] The nonsignificant results were attributed to the study's many potential flaws, particularly its small sample size, the inability of vasopressin to penetrate the blood brain barrier when administered as a nasal spray, inadequate dosing and differences in severity of head injury between the samples. However, Eames et al. (1999) found statistically significant improvements on several tests of memory with the use of a vasopressin nasal spray, with no reported ill effects.[39] Although the degree of improvement was mild, and it could be attributed to numerous other factors of the rehabilitative program, the lack of any ill effects suggests that vasopressin is, at the least, a possible enhancement for a treatment regimen.[39] ### Norepinephrine agonists[edit] Diaschisis, as mentioned earlier, has been linked to the mechanism of PTA. The noradrenergic systems may play a role in diaschisis. Norepinephrine, also known as noradrenalin, is a catecholamine neurotransmitter. Administering a norepinephrine receptor agonist (a substance that initiates a cell response when it binds with a receptor) to patients promoted the recovery of memory and many other cognitive functions after a traumatic brain injury.[18] Conversely, the administration of norpinephrine antagonists slowed recovery, and could lead to the reinstatement of deficits when administered after recovery. Noradrenergic antagonists were not prescribed for the purposes of slowing the recovery of memory. Rather, these findings are based on the effects of other commonly prescribed drugs that happen to block noradrenergic receptors. The alpha-1 adrenergic receptor is specifically implicated.[18] Although it has not yet been thoroughly investigated, there is potential for stimulants, which promote catecholamine release, to be an effective treatment in the early stages of recovery from brain trauma, and these positive effects could reduce the symptoms of PTA.[41] ## Research[edit] ### The North Star Project[edit] The North Star Project was developed by researchers at McGill University. Researchers developed a "reality orientation", which involved discussing general facts (e.g. date, time, names of family members, etc.) with amnesic patients twice a day in an attempt to lessen their confusion during the early stages of their recovery. Younger patients often had shorter amnesic episodes than older patients, especially those in the North Star group. Although more improvements were noted in the North Star group than in the control group, researchers did not find a statistically significant effect of their intervention.[42] #### Findings[edit] A comprehensive analysis of literature based on the effects of early rehabilitation of traumatic brain injury concluded that there is no strong evidence linking any one particular practice of post-injury care to a reduced severity in symptoms. However, even in the absence of a concrete correlation between a specific rehabilitation program and improved outcomes, the evidence and research available can provide many good suggestions for how to proceed with treatment. All rehabilitation strategies reviewed had positive effects on recovery, but none more so than the others.[43] The most accurate measure of determining the length of amnesia is still the a behavioural measure, the duration of the episode of post-traumatic amnesia, rather than a neuroimaging technique or an electrophysiological or biochemical technique.[44] The length of amnesia is also one of the most accurate predictors for determining later cognitive problems, even more so than the duration of either the coma or the period of loss of consciousness.[45] The duration of amnesia after TBI, therefore, can be very useful in the planning the length and intensity of rehabilitation programs for persons afflicted with PTA. ## History[edit] ### C.P. Symonds[edit] Although Franklin described PTA, it was the British physician C. P. Symonds who first discussed the specific amnesiac symptoms that often follow a cerebral contusion, which is a specific kind of traumatic brain injury. Symonds observed that the patient remains "stuperose, restless and irritable"[46] after recovering consciousness. He also identified a recovery period of days to weeks for this post-concussive state.[46] Presumably, shorter durations of PTA, which are now included in the definition, were not thought to be serious enough for documentation. Most importantly, he identified the amnesia that the patient experiences during this period of recovery, and recommended the use of "formal tests for memory and retention" to assess recovery.[46] ### In WWI soldiers[edit] Image from WWI, taken in an Australian dressing station near Ypres in 1917. The wounded soldier in the lower left of the photo has a dazed stare, a frequent symptom of "shell shock". Although there was a general lack of knowledge about its mechanisms, a review of patients seen during WWI combat reveals the symptoms of post-traumatic amnesia (PTA) in many soldiers. The term shell shock was used to refer to the acute psychological state that accompanied exposure to exploding shells, and more generally, exposure to combat conditions.[47] There are a number of documented cases of shell shock victims. These soldiers commonly displayed dizziness, varying degrees of consciousness, a loss of non-traumatic personal information, and a lack of normal self-awareness lasting anywhere from hours to days. Many of the symptoms of shell shock are highly similar to those of PTA.[47] The following excerpt from a case report illustrates the loss of personal information observed in one patient: > A soldier was assessed three days after having been admitted into a field ambulance. He was unable to give his name, regiment, or number, and he could not be identified. He could remember being found on the outskirts of a village, but his military history and all events in his past including his childhood were a complete blank.[48] Researchers found that physicians had documented reports of combatants where "[b]oth central and peripheral details of the traumatic experience were lost."[47] Patients displayed gaps in memory recollection for the period following the trauma, sometimes up to the time of hospitalization, which could be weeks later. An initial assessment supported the role of concussions in causing these symptoms. Concussions could account for the anterograde amnesia and retrograde amnesia observed in patients, as well as the periods of fluctuating consciousness or delirium that sometimes followed. However, many soldiers who showed these amnesiac effects did not suffer injuries that would have led to concussions.[47] As a result, there was controversy over the possible causes of PTA in these non-concussed soldiers, with a separation between proponents of Freudian repression and those supporting a dissociative view of the condition. This dissociative view was ultimately supported, and accounted for the fugue state seen in soldiers who were thought to have dissociated from normal consciousness.[47] ## Other psychological disorders[edit] Researchers have investigated the relationship between posttraumatic amnesia (PTA) resulting from traumatic brain injury (TBI) and the development of symptoms of posttraumatic stress disorder (PTSD) and acute stress disorder (ASD). 282 outpatients, who were an average of 53 days post-TBI in their recovery, were divided into four groups: PTA episode lasting less than one hour; PTA episode lasting between one hour and 24 hours; PTA episode lasting between 24 hours and one week; and PTA episode lasting for longer than one week. The patients' personal details were used as variables classified for age, gender, marital status, time elapsed between injury and assessment, and type of injury (motor vehicle accident, pedestrian, assault and other). Patients were given two self-report inventories: the Impact of Event Scale (IES) and the General Health Questionnaire (GHQ). The IES measures symptoms of PTSD and contains questions regarding the intrusiveness of the traumatic event (ex. nightmares) and avoidant behaviours related to the traumatic event (ex. avoiding a certain location).[49] The GHQ was used as an indicator of overall psychological health.[49] The majority of subjects were in Group 1 (PTA episode lasting less than one hour), injured in motor vehicle accidents, and male. There were no statistical differences found with regards to age, gender, marital status and type of injury. There was an increase in the severity of all indicators of brain damage for the longest durations of PTA; specifically, the GCS scores for this group decreased and the number of patients with an abnormal CT scan increased.[49] There were significant differences in IES scores when comparing the group with the least serious episode of PTA, lasting less than an hour, to all other groups, with the duration of the episode of PTA lasting longer than an hour. The group with an episode of PTA lasting less than an hour had higher IES scores and more intrusive and avoidant symptoms.[49] The fact that GHQ scores were constant throughout all groups, although there were differences in IES scores, suggests that the two scores measure different phenomena.[49] ## Aging[edit] An elderly woman Grey and white matter are both found in the many areas of the brain, as well as throughout the central nervous system. Grey matter is more involved in nerve function, and white matter is more involved in nerve maintenance, as well as the regulation of unconscious functions. However, both are important for memory and learning. The volume of grey and white matter in the brains of aging individuals has been correlated with working memory and retention of cognitive function.[50] Researchers hypothesized that the lesions of both grey and white matter would be larger in older individuals and in those with more severe traumatic brain injuries, and longer episodes of PTA, and the volume of grey and white matter would be smaller in those injured at an older age. A group of 98 participants, predominantly male, were examined using fMRI. The results supported these hypotheses, leading researchers to suggest that the impact of traumatic brain injury gets more severe as age progresses.[50] Although grey and white matter volume was reduced throughout the brain, researchers noted that the grey matter of the neocortical brain regions was particularly affected.[50] This is consistent with the fact that older individuals who had experienced PTA showed greater cognitive impairments than a control group of individuals of the same age who had not experienced PTA. The duration of the episode of PTA was related to the size of the grey matter lesion; longer episodes of PTA correlated with larger grey matter lesions. Advanced age also correlated with reduced glial activity. With less grey matter, the patient is less able to retrieve memories effectively, as neuron function is impaired.[50] ## Controversies[edit] On the topic of trauma and memory, Richard McNally (2005) wrote that memories are not videotapes of our experiences, meaning that they are not unchangeable records.[51] The mechanism that retrieves a memory involves activation of several areas of the brain. Similarly, the mechanism that encodes a memory requires the use of different parts of the brain. Any fault in the encoding-retrieval system will degrade memory, and there are many potential faults, such as distortion by emotion, or focusing on the peripheral details at the expense of central details.[51] An example of the latter is the well-known phenomenon where a person being robbed at gunpoint is so distracted by the gun that they don't have time to encode the robber's face.[51] Misconstruing retrieval failure as traumatic amnesia is not the same phenomenon as post-traumatic amnesia, which describes amnesia for the current elapsing time post-trauma, not amnesia for trauma from the past. Typically, "repressed memory" is the term used to explain this sort of traumatic amnesia; the experience was so horrific that the adult cannot process what occurred years before.[51] The topic of repressed memory is controversial within psychology; many clinicians argue for its importance, while researchers remain skeptical of its existence. 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PMID 16483114. * v * t * e Human memory Basic concepts * Encoding * Storage * Recall * Attention * Consolidation * Neuroanatomy Types Sensory * Echoic * Eidetic * Eyewitness * Haptic * Iconic * Motor learning * Visual Short-term * "The Magical Number Seven, Plus or Minus Two" * Working memory Intermediate * Long-term * Active recall * Autobiographical * Explicit * Declarative * Episodic * Semantic * Flashbulb * Hyperthymesia * Implicit * Meaningful learning * Personal-event * Procedural * Rote learning * Selective retention * Tip of the tongue Forgetting * Amnesia * anterograde * childhood * post-traumatic * psychogenic * retrograde * transient global * Decay theory * Forgetting curve * Interference theory * Memory inhibition * Motivated forgetting * Repressed memory * Retrieval-induced forgetting * Selective amnesia * Weapon focus Memory errors * Confabulation * False memory * Hindsight bias * Imagination inflation * List of memory biases * Memory conformity * Mere-exposure effect * Misattribution of memory * Misinformation effect * Source-monitoring error * Wernicke–Korsakoff syndrome Research * Art of memory * Memory and aging * Deese–Roediger–McDermott paradigm * Exceptional memory * Indirect tests of memory * Lost in the mall technique * Memory disorder * Memory implantation * Methods used to study memory * The Seven Sins of Memory * Effects of exercise on memory In society * Collective memory * Cultural memory * False memory syndrome * Memory and social interactions * Memory sport * Politics of memory * Shas Pollak * World Memory Championships Related topics * Absent-mindedness * Atkinson–Shiffrin memory model * Context-dependent memory * Childhood memory * Cryptomnesia * Effects of alcohol * Emotion and memory * Exosomatic memory * Flashbacks * Free recall * Involuntary memory * Levels-of-processing effect * Memory and trauma * Memory improvement * Metamemory * Mnemonic * Muscle memory * Priming * Intertrial * Prospective memory * Recovered-memory therapy * Retrospective memory * Sleep and memory * State-dependent memory * Transactive memory People * Robert A. Bjork * Stephen J. Ceci * Susan Clancy * Hermann Ebbinghaus * Sigmund Freud * Patricia Goldman-Rakic * Jonathan Hancock * Judith Lewis Herman * HM (patient) * Ivan Izquierdo * Marcia K. Johnson * Eric Kandel * KC (patient) * Elizabeth Loftus * Geoffrey Loftus * Chris Marker * James McGaugh * Paul R. McHugh * Eleanor Maguire * George Armitage Miller * Brenda Milner * Lynn Nadel * Dominic O'Brien * Ben Pridmore * Henry L. Roediger III * Steven Rose * Cosmos Rossellius * Daniel Schacter * Richard Shiffrin * Arthur P. Shimamura * Andriy Slyusarchuk * Larry Squire * Susumu Tonegawa * Anne Treisman * Endel Tulving * Robert Stickgold * Clive Wearing * Psychology portal * Philosophy portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Post-traumatic amnesia	c0002623	6,507	wikipedia	https://en.wikipedia.org/wiki/Post-traumatic_amnesia	2021-01-18T18:57:25	{"umls": ["C0002623"], "wikidata": ["Q1188518"]}
Human disease Tight hymenal ring SpecialtyGynecology Tight hymenal ring is a disorder of the hymen, characterized by a rigid hymen and tight introitus, whether acquired or congenital. It excludes an imperforate hymen. The condition can be relieved by outpatient surgery or manual dilation.[1] ## References[edit] 1. ^ Jonathan S. Berek, ed. (2007). "Benign Diseases of the Female Reproductive Tract". Berek & Novak's Gynecology. 2007. Emil Novak. Lippincott Williams & Wilkins. p. 459. ISBN 978-0-7817-6805-4. ## External links[edit] Classification D * ICD-10: N89.6 * ICD-9-CM: 623.3 * v * t * e Female diseases of the pelvis and genitals Internal Adnexa Ovary * Endometriosis of ovary * Female infertility * Anovulation * Poor ovarian reserve * Mittelschmerz * Oophoritis * Ovarian apoplexy * Ovarian cyst * Corpus luteum cyst * Follicular cyst of ovary * Theca lutein cyst * Ovarian hyperstimulation syndrome * Ovarian torsion Fallopian tube * Female infertility * Fallopian tube obstruction * Hematosalpinx * Hydrosalpinx * Salpingitis Uterus Endometrium * Asherman's syndrome * Dysfunctional uterine bleeding * Endometrial hyperplasia * Endometrial polyp * Endometriosis * Endometritis Menstruation * Flow * Amenorrhoea * Hypomenorrhea * Oligomenorrhea * Pain * Dysmenorrhea * PMS * Timing * Menometrorrhagia * Menorrhagia * Metrorrhagia * Female infertility * Recurrent miscarriage Myometrium * Adenomyosis Parametrium * Parametritis Cervix * Cervical dysplasia * Cervical incompetence * Cervical polyp * Cervicitis * Female infertility * Cervical stenosis * Nabothian cyst General * Hematometra / Pyometra * Retroverted uterus Vagina * Hematocolpos / Hydrocolpos * Leukorrhea / Vaginal discharge * Vaginitis * Atrophic vaginitis * Bacterial vaginosis * Candidal vulvovaginitis * Hydrocolpos Sexual dysfunction * Dyspareunia * Hypoactive sexual desire disorder * Sexual arousal disorder * Vaginismus * Urogenital fistulas * Ureterovaginal * Vesicovaginal * Obstetric fistula * Rectovaginal fistula * Prolapse * Cystocele * Enterocele * Rectocele * Sigmoidocele * Urethrocele * Vaginal bleeding * Postcoital bleeding Other / general * Pelvic congestion syndrome * Pelvic inflammatory disease External Vulva * Bartholin's cyst * Kraurosis vulvae * Vestibular papillomatosis * Vulvitis * Vulvodynia Clitoral hood or clitoris * Persistent genital arousal disorder This article about a disease of the genitourinary system is a stub. You can help Wikipedia by expanding it. * v * t * e This women's health related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Tight hymenal ring	c0156387	6,508	wikipedia	https://en.wikipedia.org/wiki/Tight_hymenal_ring	2021-01-18T18:32:10	{"umls": ["C0156387"], "icd-10": ["N89.6"], "wikidata": ["Q16999817"]}
A number sign (#) is used with this entry because Cornelia de Lange syndrome-1 (CDLS1) is caused by heterozygous mutation in the NIPBL gene (608667), which encodes a component of the cohesin complex, on chromosome 5p13. Description The Cornelia de Lange syndrome (CDLS) is a multisystem malformation syndrome recognized primarily on the basis of characteristic facial dysmorphism, including low anterior hairline, arched eyebrows, synophrys, anteverted nares, maxillary prognathism, long philtrum, thin lips, and 'carp' mouth, in association with prenatal and postnatal growth retardation, mental retardation and, in many cases, upper limb anomalies. However, there is wide clinical variability in this disorder, with milder phenotypes that may be difficult to ascertain on the basis of physical features (summary by Rohatgi et al., 2010). Boyle et al. (2015) provided a detailed review of CDLS, including clinical features, diagnosis, and genetic counseling. ### Genetic Heterogeneity of Cornelia de Lange Syndrome About 50 to 60% of the cases of CDLS are due to mutation in the NIPBL gene (Musio et al., 2006; Rohatgi et al., 2010). One X-linked form of CDLS (CDLS2; 300590) is caused by mutation in the SMC1A gene (300040), which accounts for about 5% of cases. Two milder variants of Cornelia de Lange syndrome have been identified: CDLS3 (610759), caused by mutation in the SMC3 gene (606062), and CDLS4 (614701), caused by mutation in the RAD21 gene (606462). All 4 genes, NIPBL, SMC1A, SMC3, and RAD21, encode components of the cohesin complex. Another X-linked form, CDLS5 (300882), is caused by mutation in the HDAC8 gene (300269), the vertebrate histone deacetylase of SMC3. Clinical Features Brachmann (1916) reported on a fetus with a very severe form of what is now known as the Cornelia de Lange syndrome. In Amsterdam, Cornelia de Lange (1933) described 2 infant girls with mental deficiency and other features with a less severe form of the same syndrome. The facies is curious, with eyebrows growing across the base of the nose (synophrys); hair growing well down onto the forehead and low on the neck; unusually long eyelashes; depressed bridge of nose which has uptilted tip and forward-directed nostrils; small, widely spaced teeth; small head; and low-set ears. In a review of 31 cases previously diagnosed as having de Lange syndrome, Ireland et al. (1993) concluded that the facial findings of greatest diagnostic value were the combination of the characteristic eyebrows (neat, well-defined, and arched), long philtrum, thin lips, and crescent-shaped mouth. This combination of anomalies was absent in postpubertal males but not in postpubertal females. Facial abnormalities most likely to lead to an incorrect diagnosis were hypertrichosis, synophrys, and bushy eyebrows. The ophthalmologic findings in this syndrome have been reported by Levin et al. (1990). De Lange syndrome is associated with ptosis, nystagmus and high myopia, poor macula reflex, hypertropia and nasolacrimal duct fistula. A patient with Peters anomaly was observed by Ponder et al. (1988). Schlesinger et al. (1963) described radiologic anomalies associated with BDLS: 'The hands are characteristic, with flat spade-like appearance and short tapering fingers, the fifth especially so and curved inwards. A single deep transverse crease was seen over the palms.' The thumbs appear to arise from an abnormally far proximal position. The thenar eminence is inconspicuous so that the thumb suggests a lobster claw. The metacarpophalangeal profile, as described by Halal and Preus (1979) and Filippi (1989) is characteristic: of the metacarpals, the first is shorter than the others, and the second and fifth are shorter than the third and fourth. The middle phalanx of the index fingers is always hypoplastic. Large joints show limitation of motion. At times absence deformity, usually of one arm only, is so severe that only a single finger remains on a short arm. A case was reported by Ullrich (1951). The feet are very short but not malformed. Froster and Gortner (1993) described a typically affected infant with severe involvement of the upper limbs who also had thrombocytopenia, which may have been related to cavernous hemangiomas on the elbow and buttock as in the Kasabach-Merritt syndrome (141000). Fryns and Vinken (1994) described thrombocytopenia in 2 out of 50 patients with BDLS seen over a period of 25 years. Pfeiffer and Correll (1993) reported a male infant with BDLS and ulnar hemimelia and monodactyly but also absence of both tibiae, the right distal femur being bifurcated. Meinecke (1990) reported on a patient closely resembling the case described by Brachmann (1916), with severe ulnar defects and monodactylous hands. Braddock et al. (1993) presented a review of the radiologic features of de Lange syndrome. The classic radiographic manifestations include microcephaly, limb and digital anomalies, delayed skeletal maturation, abnormal thoracic configuration, and flat acetabular angles in infancy. Unusual radiologic manifestations were related primarily to the limb anomalies, and these were often asymmetric. Gastroesophageal dysfunction was emphasized by Lachman et al. (1981), Cates et al. (1989), and Rosenbach et al. (1992). Gastroesophageal reflux (GER; 109350) with reflex esophagitis, aspiration pneumonia, and esophageal stenosis had been described. Sommer (1993) examined 17 BDLS patients, ranging in age from 9 months to 19 years, and found that 13 had evidence of Sandifer complex, i.e., gastroesophageal reflux causing paroxysmal dystonic posture including torticollis and opisthotonos. Several children with typical BDLS and congenital diaphragmatic hernia were reported by Fryns (1987), Cunniff et al. (1993), and Jelsema et al. (1993). In a series of 43 patients with CDLS, Luzzani et al. (2003) evaluated the incidence of GER and the correlation between its presence and severity and the clinical phenotype. Pathologic GER was evident in 28 (65%) of the 43 patients. The incidence was not significantly different in patients with classic (93.3%) versus mild (82.3%) phenotype, whereas a strong correlation was present between the degree of esophageal damage and the clinical phenotype. Hyperactivity was the most frequent sign associated with GER, present in 23 (85%) of the 28 patients. A spectrum of endocrinopathies may be seen in patients with BDLS (Schwartz et al., 1990). These patients may be at risk for dysfunction of gonadotropin and prolactin secretion and of osmoregulatory mechanisms. A patient with panhypopituitarism of neonatal onset was reported by Tonini and Marinoni (1990). In a psychosocial assessment of 36 patients, Beck (1987) found that the patients were particularly retarded in verbal communication but functioned relatively well in everyday self-help skills. Self-injurious behavior, frequently observed, can be treated (Menolascino et al., 1982 and Dossetor et al., 1991). Patients with normal intelligence have also been described (Gadoth et al., 1982 and Saal et al., 1993). Berney et al. (1999) used a postal questionnaire to study 49 individuals with Cornelia de Lange syndrome (both the classic and mild forms) to ascertain behavioral phenotype. Ages ranged from early childhood to adulthood (mean age of 10.2 years) and the degree of mental retardation from borderline (10%), through mild (8%), moderate (18%), and severe (20%) to profound (43%). A wide variety of symptoms occurred frequently, notably hyperactivity (40%), self injury (44%), daily aggression (49%), and sleep disturbance (55%). These correlated closely with the presence of an autistic-like syndrome and with the degree of mental retardation. BDLS has a variable phenotypic expression, which also evolves with age of the patient. In a clinical review of 310 cases of BDLS, Jackson et al. (1993) demonstrated a higher proportion of mildly affected cases. Only 27% of the cases had the upper limb deficiencies commonly associated with the syndrome. Opitz (1993) suggested that the severe limb defects associated with de Lange syndrome actually occur in a minority of cases. Several patients with a mild phenotype were reported at the Twelfth Annual David W. Smith Workshop on Malformations and Morphogenesis (Bay et al., 1993; Clericuzio, 1993; Leroy et al., 1993; Moeschler and Graham, 1993; Saul et al., 1993; Selicorni et al., 1993). The phenotype can be mild enough to be questionable (Baraitser and Papavasiliou, 1993; Greenberg and Robinson, 1989; Halal and Silver, 1992; Pashayan et al., 1970). Based on the clinical variability in de Lange syndrome, Van Allen et al. (1993) proposed a classification system. Type I, or classic, BDLS patients have the characteristic facial and skeletal changes of the diagnostic criteria established by Preus and Rex (1983). They have prenatal growth deficiency, moderate to profound psychomotor retardation, and major malformations which result in severe disability or death. Type II, or mild, BDLS patients have similar facial and minor skeletal abnormalities to those seen in type I; however, these changes may develop with time or may be partially expressed. They have mild-to-borderline psychomotor retardation, less severe pre- and postnatal growth deficiency, and the absence of (or less severe) major malformations. Type III, or phenocopy, BDLS includes patients who have phenotypic manifestations of BDLS that are causally related to chromosomal aneuploidies or teratogenic exposures. Preus and Rex (1983) proposed 30 characteristics that best distinguish the de Lange syndrome from other suggestive cases. Allanson et al. (1997) evaluated 43 subjects with de Lange syndrome, 30 with classic features and 13 with the mild phenotype. They compared gestalt, facial change with time, and detailed craniofacial measurements. Allanson et al. (1997) concluded that, in the mild phenotype, the characteristic facial appearance may not appear until 2 to 3 years of age, while it is always present at birth in the classic phenotype. They also noted that the characteristic facial appearance decreased with time in the mild phenotype. Craniofacial pattern profiles showed that both groups had microbrachycephaly, but that the dimensions of the mild group were somewhat closer to normal. The correlation coefficient between the mild and classic phenotypes was 0.83 between ages 4 and 9 years and 0.71 in adults. Allanson et al. (1997) concluded that objective assessments supported the clinical impression of 2 distinct phenotypes, and that alternative discriminators, such as birth weight greater than 2,500 grams and absence of major limb anomalies, should be used to distinguish the mild from the severe phenotype early in life because of the similarity of facial features. Allanson et al. (1997) speculated that the 2 distinct phenotypes might be due to allele specificity or to modifying genes. Least likely, in their opinion, was the possibility that mild de Lange syndrome might be a phenocopy of the classic phenotype. On the basis of 8 cases and a review of the literature, Steinbach et al. (1981) delineated the dup(3q) syndrome, which at least superficially simulates the de Lange syndrome. Features are statomotoric retardation, shortened life span, and a multiple congenital anomalies (MCA) syndrome comprising hypertrichosis, hypertelorism, anteverted nostrils, long philtrum, maxillary prognathism, carp mouth, highly arched or cleft palate, micrognathia, malformed pinnas, short and webbed neck, clinodactyly, simian crease, clubfoot, and congenital heart disease. ('Statomotoric' is a direct translation of the German 'statomotorisch,' which has the same meaning as 'psychomotor' (Opitz, 1991).) Rosenfeld et al. (1981) described a patient who did not show the hirsutism and synophrys present in other cases of dup(3q). Breslau et al. (1981) provided a clinical comparison of the de Lange and dup(3q) syndromes. Convulsions, eye and palate anomalies, clubfoot, and renal and cardiac anomalies are more common in the dup(3q) syndrome; small hands and feet, limb reduction anomalies, proximally placed thumbs, hirsutism, synophrys, low hairline, cutis marmorata, low birth weight, and growth retardation are more common in the de Lange syndrome. Wilson et al. (1985) provided further delineation of the dup(3q) syndrome. They had data on 40 reported cases. Family studies of new cases are important because only 10 of the 40 represented de novo duplications. The characteristic face (hirsutism, synophrys, broad nasal root, anteverted nares, downturned corners of the mouth, micrognathia, and malformed ears) is recognizable even in the 30-week fetus. In an earlier study, Wilson et al. (1978) concluded that intrauterine growth retardation, prominent philtrum, proximally placed thumbs, oligodactyly/phocomelia, and syndactyly of toes 2 and 3 are more frequent in de Lange syndrome, whereas craniosynostosis, cleft palate, and urinary tract anomalies are more typical of dup(3q). Selicorni et al. (2005) evaluated 61 patients with CDLS and detected structural anomalies of the kidney and urinary tract either by ultrasound or voiding cystourethrography in 25 (41%), including absent or poor corticomedullary differentiation in 8 patients, pelvic dilation in 6, vesicoureteral reflux in 5, small kidney in 3, isolated renal cyst in 3, and renal ectopia in 2. Renal function was reduced in 9 patients with renal tract abnormalities, 3 of whom had overt proteinuria. The clinical phenotype was more frequently of the classic type in patients with renal tract anomalies than in those without (p less than 0.05). In a survey of 50 children with CDLS, Marchisio et al. (2008) found that 40 (80%) had hearing loss. Forty-seven (94%) patients had otitis media with effusion that was unrelated to presence of gastroesophageal reflux or respiratory infections. Thirty (60%) children had conductive hearing loss alone due to middle ear effusion, and 10 (20%) children with sensorineural hearing loss also had conductive hearing loss associated with middle ear effusion. Ten (20%) children had normal hearing. Greater hearing loss was associated with more severe developmental impairment. Using published morphologic definitions of the ear (see, e.g., Allanson et al., 2009), Hunter et al. (2009) analyzed 119 ear photographs from CDLS patients compared to those from 57 controls. The ears of the CDLS patients were significantly different from those of the controls over a number of descriptors, the most significant of which included more frequent apparent posterior rotation, shorter and more serpiginous antihelical stem, sharper antihelical-to-inferior crus angle, shorter crus helix, more V-shaped incisura, and smaller lobe. Selicorni et al. (2009) performed echocardiographic evaluation of 87 consecutive Italian patients referred with a diagnosis of Brachmann-de Lange syndrome and identified a cardiac anomaly in 29 (33.3%) of the patients, including 28 with a structural anomaly and 1 with isolated nonobstructive CMH (see 192600). Of the 28 patients with a structural anomaly, 12 (42.9%) had an isolated defect, including 10 (36%) with pulmonary stenosis and 8 (28.6%) with an isolated left-to-right shunt. The single most common lesion was valvular pulmonary stenosis, which was present in 11 (39%) of 28 patients. Isolated late-onset mild to moderate mitral or tricuspid valve regurgitation was detected at follow-up examination in 4 patients (14.3%) older than 10 years, who had a previously normal examination and electrocardiogram. Selicorni et al. (2009) noted that in contrast to previous studies, only 2 patients required surgical intervention, 1 for closure of a large ventricular septal defect (VSD) with associated atrial septal defect, and the other for VSD closure and relief of pulmonary valve stenosis. Other Features Immunohistochemical examination of two placentae from BDLS patients revealed the absence of pregnancy-associated plasma protein A (PAPPA; 176385) from the syncytiotrophoblast (Westergaard et al., 1983). Melegh et al. (1996) described a newborn boy with clinical features of de Lange syndrome who manifested dyspnea, hypertonia, and hyperthermia. Muscle biopsy showed severe distortion of the mitochondrial architecture. Multiple deletions of mtDNA were found on Southern blot analysis. The authors suggested that clinical findings of de Lange syndrome in combination with multiple mtDNA deletions and hyperthermia may represent a distinct syndrome. Inheritance Most cases are sporadic. In rare instances (e.g., Borghi et al., 1954), multiple presumably affected sibs have had normal parents. Although Ptacek et al. (1963) suggested dominant inheritance, Opitz (1971, 1985) later thought recessive inheritance likely. Pashayan et al. (1969) concluded that the recessive hypothesis can be rejected. The empiric recurrence risk in a sib of an affected child was estimated to be between 2 and 5%. Familial occurrence and parental consanguinity were noted by Pearce et al. (1967). Opitz (1971) found normal parental age (average paternal and maternal age 30.6 and 28.9 years, respectively). Beratis et al. (1971) described 3 affected sibs with normal karyotypes and normal, nonconsanguineous parents. Discordance in dizygotic (Stevenson and Scott, 1976) and monozygotic (Carakushansky and Berthier, 1976) twins has been reported. Opitz (1985) published photographs of concordant monozygotic twins with de Lange syndrome. Carakushansky et al. (1996) gave a follow-up, with photographs, of the discordant twins at the age of 20. DNA fingerprinting with 3 multilocus probes allowed them to establish monozygosity with a high degree of certainty. Robinson and Jones (1983) supported the conclusion that the de Lange syndrome is autosomal dominant and that the sporadic occurrence in most cases reflects the genetic lethality of the disorder. Their cases were a severely affected 5-month-old boy and his mildly affected 24-year-old mother. She had mildly delayed development, with difficulties in school, and showed synophrys, long philtrum, thin upper lip, fifth finger clinodactyly, and very short right fourth metacarpal. Kumar et al. (1985) found de Lange syndrome in several members of a family in a pattern consistent with autosomal dominant inheritance. Winter (1986) suggested that the diagnosis was in fact the Ruvalcaba syndrome (180870) because of the combination of eyebrow and hand anomalies. Robinson et al. (1985) reported a mildly affected mother and her 2 severely affected sons, possibly indicating mosaicism in the mother. Mosher et al. (1985) reported the case of a 24-year-old woman with de Lange syndrome who delivered a normal child. Leavitt et al. (1985) reported seemingly typical features in mother and daughter. Fryns (1986) suggested that the disorder in the families reported by Leavitt et al. (1985), Mosher et al. (1985), and Robinson et al. (1985) was Coffin-Siris syndrome (135900), not de Lange syndrome. Bankier et al. (1986) brought to 5 the number of families in which BDLS had been inherited as an autosomal dominant. Feingold and Lin (1993) reported affected mother and daughter. Fryns et al. (1987) reported 2 infant brothers with a severe form of the syndrome. They died at the age of 3 months and 3 weeks, respectively. The parents were normal, and prometaphase chromosome studies failed to show any abnormality. This would be consistent with autosomal dominant inheritance and gonadal mosaicism. Naguib et al. (1987) described an Arab family with phenotypically normal first-cousin parents and 2 offspring showing variable features of this disorder. The proband had apparently normal chromosomes and had died at the age of 3 months. His sister was less severely affected and lived for 6 years. The authors suggested recessive inheritance. Opitz (1985) suggested that high prenatal lethality of homozygotes explains a segregation ratio that is much lower than one would expect under the recessive hypothesis. In the mother of a child with typical features, de Die-Smulders et al. (1992) observed mild manifestations. They pointed to several reports of similar situations and concluded that 'in all convincingly autosomal dominant cases' the mother was the transmitting parent, suggesting genomic imprinting. They suspected that de novo mutation causes a severe form of the syndrome and that recurrence within sibships with unaffected parents may be explained by germline mosaicism. Chodirker and Chudley (1994) reported apparent male-to-male transmission of mild BDLS. The proband's father was mentally retarded, showed synophrys and some other facial manifestations of BDLS, and was the shortest of his 13 sibs. Krajewska-Walasek et al. (1995) reported a brother and sister with variable manifestations of a less severe type of Brachmann-de Lange syndrome. There was no significant prenatal growth retardation and no reduction deformities of the forearms. They noted that, with one exception, previously reported sibs with normal parents presented with the severe type of this disorder, the so-called 'classic' or 'full' form, with major upper limb anomalies, severe growth and mental retardation, and, frequently, early death. Russell et al. (2001) reported a familial case of Cornelia de Lange syndrome transmitted from father to daughter and reviewed the literature on familial cases. They concluded that autosomal dominant inheritance is the most likely mode of transmission, with most cases arising from spontaneous mutations. Caksen et al. (2001) analyzed 7 infants with this disorder, including 2 who were monozygotic twin sisters. All had normal parents with no consanguinity. McConnell et al. (2003) reported a family with a classically affected neonate with de Lange syndrome, an affected mother, and a probably affected maternal grandmother, thus suggesting autosomal dominant inheritance. Diagnosis Diagnosis is dependent on the recognition of the distinctive facial features (Ireland and Burn, 1993). The diagnosis is seldom in doubt when there is a major longitudinal deficiency defect of the upper limb, severe prenatal and postnatal growth retardation, and severe mental retardation. Uncertainty arises when the patient has the characteristic facial findings but lacks one or more of the other manifestations. Selicorni et al. (2007) devised a clinical scoring system that assessed auxologic, malformation, and neurodevelopmental parameters to measure the clinical severity of Cornelia de Lange syndrome. A study of 62 Italian patients with a clinical diagnosis of the disorder showed wide phenotypic variability, ranging from mild to severe. Based on a survey of 65 dysmorphologists who were provided with facial photographs of 32 CDLS patients of varying severity or with features suggestive of the disorder but with another diagnosis, Rohatgi et al. (2010) found that 90% of classic CDLS cases were correctly diagnosed, but only 54% of mild or variant cases were accurately diagnosed. The disorder was most accurately diagnosed in childhood and became more difficult to diagnose with increasing age of the patient. Features used to make the correct diagnosis included penciled and arched eyebrows, high set/short anteverted nose, a long flat philtrum, thin upper lip, downturned corners of the mouth, and micrognathia. Features that proved to be misleading included full or flat brows, a prominent nasal bridge or bulbous tip, and/or a normal or prominent chin. There were some differences between severely and mildly affected patients that could be used to distinguish genotypes: those with mild NIPBL mutations had more typical features, whereas those with SMC1A mutations had mild synophrys, long eyelashes, slightly short, high-set nose with mild anteversion, box-like nose, thin upper lip, and downturned corners of the mouth. ### Prenatal Diagnosis Because there are no genetic or biochemical tests at present, the antenatal detection depends upon identification of some aspects of the phenotype in the fetus using ultrasound imaging, namely growth retardation, limb defects, hirsutism, and diaphragmatic hernia (Kliewer et al., 1993). Manouvrier et al. (1996) reported ultrasonographic prenatal diagnosis of BDLS by the association of intrauterine growth retardation, hypoplastic forearms, underdevelopment of hands, typical facial defects, and diaphragmatic hernia. Urban and Hartung (2001) reported observations on a 22-week-old female fetus with BDLS. The facial appearance was already characteristic and the associated upper limb malformations (bilateral monodactyly and ulnar agenesis) supported the diagnosis. The prenatal ultrasound images demonstrated a protruding and overhanging upper lip and severe retrognathia. Clinical Management Schrier et al. (2011) retrospectively reviewed 426 probands with a confirmed clinical diagnosis of CDLS who died in a 41-year period between 1966 and 2007. Among 295 probands with a known cause of death, respiratory causes, including aspiration/reflux and pneumonias, accounted for 31% of deaths; gastrointestinal disease, including obstruction/volvulus, accounted for 19%; congenital anomalies, including diaphragmatic hernia and congenital heart defects, accounted for 15%. Neurologic causes and accidents each accounted for 8% of deaths, sepsis for 4%, acquired cardiac disease for 3%, cancer for 2%, and renal disease for 1.7%, with other causes of death accounting for 9%. Based on these findings, Schrier et al. (2011) provided recommendations for age-specific monitoring and care. Population Genetics Beck (1976) estimated the frequency to be 0.6 per 100,000 in Denmark. The oldest patient found in a nationwide survey was 49 years old. Beck's series contained a half brother and sister (same mother), one instance of parental consanguinity out of 24, and one patient with a low normal IQ. Normal IQ or only mild mental retardation in this disorder was discussed. Mapping Krantz et al. (2001) performed linkage analysis in 10 multicase families using markers from the minimal dup(3q) critical region on 3q26.31-q27.3 that encompassed the breakpoint seen in the translocation patient reported by Ireland et al. (1991). Nineteen markers spanning a region of approximately 40 Mb (37 cM) were used. Multipoint linkage analysis demonstrated negative total lod scores across the chromosome 3q26-q27 region. In 4 families, lod scores were less than -2 in the 2-cM region encompassing the translocation, thus excluding linkage in these families. In the remaining 6 families, lod scores could not exclude linkage to this region. The authors concluded that in some multicase families, the disease locus does not map to the CDL1 region at 3q26.3. Tonkin et al. (2004) analyzed several de novo balanced translocations associated with CDLS and in 1 instance mapped the breakpoints to 5p13.1 and 13q12.1. Because of a report of CDLS in association with a 5p14.2-p13.1 deletion, they focused on the 5p breakpoint and found that it is located in a novel gene they named NIPBL for Nipped-B-like (608667), mutations in which were found to cause CDLS. They also analyzed the translocations t(3;17)(q26.3;q23.1) (Ireland et al., 1991) and t(14;21)(q32;q11) (Wilson et al., 1983). The 3q breakpoint disrupts a large gene undergoing unusual alternative splicing, but they found no mutation specific to any individual with CDLS. Molecular analyses of regions spanning the 17q23, 14q32, and 21q11 breakpoint regions also did not identify a gene likely to underlie CDLS. Krantz et al. (2004) carried out genomewide linkage exclusion analysis in 12 families with CDLS and identified 4 candidate regions, of which 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CDLS with a de novo t(5;13)(p13.1;q12.1) translocation and another with classic CDLS and a de novo chromosome 5p14.2-p13.1 deletion (Hulinsky et al., 2003), allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CDLS. Cytogenetics The large number of de Lange cases found to have one or another type of chromosomal aberration may be fortuitous, may indicate a predisposition to chromosomal change induced in some way by a point mutation (as in Bloom syndrome and in Fanconi panmyelopathy), or may indeed have a cause-and-effect relationship. According to Craig and Luzzatti (1965), 11 out of 38 patients in whom the chromosomes have been studied showed abnormalities. They felt this was more than chance association. Falek et al. (1966) described 3 affected sibs and their affected first cousins. Patients showed 46 chromosomes with loss of one small acrocentric of the G group and an additional metacentric chromosome resembling, but somewhat smaller than, chromosome 16. Six phenotypically normal relatives, including 1 parent of each of the 2 affected sibships, had the same anomalous chromosome as the affected children but in addition an apparent deletion of one chromosome 3. The authors suggested that the de Lange syndrome is the result of excessive chromosome 3 material. The anomalous chromosome was interpreted as combining one G chromosome with a fragment from one chromosome 3. McArthur and Edwards (1967) found normal chromosomes in all 20 of their cases. However, they expressed the opinion that the condition is most likely related to a chromosomal deficiency which is not usually detectable. This would explain both the usual sporadic nature and the occasional familial occurrence. Broholm et al. (1968) described a patient with de Lange syndrome and a B-D translocation inherited from the normal mother. The patient was thought to be partially trisomic for a group D chromosome. Features suggesting the de Lange syndrome are observed with partial trisomy of the distal portion of chromosome 3, specifically the area qter-3q21 (Allderdice et al., 1975). The reported familial cases of de Lange syndrome (e.g., Falek et al., 1966) may be on the basis of this chromosomal anomaly segregating from a balanced rearrangement. A small duplication of the long arm of chromosome 3 is accompanied by features suggestive of the de Lange syndrome; occurrence as an unbalanced segregation in certain families may account for some of the cases of 'familial Cornelia de Lange syndrome' (Francke, 1978). See the earlier discussion of the work of Steinbach et al. (1981), Breslau et al. (1981), and Wilson et al. (1985), comparing the Cornelia de Lange syndrome and the dup(3q) syndrome. Beck and Mikkelsen (1981) studied 45 de Lange syndrome cases clinically and karyologically, with prometaphase studies in 31. All karyotypes were normal. In 1 other patient, a girl, a 45,X karyotype was found and in a boy, a (13q14q) translocation was found which was also present in the phenotypically normal mother and grandmother. The duplication 3q syndrome was found in none. The authors cited a recurrence risk of 2 to 5% for the de Lange syndrome. A recurrence risk of this order might be observed with a genetic lethal, autosomal dominant disorder with parental gonadal mosaicism. Another case of BDLS associated with a reciprocal translocation 14q;21q was published by Wilson et al. (1983). Lakshminarayana and Nallasivam (1990) found ring chromosome 3 in an infant with presumed Cornelia de Lange syndrome. Breslau et al. (1981) analyzed the prometaphase chromosomes of 5 patients (1 pair of sibs) with the de Lange syndrome and found no chromosome abnormality in any of them. They suggested that the de Lange and dup(3q) syndromes can be distinguished on clinical and chromosomal grounds. They recommended chromosome studies in any patient with de Lange or de Lange-like manifestations. The possibility remains that the mutation responsible for the de Lange syndrome is located in the same region of 3q that is abnormal in the dup(3q) syndrome. Ireland et al. (1991) reported a typical case with unusually severe limb reduction defects. Chromosome analysis showed a de novo translocation with breakpoints at 3q26.3 and 17q23.1. After reviewing cases showing phenotypic overlap between de Lange syndrome and partial trisomy 3q and cases of deletions of 3q, they proposed that the gene for Cornelia de Lange syndrome may be located at 3q26.3. Lopez-Rangel et al. (1993) reported the case of a 13-year-old girl with a duplication in the 3q25.1-q26.1 region who had neither BDLS nor the dup(3q) phenotype. DeScipio et al. (2005) reported 2 half-sibs with clinical features suggestive of de Lange syndrome and an unbalanced chromosomal rearrangement, der(3)t(3;12)(p25.3;p13.3), inherited from a balanced translocation in their unaffected mother, t(3;12)(p25.3;p13.3). The sibs had many features consistent with de Lange syndrome, including microcephaly, growth retardation, mental retardation, hirsutism, synophrys, anteverted nares, single palmar creases, and syndactyly of toes 2 and 3, but also had significant clinical overlap with del(3)(p25) syndrome (see 607416 and 607280). DeScipio et al. (2005) reviewed all reported cases of de Lange syndrome with chromosomal rearrangements. Molecular Genetics Tonkin et al. (2004) screened multiple individuals with CDLS for mutations in the NIPBL gene (608667) and identified 9 plausible point mutations, at least 5 of which arose de novo (see, e.g., 608667.0002, 608667.0004, and 608667.0006). They found mutations in individuals with severe and mild CDLS, suggesting that phenotype variation can be explained, at least in part, by allelic heterogeneity. The spectrum and distribution of mutations that implied pathogenesis arises from loss or altered function of a single NIPBL allele. Krantz et al. (2004) identified mutations in the NIPBL gene in 4 sporadic and 2 familial cases (see, e.g., 608667.0001; 608667.0003, and 608667.0005). They noted that Drosophila Nipped-B facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways. Pehlivan et al. (2012) reported that among 162 patients with CDLS for whom mutations in the known CDLS genes were negative by sequencing, they identified deletions containing NIPBL exons in 7 subjects (approximately 5%). Breakpoint sequences in 5 of the 7 subjects implicated microhomology-mediated replicative mechanisms. Most deletions are predicted to result in haploinsufficiency due to heterozygous loss-of-function mutations, which may result in a more severe CDLS phenotype. Pehlivan et al. (2012) concluded that their findings suggested a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CDLS cases are mutation-negative by DNA sequencing studies. ### Somatic Mosaicism Huisman et al. (2013) detected pathogenic mutations in the NIPBL gene in buccal cells from 10 of 13 patients with CDLS in whom no mutations were detectable earlier in lymphocytes. Resequencing of the gene in lymphocytes from these 10 patients again failed to detect the NIPBL mutation, indicating somatic mosaicism. Statistical analysis did not show a phenotypic difference between these patients and patients with germline NIPBL mutations. The patients were part of an earlier study of 44 patients with CDLS (Bhuiyan et al., 2006) and thus accounted for 23% of the study group. Huisman et al. (2013) commented on the unusually high frequency of somatic mosaicism found in their study, and suggested that it was due to selection against lymphocytes carrying the mutation ('reversion'). The findings indicated that molecular study of buccal swabs in patients with a CDLS phenotype could facilitate molecular diagnosis. ### Exclusion Studies Smith et al. (1999) excluded the SOX2 (184429) gene as a candidate for Cornelia de Lange syndrome. In the course of studying the molecular basis of CDLS, Tonkin et al. (2004) focused on the distal 3q region because of the occurrence, in a patient with classic CDLS, of a de novo balanced translocation with a breakpoint at 3q26.3 (Ireland et al., 1991) and because of reports of phenotypic overlap between cases of mild CDLS and individuals trisomic for the 3q26-q27 region. They found that the 3q26.3 breakpoint in the t(3;17)(q26.3;q23.1) translocation severed a previously uncharacterized gene, designated NAALADL2 (608806). Mutation screening of the gene in a panel of CDLS patient DNA samples failed to identify patient-specific mutations. Genotype/Phenotype Correlations Yan et al. (2006) identified 13 different NIPBL mutations, including 11 novel mutations, in 13 (46%) of 28 Polish patients with a clinical diagnosis of CDLS. Eleven of the mutations resulted in a premature termination of the protein. Mutation-positive patients were more severely affected than mutation-negative patients with respect to prenatal growth, facial dysmorphism, and speech impairment. Bhuiyan et al. (2006) stated that to the time of their report, 161 patients were studied molecularly, of whom 63 (39%) were found to have a mutation. Reporting from the Netherlands, the country where CDLS was first described, Bhuiyan et al. (2006) described genotype-phenotype correlations in 39 patients. They found mutations of NIPBL in 56% of the patients. Bhuiyan et al. (2006) found that truncating mutations generally caused a more severe phenotype, but that this correlation was not absolute. By using 3-dimensional facial imaging, they demonstrated the potential for classifying facial features. Behavioral problems were highly correlated with a level of adaptive functioning, and also included autism. No correlation of behavior with the type of mutation was found. Selicorni et al. (2007) identified 25 different NIPBL mutations in 26 (44%) of 62 unrelated Italian patients with a clinical diagnosis of CDLS. Compared to the 36 patients without NIPBL mutations, patients with NIPBL mutations had more pronounced growth retardation, more limb reduction, and more delayed speech development. There was a correlation between severe phenotype and truncating mutation, mild disease and missense mutation, and moderate disease and splice site mutation. Among 30 unrelated patients with CDLS, Pie et al. (2010) found that 11 (37%) patients had mutations in the NIPBL gene and 3 (10%) had mutations in the SMC1A gene, with an overall molecular diagnostic yield of 47%. Nine novel NIPBL mutations were reported. None of the patients had mutations in the SMC3 gene. Most of the patients were of Spanish origin. Although those with NIPBL mutations had a more severe phenotype than those with SMC1A mutations, the incidence of palate defects was higher in those with SMC1A mutations. History De Lange (1933) (pronounced LANG-eh) described the disorder that carries her name. She was professor of pediatrics in Amsterdam and an immediate predecessor of Van Creveld (1969) in that chair. De Knecht-van Eekelen and Hennekam (1994) provided biographical information on Cornelia de Lange and a bibliography of her publications. Oostra et al. (1994) reported that a specimen of de Lange syndrome resides in the anatomical collection of the University of Amsterdam. Vrolik (1849) had described this case as an example of 'extreme oligodactyly.' Opitz (1985) gave a delightful account of his first brush with de Lange syndrome and his long association thereafter. Serendipity was responsible for his insistence on expanding the eponym to Brachmann-de Lange. 'In the fall of 1963...the former head of the...Libraries, came to ask my advice on what to do with a series of volumes of the Jahrbuch fur Kinderheilkunde, which had been damaged...by a burst water pipe. In particular, she was upset by volume 84, dated 1916, the pages of which were completely glued together except for one place, the article beginning on p. 225. I was startled to find out that here was an article on the Cornelia de Lange syndrome written 17 years before de Lange's first paper of 1933. The author, Dr. W. Brachmann, whose subsequent fate is unknown to me, was then a young physician in training, who apologized that his study of this remarkable case was interrupted by sudden orders to report for active duty (in the German Army).' INHERITANCE \- Autosomal dominant GROWTH Height \- Prenatal growth retardation \- Short stature \- Specific growth curves are available HEAD & NECK Head \- Microcephaly \- Brachycephaly Face \- Long philtrum \- Micrognathia Ears \- Low-set ears \- Sensorineural hearing loss \- Conductive hearing loss to due otitis media Eyes \- Synophrys \- Myopia \- Long curly eyelashes \- Ptosis Nose \- Anteverted nostrils \- Depressed nasal bridge Mouth \- Thin upper lip \- Downturned corners of the mouth \- High arched palate \- Cleft lip/palate Teeth \- Widely spaced teeth \- Late-erupting teeth Neck \- Short neck CARDIOVASCULAR Heart \- Congenital heart defect RESPIRATORY Lung \- Pneumonia \- Congenital diaphragmatic hernia CHEST Breasts \- Small nipples ABDOMEN Gastrointestinal \- Gastroesophageal reflux \- Pyloric stenosis GENITOURINARY External Genitalia (Male) \- Hypoplastic male genitalia Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Structural anomalies of the renal tract \- Absent/poor corticomedullary differentiation (some patients) \- Pelvic dilation (some patients) \- Vesicoureteral reflux (rare) \- Small kidney (rare) \- Isolated renal cyst (rare) \- Renal ectopia (rare) \- Reduced renal function (in some patients with structural anomalies) \- Proteinuria (rare) SKELETAL Limbs \- Limited elbow extension \- Dislocation of the radial head \- Phocomelia Hands \- Single transverse palmar crease \- Proximally placed thumbs \- Fifth finger clinodactyly \- Oligodactyly Feet \- Syndactyly of toes 2 and 3 SKIN, NAILS, & HAIR Skin \- Cutis marmorata \- Single transverse palmar crease Hair \- Hirsutism \- Low posterior hair line NEUROLOGIC Central Nervous System \- Mental retardation \- Language delay \- Hypertonicity Behavioral Psychiatric Manifestations \- Self-injurious behavior VOICE \- Low-pitched, growling cry in infancy MISCELLANEOUS \- Highly variable phenotype \- Many cases due to de novo mutation or chromosome aberration \- Empiric risk for a sib of an affected child between 2 and 5% \- Prevalence of 0.6 to 10 per 100,000 individuals MOLECULAR BASIS \- Caused by mutation in the Nipped-B-like gene (NIPBL, 608667.0001 ) ▲ 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	CORNELIA DE LANGE SYNDROME 1	c0270972	6,509	omim	https://www.omim.org/entry/122470	2019-09-22T16:42:51	{"doid": ["0080505"], "mesh": ["D003635"], "omim": ["122470"], "icd-10": ["Q87.1"], "orphanet": ["199"], "synonyms": ["Alternative titles", "CDL", "TYPUS DEGENERATIVUS AMSTELODAMENSIS", "DE LANGE SYNDROME", "BRACHMANN-DE LANGE SYNDROME"], "genereviews": ["NBK1104"]}
Factor V deficiency is a rare bleeding disorder. The signs and symptoms of this condition can begin at any age, although the most severe cases are apparent in childhood. Factor V deficiency commonly causes nosebleeds; easy bruising; bleeding under the skin; bleeding of the gums; and prolonged or excessive bleeding following surgery, trauma, or childbirth. Women with factor V deficiency can have heavy or prolonged menstrual bleeding (menorrhagia). Bleeding into joint spaces (hemarthrosis) can also occur, although it is rare. Severely affected individuals have an increased risk of bleeding inside the skull (intracranial hemorrhage), in the lungs (pulmonary hemorrhage), or in the gastrointestinal tract, which can be life-threatening. ## Frequency Factor V deficiency affects an estimated 1 in 1 million people. This condition is more common in countries such as Iran and southern India, where it occurs up to ten times more frequently than in western countries. ## Causes Factor V deficiency is usually caused by mutations in the F5 gene, which provides instructions for making a protein called coagulation factor V. This protein plays a critical role in the coagulation system, which is a series of chemical reactions that forms blood clots in response to injury. F5 gene mutations that cause factor V deficiency prevent the production of functional coagulation factor V or severely reduce the amount of the protein in the bloodstream. People with this condition typically have less than 10 percent of normal levels of coagulation factor V in their blood; the most severely affected individuals have less than 1 percent. A reduced amount of functional coagulation factor V prevents blood from clotting normally, causing episodes of abnormal bleeding that can be severe. Very rarely, a form of factor V deficiency is caused by abnormal antibodies that recognize coagulation factor V. Antibodies normally attach (bind) to specific foreign particles and germs, marking them for destruction, but the antibodies in this form of factor V deficiency attack a normal human protein, leading to its inactivation. These cases are called acquired factor V deficiency and usually occur in individuals who have been treated with substances that stimulate the production of anti-factor V antibodies, such as bovine thrombin used during surgical procedures. There is no known genetic cause for this form of the condition. ### Learn more about the gene associated with Factor V deficiency * F5 ## Inheritance Pattern Factor V deficiency is inherited in an autosomal recessive pattern, which means both copies of the F5 gene in each cell have mutations. Individuals with a mutation in a single copy of the F5 gene have a reduced amount of coagulation factor V in their blood and can have mild bleeding problems, although most have no related health effects. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Factor V deficiency	c0015499	6,510	medlineplus	https://medlineplus.gov/genetics/condition/factor-v-deficiency/	2021-01-27T08:25:33	{"gard": ["2237"], "mesh": ["D005166"], "omim": ["227400"], "synonyms": []}
A number sign (#) is used with this entry because Ehlers-Danlos syndrome arthrochalasia type 2 (EDSARTH2) is caused by heterozygous mutation in the COL1A2 (120160) gene on chromosome 7q21. Several forms of osteogenesis imperfecta (see, e.g., OI1, 166200) are also caused by mutation in the COL1A2 gene. Description Arthrochalasia-type EDS is distinguished from other types of EDS by the frequency of congenital hip dislocation and extreme joint laxity with recurrent joint subluxations and minimal skin involvement (Byers et al., 1997; Giunta et al., 2008). For a discussion of genetic heterogeneity of arthrochalasia-type EDS, see 130060. Clinical Features Lichtenstein et al. (1973) reported a patient with arthrochalasis multiplex congenita, including short stature, small mandible, considerable hyperextensibility, and increased skin bruising. Although the patient was originally thought to have deficiency of procollagen proteinase, Steinmann et al. (1980) found evidence for a structural mutation in the alpha-2 polypeptide of type I collagen in this patient. Steinmann et al. (1980) postulated that the mutation rendered the procollagen resistant to the action of the peptidase that normally cleaves off the extra piece from the NH2-end. Since equal amounts of pro-N-alpha-2 and alpha-2 chains were produced, and the parents were unaffected, the patient's abnormality was presumed to represent a dominant mutation. Eyre et al. (1985) and Steinmann et al. (1985) each reported a similar case of EDS VII. Viljoen et al. (1987) reported a Xhosa family with EDS VII. The mother and her 4 children had generalized articular laxity, joint dislocations and subluxations, and wormian bones in the skull. The authors suggested that the last feature may be more common in EDS VII than previously realized. Nicholls et al. (1991) reported a 29-year-old male with bilateral hip dislocation at birth and with other features of the Ehlers-Danlos syndrome type VIIB. The patient's affected daughter was born with bilateral hip dislocation, joint hyperflexibility, feet in the equinovarus position, and hyperextensible skin. This was 1 of the few observations of transmission of this disorder. Carr et al. (1994) reported a 32-year-old woman with EDS VIIB confirmed by genetic analysis (120160.0032). She was born with bilateral hip dislocation, bilateral knee subluxation, and generalized joint hypermobility, as well as bilateral inguinal hernias and an umbilical hernia. Throughout her life, she had multiple fractures of the small bones of her hands and feet following moderate trauma. An affected brother was born with bilateral hip dislocation which led to subsequent osteoarthritis of the hips and total hip replacement at age 35. He also had marked swan neck deformities of his hands and had multiple fractures of the metacarpals, distal radius, distal ulnar, as well as a fracture of the patella and olecranon. Frequency of fractures reduced markedly after his teenage years. Both patients had a depressed nasal bridge. Electron microscopy of the proband's dermis, as well as deep fascia and hip joint capsule from the affected brother, showed that collagen fibrils in transverse section were nearly circular but with irregular margins. The history of frequent fractures found in this family was slightly atypical for type VIIB Ehlers-Danlos syndrome and suggested a phenotypic overlap with osteogenesis imperfecta. Byers et al. (1997) reported a family in which 5 individuals spanning 3 generations had EDS VIIB confirmed by genetic analysis (120160.0042). The proband was a girl referred at age 9 months because of joint laxity and inability to sit unsupported. Her feet and wrists could be dorsiflexed 180 degrees, and her skin was soft and hyperextensible. Radiographs showed bilateral hip dislocations. Because bracing was unsuccessful in stabilizing her hips, she underwent, at 16 months, open reduction of both hips, capsular reefing, and varus osteostomies with casting and bracing. However, the procedures were not successful in preventing further dislocations. The child's father had bilateral hip dislocation identified at the age of 1 month; casting and bracing were not successful. Subluxation of the metacarpal phalangeal joint of 1 thumb, dislocation of the other, and subluxation of the first metatarsal joints were also present. A brother had bilateral congenital hip dislocation with unsuccessful correction and was of average height. This man had a son who was noted to have dislocated hips at 7 weeks of age together with dislocations of the right elbow, patellas, fingers, and toes. Radiographs of the paternal grandfather of the index case showed bilateral hip dislocations; he walked with difficulty, using crutches. No affected relatives had fractures, dental or hearing abnormalities, blue sclerae, poor wound healing, or hernias. However, based on the clinical features of 5 additional affected families and review of previously reported patients with mutations in COL1A2, Byers et al. (1997) concluded that fractures should be considered part of the phenotype of EDS VII. Molecular Genetics From studies of type I collagen in a patient with Ehlers-Danlos syndrome type VIIB (EDSARTH2), Eyre et al. (1985) determined that 1 allele of the COL1A2 gene carried a de novo mutation (120160.0001) that resulted in deletion of 15 to 20 residues in the junction domain that spans the N-propeptidase cleavage site and the N-telopeptide cross-linking sequence. In a patient with EDS VIIB reported by Steinmann et al. (1985) and Wirtz et al. (1987), Weil et al. (1988) identified a heterozygous mutation in the COL1A2 gene (120160.0002) that resulted in the skipping of exon 6 and elimination of the N-proteinase cleavage site necessary for proper collagen processing. In a patient with EDS VIIB previously reported by Lichtenstein et al. (1973) and Steinmann et al. (1980), Weil et al. (1989) identified a de novo heterozygous mutation in the COL1A2 gene (120160.0003), resulting in the skipping of exon 6 and deletion of the cleavage site necessary for proper collagen processing. The expression of the alternative splicing in this patient was found to be temperature-dependent; cellular studies showed that missplicing was effectively abolished at 31 degrees C and gradually increased to 100% at 39 degrees C. This mutation is identical to that found in COL1A1 (120150.0026). In a patient with EDS VIIB, Nicholls et al. (1991) identified a heterozygous mutation in the COL1A2 gene (120160.0021). In an affected child from a Xhosa family with EDS VIIB previously described by Viljoen et al. (1987), Watson et al. (1992) identified a heterozygous mutation in the COL1A2 gene (120160.0021) that resulted in the skipping of exon 6. In affected members of 6 unrelated families with EDS VIIB, Byers et al. (1997) identified heterozygosity for mutations in the COL1A2 gene (see, e.g., 120160.0042). INHERITANCE \- Autosomal dominant GENITOURINARY Bladder \- Bladder diverticula (rare) SKELETAL \- Fractures (in some patients) Skull \- Wormian bones \- 'Salt and pepper' stippling of calvarium (rare) Spine \- Scoliosis \- Kyphosis \- Lordosis Pelvis \- Hip dislocation Limbs \- Joint hypermobility, severe \- Recurrent joint subluxation \- Dislocation or subluxation of elbows \- Dislocation or subluxation of shoulders \- Dislocation or subluxation of wrists \- Dislocation or subluxation of knees \- Dislocation or subluxation of ankles Hands \- Hyperextensible fingers \- Subluxation of first carpometacarpal joints Feet \- Medial subluxation of great toes \- Bilateral metatarsus varus deformity \- Hallux valgus, severe \- Pes planus, severe \- Clubfeet (rare) SKIN, NAILS, & HAIR Skin \- Thin, velvety skin \- Soft skin \- Hyperextensible skin \- Fragile skin, mild \- Atrophic scars (in some patients) \- Fragile connective tissue \- Easy bruisability \- Acrogeria (rare) NEUROLOGIC Central Nervous System \- Hypotonia \- Delayed gross motor development PRENATAL MANIFESTATIONS Delivery \- Breech presentation MISCELLANEOUS \- Easy or excessive bleeding noted during surgery MOLECULAR BASIS \- Caused by mutation in the collagen I, alpha-1 polypeptide gene (COL1A2, 120160.0001 ) ▲ 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	EHLERS-DANLOS SYNDROME, ARTHROCHALASIA TYPE, 2	c0268345	6,511	omim	https://www.omim.org/entry/617821	2019-09-22T15:44:42	{"omim": ["617821"], "orphanet": ["1899"], "synonyms": ["Alternative titles", "EHLERS-DANLOS SYNDROME, TYPE VIIB, AUTOSOMAL DOMINANT", "EDS VIIB"]}
A rare, genetic, epidermal disease characterized by punctate keratoderma on palms and soles associated with irregularly shaped hypopigmented macules (typically localized on the extremities). Ectopic calcification (e.g. early-onset calcific tendinopathy, calcinosis cutis) and pachyonychia may be occasionally associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Hypopigmentation-punctate palmoplantar keratoderma syndrome	c3809781	6,512	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324561	2021-01-23T17:47:21	{"gard": ["12384"], "omim": ["615522"], "icd-10": ["Q82.8"], "synonyms": ["Cole disease", "Guttate hypopigmentation and punctate palmoplantar keratoderma", "Hypopigmentation and punctate keratosis of the palms and soles"]}
Hepatoencephalopathy due to combined oxidative phosphorylation deficiency type 1 is a rare, inherited mitochondrial disorder due to a defect in mitochondrial protein synthesis characterized by intrauterine growth retardation, metabolic decompensation with recurrent vomiting, persistent severe lactic acidosis, encephalopathy, seizures, failure to thrive, severe global developmental delay, poor eye contact, severe muscular hypotonia or axial hypotonia with limb hypertonia, hepatomegaly and/or liver dysfunction and/or liver failure, leading to fatal outcome in severe cases. Neuroimaging abnormalities may include corpus callosum thinning, leukodystrophy, delayed myelination and basal ganglia 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	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	c1836797	6,513	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137681	2021-01-23T18:08:51	{"mesh": ["C563797"], "omim": ["609060"], "umls": ["C1836797"], "icd-10": ["E88.8"], "synonyms": ["Hepatoencephalopathy due to COXPD1"]}
Myxedema psychosis Other names * Myxedematous psychosis * Myxedema madness Myxedema psychosis is a relatively uncommon consequence of hypothyroidism, such as in Hashimoto's thyroiditis or in patients who have had the thyroid surgically removed and are not taking thyroxine. A chronically under-active thyroid can lead to slowly progressive dementia, delirium, and in extreme cases to hallucinations, coma, or psychosis, particularly in the elderly. It was first recognized by Dr Richard Asher of London in 1949. Treatment is via the standard treatment for hypothyroidism with thyroxine replacement. Oral T4, or in especially acute cases liothyronine, a sodium salt of T3. Hormone replacement in these patients usually reverses the psychotic symptoms, but may not help with cognitive deficits caused by changes in metabolic activity in the CNS. The "myxedema" part of the name simply refers to the non-pitting edema common to hypothyroidism. ## See also[edit] * Hashimoto's encephalopathy ## References[edit] * Heinrich TW, Grahm G (December 2003). "Hypothyroidism Presenting as Psychosis: Myxedema Madness Revisited". Prim Care Companion J Clin Psychiatry. 5 (6): 260–266. doi:10.4088/PCC.v05n0603. PMC 419396. PMID 15213796. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Myxedema psychosis	None	6,514	wikipedia	https://en.wikipedia.org/wiki/Myxedema_psychosis	2021-01-18T18:39:30	{"wikidata": ["Q6949353"]}
A rare tumor of salivary glands characterized by a benign, well-circumscribed, slow-growing, painless mass most commonly occurring in the parotid gland (but also the palate, submandibular gland, or nasal septal mucosa), histopathologically composed of epithelial and myoepithelial / stromal components. Possible signs and symptoms depend on the location of the tumor and include facial nerve weakness, mild dysphagia, or unilateral nasal obstruction. Recurrence rates are low, although tumor rupture and spillage have been reported. Malignant transformation may occur in a small percentage of cases. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Pleomorphic salivary gland adenoma	c1519176	6,515	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=454821	2021-01-23T17:06:09	{"mesh": ["C563250"], "omim": ["181030"], "icd-10": ["D11.0"]}
A rare ciliopathy with major skeletal involvement characterized by a hypoplastic thorax with short ribs and protuberant abdomen, micromelia with particularly short tibiae with ovoid configuration, pre- and postaxial polydactyly, brachydactyly, hypoplasia or aplasia of nails, and dysmorphic craniofacial features (such as prominent forehead, low-set and malformed ears, short and flat nose, lobulated tongue, micrognathia, and cleft lip/palate). Additional reported manifestations include urogenital, gastrointestinal, cardiovascular, and cerebral malformations, among others. The condition is fetal in the neonatal period. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 rib-polydactyly syndrome, Majewski type	c0024507	6,516	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93269	2021-01-23T17:08:18	{"gard": ["4833"], "mesh": ["D012779"], "omim": ["263520", "613091"], "umls": ["C0024507"], "icd-10": ["Q77.2"], "synonyms": ["Short rib-polydactyly syndrome type 2"]}
"MEN-1" and "MEN 1" redirect here. For the associated gene and protein, see MEN1. This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Multiple endocrine neoplasia type 1" – news · newspapers · books · scholar · JSTOR (January 2017) Multiple endocrine neoplasia type 1 Other namesMEN-1 syndrome Multiple endocrine neoplasia type 1 is inherited in an autosomal dominant manner. SpecialtyOncology SymptomsWermer's syndrome Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas.[1] It was first described by Paul Wermer in 1954. [2] ## Contents * 1 Signs and symptoms * 1.1 Parathyroid * 1.2 Pancreas * 1.3 Pituitary * 1.4 Other manifestations * 2 Genetic * 3 Diagnosis * 3.1 Types * 4 Treatment * 5 Culture * 6 See also * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] ### Parathyroid[edit] Hyperparathyroidism is present in ≥ 90% of patients. Asymptomatic hypercalcemia is the most common manifestation: about 25% of patients have evidence of nephrolithiasis or nephrocalcinosis. In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia or multiple adenomas are more common than solitary adenomas. ### Pancreas[edit] Pancreatic islet cell tumors occur in 60 to 70% of patients. Tumors are usually multicentric. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs; such tumors may arise from the small bowel rather than the pancreas. About 30% of tumors are malignant and have local or distant metastases. Malignant islet cell tumors due to MEN 1 syndrome often have a more benign course than do sporadically occurring malignant islet cell tumors.[citation needed]About 40% of islet cell tumors originate from a β-cell, secrete insulin (insulinoma), and can cause fasting hypoglycemia. β-cell tumors are more common in patients < 40 years of age. About 60% of islet cell tumors originate from non-β-cell elements and tend to occur in patients > 40 years of age. Non-β-cell tumors are somewhat more likely to be malignant. Most islet cell tumors secrete pancreatic polypeptide, the clinical significance of which is unknown. Gastrin is secreted by many non–β-cell tumors (increased gastrin secretion in MEN 1 also often originates from the duodenum). Increased gastrin secretion increases gastric acid, which may inactivate pancreatic lipase, leading to diarrhea and steatorrhea. Increased gastrin secretion also leads to peptic ulcers in > 50% of MEN 1 patients. Usually the ulcers are multiple or atypical in location, and often bleed, perforate, or become obstructed. Peptic ulcer disease may be intractable and complicated. Among patients presenting with Zollinger-Ellison syndrome, 20 to 60% have MEN 1. A severe secretory diarrhea can develop and cause fluid and electrolyte depletion with non–β-cell tumors. This complex, referred to as the watery diarrhea, hypokalemia and achlorhydria syndrome (VIPoma) has been ascribed to vasoactive intestinal polypeptide, although other intestinal hormones or secretagogues (including prostaglandins) may contribute. Hypersecretion of glucagon, somatostatin, chromogranin, or calcitonin, ectopic secretion of ACTH resulting in Cushing's syndrome, and hypersecretion of somatotropin–releasing hormone (causing acromegaly) sometimes occur in non–β-cell tumors. All of these are rare in MEN 1.[citation needed]Nonfunctioning pancreatic tumors also occur in patients with MEN 1 and may be the most common type of pancreatoduodenal tumor in MEN 1. The size of the nonfunctioning tumor correlates with risk of metastasis and death. ### Pituitary[edit] Pituitary tumors occur in 15 to 42% of MEN 1 patients. From 25 to 90% are prolactinomas. About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Excess prolactin may cause galactorrhea, and excess growth hormone causes acromegaly clinically indistinguishable from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, producing Cushing's disease. Most of the remainder are nonfunctional. Local tumor expansion may cause visual disturbance, headache, and hypopituitarism. Pituitary tumors in MEN 1 patients appear to be larger and behave more aggressively than sporadic pituitary tumors. ### Other manifestations[edit] See also: List of conditions associated with café au lait macules Adenomas and adenomatous hyperplasia of the thyroid and adrenal glands occurs occasionally in MEN 1 patients. Hormone secretion is rarely altered as a result, and the significance of these abnormalities is uncertain. Carcinoid tumors, particularly those derived from the embryologic foregut, occur in isolated cases. Multiple subcutaneous and visceral lipomas, angiofibromas, and collagenomas may also occur. ## Genetic[edit] People with multiple endocrine neoplasia type 1 are born with one mutated copy of the MEN1 gene in each cell. Then, during their lifetime, the other copy of the gene is mutated in a small number of cells. These genetic changes result in no functional copies of the MEN1 gene in selected cells, allowing the cells to divide with little control and form tumors. This is known as Knudson's two-hit hypothesis[3] and is a common feature seen with inherited defects in tumor suppressor genes. Oncogenes can become neoplastic with only one activating mutation, but tumor suppressors inherited from both mother and father must be damaged before they lose their effectiveness. The exception to the "two-hit hypothesis" occurs when suppressor genes exhibit dose-response, such as ATR.[4] The exact function of MEN1 and the protein, menin, produced by this gene is not known,[5] but following the inheritance rules of the "two-hit hypothesis" indicates that it acts as a tumor suppressor. ## Diagnosis[edit] In a diagnostic workup individuals with a combination of endocrine neoplasias suggestive of the MEN1 syndrome are recommended to have a mutational analysis of the MEN1 gene if additional diagnostic criteria are sufficiently met, mainly including:[1][6] * age <40 years * positive family history * multifocal or recurrent neoplasia * two or more organ systems affected ### Types[edit] Multiple endocrine neoplasia or MEN is part of a group of disorders that affect the body's network of hormone-producing glands (the endocrine system). Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia involves tumors in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, some cases can be life-threatening. The two major forms of multiple endocrine neoplasia are called type 1 and type 2. These two types are often confused because of their similar names. However, type 1 and type 2 are distinguished by the genes involved,[1] the types of hormones made, and the characteristic signs and symptoms. These disorders greatly increase the risk of developing multiple cancerous and noncancerous tumors in glands such as the parathyroid, pituitary, and pancreas. Multiple endocrine neoplasia occurs when tumors are found in at least two of the three main endocrine glands (parathyroid, pituitary, and pancreatico-duodenum). Tumors can also develop in organs and tissues other than endocrine glands. If the tumors become cancerous, some cases can be life-threatening. The disorder affects 1 in 30,000 people. Although many different types of hormone-producing tumors are associated with multiple endocrine neoplasia, tumors of the parathyroid gland, pituitary gland, and pancreas are most frequent in multiple endocrine neoplasia type 1. MEN1-associated overactivity of these three endocrine organs are briefly described here: * Overactivity of the parathyroid gland (hyperparathyroidism) is the most common sign of this disorder. Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of the bones (osteoporosis), high blood pressure (hypertension), loss of appetite, nausea, weakness, fatigue, and depression. * Neoplasia in the pituitary gland can manifest as prolactinomas whereby too much prolactin is secreted, suppressing the release of gonadotropins, causing a decrease in sex hormones such as testosterone. Pituitary tumor in MEN1 can be large and cause signs by compressing adjacent tissues. * Pancreatic tumors associated with MEN-1 usually form in the beta cells of the islets of Langerhans, causing over-secretion of insulin, resulting in low blood glucose levels (hypoglycemia). However, many other tumors of the pancreatic Islets of Langerhans can occur in MEN-1. One of these, involving the alpha cells, causes over-secretion of glucagon, resulting in a classic triad of high blood glucose levels (hyperglycemia), a rash called necrolytic migratory erythema, and weight loss. Another is a tumor of the non-beta islet cells, known as a gastrinoma, which causes the over-secretion of the hormone gastrin, resulting in the over-production of acid by the acid-producing cells of the stomach (parietal cells) and a constellation of sequelae known as Zollinger-Ellison syndrome. Zollinger-Ellison syndrome may include severe gastric ulcers, abdominal pain, loss of appetite, chronic diarrhea, malnutrition, and subsequent weight loss. Other non-beta islet cell tumors associated with MEN1 are discussed below. ## Treatment[edit] The treatment of choice of parathyroid tumors is open bilateral exploration with subtotal (7/8) or total parathyroidectomy. Autoimplantation may be considered in case of a total parathyroidectomy. Optimal timing for this operation has not yet been established but it should be performed by an experienced endocrine surgeon. [7] ## Culture[edit] In the video game Trauma Team, Gabriel Cunningham's son, Joshua Cunningham, is diagnosed with Wermer's syndrome. It is also mentioned in the South Korean drama "Medical Top Team", as Dr. Choi Ah Jin (Oh Yeon-seo) is diagnosed with MEN-1.[citation needed] ## See also[edit] * Acromegaly * Multiple endocrine neoplasia * Multiple endocrine neoplasia type 2a * Multiple endocrine neoplasia type 2b * Prolactinoma ## References[edit] 1. ^ a b c Lemmens, I; Van De Ven, W. J.; Kas, K; Zhang, C. X.; Giraud, S; Wautot, V; Buisson, N; De Witte, K; Salandre, J; Lenoir, G; Pugeat, M; Calender, A; Parente, F; Quincey, D; Gaudray, P; De Wit, M. J.; Lips, C. J.; Höppener, J. W.; Khodaei, S; Grant, A. L.; Weber, G; Kytölä, S; Teh, B. T.; Farnebo, F; Thakker, R. V. (1997). "Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1". Human Molecular Genetics. 6 (7): 1177–83. doi:10.1093/hmg/6.7.1177. PMID 9215690. 2. ^ WERMER P (1954). "Genetic aspects of adenomatosis of endocrine glands". The American Journal of Medicine. 16 (3): 363–71. doi:10.1016/0002-9343(54)90353-8. PMID 13138607. 3. ^ Knudson, Alfred G. (1971-04-01). "Mutation and Cancer: Statistical Study of Retinoblastoma". Proceedings of the National Academy of Sciences. 68 (4): 820–823. Bibcode:1971PNAS...68..820K. doi:10.1073/pnas.68.4.820. ISSN 0027-8424. PMC 389051. PMID 5279523. 4. ^ Fang, Yanan; Tsao, Cheng-Chung; Goodman, Barbara K; Furumai, Ryohei; Tirado, Carlos A; Abraham, Robert T; Wang, Xiao-Fan (2004-08-04). "ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background". The EMBO Journal. 23 (15): 3164–3174. doi:10.1038/sj.emboj.7600315. ISSN 0261-4189. PMC 514932. PMID 15282542. 5. ^ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C. (2014-09-05). Robbins & Cotran Pathologic Basis of Disease. Elsevier Health Sciences. p. 291. ISBN 9780323296359. 6. ^ Karges, W.; Schaaf, L.; Dralle, H.; Boehm, B. O. (2000). "Concepts for screening and diagnostic follow-up in multiple endocrine neoplasia type 1 (MEN1)". Experimental and Clinical Endocrinology & Diabetes. 108 (5): 334–340. doi:10.1055/s-2000-8146. PMID 10989951. 7. ^ [1] Thakker R, Newey P, Walls G, Bilezikian J, Dralle H, Ebeling P et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). The Journal of Clinical Endocrinology & Metabolism [Internet]. 2012 [cited 17 January 2020];97(9):2990-3011. Available from: https://doi.org/10.1210/jc.2012-1230 ## Further reading[edit] GeneReview/NIH/UW entry on Multiple Endocrine Neoplasia Type 1 * This article incorporates public domain text from The U.S. National Library of Medicine ## External links[edit] Classification D * ICD-10: D44.8 * ICD-9-CM: 258.01 * ICD-O: 8360/1 * OMIM: 131100 * MeSH: D018761 * DiseasesDB: 7971 External resources * MedlinePlus: 000398 * eMedicine: med/2404 * Orphanet: 652 * v * t * e Disorders involving multiple endocrine glands * Autoimmune polyendocrine syndrome * APS1 * APS2 * Carcinoid syndrome * Multiple endocrine neoplasia * 1 * 2A * 2B * Progeria * Werner syndrome * Acrogeria * Metageria * Woodhouse–Sakati syndrome * v * t * e Tumours of endocrine glands Pancreas * Pancreatic cancer * Pancreatic neuroendocrine tumor * α: Glucagonoma * β: Insulinoma * δ: Somatostatinoma * G: Gastrinoma * VIPoma Pituitary * Pituitary adenoma: Prolactinoma * ACTH-secreting pituitary adenoma * GH-secreting pituitary adenoma * Craniopharyngioma * Pituicytoma Thyroid * Thyroid cancer (malignant): epithelial-cell carcinoma * Papillary * Follicular/Hurthle cell * Parafollicular cell * Medullary * Anaplastic * Lymphoma * Squamous-cell carcinoma * Benign * Thyroid adenoma * Struma ovarii Adrenal tumor * Cortex * Adrenocortical adenoma * Adrenocortical carcinoma * Medulla * Pheochromocytoma * Neuroblastoma * Paraganglioma Parathyroid * Parathyroid neoplasm * Adenoma * Carcinoma Pineal gland * Pinealoma * Pinealoblastoma * Pineocytoma MEN * 1 * 2A * 2B [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Multiple endocrine neoplasia type 1	c3149237	6,517	wikipedia	https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_1	2021-01-18T18:51:59	{"gard": ["3829"], "mesh": ["D018761"], "umls": ["C3149237"], "orphanet": ["652"], "wikidata": ["Q3347154"]}
A rare subtype of autosomal dominant limb-girdle muscular dystrophy ,with a variable age of onset, characterized by progressive, proximal weakness and wasting of the shoulder and pelvic musculature (with the pelvic girdle, and especially the ileopsoas muscle, being more affected) and frequent association of calf hypertrophy, dysphagia, arachnodactyly with or without finger contractures and/or distal and axial muscle involvement. Additional features include an abnormal gait, exercise intolerance, myalgia, fatigue and respiratory insufficiency. Cardiac conduction defects are typically not 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	TNP03-related limb-girdle muscular dystrophy D2	c1842062	6,518	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=55595	2021-01-23T17:53:47	{"gard": ["12530"], "mesh": ["C564242"], "omim": ["608423"], "umls": ["C1842062"], "icd-10": ["G71.0"], "synonyms": ["Autosomal dominant limb-girdle muscular dystrophy type 1F", "LGMD type 1F", "LGMD1F", "Limb-girdle muscular dystrophy type 1F", "TNP03-related LGMD D2"]}
A number sign (#) is used with this entry because Fanconi anemia of complementation group B is caused by mutation in the FANCB gene (300515) on chromosome Xp22. Description Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011). Patients with FANCB mutations often present with multiple additional congenital anomalies, including the constellation of features designated VACTERL-H, for vertebral defects, anal atresia, tracheoesophageal fistula, esophageal atresia, radial or renal dysplasia, and hydrocephalus. Many patients with these features die in early infancy before developing anemia (McCauley et al., 2011). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650. Clinical Features The existence of at least 2 separate loci, homozygosity at either of which can result in the Fanconi syndrome, was indicated by the complementation observed by Zakrzewski and Sperling (1980) in cell hybrid studies. They found no complementation between cells of classic Fanconi syndrome and those from patients lacking skeletal malformation. However, cells from a late-onset case complemented cells from an early-onset case. Sensitivity to the cytogenetic effects of mitomycin C was the phenotype of which complementation was studied. From comparable complementation studies, Duckworth-Rysiecki et al. (1985) likewise concluded that there are at least 2 complementation groups. Digweed et al. (1988) showed that the complementation grouping established by fibroblast fusion studies correlates with the rate of semiconservative DNA synthesis after 8-methoxypsoralen/UVA-irradiation treatment (Moustacchi et al., 1987). Because of the general nature of the disorder, FA appears to be a prime candidate for somatic cell gene therapy. Diatloff-Zito et al. (1990) reported studies in which transfectants were obtained by mouse DNA-mediated gene transfer into FA primary fibroblasts. These studies again demonstrated differences between complementation groups A and B. Cells from group A, which are the most sensitive to the effects of crosslinking agents, were partially corrected for both the chromosomal aberrations and the cytotoxicity to 8-methoxypsoralen photoaddition. In contrast, after treatment with mitomycin C, only the chromosomal sensitivity was reestablished to a near-normal level. The opposite was true for group B cells, i.e., cell survival to MMC was partially corrected, whereas the frequency of MMC-induced chromosomal aberrations remained close to that of the untransfected cells. Wang et al. (1993) reported a pedigree in which 4 affected males in 3 sibships connected through possible carrier females in 2 generations of a family presented with a VACTERL phenotype with hydrocephalus. This family had previously been reported by Hunter and MacMurray (1987), Evans et al. (1989), and Sommer et al. (1989). Wang et al. (1993) found that affected members of this family had spontaneous chromosome breakage and rearrangements, suggesting that some cases of VACTERL-H hydrocephalus represent severe Fanconi anemia. McCauley et al. (2011) reported 4 unrelated males with variable manifestations of VACTERL-H associated with mutations in the FANCB gene. Two of the affected pregnancies were terminated at 20 weeks' gestation, 1 proband died at age 15 weeks, and 1 died at age 2 years, 10 months. All presented in utero or at birth with multiple variable congenital anomalies including intrauterine growth retardation, dysmorphic ears, vertebral anomalies, esophageal, duodenal, or anal atresia, ventriculomegaly, renal agenesis, and radial agenesis. Two had cardiac defects, 2 had tracheoesophageal fistula, and 2 had small genitalia. Only the patient who lived beyond infancy developed anemia. Three patients studied had evidence of chromosome breakage. Two of the patients had male family members with a similar phenotype, both of whom died within the first month of life. One of the patients belonged to the family previously reported by Hunter and MacMurray (1987) and Wang et al. (1993) as having X-linked VACTERL-H. Diagnosis McCauley et al. (2011) proposed criteria for the diagnosis of FANCB. Ventriculomegaly, absent thumbs and radii, or hypoplastic thumbs, and abnormal chromosome breakage are cardinal features. Major manifestations include renal agenesis or renal tract malformations, vertebral defects, gastrointestinal atresias, hypogonadism, and growth retardation. Minor features include tracheoesophageal fistula, cardiac malformations, lung lobation defects, structural brain malformations, low-set ears, and X-linked recessive inheritance. Molecular Genetics In individuals with Fanconi anemia of complementation group B, Meetei et al. (2004) found mutations in the FANCB gene, which they designated FAAP95 (300515.0001-300515.0004). They transfected lymphoblasts from individuals with FA with cDNA encoding FAAP95 and demonstrated that hypersensitivity to mitomycin C (MMC) and monoubiquitination of FANCD2 (227646) were both restored to normal. These data proved that FAAP95 is the gene associated with Fanconi anemia complementation group B. Meetei et al. (2004) suggested that evidence that the BRCA2 gene (600185) underlies complementation group B, as suggested by the work of Howlett et al. (2002), was inconclusive. No complementation of a FANCB cell line by BRCA2 was reported, and no BRCA2 mutation was detected in another FANCB cell line; furthermore, cells with defective or depleted BRCA2 show normal monoubiquitination of FANCD2, unlike FANCB cells, which show defective FANCD2 monoubiquitination. Holden et al. (2006) studied a family in which 2 male fetuses related to each other as nephew and maternal uncle presented with the VACTERL-H phenotype (314390). A fibroblast culture established from the proband fetus showed an increased number of chromosome breaks within the affected range observed in Fanconi anemia cells on breakage studies with diepoxybutane. X-inactivation studies in the mother and maternal grandmother of the proband fetus showed 100% skewing of X inactivation, a feature consistently found in females heterozygous for FANCB mutations. On screening of the 8 coding exons of FANCB, Holden et al. (2006) identified a splice site mutation (300515.0005). Sequencing of both obligate carrier females, mother and maternal grandmother, confirmed that they were heterozygous for the mutation. McCauley et al. (2011) found that 4 of 10 probands presenting with a VACTERL-H phenotype had mutations in the FANCB gene (see, e.g., 300515.0006 and 300515.0007). All patients were male, and all unaffected mothers had skewed X inactivation in peripheral blood. INHERITANCE \- X-linked recessive GROWTH Other \- Growth retardation HEAD & NECK Head \- Head abnormalities GENITOURINARY Kidneys \- Kidney abnormalities SKELETAL Limbs \- Radial ray abnormalities Hands \- Thumb abnormalities SKIN, NAILS, & HAIR Skin \- Pigmentation abnormalities NEUROLOGIC Central Nervous System \- Mental retardation (rare) ENDOCRINE FEATURES \- Hypergonadotropic hypogonadism HEMATOLOGY \- Thrombocytopenia \- Anemia MOLECULAR BASIS \- Caused by mutation in the Fanconi anemia, complementation group B gene (FANCB, 300515.0001 ) ▲ 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	FANCONI ANEMIA, COMPLEMENTATION GROUP B	c0015625	6,519	omim	https://www.omim.org/entry/300514	2019-09-22T16:20:08	{"doid": ["0111098"], "mesh": ["D005199"], "omim": ["300514"], "orphanet": ["84"], "synonyms": ["Alternative titles", "FACB", "FANCONI PANCYTOPENIA, TYPE 2"], "genereviews": ["NBK1401", "NBK5192"]}
## Clinical Features In 2 sisters and 5 unrelated patients, Neuhauser et al. (1976) described a 'new' type of craniosynostosis-craniofacial dysostosis with short stature. Premature closure of the lambdoid and posterior part of the sagittal sutures caused a posteriorly narrow, dolichocephalic skull with small, flat, or bulging occiput and protuberance of the forehead. The disturbance of growth of basal skull structures led to craniofacial dysostosis and secondarily to facial anomalies. The sisters and 2 of the others patients were of Spanish, Mexican, or Puerto Rican ancestry. Mental retardation occurred when surgery was not done. In 3 cases, craniosynostectomy permitted normal development. Al-Torki et al. (1998) described an Arab boy with craniofacial dyssynostosis. They suggested that cryptorchidism may be part of the syndrome and that the presence of normal stature does not preclude the diagnosis. Morton (1998) described an English boy thought to have the same disorder. He had lambdoid craniosynostosis, severe global developmental delay, epilepsy, oculomotor dyspraxia, very thin corpus callosum, and minor anomalies. MRI scan showed thinning of the gray matter on the right side and nodular gray matter heterotopia in both cerebral hemispheres consistent with a neuronal migration defect. Grosso et al. (2004) described a patient who, in addition to having craniofacial dyssynostosis, had hydronephrosis and partially empty sella turcica. Brain MRI showed agenesis of the splenium and posterior portion of the corpus callosum. Bermejo et al. (2005) described 4 unrelated Spanish patients with craniofacial dyssynostosis and reviewed previously reported cases. Because of phenotypic variability of reported cases, they recommended that additional studies (ophthalmologic, cardiologic, and renal) be performed to rule out associated anomalies. Hing et al. (2009) described 11 patients (3 female; 8 male) with bilateral lambdoid and sagittal synostosis (BLSS); 5 of the patients were Hispanic/Latino. None of the patients reported a family history of craniosynostosis or consanguinity. All patients had brachyturricephaly, frontal bossing, sagittal/lambdoid sutural ridging, and inferior displacement of the ears. Development was normal in 8 patients (73%), only 1 patient was noted to have an associated malformation (a ventricular septal defect), and all demonstrated normal linear growth. Characteristic CT findings included posterior displacement of the coronal sutures, brachycephaly with a narrow pointed occiput, lambdoid, sagittal suture fusion, and the concave occipital bone deformity. Cytogenetics Shiihara et al. (2004) described a 2-year-old girl with craniosynostosis with early closure of the sagittal and lambdoid sutures, atrial septal defect, patent ductus arteriosus, and a karyotype showing 46,XX,der(13)t(5;13)(q33.3;q34). FISH analysis demonstrated 3 copies of the MSX2 gene. Shiihara et al. (2004) suggested that the patient's clinical findings were explained by either partial 13q deletion or partial 5q trisomy, or both, and that the overdose of MSX2 is related to her craniosynostosis through the MSX2-mediated pathway of calvarial osteogenic differentiation. Tagariello et al. (2006) described a male infant presenting with brachycephaly, proptosis, midfacial hypoplasia, and low-set ears. Three-dimensional cranial computer tomography showed fusion of the lambdoid sutures and distal part of the sagittal suture with a gaping anterior fontanel. Mutations in the coding sequence of FGFR2 and FGFR3 were excluded, and the P252R mutation in FGFR1 (136350.0001) was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupted SOX6. The breakpoint on chromosome 9 was located in a region with no known or predicted genes. Tagariello et al. (2006) suggested that the translocation may lead to dysregulation of flanking genes on chromosome 9 or 11 involved in skull vault development and the possible function of SOX6, TLR4, and CALCA in cranial suture biology. Hing et al. (2009) performed chromosome analysis in 5 patients with BLSS and found that 1 had an Xp11.22 deletion. Because of the significant number of unique chromosomal aberrations that have been detected in this disorder, Hing et al. (2009) suggested that the disorder is heterogeneous. Inheritance Although autosomal recessive inheritance had been suggested based on the 2 sisters reported by Neuhauser et al. (1976), Bermejo et al. (2005) noted that parental consanguinity was not present in any of the cases. Clinical Management Bermejo et al. (2005) recommended early neurologic evaluation to plan early interventions to avoid the consequences of craniosynostosis. Molecular Genetics After identifying a translocation disrupting the SOX6 gene in a patient with craniofacial dyssynostosis, Tagariello et al. (2006) performed a mutation screen of the gene in 104 craniosynostosis patients. They identified 1 missense mutation leading to the exchange of a highly conserved amino acid (D68N) in a single patient with complex craniosynostosis involving the coronal and sagittal sutures; however, the same mutation was found in his healthy mother. Hing et al. (2009) performed molecular analysis in 8 patients with BLSS; no mutations were identified at the FGFR1 P252 (136350.0001) or FGFR3 P250R (134934.0014) sites, in FGFR2 exons 7 and 9, or in TWIST1, MSX2, or SOX6 coding regions. INHERITANCE \- Isolated cases GROWTH Height \- Short stature \- Normal linear growth HEAD & NECK Head \- Brachyturricephaly \- Brachycephaly \- Frontal bossing \- Sagittal/lambdoid sutural ridging \- Narrow occiput \- Suboccipital indentation \- Asymmetric occiput Face \- Bitemporal narrowing \- Tall forehead \- Midface hypoplasia, mild \- Flat midface Ears \- Inferior displacement of the ears Eyes \- Esotropia \- Oculomotor dyspraxia CARDIOVASCULAR Heart \- Ventricular septal defect Vascular \- Patent ductus arteriosus ABDOMEN Gastrointestinal \- Pyloric stenosis GENITOURINARY External Genitalia (Male) \- Cryptorchidism \- Hypospadias Kidneys \- Horseshoe kidney NEUROLOGIC Central Nervous System \- Mental retardation \- Normal development \- Seizures \- Agenesis corpus callosum \- Thin corpus callosum \- Ventriculomegaly \- Nerve palsy \- Mega cisterna magna \- Hydrocephalus \- Chiari type I \- Hypotonia ▲ 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	CRANIOFACIAL DYSSYNOSTOSIS WITH SHORT STATURE	c1857511	6,520	omim	https://www.omim.org/entry/218350	2019-09-22T16:29:17	{"mesh": ["C536455"], "omim": ["218350"], "orphanet": ["1516"], "synonyms": ["Alternative titles", "BILATERAL LAMBDOID AND SAGITTAL SYNOSTOSIS"]}
HIV disease-related drug reactions present in HIV-infected patients, especially those with helper T-cell counts between 25 and 200, immunosuppression that increases the risk for the development of adverse reactions to medications.[1]:131 ## See also[edit] * HIV * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	HIV disease–related drug reaction	None	6,521	wikipedia	https://en.wikipedia.org/wiki/HIV_disease%E2%80%93related_drug_reaction	2021-01-18T18:40:47	{"wikidata": ["Q5629931"]}
A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-11 (CLN11) is caused by homozygous mutation in the GRN gene (138945) on chromosome 17q. Heterozygous mutation in the GRN gene causes frontotemporal lobar degeneration with TDP43-inclusions (607485). Description Neuronal ceroid lipofuscinosis-11 is an autosomal recessive neurologic disorder characterized by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. Cognitive decline may also occur (summary by Smith et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). Clinical Features Smith et al. (2012) reported 2 Italian sibs with young-adult onset of neuronal ceroid lipofuscinosis. Their healthy parents, who were in their fifties, came from nearby villages in Lombardy, Italy, and were demonstrated to be distantly related. The proband was a 28-year-old man who presented with rapidly progressive visual failure at age 22, followed by major convulsions at age 25 and myoclonic seizures at age 26. He had mild cerebellar ataxia, early cognitive deterioration, and retinal dystrophy. Electroencephalogram (EEG) showed generalized polyspike wave discharges, electroretinogram showed severe attenuation of both rod and cone responses, and MRI showed cerebellar atrophy. Electron microscopic examination of a skin biopsy demonstrated numerous fingerprint profiles in membrane-bound structures in eccrine secretory cells and in endothelium, consistent with CLN. The proband's 26-year-old sister developed recurrent seizures at age 23 years, sometimes preceded by visual distortions, and she later had visual deterioration. Clinical examination showed cerebellar ataxia and retinal dystrophy. EEG results showed polyspike wave discharges with a posterior emphasis, and MRI indicated cerebellar atrophy. Inheritance The transmission pattern of adult-onset neuronal ceroid lipofuscinosis in the family reported by Smith et al. (2012) was consistent with autosomal recessive inheritance. Molecular Genetics By exome sequencing of 2 Italian sibs with young-adult onset of CLN, Smith et al. (2012) identified a homozygous 4-bp deletion in the GRN gene (138945.0015). Heterozygosity for this mutation had previously been identified in patients with late-onset frontotemporal dementia (607485). Plasma progranulin levels in the homozygous patients were undetectable and were about 50% decreased in the heterozygous parents. Family history revealed 3 cases of late-onset dementia in both sides of the family, but DNA was not available from these patients. The healthy parents were in their fifties; the molecular findings suggested that they may be at risk for later-onset dementia. Smith et al. (2012) commented on the remarkable phenotypic differences between heterozygous and homozygous GRN mutations, and suggested that progranulin may have a lysosomal function. Animal Model Ahmed et al. (2010) found that Grn-null mice developed abnormal accumulation of abnormal intraneuronal ubiquitin-positive autofluorescent lipofuscin detected by light microscopy. Electron microscopic examination of fixed brain tissue from Grn-null showed abundant rectilinear profiles diagnostic of CLN (Smith et al., 2012). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Visual impairment, progressive \- Optic atrophy \- Retinal dystrophy NEUROLOGIC Central Nervous System \- Seizures \- Myoclonic seizures \- Ataxia \- Cognitive decline (1 patient) \- EEG abnormalities \- Cerebellar atrophy LABORATORY ABNORMALITIES \- 'Fingerprint' profiles ultrastructurally MISCELLANEOUS \- Onset in early twenties \- Rapidly progressive \- One Italian family has been reported (last curated July 2012) MOLECULAR BASIS \- Caused by mutation in the granulin precursor gene (GRN, 138945.0015 ) ▲ 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	CEROID LIPOFUSCINOSIS, NEURONAL, 11	c0022797	6,522	omim	https://www.omim.org/entry/614706	2019-09-22T15:54:28	{"doid": ["0110732"], "mesh": ["D009472"], "omim": ["614706"], "orphanet": ["79262", "314629"]}
A rare coronary artery congenital malformation characterized by an anomalous origin and course of the right coronary artery, which originates from the left aortic sinus of Valsalva and has an abnormal proximal course, which may be intramural, prepulmonic, subpulmonic, retroaortic, retrocardiac or wrapped around the apex. Patients are frequently asymptomatic, although chest pain, dyspnea, palpitations, dizziness, syncope, and sudden cardiac arrest/death (typically following intense physical exertion) may be observed. This malformation is associated with a lower risk of sudden cardiac death therefore surgical revascularization is recommended only when signs and/or symptoms of ischemia are present. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Anomalous aortic origin of the right coronary artery	None	6,523	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=541454	2021-01-23T18:00:09	{"icd-10": ["Q24.5"], "synonyms": ["AORCA", "R-ACAOS", "Right coronary artery from left aortic sinus"]}
A number sign (#) is used with this entry because of evidence that lipoprotein glomerulopathy can be caused by heterozygous mutation in the APOE gene (107741). Description Lipoprotein glomerulopathy is an uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries (Saito et al., 2006). It mainly affects people of Japanese and Chinese origin; in these populations, it is associated with mutations in the gene that encodes apolipoprotein E (APOE; 107741). The disorder had rarely been described in Caucasians. Clinical Features Lipoprotein glomerulopathy is characterized by abnormal lipoprotein deposition in the glomeruli, usually with lipoprotein thrombi distending and occluding the glomerular capillary lumina, a variable degree of mesangial proliferation, dysbetalipoproteinemia, and high levels of APOE and APOE2/3 phenotype in most cases (Matsunaga et al., 1999). It has been described predominantly in Japanese and Chinese (Rovin et al., 2007). Rovin et al. (2007) described 2 European American families in each of which a single male presented with edema and proteinuria in the nephrotic range. In both, kidney biopsy showed an amorphous material that stained positive for neutral lipids in almost all glomerular capillaries. One clinically unaffected heterozygous female, an aunt of one of the probands, showed in a nephrectomy specimen obtained for therapy of renal cell carcinoma a glomerulus with dilated capillary loops containing amorphous material similar to that found in the patients with lipoprotein glomerulopathy. Molecular Genetics Oikawa et al. (1997) identified 3 Japanese patients with lipoprotein glomerulopathy who were heterozygous for an arg145-to-pro mutation in APOE (R145P; 107741.0032). The authors designated this variant 'APOE Sendai.' Matsunaga et al. (1999) reported a Japanese man with lipoprotein glomerulopathy who carried an arg25-to-cys mutation in APOE (R25C; 107741.0033). The patient's mother, a heterozygous carrier, had dysbetalipoproteinemia but no lipoprotein glomerulopathy. Matsunaga et al. (1999) termed this variant 'APOE Kyoto.' In 2 unrelated American men of European ancestry with lipoprotein glomerulopathy, Rovin et al. (2007) detected an R25C substitution in APOE. Heterozygous female carriers were clinically unaffected. Rovin et al. (2007) remarked that the APOE Kyoto mutation appears to be sufficient to lead to glomerular lipoprotein deposition but not to clinical lipoprotein glomerulopathy. Apolipoprotein E may accumulate in glomerular capillaries because the mutation diminishes the capacity of apolipoprotein E to bind to the low-density lipoprotein (LDL) receptor and also decreases its uptake by endothelial cells. Impaired LPL binding was also seen with APOE Sendai (Ishigaki et al., 2000). Rovin et al. (2007) suggested that APOE Kyoto carriers in whom the disease develops may have a second defect that reduces clearance of abnormal lipoprotein through pathways that are independent of the LDL receptor. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	LIPOPROTEIN GLOMERULOPATHY	c2673196	6,524	omim	https://www.omim.org/entry/611771	2019-09-22T16:02:51	{"mesh": ["C567089"], "omim": ["611771"], "orphanet": ["329481"]}
Hypersalivation Other namesPtyalism,[1] sialorrhea,[2] water brash SpecialtyOral and maxillofacial surgery Hypersalivation is the excessive production of saliva.[3] It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva.[4] Hypersalivation can contribute to drooling if there is an inability to keep the mouth closed or difficulty in swallowing the excess saliva (dysphagia), which can lead to excessive spitting. Hypersalivation also often precedes emesis (vomiting), where it accompanies nausea (a feeling of needing to vomit).[5] ## Contents * 1 Causes * 1.1 Excessive production * 1.2 Decreased clearance * 2 Treatment * 3 References * 4 External links ## Causes[edit] ### Excessive production[edit] Conditions that can cause saliva overproduction include:[4] * Rabies * Pellagra (niacin or Vitamin B3 deficiency)[6] * Gastroesophageal reflux disease, in such cases specifically called a water brash (a loosely defined layman term), and is characterized by a sour fluid or almost tasteless saliva in the mouth[7] * Gastroparesis (main symptoms are nausea, vomiting, and reflux) * Pregnancy * Excessive starch intake * Anxiety (common sign of separation anxiety in dogs) * Pancreatitis * Liver disease * Serotonin syndrome * Mouth ulcers[medical citation needed] * Oral infections * Sjögren syndrome (an early symptom in some patients) [8] Medications that can cause overproduction of saliva include:[4] * aripiprazole * clozapine * pilocarpine * ketamine * potassium chlorate * risperidone * pyridostigmine Substances that can cause hypersalivation include:[4] * mercury * copper * organophosphates (insecticide) * arsenic * nicotine * thallium ### Decreased clearance[edit] Causes of decreased clearance of saliva include:[4] * Infections such as tonsillitis, retropharyngeal and peritonsillar abscesses, epiglottitis and mumps. * Problems with the jaw, e.g., fracture or dislocation * Radiation therapy * Neurologic disorders such as Amyotrophic lateral sclerosis, myasthenia gravis, Parkinson's disease, multiple system atrophy, rabies, bulbar paralysis, bilateral facial nerve palsy, and hypoglossal nerve palsy ## Treatment[edit] Hypersalivation is optimally treated by treating or avoiding the underlying cause.[4] Mouthwash and tooth brushing may have drying effects.[4] In the palliative care setting, anticholinergics and similar drugs that would normally reduce the production of saliva causing a dry mouth could be considered for symptom management: scopolamine, atropine, propantheline, hyoscine, amitriptyline, glycopyrrolate.[9] As of 2008 it is unclear if medication for people who have too much saliva due to clozapine treatment is useful.[10] ## References[edit] 1. ^ thefreedictionar.com > ptyalism Citing: * Dorland's Medical Dictionary for Health Consumers. 2007 * Mosby's Medical Dictionary, 8th edition. 2009 * Saunders Comprehensive Veterinary Dictionary, 3 ed. 2007 2. ^ thefreedictionary.com > sialorrhea Citing: * The American Heritage Dictionary of the English Language, Fourth Edition, Updated in 2009. 3. ^ "hypersalivation". Merriam-Webster's Medical Desk Dictionary. Springfield, Massachusetts: Merriam-Webster. 1986. p. 371 – via Internet Archive. 4. ^ a b c d e f g Medscape > Hypersalivation By Erica Brownfield. Posted: 05/19/2004(registration required) 5. ^ Clark], [edited by Parveen Kumar, Michael (2005). Kumar & Clark clinical medicine (6th ed.). Edinburgh: Elsevier Saunders. p. 266. ISBN 978-0702027635.CS1 maint: extra text: authors list (link) 6. ^ Reynolds, Gretchen. "Well". The New York Times. 7. ^ thefreedictionary.com > water brash Citing: Dorland's Medical Dictionary for Health Consumers. 2007 8. ^ [1] Rheumatology 9. ^ Medical Care of the Dying, 4th Edition, 2006, Edited by G.Michael Downing MD and Wendy Wainwright, MEd 10. ^ Syed, R; Au, K; Cahill, C; Duggan, L; He, Y; Udu, V; Xia, J (16 July 2008). Syed, Rebecca (ed.). "Pharmacological interventions for clozapine-induced hypersalivation". The Cochrane Database of Systematic Reviews (3): CD005579. doi:10.1002/14651858.CD005579.pub2. PMC 4160791. PMID 18646130. ## External links[edit] Classification D * MeSH: D012798 * DiseasesDB: 20764 External resources * MedlinePlus: 003048 * eMedicine: ent/629 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Hypersalivation	c0037036	6,525	wikipedia	https://en.wikipedia.org/wiki/Hypersalivation	2021-01-18T18:50:38	{"mesh": ["D012798"], "umls": ["C0037036", "C0013132"], "icd-9": ["527.7"], "icd-10": ["K11.7"], "wikidata": ["Q761862"]}
Neuroacanthocytosis (NA) refers to a group of genetic disorders that are characterized by misshapen, spiny red blood cells (acanthocytosis) and neurological abnormalities, especially movement disorders. The onset, severity and specific physical findings vary depending upon the specific type of NA present. Signs and symptoms usually include chorea (involuntary, dance-like movements), involuntary movements of the face and tongue, progressive cognitive impairment, muscle weakness, seizures and behavioral or personality changes. NA syndromes typically progress to cause serious, disabling complications and are usually fatal. NA is inherited, but the disease-causing gene and inheritance pattern varies for each type. Although there is some disagreement in the medical literature about what disorders should be classified as forms of NA, four distinct disorders are usually classified as the "core" NA syndromes - chorea-acanthocytosis, McLeod syndrome, Huntington's disease-like 2 and pantothenate kinase-associated neurodegeneration (PKAN). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Neuroacanthocytosis	c0393576	6,526	gard	https://rarediseases.info.nih.gov/diseases/10902/neuroacanthocytosis	2021-01-18T17:58:45	{"mesh": ["D054546"], "orphanet": ["263440"], "synonyms": ["Neuroacanthocytosis syndrome"]}
This article is about the cutaneous condition Bazex syndrome. For the inherited condition Bazex syndrome, see Bazex–Dupré–Christol syndrome. Paraneoplastic acrokeratosis Other namesAcrokeratosis paraneoplastica of Bazex and Acrokeratosis neoplastica)[1] SpecialtyDermatology Paraneoplastic acrokeratosis, or Bazex syndrome is a cutaneous condition characterized by psoriasiform changes of hands, feet, ears, and nose, with involvement of the nails and periungual tissues being characteristic and indistinguishable from psoriatic nails. The condition is associated with carcinomas of the upper aerodigestive tract.[2]:665 ## Contents * 1 History * 2 See also * 3 References * 4 External links ## History[edit] This was first reported by the French dermatologist, Andre Bazex (1911–1988), in 1945. Contrary to some publications, he did not die in 1944, as a victim of the Battle for France, but instead, was alive and well and continued his research on skin diseases up until his retirement in 1980.[3] ## See also[edit] * List of cutaneous conditions * Nail anatomy * List of cutaneous conditions associated with increased risk of nonmelanoma skin cancer ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 3. ^ Eric Ehrsam (February 20, 2008). "Acrokeratosis paraneoplastica in a 45-yr-old man". ## External links[edit] Classification D * ICD-10: L85.1 (ILDS L85.150) * DiseasesDB: 31294 External resources * eMedicine: article/1093193 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Paraneoplastic acrokeratosis	c0406355	6,527	wikipedia	https://en.wikipedia.org/wiki/Paraneoplastic_acrokeratosis	2021-01-18T19:00:23	{"umls": ["C0406355"], "icd-10": ["L85.1"], "orphanet": ["166113"], "wikidata": ["Q4675787"]}
A rare, genetic multiple congenital anomalies syndrome characterized by atrioventricular septal defects and blepharophimosis, in addition to radial (e.g. aplastic radius, shortened ulna, fifth finger clinodactyly, absent first metacarpal and thumb) and anal (e.g. imperforate or anteriorly place anus, rectovaginal fistula) defects. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Atrioventricular defect-blepharophimosis-radial and anal defect syndrome	c1838606	6,528	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1352	2021-01-23T17:33:21	{"gard": ["2742"], "mesh": ["C563994"], "omim": ["600123"], "umls": ["C1838606"], "icd-10": ["Q87.8"], "synonyms": ["Houlston-Ironton-Temple syndrome"]}
A rare primary bone dysplasia characterized by severe intrauterine and postnatal growth retardation and short stature in association with craniofacial dysmorphism (such as large forehead, triangular face, low-set ears, and micro-retrognathism) and osteochondrodysplastic lesions. Radiographic findings include epiphyseal maturation delay, abnormal metaphyses, a narrow thorax, small pelvis, and short and broad metacarpal bones and phalanges. There have been no further descriptions in the literature since 1996. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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, Brussels type	c1832439	6,529	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2867	2021-01-23T17:23:39	{"gard": ["4838"], "mesh": ["C537121"], "omim": ["601350"], "umls": ["C1832439"], "icd-10": ["Q87.1"], "synonyms": ["Mievis-Verellen-Dumoulin syndrome"]}
Papular eruption of blacks SpecialtyDermatology Papular eruption of blacks is a cutaneous condition characterized clinically by small, pruritic papules and histologically by a mononuclear cell-eosinophil perivascular infiltrate.[1][2] ## See also[edit] * Pachydermatous eosinophilic dermatitis * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ "Papular Eruption in Black Men." Theodore Rosen, MD; Ronald J. Algra, MD. Arch Dermatol. 1980;116(4):416-418. This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Papular eruption of blacks	c0406789	6,530	wikipedia	https://en.wikipedia.org/wiki/Papular_eruption_of_blacks	2021-01-18T18:34:13	{"umls": ["C0406789"], "wikidata": ["Q16920098"]}
Majeed syndrome is a rare condition characterized by recurrent episodes of fever and inflammation in the bones and skin. One of the major features of Majeed syndrome is an inflammatory bone condition known as chronic recurrent multifocal osteomyelitis (CRMO). This condition causes recurrent episodes of pain and joint swelling beginning in infancy or early childhood. These symptoms persist into adulthood, although they may improve for short periods. CRMO can lead to complications such as slow growth and the development of joint deformities called contractures, which restrict the movement of certain joints. Another feature of Majeed syndrome is a blood disorder called congenital dyserythropoietic anemia. This disorder is one of many types of anemia, all of which involve a shortage of red blood cells. Without enough of these cells, the blood cannot carry an adequate supply of oxygen to the body's tissues. The resulting symptoms can include tiredness (fatigue), weakness, pale skin, and shortness of breath. Complications of congenital dyserythropoietic anemia can range from mild to severe. Most people with Majeed syndrome also develop inflammatory disorders of the skin, most often a condition known as Sweet syndrome. The symptoms of Sweet syndrome include fever and the development of painful bumps or blisters on the face, neck, back, and arms. ## Frequency Majeed syndrome appears to be very rare; it has been reported in three families, all from the Middle East. ## Causes Majeed syndrome results from mutations in the LPIN2 gene. This gene provides instructions for making a protein called lipin-2. Researchers believe that this protein may play a role in the processing of fats (lipid metabolism). However, no lipid abnormalities have been found with Majeed syndrome. Lipin-2 also may be involved in controlling inflammation and in cell division. Mutations in the LPIN2 gene alter the structure and function of lipin-2. It is unclear how these genetic changes lead to bone disease, anemia, and inflammation of the skin in people with Majeed syndrome. ### Learn more about the gene associated with Majeed syndrome * LPIN2 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene. Although carriers typically do not show signs and symptoms of the condition, some parents of children with Majeed syndrome have had an inflammatory skin disorder called psoriasis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Majeed syndrome	c1864997	6,531	medlineplus	https://medlineplus.gov/genetics/condition/majeed-syndrome/	2021-01-27T08:25:05	{"gard": ["10088"], "mesh": ["C537839"], "omim": ["609628"], "synonyms": []}
A rare, mild subtype of autosomal dominant limb-girdle muscular dystrophy characterized by a typically adult onset of mild, progressive, proximal weakness of pelvic and shoulder girdle muscles and progressive, permanent finger and toes flexion limitation without flexion contractures. Normal to highly elevated creatine kinase serum levels are 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	HNRNPDL-related limb-girdle muscular dystrophy D3	c1836765	6,532	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=55596	2021-01-23T17:53:55	{"gard": ["12531"], "mesh": ["C563794"], "omim": ["609115"], "umls": ["C1836765"], "icd-10": ["G71.0"], "synonyms": ["Autosomal dominant limb-girdle muscular dystrophy type 1G", "HNRNPDL-related LGMD D3", "LGMD type 1G", "LGMD1G", "Limb-girdle muscular dystrophy type 1G"]}
Non-X histiocytosis SpecialtyDermatology Non-X histiocytoses are a clinically well-defined group of cutaneous syndromes characterized by infiltrates of monocytes/macrophages, as opposed to X-type histiocytoses in which the infiltrates contain Langerhans cells.[1]:714 Conditions included in this group are:[1]:714–20 * Juvenile xanthogranuloma * Benign cephalic histiocytosis * Generalized eruptive histiocytoma * Xanthoma disseminatum * Progressive nodular histiocytosis * Papular xanthoma * Hereditary progressive mucinous histiocytosis * Reticulohistiocytosis * Indeterminate cell histiocytosis * Sea-blue histiocytosis * Erdheim–Chester disease ## See also[edit] * X-type histiocytosis * Histiocytosis ## References[edit] 1. ^ a b James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. * v * t * e Histiocytosis WHO-I/Langerhans cell histiocytosis/ X-type histiocytosis * Letterer–Siwe disease * Hand–Schüller–Christian disease * Eosinophilic granuloma * Congenital self-healing reticulohistiocytosis WHO-II/non-Langerhans cell histiocytosis/ Non-X histiocytosis * Juvenile xanthogranuloma * Hemophagocytic lymphohistiocytosis * Erdheim-Chester disease * Niemann–Pick disease * Sea-blue histiocyte * Benign cephalic histiocytosis * Generalized eruptive histiocytoma * Xanthoma disseminatum * Progressive nodular histiocytosis * Papular xanthoma * Hereditary progressive mucinous histiocytosis * Reticulohistiocytosis (Multicentric reticulohistiocytosis, Reticulohistiocytoma) * Indeterminate cell histiocytosis WHO-III/malignant histiocytosis * Histiocytic sarcoma * Langerhans cell sarcoma * Interdigitating dendritic cell sarcoma * Follicular dendritic cell sarcoma Ungrouped * Rosai–Dorfman disease This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Non-X histiocytosis	c0019624	6,533	wikipedia	https://en.wikipedia.org/wiki/Non-X_histiocytosis	2021-01-18T19:10:36	{"gard": ["8231"], "mesh": ["D015616"], "umls": ["C0019624"], "orphanet": ["157987"], "wikidata": ["Q3136521"]}
Phlebothrombosis occurs when a blood clot (thrombosis) in a vein (phlebo) forms independently from the presence of inflammation of the vein (phlebitis). Thrombophlebitis is phlebitis (vein inflammation) related to a thrombus (blood clot). These conditions are usually of the superficial veins and are generally mild and uncomplicated as opposed to deep vein thromboses, which can be life-threatening.[1][better source needed] ## References[edit] 1. ^ * Andreozzi, GM and Verlato, F. Superficial thrombophlebitis. Minerva Cardioangiol.2000 Dec;48(12 Suppl):9-14 PMID 11253344 * Jahangir Moini (22 October 2008). Fundamental pharmacology for pharmacy technicians. Cengage Learning. p. 218. ISBN 978-1-4180-5357-4. Retrieved 12 January 2012. This cardiovascular system article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Phlebothrombosis	c0042487	6,534	wikipedia	https://en.wikipedia.org/wiki/Phlebothrombosis	2021-01-18T18:55:52	{"mesh": ["D020246"], "wikidata": ["Q3746554"]}
A number sign (#) is used with this entry because of evidence that Joubert syndrome-8 (JBTS8) is caused by homozygous or compound heterozygous mutation in the ARL13B gene (608922) on chromosome 3q11. For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300. Clinical Features Cantagrel et al. (2008) studied 2 families with Joubert syndrome in which novel mutations in the ARL13B gene were subsequently found. The phenotype consisted predominantly of classical Joubert syndrome, with all patients displaying the molar tooth sign. In the Pakistani pedigree in which the disorder was mapped, 2 of the 3 affected individuals had a small occipital encephalocele. In the other family, from the United States, there was no occipital encephalocele, and there were no other supratentorial cerebral abnormalities. Diagnostic ultrasound, performed on both families, found no renal abnormalities. The possibility that renal symptoms could develop in the affected individuals was considered, as studies of urinary concentration defects, a more sensitive measure of early kidney involvement, were not available from any of the patients. Thomas et al. (2015) reported a boy, born of consanguineous Tunisian parents, with Joubert syndrome. He was noted to have abnormal eye movements since birth. At age 1 month, he had jaundice, hepatomegaly, hyperventilation, hypertonia, and absence of eye contact. Later in early childhood, the liver abnormalities had disappeared, but he showed delayed psychomotor development with absent speech, pale optic discs, absent electroretinogram, ataxic gait, and the molar tooth sign on brain imaging. He was also obese. Mapping Using linkage analysis in a consanguineous Pakistani family, Cantagrel et al. (2008) assigned the JBTS8 interval to a 107- to 112-cM region on chromosome 3p12.3-q12.3. Molecular Genetics The JBTS8 interval defined by Cantagrel et al. (2008) contained 41 genes, of which 4 were considered strong candidates based on their identification within the cilia proteome. In the Pakistani family in which linkage to 3p12.3-q12.3 was established, Cantagrel et al. (2008) identified a homozygous missense mutation in exon 3 of the ARL13B gene (R79Q; 608922.0001). The affected individual from another family was compound heterozygous for a nonsense mutation (W82X; 608922.0002) and a missense mutation (R200C; 608922.0003). Overexpression of human wildtype, but not patient mutant, ARL13B rescued the Arl13b 'scorpion' zebrafish mutant, demonstrating that ARL13B has an evolutionarily conserved role in mediating cilia function in multiple organs. In a boy, born of consanguineous Tunisian parents, with JBTS8, Thomas et al. (2015) identified a homozygous missense mutation in the ARL13B gene (Y86C; 608922.0004). The mutation was found by a combination of homozygosity mapping and candidate gene sequencing. Expression of the mutation in arl13b-null zebrafish and mouse embryonic fibroblasts null for Arl13b showed only partial rescue of the null phenotype, consistent with a hypomorphic allele. Thomas et al. (2015) found expression of the ARL13B gene within cilia in ventromedial hypothalamic neurons, and noted that the patient also had obesity. The patient had previously been reported as patient 3 by Romano et al. (2006). INHERITANCE \- Autosomal recessive GROWTH Weight \- Obesity (in 1 patient) HEAD & NECK Eyes \- Pigmentary retinopathy \- Optic disc pallor \- Extinguished ERG \- Abnormal eye movements RESPIRATORY \- Breathing anomalies NEUROLOGIC Central Nervous System \- Molar tooth sign \- Occipital encephalocele (in some patients) \- Psychomotor delay \- Mental retardation \- Oculomotor apraxia \- Hypotonia \- Ataxia MOLECULAR BASIS \- Caused by mutation in the ADP-ribosylation factor-like 13B gene (ARL13B, 608922.0001 ) ▲ 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	JOUBERT SYNDROME 8	c2676771	6,535	omim	https://www.omim.org/entry/612291	2019-09-22T16:01:56	{"doid": ["0111003"], "mesh": ["C567358"], "omim": ["612291", "213300"], "orphanet": ["475"], "synonyms": ["CPD IV", "Cerebelloparenchymal disorder IV", "Classic Joubert syndrome", "Joubert syndrome type A", "Joubert-Boltshauser syndrome", "Pure Joubert syndrome"], "genereviews": ["NBK1325"]}
A number sign (#) is used with this entry because of evidence that spastic paraplegia-31 (SPG31) is caused by heterozygous mutation in the receptor expression-enhancing protein-1 gene (REEP1; 609139) on chromosome 2p11. Mutation in the REEP1 gene can also cause distal hereditary motor neuronopathy, type VB (HMN5B; 614751). Some patients with REEP1 mutations show overlapping signs of HMN5B and SPG31, indicating that there is a phenotypic spectrum of manifestations associated with REEP1 mutations. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600). Clinical Features Zuchner et al. (2006) described 2 multigenerational Caucasian families with an autosomal dominant form of uncomplicated spastic paraplegia. All patients studied had typical signs of spastic paraplegia mainly characterized by proximal weakness of the lower extremities with brisk reflexes and spastic gait abnormalities. The upper extremities showed normal tone and only very mild weakness of the small hand muscles. The sensory system was not involved. No additional neurologic symptoms were present that suggested cerebellar or visual involvement. The average age of onset in one pedigree was 27.7 years. In the second smaller family, the average age of onset was 11.8 years. However, some affected individuals developed symptoms in their fifties and sixties. Hewamadduma et al. (2009) reported 3 unrelated British families with genetically confirmed SPG31. In 1 family, the age of onset ranged between 15 and 30 years and was associated with spasticity affecting all 4 limbs, pes cavus, severe gait disturbance, lower limb muscle atrophy, and loss of distal joint position and vibration sense. All required a wheelchair by age 30 to 35 years. The proband of the second family developed progressive unsteadiness of gait with increased tone and hyperreflexia in the upper and lower limbs at the age of 25. Her gait deteriorated significantly, and she became wheelchair-bound. She also had mild distal sensory loss. There was no muscle wasting. The proband of the third family had difficulty in walking and running since age 9 years. At age 27, she had severe spastic tetraparesis with bulbar dysfunction, including dysarthria and dysphagia. Hewamadduma et al. (2009) noted that SPG31 can be associated with both pure and complicated phenotypes. Mapping Zuchner et al. (2006) conducted a genomewide linkage analysis in 2 families with HSP and demonstrated linkage to chromosome 2p12 (lod = 4.7). Molecular Genetics On the basis of emerging pathways for spastic paraplegia and conserved protein domains contained in proteins that cause neurodegenerative diseases, Zuchner et al. (2006) chose 9 candidate genes in the critical linkage region. Sequencing all exons and flanking intronic and UTR sequences of these genes, they identified a single-bp deletion in the REEP1 gene, 507delC, in 1 family (609139.0001). In a second family they found a splice site mutation, 182-2A-G (609139.0002). These sequence changes resulted in frameshifts leading to altered stop codons. For additional REEP1 mutations, Zuchner et al. (2006) screened a sample of 90 independent HSP-affected families of European descent, neither selected for pure HSP phenotype nor tested for mutations in other HSP genes. They identified 4 more mutations that led to significant sequence changes in REEP1. Altogether Zuchner et al. (2006) found that REEP1 mutations occurred in 6.5% of patients with HSP in their sample, making it the third most common HSP gene. Since REEP1 is widely expressed and localized to mitochondria, the findings underscored the importance of mitochondrial function in neurodegenerative disease. Beetz et al. (2008) identified 16 different mutations, including 14 novel mutations, in the REEP1 gene (see, e.g., 609139.0003-609139.0004) in 16 (3.0%) of 535 unrelated patients with familial or sporadic SPG. Small frameshift mutations were the most common type of REEP1 mutation. Most patients with confirmed SPG31 had a pure phenotype, although some also reported impaired distal vibration sense, urge incontinence, or distal amyotrophy. There was a bimodal distribution of age onset: most (71%) patients had onset in the first or second decade, whereas the rest had onset after age 30 years. Mutations were distributed throughout the gene, except for exon 3, and there were no apparent genotype/phenotype correlations. Beetz et al. (2008) postulated haploinsufficiency as the main molecular genetic mechanism. In affected members of 3 unrelated British families with SPG31, Hewamadduma et al. (2009) identified 2 different heterozygous mutations in the REEP1 gene (609139.0003 and 609139.0005). The REEP1 mutation frequency in their overall cohort of 133 probands was 2.3%. INHERITANCE \- Autosomal dominant ABDOMEN Gastrointestinal \- Dysphagia (less common) GENITOURINARY Bladder \- Urinary urgency (less common) SKELETAL Feet \- Pes cavus (less common) MUSCLE, SOFT TISSUES \- Muscle wasting due to chronic denervation \- Amyotrophy NEUROLOGIC Central Nervous System \- Lower limb spasticity \- Lower limb weakness \- Upper limbs may be affected \- Spastic gait \- Hyperreflexia \- Proximal weakness of the lower extremities \- Dysarthria \- Extensor plantar responses \- Ankle clonus Peripheral Nervous System \- Distal sensory loss MISCELLANEOUS \- Variable severity \- Most patients have pure spastic paraplegia, some have complicated spastic paraplegia \- Bimodal age of onset \- Most have onset in first or second decade \- A minority of patients have onset after age 30 years MOLECULAR BASIS \- Caused by mutation in the receptor expression-enhancing protein-1 gene (REEP1, 609139.0001 ) ▲ 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	SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT	c1853247	6,536	omim	https://www.omim.org/entry/610250	2019-09-22T16:04:50	{"doid": ["0110782"], "mesh": ["C565210"], "omim": ["610250"], "orphanet": ["101011"]}
A number sign (#) is used with this entry because of evidence that erythrokeratodermia variabilis et progressiva-2 (EKVP2) is caused by heterozygous mutation in the gene encoding connexin-30.3 (GJB4; 605425) on chromosome 1p34. Description Erythrokeratodermia variabilis et progressiva-2 is a genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The severity and dominating features of the disease vary strikingly within families and also during an individual's course of disease. The erythematous component usually prevails in young children, whereas hyperkeratosis is the dominant or sole feature in adults. Some patients with EKVP2 display lesions resembling erythema gyratum repens (summary by Richard et al., 2003). EKVP was previously thought to be separate disorders: erythrokeratodermia variabilis (EKV) and progressive symmetric erythrokeratodermia (PSEK) (van Steensel et al., 2009). For a discussion of genetic heterogeneity of EKVP, see EKVP1 (133200). Clinical Features Macari et al. (2000) studied 8 affected and 3 healthy individuals over 3 generations of an Israeli family of Kurdish origin with the migratory form of EKVP, originally described by Hacham-Zadeh and Even-Paz (1978). The dermatosis started at birth or shortly thereafter, but the patients were usually in good general health. Migratory erythematous lesions tended to turn gradually into more or less fixed keratotic plaques. In some patients, these erythematous lesions appeared as erythema gyratum repens, characterized by rapidly migrating figurata erythema 1 to 2 cm wide in an annular, garland, or spiral arrangement (Braun-Falco et al., 1991), which Macari et al. (2000) stated had not previously been reported in EKV. Generally, the palms and soles were spared. Lesions started to become worse in summer and to improve in winter. In 1 patient, lesions worsened during pregnancy. Audiograms in 2 affected patients were normal. Richard et al. (2003) studied 57 patients with the migratory form of EKVP from 13 unrelated families. The hyperkeratosis was confined to localized plaques in 10 families, and individuals from the remaining 3 families had more widespread involvement. In 3 families, patchy or diffuse glove-like palmoplantar keratoderma (PPK; see 144200) was observed. In 2 families, children but not adults displayed rapidly changing erythematous patches with prominent circinate or gyrate borders (erythema gyratum repens). Richard et al. (2003) observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors. Mapping Macari et al. (2000) performed linkage analysis in an Israeli family of Kurdish origin with the migratory form of EKVP, associated with erythema gyratum repens in some patients, originally described by Hacham-Zadeh and Even-Paz (1978). Macari et al. (2000) mapped the disorder to chromosome 1p35-p34, obtaining a maximum 2-point lod score of 2.343 (theta = 0) with marker D1S472, and noted that all affected individuals shared a common allele. Molecular Genetics In affected members of an Israeli family of Kurdish origin with the migratory form of erythrokeratodermia (EKV), originally described by Hacham-Zadeh and Even-Paz (1978), in which some patients displayed erythema gyratum repens, Macari et al. (2000) identified heterozygosity for a missense mutation in the GJB4 gene (F137L; 605425.0001). Richard et al. (2003) analyzed the GJB4 gene in 13 unrelated families with EKV who were known to be negative for mutation in GJB3, and identified 6 distinct mutations (605425.0001-605425.0006) in 5 families and a sporadic patient. The F137L substitution, previously identified in an Israeli family of Kurdish origin with EKV and erythema gyratum repens by Macari et al. (2000), was found in 2 families: the identical 409T-C transition was detected in a family with typical EKV, whereas in a 2-year-old boy with EKV and erythema gyratum repens, a 411C-A transversion that also resulted in the F137L substitution was identified (605425.0002). No mutations were found in the remaining 7 families; Richard et al. (2003) stated that they did not observe any discriminatory or consistently deviant clinical features of EKV that would allow clinical differentiation of these patients from others harboring mutations in the GJB3 or GJB4 genes. In 2 unrelated Dutch patients diagnosed with PSEK, van Steensel et al. (2009) identified heterozygosity for the G12D mutation in the GJB4 gene (605425.0004) that had previously been found in affected members of a Dutch family with typical EKV by Richard et al. (2003). Haplotype analysis of the 2 PSEK patients and 3 patients from the EKV family showed a shared haplotype extending over 2 Mb including the GJB4 gene. Van Steensel et al. (2009) concluded that PSEK and EKV can be manifestations of the same genetic defect and proposed the designation 'erythrokeratodermia variabilis et progressiva' to indicate the protean nature of the disorder. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Migratory erythematous lesions \- Erythema (rapidly migrating figurate in annular, garland, or spiral pattern--erythema gyratum repens) \- Hyperkeratotic plaques (well demarcated, symmetric with irregular borders) \- Palmoplantar keratoderma (uncommon) Skin Histology \- Hyperkeratosis of epidermis, mild \- Edema in upper dermis, mild Hair \- Hypertrichosis (uncommon) MISCELLANEOUS \- Variable age of onset (early infancy to 6 years) \- Inter- and intrafamilial variability \- Lesions primarily involve trunk and extremities \- Lesions worsen with exposure to sunlight (in some patients) \- Lesions worsen with exposure to cold (uncommon) MOLECULAR BASIS \- Caused by mutation in the beta-4 gap junction protein (GJB4, 605425.0001 ) ▲ 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	ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 2	c0265961	6,537	omim	https://www.omim.org/entry/617524	2019-09-22T15:45:38	{"doid": ["0080248"], "mesh": ["D056266"], "omim": ["617524"], "orphanet": ["317"]}
Aniridia is an eye disorder characterized by a complete or partial absence of the colored part of the eye (the iris). These iris abnormalities may cause the pupils to be abnormal or misshapen. Aniridia can cause reduction in the sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). People with aniridia can also have other eye problems. Increased pressure in the eye (glaucoma) typically appears in late childhood or early adolescence. Clouding of the lens of the eye (cataracts), occur in 50 percent to 85 percent of people with aniridia. In about 10 percent of affected people, the structures that carry information from the eyes to the brain (optic nerves) are underdeveloped. Individuals with aniridia may also have involuntary eye movements (nystagmus) or underdevelopment of the region at the back of the eye responsible for sharp central vision (foveal hypoplasia). Many of these eye problems contribute to progressive vision loss in affected individuals. The severity of symptoms is typically the same in both eyes. Rarely, people with aniridia have behavioral problems, developmental delay, and problems detecting odors. ## Frequency Aniridia occurs in 1 in 50,000 to 100,000 newborns worldwide. ## Causes Aniridia is caused by mutations in the PAX6 gene. The PAX6 gene provides instructions for making a protein that is involved in the early development of the eyes, brain and spinal cord (central nervous system), and the pancreas. Within the brain, the PAX6 protein is involved in the development of a specialized group of brain cells that process smell (the olfactory bulb). The PAX6 protein attaches (binds) to specific regions of DNA and regulates the activity of other genes. On the basis of this role, the PAX6 protein is called a transcription factor. Following birth, the PAX6 protein regulates several genes that likely contribute to the maintenance of different eye structures. Mutations in the PAX6 gene result in the production of a nonfunctional PAX6 protein that is unable to bind to DNA and regulate the activity of other genes. A lack of functional PAX6 protein disrupts the formation of the eyes during embryonic development. ### Learn more about the gene associated with Aniridia * PAX6 ## Inheritance Pattern Aniridia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In approximately two-thirds of cases, an affected person inherits the mutation from one affected parent. The remaining one-third of cases result from new mutations in the gene and occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Aniridia	c0003076	6,538	medlineplus	https://medlineplus.gov/genetics/condition/aniridia/	2021-01-27T08:24:56	{"gard": ["5816"], "mesh": ["D015783"], "omim": ["106210"], "synonyms": []}
For a phenotypic description and a discussion of genetic heterogeneity of body mass index (BMI), see 606641. Mapping In a genomewide linkage analysis of body mass index (BMI) in 8 extended Costa Rican families involving 415 parent-child trios originally ascertained on asthma affection status (see 611064 and Celedon et al., 2007), Murphy et al. (2009) found significant linkage to BMI in females on chromosome 17q, with a peak lod score of 3.39 and a 1.5-lod unit support interval encompassing chromosome 17q23.2-q25.1, the location of the PRKCA gene (176960). Analysis of 39 PRKCA SNPs in the Costa Rican pedigrees, as well as in 457 Caucasian families with 493 offspring diagnosed with asthma, revealed 2 SNPs, rs228883 and rs1005651, that were significantly associated with BMI (corrected combined p = 5.6 x 10(-5) and 9.5 x 10(-5), respectively). Population-based longitudinal analysis of BMI for 4 SNPs of interest (including rs228875 and rs224497, which had shown suggestive association) showed a consistent increase in mean BMI over time in probands with 2 copies of the minor allele compared to those with 1 or 2 copies of the wildtype allele. Testing for association between PRKCA SNPs and asthma affection status also identified a significantly associated SNP, rs11079657 (combined corrected p = 2.6 x 10(-5)). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 15	c2751823	6,539	omim	https://www.omim.org/entry/612967	2019-09-22T16:00:09	{"omim": ["612967"]}
GABA (gamma-aminobutyric acid) is an important molecule which slows down the activity of cells in the brain.[1] GABA is broken down in the body by a substance known as 4-aminobutyrate aminotransferase, also known as GABA-transaminase or GABA-T.[1] Mutations in the ABAT gene can cause less GABA-T to be made, a condition known as GABA-T deficiency.[1] The symptoms for an individual with GABA-T deficiency can include: psychomotor retardation (a slowing down of thought and activity), low muscle tone, hyperactive responses, lethargy, seizures, and EEG abnormalities.[1] GABA-T deficiency is very rare, with fewer than 5 cases reported in the literature.[2] It is thought to be inherited in an autosomal recessive manner.[3][4] [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Gamma aminobutyric acid transaminase deficiency	c0342708	6,540	gard	https://rarediseases.info.nih.gov/diseases/194/gamma-aminobutyric-acid-transaminase-deficiency	2021-01-18T18:00:22	{"mesh": ["C535407"], "omim": ["137150"], "umls": ["C0342708"], "orphanet": ["2066"], "synonyms": ["GABA transaminase deficiency", "Gamma aminobutyrate transaminase deficiency", "GABAT", "4 alpha aminobutyrate transaminase deficiency", "ABAT"]}
Vici syndrome Other namesDionisi–Vici–Sabetta–Gambarara syndrome Vici syndrome has an autosomal recessive pattern of inheritance. Vici syndrome, also called immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum (or absent corpus callosum cataract immunodeficiency),[1] is a rare autosomal recessive[2] congenital disorder characterized by albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, severe psychomotor retardation, seizures, immunodeficiency and recurrent severe infections.[3][4] To date, about 50 cases have been reported.[5] ## Contents * 1 Presentation * 2 Genetics * 2.1 Inheritance * 2.2 Gene * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 5 Eponym * 6 References * 7 External links ## Presentation[edit] This syndrome consists of a number of typical features. These include[citation needed] * Agenesis of the corpus callosum (80–99% patients) * Hypopigmentation of the eyes and hair (80–99% patients) * Cardiomyopathy (80–99% patients) * Combined immunodeficiency (80–99% patients) * Muscular hypotonia (80–99% patients) * Abnormality of retinal pigmentation (80–99% patients) * Recurrent chest infections (80–99% patients) * Abnormal EEG (80–99% patients) * Intellectual disability (80–99% patients) * Cataracts (75%) * Seizures (65%) * Renal abnormalities (15%) Infections of the gastrointestinal and urinary tracts are common. Swallowing and feeding difficulties early on may result in a failure to thrive. Optic nerve hypoplasia, nystagmus and photophobia may occur. Facial dysmorphism (cleft lip/palate and micrognathia) and syndactyly may be present. Sensorineural hearing loss may also be present.[citation needed] Death in infancy is not uncommon and is usually due to cardiac complications or severe infections.[citation needed] ## Genetics[edit] ### Inheritance[edit] Vici syndrome is inherited in an autosomal recessive manner.[2] This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. The hypothesis of autosomal recessive inheritance of Vici syndrome was strengthened in 2002 with the clinical description of two new cases, one brother and one sister, by Chiyonobu et al.[6] ### Gene[edit] Vici syndrome is caused by mutations in the gene EPG5 (OMIM # 615068), which encodes an important regulator of the autophagy pathway, the ectopic P-granules autophagy protein 5, involved in the formation of lysosomes. EPG5 is the human homolog of the C.elegans epg5 gene. The gene EPG5 has been cloned for the first time by Nagase et al. by sequencing clones obtained from a size-fractionated fetal brain cDNA library, and was initially named KIAA1632.[7] The EPG5 human gene is located on chromosome 18q12.3, has a length of 119,67Kb (NC_000018.10), consists of 44 exons and is transcriptionally driven from the centromere toward the telomere. The messenger RNA (mRNA) is 12633bp long (NM_020964.2) and contains a CDS of 7740 bp translated into a protein sequence of 2579 amino acids (NP_066015.2) with a molecular weight of 280kDa, presumed. The protein EPG5 is expressed primarily in the central nervous system (CNS), skeletal muscle, heart, thymus, cells of the immune system, lungs and kidneys.[8] Mutations in the EPG5 gene interfere with the autophagy. This appears to be due to a block in the autophagosome-lysosome fusion mechanism.[9] ## Diagnosis[edit] The diagnostic workup usually includes an MRI of the brain, an EEG, ophthalmic examination and a cardiac ECHO. Muscle biopsy – which is not commonly done – may show storage of abnormal material and secondary mitochondrial abnormalities in skeletal muscle. Other features that may be seen on muscle biopsy include variability in fibre size, increase in internal and centralized nuclei, type 1 fibre hypotrophy with normally sized type 2 fibres, increased glycogen storage and variable vacuoles on light microscopy The diagnosis is confirmed by sequencing of the EPG5. ### Differential diagnosis[edit] This includes ataxia–telangiectasia, Chédiak–Higashi syndrome, DiGeorge syndrome, Griscelli syndrome and Marinesco–Sjögren syndrome. ## Treatment[edit] There is no known curative treatment presently. Hearing aids and cataract surgery may be of use. Control of seizures, heart failure, and treatment of infection is essential. Tube feeding may be needed. ## Eponym[edit] Vici syndrome was first described by Carlo Dionisi-Vici et al. (Rome, Italy) in an article from 1988 about two brothers with a previously unreported disorder.[4] Since then, a few articles have reported the same disorder, which subsequently obtained the name Vici syndrome.[10][2] About 10 years later, del Campo et al. described 4 patients (including 2 sibs, a male and a female) with clinical features very similar to those reported by Dionisi Vici.[11] In 2007 the renal tubular acidosis was another clinical complication described in only one case report of two brothers with Vici syndrome.[12] In 2010 and 2012 it has also been reported a neuromuscular involvement in patients suffering from this syndrome.[13][14] In 2013 Vici syndrome has been associated with mutations in the gene EPG5 (OMIM # 615068), which encodes an important regulator of the autophagy pathway, the ectopic P-granules autophagy protein 5, involved in the formation of lysosomes.[15] In 2014 the ophthalmologic features of Vici syndrome were carefully evaluated.[16] In 2015 the doctoral thesis entitled "Deciphering the mechanism of immune dysfunction in Vici Syndrome", University of Rome "La Sapienza" by Dr. Evangelos Axiotis, clarifies the molecular mechanisms and the role of the mutations in EPG5, all responsible for the immunodeficiency present in patients with Vici Syndrome. ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 242840 2. ^ a b c Chiyonobu T, Y. T.; Yoshihara, T.; Fukushima, Y.; Yamamoto, Y.; Tsunamoto, K.; Nishimura, Y.; Ishida, H.; Toda, T.; Kasubuchi, Y. (April 2002). "Sister and brother with Vici syndrome: Agenesis of the corpus callosum, albinism, and recurrent infections". American Journal of Medical Genetics. 109 (1): 61–66. doi:10.1002/ajmg.10298. PMID 11932994. 3. ^ "Vici syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 17 April 2018. 4. ^ a b Vici CD, Sabetta G, Gambarara M, et al. (1988). "Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers". Am. J. Med. Genet. 29 (1): 1–8. doi:10.1002/ajmg.1320290102. PMID 3344762. 5. ^ Byrne S, Dionisi-Vici C, Smith L, Gautel M and Jungbluth H (2016) Vici syndrome: a review. Orphanet Journal of Rare Diseases 11:21 DOI: 10.1186/s13023-016-0399-x 6. ^ Chiyonobu T, Yoshihara T, Fukushima Y, Yamamoto Y, Tsunamoto K et al. (2002) "Sister and brother with Vici syndrome: agenesis of the corpus callosum, albinism, and recurrent infections". American Journal of Medical Genetics 109(1): 61-66. 7. ^ Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O (2000) Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 7(4): 273-281. 8. ^ Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F et al. (2013) Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nature genetics 45(1): 83-87 9. ^ Hori I, Otomo T, Nakashima M, Miya F, Negishi Y, Shiraishi H, Nonoda Y, Magara S, Tohyama J, Okamoto N, Kumagai T, Shimoda K, Yukitake Y, Kajikawa D, Morio T, Hattori A, Nakagawa M, Ando N, Nishino I, Kato M, Tsunoda T, Saitsu H, Kanemura Y, Yamasaki M, Kosaki K, Matsumoto N, Yoshimori T, Saitoh S (2017) Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. Sci Rep 7(1):3552. doi: 10.1038/s41598-017-02840-8 10. ^ del Campo M, Hall BD, Aeby A, et al. (1999). "Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance". Am. J. Med. Genet. 85 (5): 479–485. doi:10.1002/(SICI)1096-8628(19990827)85:5<479::AID-AJMG9>3.0.CO;2-D. PMID 10405446. 11. ^ del Campo M, Hall BD, Aeby A, Nassogne MC, Verloes A et al. (1999) "Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance". American Journal of Medical Genetics 85(5): 479-485. 12. ^ Miyata R, Hayashi M, Sato H, Sugawara Y, Yui T et al. (2007) "Sibling cases of Vici syndrome: sleep abnormalities and complications of renal tubular acidosis". Am J Med Genet A 143(2): 189-194. 13. ^ Al-Owain M, Al-Hashem A, Al-Muhaizea M, Humaidan H, Al-Hindi H et al. (2010) Vici syndrome associated with unilateral lung hypoplasia and myopathy. Am J Med Genet A 152A(7): 1849–1853. 14. ^ McClelland V, Cullup T, Bodi I, Ruddy D, Buj-Bello A et al. (2010) Vici syndrome associated with sensorineural hearing loss and evidence of neuromuscular involvement on muscle biopsy. Am J Med Genet A 152A(3): 741-747. 15. ^ Cullup T, Kho AL, Dionisi-Vici C, Brandmeier B, Smith F et al. (2013) "Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy". Nature genetics 45(1): 83-87. 16. ^ J Pediatr Ophthalmol Strabismus. 2014 July 1;51(4):214–20 ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 242840 * MeSH: C535566 External resources * Orphanet: 1493 * 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	Vici syndrome	c1855772	6,541	wikipedia	https://en.wikipedia.org/wiki/Vici_syndrome	2021-01-18T18:40:37	{"gard": ["448"], "mesh": ["C535566"], "umls": ["C1855772"], "orphanet": ["1493"], "wikidata": ["Q7925271"]}
A number sign (#) is used with this entry because T cell-negative (T-), B cell-negative (B-), natural killer cell-negative (NK-) severe combined immunodeficiency (SCID) is caused by homozygous or compound heterozygous mutation in the adenosine deaminase gene (ADA; 608958) on chromosome 20q13. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457. Clinical Features Inherited ADA deficiency causes a variable phenotypic spectrum, the most severe being SCID presenting in infancy and usually resulting in early death. Ten to 15% of patients have a 'delayed' clinical onset by age 6 to 24 months, and a smaller percentage of patients have 'later' onset, diagnosed from ages 4 years to adulthood, showing less severe infections and gradual immunologic deterioration. Finally, 'partial' ADA deficiency occurs in a subset of immunocompetent individuals who show decreased enzyme activity in erythrocytes, but retain substantial enzyme activity ranging from 5 to 80% of normal in leukocytes and other nucleated cells (Arredondo-Vega et al., 1994). ADA deficiency accounts for approximately 15% of all SCID cases and one-third of cases of autosomal recessive SCID (Hershfield, 2003). ### Early Onset Giblett et al. (1972) reported 2 unrelated girls with impaired cellular immunity and absence of red cell adenosine deaminase activity. One child, aged 22 months, had recurrent respiratory infections, candidiasis, and marked lymphopenia from birth. The other, aged 3.5 years, was allegedly normal in the first 2 years of life. Mild upper respiratory infections began at age 24 months and progressed to severe pulmonary insufficiency and hepatosplenomegaly by age 30 months. The parents of the first child were related and the second child had a sister who died as a result of a major immunologic defect (Hong et al., 1970). The finding that both pairs of parents had an intermediate level of red cell ADA supported recessive inheritance; the parents of the first child had about a 50% level of normal, whereas the parents of the second child had about a 66% level. Parkman et al. (1975) reported 3 affected infants from 2 families with SCID due to ADA deficiency inherited in an autosomal recessive pattern. None of the infants had detectable erythrocyte ADA activity. Two infants had successful bone marrow transplantation with restoration of normal cellular and humoral immunity, but erythrocytic ADA deficiency persisted. Reporting on a workshop on SCID due to ADA deficiency, Meuwissen et al. (1975) noted that the phenotype is transmitted as an autosomal recessive disorder. Some patients had characteristic skeletal abnormalities, and all had thymic involution with Hassall's corpuscles and differentiated germinal epithelium. Hershfield (2003) stated that red cell 2-prime-deoxyadenosine triphosphate (dATP; dAXP), a substrate of adenosine deaminase, is elevated by 30-fold to greater than 1,500-fold in SCID patients. ### Delayed or Late Onset Santisteban et al. (1993) reported 7 patients with 'delayed' or 'late' onset of SCID due to ADA deficiency. Three of these patients had onset of symptoms at ages 9, 12, and 12 months, respectively, although diagnosis of ADA deficiency was not made until ages 14 months, 2, and 3 years, respectively. Four patients were relatively asymptomatic until ages 2 to 5 years, when recurrent respiratory infections became prominent. ADA activity in cultured T cells and deoxyadenosine nucleotide levels in red cells in all 7 patients were intermediate between typical early-onset SCID patients and immunocompetent individuals with partial ADA deficiency. Umetsu et al. (1994) reported 2 sisters with SCID due to ADA deficiency. The second-born child presented first with serious infections and failure to thrive at age 4 months; the diagnosis of SCID was made at age 9 months when the child was hospitalized for Pseudomonas sepsis and Pneumocystis pneumonia. Her healthy 39-month-old sister was then tested and found to be ADA deficient. She had an unremarkable history, including normal development and uncomplicated varicella zoster at age 6 months. Although she was lymphopenic, antibody production, delayed hypersensitivity, and in vitro T-cell function were intact. She became more lymphopenic over a period of 6 to 7 months and developed persistent upper respiratory infections. Both sisters were treated by enzyme replacement with polyethylene glycol (PEG)-ADA. Shovlin et al. (1993) described adult onset of ADA deficiency in 2 sisters who presented with recurrent infections together with laboratory phenotypes similar to those of advanced HIV disease, including severe CD4 lymphopenia. Both were HIV-negative. A 34-year-old woman reported asthma and recurrent chest infections from childhood. As an adult, she had widespread viral warts, recurrent oral and vaginal candidosis, and reported 2 episodes of dermatomal zoster. Her 35-year-old sister was well until age 17 when she developed idiopathic thrombocytopenic purpura necessitating splenectomy, azathioprine for 7 years, and prednisolone until the time of report. By age 20 she had asthma, recurrent chest infections, vaginal and oral candidosis, widespread viral warts, and recurrent dermatomal zoster. Both sisters had clinical and radiologic evidence of extensive lung damage. Medical records showed lymphopenia in both sisters from ages 20 and 17 years, respectively. These were the oldest patients ever described with a new diagnosis of primary ADA deficiency. Ozsahin et al. (1997) reported metabolic, immunologic, and genetic findings in 2 ADA-deficient adults with distinct phenotypes. A 39-year-old woman had combined immunodeficiency with frequent infections, lymphopenia, and recurrent hepatitis as a child, but did relatively well in her second and third decades. She later developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease, and died of viral leukoencephalopathy at 40 years of age. The second patient was a healthy 28-year-old man with normal immune function who was identified after his niece died of SCID. Both adult patients lacked erythrocyte ADA activity, but had only modestly elevated deoxyadenosine nucleotides. Hershfield (2003) stated that red cell dATP (dAXP) is elevated by 30- to 300-fold in delayed or late-onset patients. ### Partial ADA Deficiency Jenkins (1973) and Jenkins et al. (1976) reported a South African Kalahari San ('Bushman') patient with 'partial' ADA deficiency not associated with immunodeficiency. ADA activity was 2 to 3%, 10 to 12%, and 10 to 30% of normal in red blood cells, white blood cells, and fibroblasts, respectively. Multiple tests showed that the child had normal humoral and cellular immunity. A sib had similar ADA levels and the parents had intermediate levels. In a study of 36 South African populations comprising more than 3,000 individuals, Jenkins et al. (1976) found that many members of the Kung Bushman population had red cell ADA deficiency not associated with immunodeficiency. The authors concluded that the phenotype was due to a polymorphic allele, designated ADA-8, with a frequency of approximately 0.11 in the Kung population. Hart et al. (1986) reported a second Bantu-speaking Xhosa man from South Africa with partial ADA deficiency similar to the type previously reported by Jenkins et al. (1976). Erythrocyte ADA levels were decreased at 6 to 9% of normal, whereas white cell ADA was approximately 30% of normal, and the enzyme showed decreased stability in vitro. Levels of dATP were 2- to 3-fold above normal in red blood cells. Electrophoretic studies suggested compound heterozygosity. Hirschhorn et al. (1979) reported a patient with ADA deficiency without immunodeficiency in whom the mutant ADA enzyme was unstable. Daddona et al. (1983) reported another patient with partial ADA deficiency and normal immune function. ADA activity and protein were undetectable in red blood cells, 0.9% of normal in lymphocytes, 4% in lymphoblasts, and 14% in fibroblasts. The ADA protein was abnormally acidic. Hirschhorn et al. (1983) reported 4 unrelated children with partial ADA deficiency who lacked ADA in their erythrocytes but retained variable amounts of activity in their lymphoid cells. None had significant immunologic deficiency. Electrophoretic mobility studies showed different forms of the enzyme: one form was acidic, had very low activity, and was heat-stable; a second was basic, had low activity, and was heat-labile; a third was heat-labile and retained relatively normal activity; and a fourth had decreased activity without qualitative abnormalities. Hirschhorn et al. (1983) concluded that 3 of the individuals had mutations at the structural locus for ADA, and that the fourth may have had a mutation at a regulatory locus. Noting that 2 of the partially deficient families were of African descent and a third came from the Mediterranean basin, Hirschhorn et al. (1983) suggested that partial ADA deficiency may confer an advantage against intraerythrocytic parasites, such as malaria or babesiosis, which require exogenous purines derived from the host to survive. Hirschhorn and Ellenbogen (1986) reported 5 unrelated patients with partial ADA deficiency identified through a New York state neonatal screening program. None of them had immunologic abnormalities. Three patients were shown to be genetic compounds by the presence of 2 electrophoretically distinguishable allozymes or by family studies that demonstrated a null allele in addition to an electrophoretically abnormal enzyme. All 5 of the children were either black or of West Indian descent, suggesting a clustering of the partial ADA deficiency phenotype in this ethnic group. The genetically distinct enzymes excluded a founder effect, and the authors again concluded a selective advantage for partial ADA deficiency. Hershfield (2003) stated that red cell dATP (dAXP) is elevated by zero to approximately 30-fold in patients with partial ADA deficiency. Other Features Ratech et al. (1985) reported postmortem findings in 8 patients with SCID due to ADA deficiency. Seven patients had renal mesangial sclerosis, and 6 had adrenal cortical sclerosis. Tissue from vertebrae and costochondral junctions in 4 patients showed short growth plates with few proliferating and some hypertrophic chondrocytes. Two patients who had received bone marrow or enzyme infusions had milder changes. The authors concluded that disordered nucleoside metabolism due to absent ADA activity results in multisystem pathologic changes. Bollinger et al. (1996) described a human neonate with ADA deficiency, confirmed by genetic analysis, who developed prolonged hyperbilirubinemia with hepatitis that resolved after the institution of ADA replacement therapy. Percutaneous liver biopsy showed early giant-cell transformation, with enlarged foamy hepatocytes and portal and lobular eosinophilic infiltrates. Hirschhorn et al. (1980) referred to neurologic abnormalities that had been reported in 2 of 23 ADA-deficient patients and reported a third who showed improvement of these features with enzyme replacement by red cell infusion. Neurologic abnormalities included movement disorders, nystagmus, and sensorineural deafness. Rogers et al. (2001) evaluated the cognitive, behavioral, and neurodevelopmental function in 11 case-matched pairs of patients with ADA-SCID and non-ADA-deficient SCID, all of whom had undergone bone marrow transplantation. Cognitive ability was not significantly different between the 2 groups, but patients with ADA-SCID had a significant inverse correlation between dATP levels at diagnosis and IQ. Behavioral assessment showed that patients with ADA-SCID functioned in the pathologic range on all domains, whereas mean scores for the control group were within normal limits. Behavioral impairment in patients with ADA-SCID also showed a significant positive correlation with age. Mapping Koch and Shows (1980) showed that ADA deficiency in SCID segregated with chromosome 20 in interspecific somatic cell hybrids, suggesting that a structural gene mutation at the ADA locus was the primary cause of ADA-deficient SCID. Pathogenesis Mitchell et al. (1978) found that deoxyadenosine and deoxyguanosine were particularly toxic to T cells but not to B cells. Addition of deoxycytidine or dipyridamole prevented deoxyribonucleoside toxicity. Boss et al. (1981) concluded that ecto-5-prime-nucleotidase deficiency is secondary to the primary defect of ADA. In cells from a patient with ADA-deficient SCID, Herbschleb-Voogt et al. (1983) found a deficiency of ADA activity and a comparable deficiency of ADA-specific cross-reacting material, indicating a decrease of the enzyme. Cohen et al. (1978) observed greater than 50-fold elevations of 2-prime-deoxyadenosine triphosphate (dATP) in the erythrocytes of 3 SCID ADA-deficient patients, but not in the erythrocytes of an immunocompetent ADA-deficient patient or 2 unrelated immunodeficient patients with normal ADA. In vivo infusion of normal erythrocytes containing normal ADA activity in 2 SCID ADA-deficient patients resulted in a dramatic decrease in dATP and some clinical response. Cohen et al. (1978) concluded that deoxyadenosine is the toxic substrate in ADA deficiency, and that the toxic effect is mediated by dATP inhibition of ribonucleotide reductase (see, e.g., 180410), which is responsible for the reduction of all the purine and pyrimidine ribonucleotides to their respective 2-prime-deoxyribonucleotides, the necessary precursors for DNA synthesis. Immunodeficiency is the consequence of the particular sensitivity of immature lymphoid cells to the toxic effects of ADA substrates. Van de Wiele et al. (2002) noted that most immature thymocytes undergo apoptosis as a result of lymphocyte selection in the thymus. Degradation of cell DNA and RNA by ADA generates adenosine and deoxyadenosine. Accumulation of these metabolites and their derivatives in ADA deficiency is lymphotoxic, resulting in reduced production of T cells. In addition, dATP inhibits ribonucleotide reductase, which is necessary for DNA synthesis, and dATP and adenosine inhibit S-adenosylhomocysteine hydrolase (SAHH; 180960), which is necessary for methylation reactions that are required for cell viability. In cell cultures (fetal thymic organ culture, FTOC) from a mouse model of ADA deficiency, van de Wiele et al. (2002) found that inhibition of adenosine kinase (102750) resulted in an increase in T-cell recovery, indicating that toxicity in ADA deficiency is due to a phosphorylated form of an ADA substrate and not adenosine or deoxyadenosine. Further studies suggested that inhibition of SAH or ribonucleotide reductase was not sufficient to cause toxicity. Van de Wiele et al. (2002) concluded that the mechanism of dATP toxicity involves dATP-induced cytochrome c release from mitochondria, which initiates the apoptotic cascade. Apasov et al. (2001) found that Ada -/- mice had a pronounced decrease in the size and lymphocyte content of spleen, lymph nodes, and thymus at 3 weeks of age compared to wildtype mice. There was increased apoptosis of immature T cells in the thymi of mutant mice, but not in the peripheral lymphoid organs, indicating specific effects on developing T cells. In addition, mature CD4- and CD8-positive T cells from Ada -/- mice showed decreased T cell receptor (TCR; see 186880)-triggered activation in vivo and in vitro as a result of increased exogenous adenosine, to a lesser extent than in mature T cells of wildtype mice, indicating that adenosine can affect normal T cell activation. The nucleoside 2-prime-deoxyadenosine was directly cytotoxic to lymphocytes. Apasov et al. (2001) concluded that T-cell depletion in ADA-deficient SCID results from at least 2 mechanisms: intracellular toxicity of adenosine, dATP, and 2-prime-deoxyadenosine, and inhibition of T-cell signaling by elevated levels of adenosine. Diagnosis ### Prenatal Diagnosis Hirschhorn et al. (1975) diagnosed ADA deficiency in a fetus by finding less than 1.5% ADA activity in cultured amniotic fluid cells. An older sib had died from SCID due to ADA deficiency. Aitken et al. (1980) used a microradioassay to evaluate ADA activity in cultured amniotic fluid cells in a pregnancy at risk for ADA deficiency and SCID. A low-normal level of activity consistent with the heterozygous state was found in the fetus, which was confirmed after birth. In 2 subsequent pregnancies of a mother of a child with SCID due to ADA deficiency, Ziegler et al. (1981) assayed ADA activity in amniotic fluid fibroblasts and diagnosed a normal fetus and a homozygous ADA-deficient fetus, respectively. The diagnoses were confirmed after birth and in abortus tissue. Clinical Management ### Enzyme Replacement Therapy Polmar et al. (1976) reported successful treatment of a child with SCID due to ADA deficiency by 'enzyme replacement therapy' using frozen irradiated red blood cells with normal ADA activity. After treatment, a thymic shadow appeared radiographically, lymphocytic responses were demonstrated in vitro, and there was immunoglobulin synthesis. With infusions at 4-week intervals, the child remained free of infection for 17 months. Ziegler et al. (1980) reported a patient with SCID due to ADA deficiency who was treated with ADA-positive red cell infusions. Although there was some resolution of interstitial pneumonitis and skeletal abnormalities, there was no evidence of immunologic reconstitution, and the patient died at age 17 months. The authors noted that severe cases of SCID due to ADA deficiency may not respond to exogenous enzyme therapy. Markert et al. (1987) reported 5 ADA-deficient patients who showed no lasting benefit from red blood cell transfusions. Hershfield et al. (1987) reported successful treatment of 2 SCID ADA-deficient patients with polyethylene glycol-modified bovine intestinal ADA (PEG-ADA). The modified enzyme was rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses maintained plasma ADA activity at 2 to 3 times the level of red cell ADA in normal subjects, resulting in a decrease in toxic deoxyadenosine nucleotides to less than 0.5% of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of cellular immune function of each patient showed marked improvement, together with an increase in T lymphocytes. Covalent attachment of polyethylene glycol to ADA blocked access to vulnerable sites on the surface of the protein, inhibiting clearance from the circulation, attack by degrading enzymes, binding of antibodies, and processing by antigen-presenting cells. Levy et al. (1988) reported a child who developed symptoms of SCID due to ADA deficiency at age 3 years. She had 0.6% and 1% of normal ADA activity in erythrocytes and mononuclear cells, respectively. Weekly treatment with PEG-modified ADA was well tolerated and her T lymphocyte numbers and response to mitogens became normal. In a review, Hershfield (1995) noted that PEG-ADA works in the plasma by degrading adenosine (Ado) and deoxyadenosine (dAdo), followed by rapid equilibration with intracellular concentrations via a plasma membrane nucleoside transporter. After approximately 2 months of treatment, lymphocyte counts increase and show a proliferative response to mitogens in vitro, a thymic shadow may appear, and patients often develop persistent antibody titers. Although immune function is not normal, serious opportunistic infections usually resolve. Development of anti-ADA antibodies rarely occurs. Hershfield (1995) noted that PEG-ADA treatment is indicated for patients who lack an HLA-identical bone marrow donor, but are at too high a risk for HLA-haploidentical marrow transplantation. Mortality with PEG-ADA is lower than that with haploidentical bone marrow transplantation. ### Bone Marrow Transplantation Bortin and Rimm (1977) reported on the characteristics and results of treatment in 69 patients with SCID due to various causes; 4 of 25 (16%) patients tested had ADA deficiency. The highest 6-month survival rate occurred in those who had undergone bone marrow transplant (BMT) from HLA genotypically identical donors. In surveying 18 of 80 SCID patients who survived bone marrow transplantation, Kenny and Hitzig (1979) found that 3 of the 18 patients had ADA deficiency. Buckley et al. (1999) reported survival of 11 of 13 ADA-deficient patients who underwent bone marrow transplantation. Seven of 9 children who underwent haploidentical BMT were alive 1.6 to 15.6 years after transplantation, with hematopoietic chimerism demonstrable in 6. T-cell numbers and function improved approximately 3 to 4 months after transplantation; B-cell numbers and function improved to a lesser degree. Molecular Genetics ### Severe Combined Immunodeficiency due to ADA Deficiency In a patient with SCID due to ADA deficiency who was originally reported by Hirschhorn et al. (1975), Valerio et al. (1986) identified compound heterozygosity for 2 mutations in the ADA gene (608958.0001; 608958.0005). Akeson et al. (1987) reported several mutation in the ADA gene in patients with ADA-deficient SCID (see, e.g., 608958.0004; 608958.0006; 608958.0017). In 2 sisters with SCID due to ADA deficiency reported by Umetsu et al. (1994), Arredondo-Vega et al. (1994) identified compound heterozygosity for 2 splice site mutations in the ADA gene (608598.0022; 608598.0023). ### Delayed or Late-Onset SCID In 7 patients with delayed or late onset of SCID due to ADA deficiency, Santisteban et al. (1993) identified mutations in the ADA gene (see, e.g., 608958.0020 and 608958.0032). ### Partial ADA Deficiency In patients with partial ADA deficiency, Hirschhorn et al. (1989, 1990) identified several mutations in the ADA gene (608958.0009-608958.0015). Genotype/Phenotype Correlations Hirschhorn et al. (1994) reported a patient diagnosed with SCID due to ADA deficiency at age 2.5 years because of life-threatening pneumonia, recurrent infections, failure of normal growth, and lymphopenia. However, he retained significant cellular immune function. His condition improved dramatically in the absence of specific therapy, and he was a healthy adolescent at age 16 years with no medical problems at age 20 years. A fibroblast cell line and a B-cell line, established at the time of diagnosis, lacked ADA activity. Genetic analysis identified compound heterozygosity for a splice site mutation (608958.0024) and a missense mutation (608958.0003). All clones isolated from the B-cell mRNA carried the missense mutation, indicating that the allele with the splice site mutation produced unstable mRNA. In striking contrast, a B-cell line established at age 16 expressed 50% of normal ADA; 50% of ADA mRNA had normal sequence, and 50% had the missense mutation. Genomic DNA contained the missense mutation, but not the splice site mutation. Genomic DNA from peripheral blood cells obtained at 16 years of age indicated in vivo somatic mosaicism; less than half the DNA carried the splice site mutation (P less than 0.002, vs original B-cell line). Consistent with the mosaicism, erythrocyte content of the toxic metabolite deoxy-ATP was only minimally elevated. Hirschhorn et al. (1994) postulated that somatic mosaicism could have arisen by somatic mutation or by reversion at the site of mutation. Selection in vivo for ADA normal hematopoietic cells likely played a role in the return to normal health in the absence of therapy. Hirschhorn et al. (1996) reported a patient who presented during the first years of life with recurrent infections and lymphopenia. A prior sib died before age 3 years of SCID affecting both T and B cells. At age 5 years, the proband lacked ADA activity in erythrocytes, but concentrations of deoxy-ATP in red blood cells were only mildly elevated compared to concentrations found in severe SCID patients. Mononuclear cells had 15% of normal ADA activity. Both the mother and father had 50% and 20 to 25% normal activity in erythrocytes and lymphocytes, respectively. Between the ages of 8 and 12 years, the proband was clinically healthy, with normal growth and development, although he had persistent hyper-IgE, decreased numbers of CD4+ T cells and B cells, and increased numbers of CD8+ T cells. Genetic analysis identified compound heterozygosity for 2 mutations in the ADA gene: a splice site mutation (608958.0026), inherited from the father, and an R156H mutation (608958.0032) inherited from the mother. Peripheral blood from the proband at age 11 years showed the splice site and R156H mutations in 50% and 34%, respectively, of cells, whereas 17% of cells did not carry either mutation. Cell lines established showed virtual absence of the maternally derived R156H mutation, indicating in vivo reversion of the mutation to normal. A similar moderation of phenotype had been observed involving a revertant mutation in the IL2RG gene (308380) in X-linked SCID (300400) (Stephan et al., 1996). Revertant cells have also been identified in patients with Fanconi anemia (see 227650 and 227645), Bloom syndrome (210900), Wiskott-Aldrich syndrome (277970), and epidermolysis bullosa (226650) due to mutations in the COL17A1 gene (113811). In addition to back mutation, allele function has been restored by mitotic recombination or gene conversion, which can eliminate the original mutation, and by 'second-site' events that restore reading frame or led to an amino acid substitution better tolerated than the original. In Bloom syndrome, intragenic recombination or gene conversion are the usual mechanisms, consistent with reversion being much more common in heteroallelic than in homoallelic patients (Ellis et al., 1995). Arredondo-Vega et al. (2002) reported 1 member of a Saudi Arabian family with delayed onset of SCID due to a homozygous splice site mutation in the ADA gene (608958.0030) who also carried an acquired second distinct splice site mutation (608958.0031) that suppressed the defect of the first mutation. The patient had a milder phenotype than his sister who did not carry the second mutation. Arredondo-Vega et al. (1998) noted that the phenotype of ADA deficiency is strongly associated with the sum of ADA activity provided by both alleles. Many mutations are private and patients are often heteroallelic, precluding definite genotype/phenotype correlations. Functional expression analysis of 29 different missense mutations expressed in an ADA-deleted E. coli strain showed that alleles from immunodeficient patients expressed 0.001 to 0.6% ADA activity compared to wildtype. Alleles found only in healthy individuals with partial deficiency showed 1 to 28% of normal activity. In all, the activity levels spanned 5 orders of magnitude. The authors found that 1 to 1.5% residual ADA activity was consistent with sustaining immune function. There was a strong inverse correlation between red cell dAXP concentration and the sum of ADA activity expressed by both alleles, establishing a direct link between the effects of genotype on residual ADA activity, metabolism, and clinical expression. Animal Model Abbott et al. (1986) presented evidence that 'wasted' (wst) in mice is caused by a mutation in the structural gene for ADA. As occurs in humans with ADA deficiency, wasted mice are immunodeficient, develop neurologic abnormalities, and die soon after weaning. Unlike humans, mice that express no adenosine deaminase die perinatally of severe hepatocellular degeneration (Migchielsen et al., 1995; Wakamiya et al., 1995). Blackburn et al. (1998) reported the use of a 2-stage genetic engineering strategy to generate ADA-deficient mice that retained many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T- and B-cell lymphopenia was accompanied by a pronounced accumulation of 2-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in the same organs. Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathology. INHERITANCE \- Autosomal recessive \- Somatic mosaicism GROWTH Other \- Failure to thrive RESPIRATORY Nasopharynx \- Sinusitis Airways \- Asthma Lung \- Pneumonia CHEST External Features \- Cupping and flaring of costochondral junctions ABDOMEN Liver \- Hepatomegaly Spleen \- Splenomegaly Gastrointestinal \- Diarrhea GENITOURINARY Kidneys \- Mesangial sclerosis SKELETAL Spine \- Platyspondyly Pelvis \- Pelvic dysplasia Limbs \- Thick growth arrest lines HEMATOLOGY \- Autoimmune hemolytic anemia \- Idiopathic thrombocytopenia \- Eosinophilia IMMUNOLOGY \- Frequent fungal, viral, and opportunistic infections \- Lymphopenia \- Absent B cells \- Absent T cells \- Absent or reduced CD3+ cells \- Absent or small dysplastic thymus \- Absent specific antibody response NEOPLASIA \- B-cell lymphoma LABORATORY ABNORMALITIES \- Reduced erythrocyte adenosine deaminase activity \- Increased IgE levels \- Low or absent IgA levels \- Low or absent IgM levels \- Absent IgG2 subclass \- CD4+/CD8+ ratio often reversed \- Elevated serum levels of adenosine \- Elevated serum levels of 2-prime deoxyadenosine MISCELLANEOUS \- Late onset combined immunodeficiency with allelic variant 102700.0020 \- 85-90% with manifestations in first months of life \- 10-15% with primarily defects of cellular immunity, not manifesting until >2yrs of age \- Recurrent bacterial, viral, and fungal infections \- Treatment with polyethylene glycol-modified bovine ADA, bone marrow transplantation, and/or gene therapy MOLECULAR BASIS \- Caused by mutation in the adenosine deaminase gene (ADA, 102700.0001 ) ▲ 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	SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY	c0392607	6,542	omim	https://www.omim.org/entry/102700	2019-09-22T16:45:25	{"doid": ["5810"], "mesh": ["C531816"], "omim": ["102700"], "orphanet": ["277"], "synonyms": ["Alternative titles", "SCID DUE TO ADA DEFICIENCY", "ADA-SCID", "SCID DUE TO ADA DEFICIENCY, EARLY-ONSET"], "genereviews": ["NBK1483"]}
## Clinical Features A common form of X-linked ichthyosis (308100), also known as steroid sulfatase deficiency, is caused by mutation in the STS gene (300747). Robledo et al. (1995) described a Sardinian kindred in which congenital ichthyosis was associated with normal levels of steroid sulfatase and a normal pattern on Southern blot analysis suggesting the presence of an intact STS gene. Mapping Although the pedigree pattern in the kindred with ichthyosis studied by Robledo et al. (1995) was entirely consistent with X-linked recessive inheritance, the disorder was found to segregate independently of genetic polymorphisms detected by probes mapping to Xp22.3, where the STS gene maps. The search for linkage to markers elsewhere on the X chromosome had not been successful. Robledo et al. (1995) concluded that there may be a form of X-linked ichthyosis due to some mechanism other than STS deficiency. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	ICHTHYOSIS, X-LINKED, WITHOUT STEROID SULFATASE DEFICIENCY	c2720163	6,543	omim	https://www.omim.org/entry/300001	2019-09-22T16:21:09	{"mesh": ["D016114"], "omim": ["300001"], "orphanet": ["461"]}
A number sign (#) is used with this entry because of evidence that Eiken syndrome is caused by homozygous mutation in the PTHR1 gene (168468) on chromosome 3p21. Clinical Features In a consanguineous Turkish family living in Denmark, Eiken et al. (1984) described 3 brothers with a skeletal dysplasia characterized by severely retarded ossification, principally of the epiphyses, pelvis, hands, and feet. In the hands and feet, the retarded ossification was combined with a strikingly abnormal modeling of the bones. All the children appeared normal at birth. There was no mental retardation. The possibility of recessive inheritance was increased by the report of a maternal aunt, married to a cousin of both parents, who had a son and a daughter with dwarfism and characteristics similar to those in the 3 brothers. Eiken et al. (1984) concluded that the disorder in this kindred was quite different from any previously described disorder. Duchatelet et al. (2005) noted that the skeletal features of Eiken syndrome are opposite to those in Blomstrand chondrodysplasia (215045), in which patients have advanced skeletal maturation. Moirangthem et al. (2018) reported a 7-year-old boy, born to first-cousin parents, with several features consistent with Eiken syndrome, including type A1 brachydactyly, coarse bone trabeculae in the tubular bones, and delayed ossification of the pubic symphysis, carpal bones, and the epiphyses of the hands. In addition, the patient had failure of eruption of primary teeth and supernumerary epiphyses of the tubular bones of the hands. He had an elevated PTH with normal serum calcium levels; nutritional vitamin D deficiency was also present in the patient and may have been responsible for some of the findings. His parents were unaffected and did not have delayed tooth eruption or any tooth impaction. Mapping By linkage analysis with the original pedigree, Duchatelet et al. (2005) mapped Eiken syndrome to an approximately 50-cM region of chromosome 3p, between markers D3S2338 and D3S1285. Molecular Genetics Because of its implication in forms of chondrodysplasia and its role in bone development, Duchatelet et al. (2005) examined the PTHR1 gene as a candidate for Eiken syndrome. They identified a nonsense mutation in the C-terminal cytoplasmic tail of the PTHR1 gene (168468.0009) in homozygosity in affected individuals. Eiken syndrome is clinically distinct from Jansen (156400) and Blomstrand (215045) chondrodysplasias and from enchondromatosis (166000), which are also caused by PTHR1 mutations. In a 7-year-old boy with Eiken syndrome, who was born to unaffected first-cousin parents, Moirangthem et al. (2018) identified a homozygous missense mutation at a conserved residue in the PTHR1 gene (E35K; 168468.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in his parents. The variant was not found in several public databases (ExAC, gnomAD, and 1000 Genomes Project) or in an in-house exome database of 417 families. Protein modeling predicted that the mutation would disrupt normal protein function. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (<0.3 SD) HEAD & NECK Teeth \- Failure of eruption of primary teeth SKELETAL Spine \- Agenesis of the sacrum, partial Pelvis \- Delayed ossification of the pelvis, severe \- Narrow pelvis Limbs \- Short fibulae \- Delayed ossification of the epiphyses, severe \- Reduced elbow flexion Hands \- Delayed ossification of the bones in the hands \- Abnormal modeling of bones of the hands \- Short fingers \- Brachydactyly, type A1 Feet \- Delayed ossification of bones in the feet, severe \- Abnormal modeling of bones of the feet NEUROLOGIC Central Nervous System \- Normal intelligence MISCELLANEOUS \- Ossification of bones improves with age \- Based on reports of 3 Turkish brothers and an unrelated boy (last curated January 2019) MOLECULAR BASIS \- Caused by mutation in the parathyroid hormone receptor-1 gene (PTHR1, 168468.0009 ) ▲ 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	EIKEN SYNDROME	c1838779	6,544	omim	https://www.omim.org/entry/600002	2019-09-22T16:16:45	{"mesh": ["C564010"], "omim": ["600002"], "orphanet": ["79106"], "synonyms": ["Alternative titles", "EIKEN SKELETAL DYSPLASIA", "BONE MODELING DEFECT OF HANDS AND FEET"]}
A number sign (#) is used with this entry because neonatal Bartter syndrome type 4A with sensorineural deafness (BARTS4A) is caused by homozygous or compound heterozygous mutation in the BSND gene (606412) on chromosome 1p32. Description Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal (or neonatal) forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364. Clinical Features Seyberth et al. (1985) described an infantile variant of Bartter syndrome. that was usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis, and a typical appearance. Some of the infants with the infantile variant of Bartter syndrome had been described as having a prominent forehead, triangular facies with drooping mouth, and large eyes and pinnae. In 5 children of an extended consanguineous Bedouin family, Landau et al. (1995) observed the combination of the infantile variant of Bartter syndrome and sensorineural deafness. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. Deafness was detected as early as age 1 month. Shalev et al. (2003) evaluated 13 affected members of the family described by Landau et al. (1995). Most did not have persistent hypercalciuria and nephrocalcinosis nor was early renal function deterioration uniformly present. Jeck et al. (2001) reported clinical findings in 8 patients from 6 consanguineous families with hypokalemic salt-losing tubulopathy showing linkage to 1p31. Clinical presentation was homogeneous and included premature birth attributable to polyhydramnios, severe renal salt loss, stimulation of the renin-angiotensin-aldosterone axis, hypokalemic alkalosis, and hyperprostaglandin E-uria. Patients later developed potassium-wasting, inability to concentrate the urine, and chronic renal failure. All patients showed severe muscle hypotonia, motor retardation, and complete sensorineural hearing loss. Response to indomethacin was poor. Miyamura et al. (2003) reported a Japanese man who was born of consanguineous parents and had congenital sensorineural deafness but was not diagnosed with Bartter syndrome until age 28 years, when he presented with fatigue, numbness and weakness in both legs, and polydipsia. Characteristic features such as maternal polyhydramnios, premature labor, or severe salt loss in the neonatal period were not present in this patient, although he reportedly had polydipsia with polyuria in childhood. On examination, he had a peculiar facies similar to that reported in Costa Rican children with antenatal-onset Bartter syndrome (601678), characterized by a triangularly shaped face, protruding ears, and drooping mouth (Madrigal et al., 1997). Plasma renin activity, aldosterone, angiotensin II, and vasopressin levels were elevated, and he had impaired urine-concentrating ability. A routine abdominal x-ray showed nephrocalcinosis, although he did not have hypercalciuria or a history of renal calculi. Neither parent manifested any clinical symptoms of Bartter syndrome, and audiograms revealed moderate hearing loss consistent with their age. Miyamura et al. (2003) stated that this was the first case report of Bartter syndrome from Japan. Mapping Using a DNA-pooling strategy, Brennan et al. (1998) performed a genomewide linkage screen in the kindred reported by Landau et al. (1995) and demonstrated linkage of Bartter syndrome with sensorineural deafness to 1p31. They excluded the CLCNKA and CLCNKB genes, which encode kidney-specific chloride channels and map to 1p36. They also excluded the gene encoding amiloride-sensitive Na(+)-H(+) antiporter (SLC9A1; 107310), which maps to 1p36.1-p35. The findings in this family demonstrate further genetic heterogeneity of Bartter syndrome. In addition, the cosegregation of deafness in Bartter syndrome in individuals in 5 separate sibships, some of whom are moderately distantly related, with the same haplotype of markers surrounding the locus appear to prove that this syndrome is due to the pleiotropic effects of a single gene. Vollmer et al. (2000) demonstrated linkage to 1p31 in 9 consanguineous families with antenatal Bartter syndrome with sensorineural deafness. They refined the critical disease region to a 4.0-cM interval flanked by markers D1S2661 and D1S475. ### Sensorineural Deafness With Mild Renal Dysfunction Riazuddin et al. (2009) performed genomewide linkage analysis in 2 consanguineous Pakistani families segregating apparent nonsyndromic deafness, designated DFNB73, and found linkage to chromosome 1p32. Screening of approximately 700 Pakistani families using microsatellite markers in the DFNB73 linkage interval revealed 2 additional consanguineous families segregating deafness linked to DFNB73. Meiotic breakpoint information in the 4 families defined a 4.04-cM interval containing 26 genes, including BSND (606412). Molecular Genetics Birkenhager et al. (2001) identified 7 different mutations in the BSND gene (606412.0001-606412.0007) in 10 families with Bartter syndrome with sensorineural deafness. To clone the BSND gene, Birkenhager et al. (2001) generated combined YAC/BAC contigs spanning the 4-cM interval between flanking markers D1S2661 and D1S475. Extensive haplotype sharing was detected between 5 families of Turkish descent, which narrowed the critical genetic interval to less than 900 kb. Within this interval a cloning gap persisted even after extensive screening, prompting submission of a clone bridging this gap to the Sanger Center for sequencing. Ten genes other than BSND were identified within the critical region; no mutations were found other than those in BSND. In a Japanese man who was born of consanguineous parents and had congenital sensorineural deafness and mild Bartter syndrome that went undiagnosed until 28 years of age, Miyamura et al. (2003) identified homozygosity for a missense mutation in the BSND gene (G47R; 606412.0008). The unaffected parents were heterozygous for the mutation. ### Sensorineural Deafness With Mild Renal Dysfunction In affected individuals of 3 consanguineous Pakistani families segregating apparent nonsyndromic deafness, designated DFNB73, and mapping to chromosome 1p32, Riazuddin et al. (2009) identified homozygosity for a missense mutation, ile12 to thr (I12T; 606412.0009), in the BSND gene. In a fourth consanguineous Pakistani DFNB73 family, 22 of 25 affected individuals were homozygous for I12T, whereas 3 were compound heterozygous for I12T and another missense mutation, glu4 to ter (E4X; 606412.0010). Neither mutation was found in 384 Pakistani control chromosomes. Audiometric evaluation showed severe hearing loss across all frequencies, with no difference between homozygotes and compound heterozygotes. Further evaluation revealed minimal renal dysfunction in the I12T homozygotes involving only elevated renin levels and hypocalciuria, whereas the 3 compound heterozygotes displayed nephrocalcinosis, elevated renin levels, and electrolyte levels consistent with borderline but clinically insignificant metabolic alkalosis and hypokalemia. INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Ears \- Deafness, sensorineural GENITOURINARY Kidneys \- Renal salt wasting \- Inability to concentrate urine \- Polyuria \- Decreased glomerular filtration rate \- Renal failure, chronic \- Ultrasound shows hyperechoic kidneys \- Renal biopsy shows tubulointerstitial fibrosis \- Global glomerulosclerosis \- Loss of definition of corticomedullary differentiation MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed motor development \- Hyporeflexia \- Mental retardation \- Motor retardation METABOLIC FEATURES \- Hypokalemic hypochloremic metabolic alkalosis ENDOCRINE FEATURES \- Stimulation of the renin/angiotensin/aldosterone axis \- Hyperaldosteronism PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios \- Fetal hydrops \- Fetal polyuria Delivery \- Premature delivery LABORATORY ABNORMALITIES \- Hypokalemia \- Hyponatremia \- Hypochloremia \- Urinary prostaglandin E \- Increased urinary sodium \- Increased urinary potassium \- Increased urinary chloride MISCELLANEOUS \- Onset in utero \- Severe volume depletion \- Genetic heterogeneity \- See also antenatal Bartter syndrome type 1 ( 601678 ), Bartter syndrome type 2 ( 241200 ), Bartter syndrome 3 ( 607364 ), and Bartter syndrome 4b digenic ( 613090 ) MOLECULAR BASIS \- Caused by mutation in the barttin gene (BSND, 606412.0001 ) ▲ 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	BARTTER SYNDROME, TYPE 4A, NEONATAL, WITH SENSORINEURAL DEAFNESS	c0004775	6,545	omim	https://www.omim.org/entry/602522	2019-09-22T16:13:38	{"doid": ["0110145"], "mesh": ["D001477"], "omim": ["602522"], "orphanet": ["89938", "112"], "synonyms": ["Alternative titles", "Bartter syndrome type IV", "Bartter syndrome type 4", "BARTTER SYNDROME, NEONATAL, WITH SENSORINEURAL DEAFNESS"]}
A rare acute myeloid leukemia that occurs predominantly in childhood and particularly in children with Down syndrome (DS-AMKL). Nonspecific symptoms may be irritability, weakness, and dizziness while specific symptoms include pallor, fever, mucocutaneous bleeding, hepatosplenomegaly, neurological manifestations and rarely lymphadenopathy. Acute panmyelosis with myelofibrosis may also be associated with AMKL. In contrast to DS-AMKL (around 80 % survival), non-DS-AMKL is an AML subgroup associated with poor prognosis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Acute megakaryoblastic leukemia	c0023462	6,546	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=518	2021-01-23T18:36:59	{"gard": ["524"], "mesh": ["D007947"], "umls": ["C0023462"], "icd-10": ["C94.2"], "synonyms": ["AMKL", "AML M7", "Acute megakaryocytic leukemia", "Acute myeloid leukemia M7"]}
Epidermolysis bullosa dystrophica Other namesDystrophic EB SpecialtyMedical genetics Epidermolysis bullosa dystrophica or dystrophic EB (DEB) is an inherited disease affecting the skin and other organs.[1][2] "Butterfly child" is the colloquial name for a child born with the disease, as their skin is seen to be as delicate and fragile as the wings of a butterfly.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Classification * 5 See also * 6 References * 6.1 Sources * 7 External links ## Signs and symptoms[edit] The deficiency in anchoring fibrils impairs the adherence between the epidermis and the underlying dermis. The skin of DEB patients is thus highly susceptible to severe blistering.[citation needed] Collagen VII is also associated with the epithelium of the esophageal lining, and DEB patients may suffer from chronic scarring, webbing, and obstruction of the esophagus. Affected individuals are often severely malnourished due to trauma to the oral and esophageal mucosa and require feeding tubes for nutrition. They also suffer from iron-deficiency anemia of uncertain origin, which leads to chronic fatigue. Open wounds on the skin heal slowly or not at all, often scarring extensively, and are particularly susceptible to infection. Many individuals bathe in a bleach and water mixture to fight off these infections.[citation needed] The chronic inflammation leads to errors in the DNA of the affected skin cells, which in turn causes squamous cell carcinoma (SCC). The majority of these patients die before the age of 30, either of SCC or complications related to DEB. The chronic inflammatory state seen in recessive dystrophic epidermolysis bullosa (RDEB) may cause small fiber peripheral neuropathy (SFN);[4] RDEB patients have reported the sensation of pain in line with neuropathic pain qualities.[5] ## Causes[edit] DEB is caused by genetic defects (or mutations) within the human COL7A1 gene encoding the protein type VII collagen (collagen VII).[6] DEB-causing mutations can be either dominant or recessive.[citation needed] Most families with family members with this condition have distinct mutations.[7] Collagen VII is a very large molecule (300 kDa) that dimerizes to form a semicircular looping structure: the anchoring fibril. Anchoring fibrils are thought to form a structural link between the epidermal basement membrane and the fibrillar collagens in the upper dermis. ## Pathophysiology[edit] In the absence of mutations of the COL7A1 gene, an autoimmune response against type VII collagen can result in an acquired form of epidermolysis bullosa called epidermolysis bullosa acquisita.[8] There exist other types of inherited epidermolysis bullosa, junctional epidermolysis bullosa and epidermolysis bullosa simplex, which are not related to type VII collagen deficiency. These arise from mutations in the genes encoding other proteins of the epidermis or the basement membrane at the junction between the epidermis and the dermis.[9] ## Diagnosis[edit] ### Classification[edit] Name Locus & Gene OMIM Dominant dystrophic epidermolysis bullosa (DDEB) Also known as "Cockayne-Touraine disease", this variant is characterized by vesicles and bullae on the extensor surfaces of the extremities.[10][11] 3p21.3 (COL7A1) 131750 Recessive dystrophic epidermolysis bullosa (RDEB) Also known as "Hallopeau–Siemens variant of epidermolysis bullosa"[12] and "Hallopeau–Siemens disease",[13] this variant results from mutations in the gene encoding type VII collagen, COL7A1, characterized by debilitating oral lesions that produce pain, scarring, and microstomia.[14][11] It is named for François Henri Hallopeau and Hermann Werner Siemens. 3q22-q23 (COL7A1), 3p21.3 (MMP1) 226600 Epidermolysis bullosa dystrophica, pretibial 3p21.3 (COL7A1) 131850 Epidermolysis bullosa pruriginosa 3p21.3 (COL7A1) 604129 Epidermolysis bullosa with congenital localized absence of skin and deformity of nails 3p21.3 (COL7A1) 132000 Transient bullous dermolysis of the newborn (TBDN) 3p21.3 (COL7A1) 131705 ## See also[edit] * Epidermolysis bullosa ## References[edit] 1. ^ Reference, Genetics Home. "dystrophic epidermolysis bullosa". Genetics Home Reference. Retrieved 2017-04-03. 2. ^ Bardhan, Ajoy; Bruckner-Tuderman, Leena; Chapple, Iain L. C.; Fine, Jo-David; Harper, Natasha; Has, Cristina; Magin, Thomas M.; Marinkovich, M. Peter; Marshall, John F.; McGrath, John A.; Mellerio, Jemima E. (2020-09-24). "Epidermolysis bullosa". Nature Reviews Disease Primers. 6 (1): 1–27. doi:10.1038/s41572-020-0210-0. ISSN 2056-676X. S2CID 221861310. 3. ^ Pittman, Taylor (2015-04-21). "'Butterfly Child' With Rare, Painful Condition Displays Strength That Will Blow You Away". Huffington Post. Retrieved 2017-07-14. 4. ^ [1], Recessive dystrophic epidermolysis bullosa results in painful small fibre neuropathy. 5. ^ Schräder NHB, Yuen WY, Jonkman MF (2018). "Pain Quality Assessment Scale for Epidermolysis Bullosa". Acta Derm Venereol. 98 (3): 346–349. doi:10.2340/00015555-2827. PMID 29057428.CS1 maint: multiple names: authors list (link) 6. ^ Varki, R.; Sadowski, S.; Uitto, J.; Pfendner, E. (March 2007). "Epidermolysis bullosa. II. Type VII collagen mutations and phenotype–genotype correlations in the dystrophic subtypes". Journal of Medical Genetics. 44 (3): 181–92. doi:10.1136/jmg.2006.045302. PMC 2598021. PMID 16971478. 7. ^ Csikós, M.; Szőcs, H. I.; Lászik, A.; Mecklenbeck, S.; Horváth, A.; Kárpáti, S.; Bruckner-Tuderman, L. (May 2005). "High frequency of the 425A→G splice-site mutation and novel mutations of the COL7A1 gene in central Europe: significance for future mutation detection strategies in dystrophic epidermolysis bullosa". British Journal of Dermatology. 152 (5): 879–886. doi:10.1111/j.1365-2133.2005.06542.x. PMID 15888141. S2CID 44394902. 8. ^ Mihai, Sidonia; Sitaru, Cassian (May–June 2007). "Immunopathology and molecular diagnosis of autoimmune bullous diseases". Journal of Cellular and Molecular Medicine. 11 (3): 462–481. doi:10.1111/j.1582-4934.2007.00033.x. PMC 3922353. PMID 17521373. 9. ^ Fine, Jo-David; Eady, Robin A. J.; Bauer, Eugene A.; Bauer, Johann W.; Bruckner-Tuderman, Leena; Heagerty, Adrian; Hintner, Helmut; Hovnanian, Alain; Jonkman, Marcel F.; Leigh, Irene; McGrath, John A.; Mellerio, Jemima E.; Murrell, Dedee F.; Shimizu, Hiroshi; Uitto, Jouni; Vahlquist, Anders; Woodley, David; Zambruno, Giovanna (2008). "The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB". Journal of the American Academy of Dermatology. 58 (6): 931–950. doi:10.1016/j.jaad.2008.02.004. PMID 18374450. 10. ^ James, Berger & Elston 2005, p. 558 11. ^ a b Freedberg et al. 2003, p. 601 12. ^ Freedberg et al. 2003 13. ^ Rapini, Bolognia & Jorizzo 2007, p. 458 14. ^ James, Berger & Elston 2005, pp. 558–9 ### Sources[edit] * Freedberg, Irwin M.; Eisen, Arthur Z.; Wolff, Klauss; Austen, K. Frank; Goldsmith, Lowell A.; Katz, Stephen I., eds. (2003). Fitzpatrick's Dermatology in General Medicine (6th ed.). McGraw-Hill. ISBN 978-0-07-138076-8.CS1 maint: ref=harv (link) * James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 978-0-7216-2921-6.CS1 maint: ref=harv (link) * Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.CS1 maint: ref=harv (link) ## External links[edit] Classification D * ICD-10: Q81.2 * ICD-9-CM: 757.39 * OMIM: 131750 * MeSH: D016108 * DiseasesDB: 29580 * SNOMED CT: 254185007 * ebd at NIH/UW GeneTests * v * t * e Congenital malformations and deformations of integument / skin disease Genodermatosis Congenital ichthyosis/ erythrokeratodermia AD * Ichthyosis vulgaris AR * Congenital ichthyosiform erythroderma: Epidermolytic hyperkeratosis * Lamellar ichthyosis * Harlequin-type ichthyosis * Netherton syndrome * Zunich–Kaye syndrome * Sjögren–Larsson syndrome XR * X-linked ichthyosis Ungrouped * Ichthyosis bullosa of Siemens * Ichthyosis follicularis * Ichthyosis prematurity syndrome * Ichthyosis–sclerosing cholangitis syndrome * Nonbullous congenital ichthyosiform erythroderma * Ichthyosis linearis circumflexa * Ichthyosis hystrix EB and related * EBS * EBS-K * EBS-WC * EBS-DM * EBS-OG * EBS-MD * EBS-MP * JEB * JEB-H * Mitis * Generalized atrophic * JEB-PA * DEB * DDEB * RDEB * related: Costello syndrome * Kindler syndrome * Laryngoonychocutaneous syndrome * Skin fragility syndrome Ectodermal dysplasia * Naegeli syndrome/Dermatopathia pigmentosa reticularis * Hay–Wells syndrome * Hypohidrotic ectodermal dysplasia * Focal dermal hypoplasia * Ellis–van Creveld syndrome * Rapp–Hodgkin syndrome/Hay–Wells syndrome Elastic/Connective * Ehlers–Danlos syndromes * Cutis laxa (Gerodermia osteodysplastica) * Popliteal pterygium syndrome * Pseudoxanthoma elasticum * Van der Woude syndrome Hyperkeratosis/ keratinopathy PPK * diffuse: Diffuse epidermolytic palmoplantar keratoderma * Diffuse nonepidermolytic palmoplantar keratoderma * Palmoplantar keratoderma of Sybert * Meleda disease * syndromic * connexin * Bart–Pumphrey syndrome * Clouston's hidrotic ectodermal dysplasia * Vohwinkel syndrome * Corneodermatoosseous syndrome * plakoglobin * Naxos syndrome * Scleroatrophic syndrome of Huriez * Olmsted syndrome * Cathepsin C * Papillon–Lefèvre syndrome * Haim–Munk syndrome * Camisa disease * focal: Focal palmoplantar keratoderma with oral mucosal hyperkeratosis * Focal palmoplantar and gingival keratosis * Howel–Evans syndrome * Pachyonychia congenita * Pachyonychia congenita type I * Pachyonychia congenita type II * Striate palmoplantar keratoderma * Tyrosinemia type II * punctate: Acrokeratoelastoidosis of Costa * Focal acral hyperkeratosis * Keratosis punctata palmaris et plantaris * Keratosis punctata of the palmar creases * Schöpf–Schulz–Passarge syndrome * Porokeratosis plantaris discreta * Spiny keratoderma * ungrouped: Palmoplantar keratoderma and spastic paraplegia * desmoplakin * Carvajal syndrome * connexin * Erythrokeratodermia variabilis * HID/KID Other * Meleda disease * Keratosis pilaris * ATP2A2 * Darier's disease * Dyskeratosis congenita * Lelis syndrome * Dyskeratosis congenita * Keratolytic winter erythema * Keratosis follicularis spinulosa decalvans * Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome * Keratosis pilaris atrophicans faciei * Keratosis pilaris Other * cadherin * EEM syndrome * immune system * Hereditary lymphedema * Mastocytosis/Urticaria pigmentosa * Hailey–Hailey see also Template:Congenital malformations and deformations of skin appendages, Template:Phakomatoses, Template:Pigmentation disorders, Template:DNA replication and repair-deficiency disorder Developmental anomalies Midline * Dermoid cyst * Encephalocele * Nasal glioma * PHACE association * Sinus pericranii Nevus * Capillary hemangioma * Port-wine stain * Nevus flammeus nuchae Other/ungrouped * Aplasia cutis congenita * Amniotic band syndrome * Branchial cyst * Cavernous venous malformation * Accessory nail of the fifth toe * Bronchogenic cyst * Congenital cartilaginous rest of the neck * Congenital hypertrophy of the lateral fold of the hallux * Congenital lip pit * Congenital malformations of the dermatoglyphs * Congenital preauricular fistula * Congenital smooth muscle hamartoma * Cystic lymphatic malformation * Median raphe cyst * Melanotic neuroectodermal tumor of infancy * Mongolian spot * Nasolacrimal duct cyst * Omphalomesenteric duct cyst * Poland anomaly * Rapidly involuting congenital hemangioma * Rosenthal–Kloepfer syndrome * Skin dimple * Superficial lymphatic malformation * Thyroglossal duct cyst * Verrucous vascular malformation * Birthmark * v * t * e Diseases of collagen, laminin and other scleroproteins Collagen disease COL1: * Osteogenesis imperfecta * Ehlers–Danlos syndrome, types 1, 2, 7 COL2: * Hypochondrogenesis * Achondrogenesis type 2 * Stickler syndrome * Marshall syndrome * Spondyloepiphyseal dysplasia congenita * Spondyloepimetaphyseal dysplasia, Strudwick type * Kniest dysplasia (see also C2/11) COL3: * Ehlers–Danlos syndrome, types 3 & 4 * Sack–Barabas syndrome COL4: * Alport syndrome COL5: * Ehlers–Danlos syndrome, types 1 & 2 COL6: * Bethlem myopathy * Ullrich congenital muscular dystrophy COL7: * Epidermolysis bullosa dystrophica * Recessive dystrophic epidermolysis bullosa * Bart syndrome * Transient bullous dermolysis of the newborn COL8: * Fuchs' dystrophy 1 COL9: * Multiple epiphyseal dysplasia 2, 3, 6 COL10: * Schmid metaphyseal chondrodysplasia COL11: * Weissenbacher–Zweymüller syndrome * Otospondylomegaepiphyseal dysplasia (see also C2/11) COL17: * Bullous pemphigoid COL18: * Knobloch syndrome Laminin * Junctional epidermolysis bullosa * Laryngoonychocutaneous syndrome Other * Congenital stromal corneal dystrophy * Raine syndrome * Urbach–Wiethe disease * TECTA * DFNA8/12, DFNB21 see also fibrous 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	Epidermolysis bullosa dystrophica	c0079294	6,547	wikipedia	https://en.wikipedia.org/wiki/Epidermolysis_bullosa_dystrophica	2021-01-18T19:10:35	{"gard": ["2150"], "mesh": ["D016108"], "umls": ["C0079294"], "icd-9": ["757.39"], "orphanet": ["303"], "wikidata": ["Q3589131"]}
Neurodegeneration with brain iron accumulation (NBIA, formerly Hallervorden-Spatz syndrome) encompasses a group of rare neurodegenerative disorders characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation in the brain and the presence of axonal spheroids, usually limited to the central nervous system. ## Epidemiology An estimated prevalence of 1-3/1,000,000 has been suggested based on observed cases in a population. The most common form of NBIA is pantothenate kinase-associated neurodegeneration (PKAN; see this term), which accounts for approximately 50% of cases. ## Clinical description NBIA can present as early onset with rapid progression: classic pantothenate kinase-associated neurodegeneration (PKAN), infantile neuroaxonal dystrophy (INAD) and atypical neuroaxonal dystrophy (atypical NAD) (see these terms); or later onset with slower progression: atypical PKAN, neuroferritinopathy and aceruloplasminemia (see these terms). Idiopathic NBIA can have either type of onset and progression. ## Etiology Classic and atypical PKAN are caused by mutations in the PANK2 gene (20p13-p12.3), infantile and atypical neuroaxonal dystrophy are caused by mutation in the PLA2G6 gene (22q13.1), aceruloplasminemia is caused by mutation of the ceruloplasmin (CP) gene (3q23-q24) and neuroferritinopathy is caused by mutations in the ferritin light chain (FTL1) gene (19q13.3-q13.4). Idiopathic NBIA is likely caused by several additional, as yet undiscovered genes. ## Diagnostic methods This heterogeneous group of disorders can be differentiated by clinical, radiographic, and molecular features. Brain MRI is standard in the diagnostic evaluation of all forms of NBIA. Individuals with PKAN and HARP syndrome, which is considered part of the PKAN disease spectrum, show a characteristic "eye of the tiger''sign on MRI, a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. Infantile and atypical NAD have characteristic axonal swellings throughout the central and peripheral nervous system. Diagnosis of aceruloplasminemia is based on the absence of serum ceruloplasmin in combination with MRI findings of iron accumulation. ## Genetic counseling The majority of NBIA types are transmitted in an autosomal recessive manner, except neuroferritinopathy which is transmitted in an autosomal dominant manner with high penetrance. ## Management and treatment At this time most treatments for NBIA are palliative. Research is currently underway to identify additional NBIA genes and improve treatment possibilities by characterizing the underlying causes of these disorders. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Neurodegeneration with brain iron accumulation	c2931845	6,548	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=385	2021-01-23T18:24:13	{"gard": ["11899"], "mesh": ["C538421"], "umls": ["C2931845"], "icd-10": ["G23.0"], "synonyms": ["NBIA"]}
Anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome is a multiple congenital anomalies syndrome, reported in the offsprings of a consanguineous couple and characterized by multiple congenital skeletal (dolichocephaly, skull asymmetry, camptodactyly, clubfoot), muscular (muscle hypoplasia), ocular (anophthalmia, buphthalmos, retinal detachment, aniridia (see this term)) and cardiac (prolapse of tricuspid valves, mitral and tricuspid insufficiency) abnormalities. An autosomal recessive inheritance with variable expressivity was suspected. There have been no further descriptions in the literature since 1992. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome	c4304035	6,549	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1101	2021-01-23T18:46:11	{"gard": ["717"], "icd-10": ["Q87.8"], "synonyms": ["Cassia Stocco dos Santos syndrome"]}
A number sign (#) is used with this entry because of evidence that familial erythrocytosis-5 (ECYT5) is caused by heterozygous mutation in the EPO gene (133170) on chromosome 7q22. Description Erythrocytosis-5 is an autosomal dominant clinical condition characterized by increased red cell mass and typically elevated hemoglobin concentration and hematocrit. Some patients have increased serum EPO levels (summary by Zmajkovic et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (133100). Clinical Features Ly et al. (1983) reported 5 persons in 3 generations with familial erythrocytosis associated with decreased erythropoietin as measured by a cell culture assay. Hemoglobin function and 2,3-diphosphoglycerate were normal. Zmajkovic et al. (2018) reported follow-up of the family reported by Ly et al. (1983). Affected individuals typically had headaches and dizziness that disappeared after phlebotomy. Most had increased hemoglobin and elevated serum EPO. Camps et al. (2016) reported a 3-year-old girl with asymptomatic erythrocytosis. She had increased hemoglobin and hematocrit. Her father and paternal grandmother were similarly affected. Inheritance The transmission pattern of ECYT5 in the family reported by Ly et al. (1983) and Zmajkovic et al. (2018) was consistent with autosomal dominant inheritance. Molecular Genetics In 10 affected members of a 4-generation Norwegian family with ECYT5, Zmajkovic et al. (2018) identified a heterozygous 1-bp deletion (c.32delG; 133170.0002) in exon 2 of the EPO gene, within the signal peptide. The mutation, which was found by linkage analysis and candidate gene sequencing, segregated with the disorder in the family. The authors were unable to study patient tissue, so they used CRISPR to introduce the mutation into Hep3B human cells. The supernatant of mutant cells contained an 8- to 10-fold increase in biologically active EPO, indicating that the mutation paradoxically results in a gain of function, not a loss of function. Analysis of mRNA in wildtype Hep3B cells identified the wildtype EPO transcript produced from the physiologic promoter (P1) as well as 2 additional noncoding transcripts, a long and a short transcript, from use of an alternative promoter (P2) in intron 1. These 2 alternative transcripts were detected at higher levels in cells with the c.32delG mutation, and further studies indicated that the P2 transcripts in mutant cells had increased stability compared to wildtype and produced functional transcripts using another start codon in exon 2, resulting in excess production of EPO. In a 3-year-old girl with ECYT5, Camps et al. (2016) identified a heterozygous 1-bp deletion (c.19delC; 133170.0003) in the EPO gene. The mutation, which was found by targeted next-generation sequencing using a gene panel of 21 candidate genes in 125 patients with erythrocytosis, was confirmed by Sanger sequencing. Functional studies of the variant were not performed. However, Zmajkovic et al. (2018) demonstrated that the mutation resulted in the use of an alternative promoter (P2) in intron 1, causing the production of functional transcripts and increased amounts of biologically active EPO compared to controls. The mechanism was similar to that observed with another mutation in the same region (c.32delG; 133170.0002). INHERITANCE \- Autosomal dominant HEMATOLOGY \- Erythrocytosis \- Increased red cell mass \- Increased hemoglobin \- Increased hematocrit LABORATORY ABNORMALITIES \- Increased serum EPO levels MISCELLANEOUS \- Two unrelated families have been reported (last curated March 2018) MOLECULAR BASIS \- Caused by mutation in the erythropoietin gene (EPO, 133170.0002 ) ▲ 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	ERYTHROCYTOSIS, FAMILIAL, 5	c4693552	6,550	omim	https://www.omim.org/entry/617907	2019-09-22T15:44:27	{"omim": ["617907"]}
A congenital, X-linked, clinical subtype of L1 syndrome, characterized by spastic paraplegia, mild to moderate intellectual disability and normal brain morphology. This subtype represents the milder end of the L1 syndrome spectrum. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 complicated spastic paraplegia type 1	c0795953	6,551	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=306617	2021-01-23T17:02:01	{"gard": ["12525"], "mesh": ["C536029"], "synonyms": ["SPG1"]}
Familial encephalopathy with neuroserpin inclusion bodies SpecialtyNeurology Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive disorder of the nervous system that is characterized by a loss of intellectual functioning (dementia) and seizures. At first, affected individuals may have difficulty sustaining attention and concentrating. Their judgment, insight, and memory become impaired as the condition progresses. Over time, they lose the ability to perform the activities of daily living, and most people with this condition eventually require comprehensive care. The signs and symptoms of familial encephalopathy with neuroserpin inclusion bodies vary in their severity and age of onset. In severe cases, the condition causes seizures and episodes of sudden, involuntary muscle jerking or twitching (myoclonus) in addition to dementia. These signs can appear as early as a person's teens. Less severe cases are characterized by a progressive decline in intellectual functioning beginning in a person's forties or fifties. Mutations in the SERPINI1 gene cause familial encephalopathy with neuroserpin inclusion bodies. The SERPINI1 gene provides instructions for making a protein called neuroserpin. This protein is found in nerve cells, where it plays a role in the development and function of the nervous system. Neuroserpin helps control the growth of nerve cells and their connections with one another, which suggests that this protein may be important for learning and memory. Mutations in the gene result in the production of an abnormally shaped, unstable version of neuroserpin. Abnormal neuroserpin proteins can attach to one another and form clumps (called neuroserpin inclusion bodies or Collins bodies) within nerve cells. These clumps disrupt the cells' normal functioning and ultimately lead to cell death. Progressive dementia results from this gradual loss of nerve cells in certain parts of the brain. Researchers believe that a buildup of related, potentially toxic substances in nerve cells may also contribute to the signs and symptoms of this condition. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In many cases, an affected person has a parent with the condition. ## See also[edit] * PI12 ## References[edit] * National Library of Medicine. Genetics Home Reference - Familial encephalopathy with neuroserpin inclusion bodies ## External links[edit] Classification D * OMIM: 604218 * MeSH: C536841 C536841, C536841 External resources * Orphanet: 85110 * v * t * e Disorders of globin and globulin proteins Globin * Hemoglobinopathy * Thalassemia * alpha * beta * delta * Sickle-cell disease * trait * HPFH Globulin * IGHM: AGM1 * IGLL1: AGM2 Serpin * Serpinopathy: Alpha-1 antitrypsin deficiency * Antithrombin III deficiency * Hereditary angioedema * FENIB See also * globular proteins * globins * antibodies * serpins [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 encephalopathy with neuroserpin inclusion bodies	c1858680	6,552	wikipedia	https://en.wikipedia.org/wiki/Familial_encephalopathy_with_neuroserpin_inclusion_bodies	2021-01-18T18:36:58	{"gard": ["10037"], "mesh": ["C536841"], "umls": ["C1858680"], "orphanet": ["85110"], "wikidata": ["Q5432935"]}
Pyruvate kinase deficiency is an inherited disorder that affects red blood cells, which carry oxygen to the body's tissues. People with this disorder have a condition known as chronic hemolytic anemia, in which red blood cells are broken down (undergo hemolysis) prematurely, resulting in a shortage of red blood cells (anemia). Specifically, pyruvate kinase deficiency is a common cause of a type of inherited hemolytic anemia called hereditary nonspherocytic hemolytic anemia. In hereditary nonspherocytic hemolytic anemia, the red blood cells do not assume a spherical shape as they do in some other forms of hemolytic anemia. Chronic hemolytic anemia can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), extreme tiredness (fatigue), shortness of breath (dyspnea), and a rapid heart rate (tachycardia). An enlarged spleen (splenomegaly), an excess of iron in the blood, and small pebble-like deposits in the gallbladder or bile ducts (gallstones) are also common in this disorder. In people with pyruvate kinase deficiency, hemolytic anemia and associated complications may range from mild to severe. Some affected individuals have few or no symptoms. Severe cases can be life-threatening in infancy, and such affected individuals may require regular blood transfusions to survive. The symptoms of this disorder may get worse during an infection or pregnancy. ## Frequency Pyruvate kinase deficiency is the most common inherited cause of nonspherocytic hemolytic anemia. More than 500 affected families have been identified, and studies suggest that the disorder may be underdiagnosed because mild cases may not be identified. Pyruvate kinase deficiency is found in all ethnic groups. Its prevalence has been estimated at 1 in 20,000 people of European descent. It is more common in the Old Order Amish population of Pennsylvania. ## Causes Pyruvate kinase deficiency is caused by mutations in the PKLR gene. The PKLR gene is active in the liver and in red blood cells, where it provides instructions for making an enzyme called pyruvate kinase. The pyruvate kinase enzyme is involved in a critical energy-producing process known as glycolysis. During glycolysis, the simple sugar glucose is broken down to produce adenosine triphosphate (ATP), the cell's main energy source. PKLR gene mutations result in reduced pyruvate kinase enzyme function, causing a shortage of ATP in red blood cells and increased levels of other molecules produced earlier in the glycolysis process. The abnormal red blood cells are gathered up by the spleen and destroyed, causing hemolytic anemia and an enlarged spleen. A shortage of red blood cells to carry oxygen throughout the body leads to fatigue, pallor, and shortness of breath. Iron and a molecule called bilirubin are released when red blood cells are destroyed, resulting in an excess of these substances circulating in the blood. Excess bilirubin in the blood causes jaundice and increases the risk of developing gallstones. Pyruvate kinase deficiency may also occur as an effect of other blood diseases, such as leukemia. These cases are called secondary pyruvate kinase deficiency and are not inherited. ### Learn more about the gene associated with Pyruvate kinase deficiency * PKLR ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Pyruvate kinase deficiency	c0340968	6,553	medlineplus	https://medlineplus.gov/genetics/condition/pyruvate-kinase-deficiency/	2021-01-27T08:24:42	{"gard": ["7514"], "mesh": ["C564858"], "omim": ["266200"], "synonyms": []}
Cataract-microcornea syndrome is characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. ## Epidemiology To date, more than 15 families showing microcornea-cataract syndrome have been described. ## Clinical description Clinical findings include a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye, and an inherited cataract, which is most often bilateral posterior polar with opacification in the lens periphery. The cataract progresses to form a total cataract after visual maturity has been achieved, requiring cataract extraction in the first to third decade of life. Microcornea-cataract syndrome can be associated with other rare ocular manifestations, including myopia, iris coloboma, sclerocornea and Peters anomaly (see this term). ## Etiology There is marked genetic heterogeneity. Mutations have been described in several crystallin genes (CRYAA, CRYBB1, CRYGD), and in the gap junction protein alpha 8 gene (GJA8). ## Diagnostic methods Ophthalmologic and general examination allows other syndromes to be excluded. ## Genetic counseling Transmission is in most cases autosomal dominant, but cases of autosomal recessive transmission have recently been described. ## Management and treatment Cataract surgery has to be performed in order to restore visual acuity and avoid amblyopia. ## Prognosis Visual acuity after uncomplicated cataract extraction is relatively good. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Cataract-microcornea syndrome	c1861829	6,554	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1377	2021-01-23T18:43:42	{"gard": ["1155"], "mesh": ["C538287"], "omim": ["115700", "116200", "601547", "604219"], "umls": ["C1861829"], "icd-10": ["Q13.8"]}
A number sign (#) is used with this entry because of evidence that microphthalmia with associated features (MCOPS5), including pituitary dysfunction, is caused by heterozygous mutation in the OTX2 gene (600037) on chromosome 14q22. There is also evidence that early-onset retinal dystrophy with or without pituitary dysfunction is caused by heterozygous mutation in the OTX2 gene. Nomenclature The term 'anophthalmia' has been misused in the medical literature. True or primary anophthalmia is rarely compatible with life; in such cases, the primary optic vesicle has stopped developing and the abnormal development involves major defects in the brain as well (Francois, 1961). The diagnosis can only be made histologically (Reddy et al., 2003; Morini et al., 2005; Smartt et al., 2005), but this is rarely done. In most published cases, the term 'anophthalmia' is used as a synonym for the more appropriate terms 'extreme microphthalmia' or 'clinical anophthalmia.' Clinical Features Ragge et al. (2005) described affected members of 8 unrelated families with unilateral or bilateral microphthalmia/clinical anophthalmia and variable additional features including coloboma, microcornea, cataract, retinal dystrophy, hypoplasia or agenesis of the optic nerve, agenesis of the corpus callosum, developmental delay, joint laxity, hypotonia, and seizures. A mother of 2 patients, who was a gonosomal mosaic, had a later-onset phenotype resembling pigmentary retinopathy (see 193220). Dateki et al. (2008) described an 8.5-year-old Japanese girl who was born with bilateral clinical anophthalmia and cleft palate. She underwent evaluation for short stature at 3.75 years of age and was found to have partial growth hormone (GH; 139250) deficiency. Brain MRI showed bilateral anophthalmia and optic nerve hypoplasia, but brain structure as well as the pituitary gland appeared normal, with an intact stalk and hyperintense signal in the posterior lobe. The patient also showed developmental retardation. Her parents and 2 older brothers were unaffected. Tajima et al. (2009) reported a 6-year-old Japanese boy with bilateral clinical anophthalmia who upon examination for evaluation of short stature at 4 years of age was also found to have markedly delayed psychomotor retardation, a small penis, and bilateral undescended testes. Laboratory evaluation revealed central hypothyroidism and deficiencies of GH, gonadotropins, and cortisol. Brain MRI showed a small anterior pituitary, invisible pituitary stalk, ectopic posterior lobe, bilateral anophthalmia, absence of optic nerve and chiasm, and Chiari malformation (see 118420). Chassaing et al. (2012) studied a large 4-generation French family in which 17 individuals had microphthalmia or clinical anophthalmia, 3 were diagnosed with otocephaly-dysgnathia complex (see 202650), and 2 exhibited an intermediate, overlapping phenotype. One affected woman had 2 sons with otocephaly, 1 of whom died soon after birth from respiratory distress and unsuccessful intubation; the second pregnancy was electively terminated after ultrasonography showed recurrence of facial malformations consistent with otocephaly. An affected male cousin also had a son who died soon after birth from respiratory distress with a probable diagnosis of otocephaly. The cousin's half sister exhibited an intermediate phenotype of unilateral anophthalmia and micrognathia. In addition, a half sister of the woman with the otocephalic sons gave birth to a boy who also had an intermediate phenotype and died at birth of respiratory distress with hypoplasia of maxilla and upper pharynx, noncommunication between proboscis and hypopharynx, and rudimentary tongue. Additional features revealed on autopsy included bilateral microphthalmia, absence of anterior ocular chamber, cataract, and focal retinal dysplasia, as well as microretrognathia, microglossia, thymic hyperplasia, 11 ribs, and micropenis. Detailed examinations of the patients with microphthalmia/clinical anophthalmia were not reported, although it was noted that in the fourth generation, 3 male cousins with bilateral clinical anophthalmia had moderate to severe mental retardation. Chassaing et al. (2012) also reported a 12-year-old Caucasian girl who had maxillary hypoplasia, microstomia, absent tongue, agnathia, and a long tubular nose. Her eyes and ears were normally formed, and she had patent external auditory canals. She had no known associated limb or internal organ anomalies or hormonal dysfunction. Her mother had 8 miscarriages, mostly in the first trimester, but there was no family history of ophthalmic or mandibular malformations. Patat et al. (2013) reported a 4-generation family in which a mother, her father, and her paternal grandmother all had severe unilateral microphthalmia, and the mother terminated a pregnancy at 16 weeks of gestation because of agnathia associated with bilateral microphthalmia. The male fetus had agnathia, astomia, and aglossia, with low, posteriorly rotated, paramedian, and convergent ears. The pharyngeal floor was absent. He had bilateral microphthalmia with downslanted palpebral fissures, and the optic chiasm and pituitary gland could not be detected. X-rays confirmed the absence of mandibular bone. Abnormalities of the extremities included brachymesophalangy of the fifth finger and bilateral talus valgus. Patat et al. (2013) also described a male infant born at 30 weeks of gestation who died shortly after birth of respiratory insufficiency due to absence of the mandible and severe microstomia. He also had persistent buccopharyngeal membrane and dysmorphic anterocaudally positioned ears, as well as mild clubfeet, but his eyes appeared normal on external inspection. ### Early-Onset Retinal Dystrophy with or without Pituitary Dysfunction Vincent et al. (2014) studied 2 Caucasian Canadian families with pattern retinal dystrophy. One was a 3-generation family in which 5 affected individuals underwent detailed eye examination. All 5 presented with reduced distance vision and myopia with or without astigmatism. Color vision was mildly impaired only in the 2 older individuals (fifth decade of life). Horizontal corneal diameters and axial eye lengths were normal. The retina showed a butterfly pattern dystrophy with pigment deposition in 3 patients, an annular pigmentary pattern in 1, and a dull foveal reflex in 1. Optic nerve head dysplasia was noted in 3 patients, and 1 patient had unilateral macular scarring. Spectral-domain optical coherence tomography (SD-OCT) showed distinct areas of photoreceptor outer-segment separation from the retinal pigment epithelium (RPE), with deposition and clumping on the RPE in areas of pigmentation, but the external limiting membrane appeared preserved. The Arden ratio was normal in the 3 children but borderline or abnormally low in the 2 adults. Electroretinography (ERG) showed moderately decreased cone responses in an affected 13-year-old girl, and her 46-year-old father showed mildly reduced rod and cone responses; the other 3 patients had normal ERGs. Pituitary hormone, cortisol, and serum electrolyte levels were normal in the 6 affected individual in whom they were tested; brain MRI was normal in 4 patients and showed a 0.5-cm Rathke's cleft cyst displacing the posterior aspect of the pituitary in 1. Vincent et al. (2014) also studied a 39-year-old man and his 8-year-old son with pattern retinal dystrophy. The son had nystagmus and photophobia since 2 years of age, and both patients had reduced distance vision. The father had compound myopic astigmatism, whereas the son had myopia. The father also had microcornea, posterior embryotoxon, and optic nerve head dysplasia. The macula showed an atypical pattern with mild RPE changes in the father, and a grouped pigmentation pattern was seen in the son. SD-OCT changes were characteristic and identical to those of the first family. Growth and stature were normal in both father and son. Vincent et al. (2014) noted that, like pattern dystrophies associated with mutation in the PRPH2 (179605) or BEST1 (607854) genes, the phenotype appeared to be very slowly progressive, with only 1 patient from each family showing worsening of vision parameters over a 3- to 5-year follow-up period. Cytogenetics Deletions of chromosome 14q22-q23, frequently spanning both the BMP4 (112262) and OTX2 genes, have been reported in patients with microphthalmia/anophthalmia and pituitary anomalies, see CYTOGENETICS in MCOPS6 (607932). Molecular Genetics Using a candidate gene approach, Ragge et al. (2005) analyzed 333 patients with ocular malformation spectrum defects and identified heterozygous mutations in the OTX2 gene in 11 affected individuals from 8 families. In 2 families, the mutations occurred de novo in severely affected offspring (600037.0001 and 600037.0002, respectively), and in 2 other families, the mutations were inherited from a gonosomal mosaic parent (600037.0003 and 600037.0004, respectively). Ragge et al. (2005) stated that data from these 4 families supported a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. The other 4 families displayed complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. Wyatt et al. (2008) analyzed the OTX2 gene in 165 patients with ocular malformations, primarily clinical anophthalmia, microphthalmia, and/or coloboma, and identified heterozygosity for 2 whole gene deletions and 4 truncating mutations in 8 patients from 6 families. Two of the patients, 1 with a whole gene deletion and 1 with a frameshift mutation, had developmental delay, but the other patients were apparently normal apart from the ocular phenotype. In an 8.5-year-old Japanese girl with bilateral clinical anophthalmia, short stature, developmental delay, and partial GH deficiency, who was negative for mutation in the HESX1 (601802) and POU1F1 (173110) genes, Dateki et al. (2008) identified a de novo heterozygous frameshift mutation in the OTX2 gene (600037.0005). In a 6-year-old Japanese boy with bilateral clinical anophthalmia, short stature, and combined pituitary hormone deficiency, Tajima et al. (2009) identified a de novo heterozygous frameshift mutation in the OTX2 gene (600037.0007). Dateki et al. (2010) analyzed the OTX2 gene in 16 patients with ocular anomalies, short stature, and pituitary dysfunction, 12 patients with ocular anomalies with or without short stature in whom pituitary function was not investigated, and 66 patients with pituitary dysfunction without ocular anomalies. The patients were negative for mutation in genes known to be associated with their respective phenotypes. Dateki et al. (2010) identified 3 heterozygous OTX2-truncating mutations in 4 unrelated patients (see, e.g., 600037.0009 and 600037.0010) and a microdeletion involving the OTX2 gene in 1 patient. The authors concluded that OTX2 mutations are associated with variable pituitary phenotype, with no genotype-phenotype correlations. In a 13.5-year-old boy of Sephardic Jewish descent who had unilateral clinical anophthalmia, short stature, and isolated GH deficiency, Ashkenazi-Hoffnung et al. (2010) analyzed the HESX1, SOX2 (184429), and OTX2 genes, and identified heterozygosity for a missense mutation in OTX2 (600037.0011). His father, who had short stature but normal eye structure and unknown endocrine status, was also heterozygous for the mutation. The proband had a younger brother with bilateral anophthalmia and normal height, and 2 clinically healthy sibs; his mother also reported 4 pregnancy terminations due to anophthalmia detected on fetal ultrasound. A paternal uncle and cousin both had bilateral clinical anophthalmia; a second cousin, who had severe microphthalmia, had hypoplastic pituitary with absence of optic nerves and chiasm on brain MRI, but endocrine evaluation at 4 months of age showed normal pituitary function. Mutation status of the relatives was unknown, as they refused genetic analysis. Ashkenazi-Hoffnung et al. (2010) reviewed the wide variability of phenotypes associated with previously published OTX2 mutations, even within families and in patients carrying identical mutations, and noted that the lack of genotype-phenotype correlation strengthened the need for continuous endocrine follow-up of affected patients, since the clinical course could not be anticipated. In a large 4-generation French family in which 17 individuals had microphthalmia or clinical anophthalmia, Chassaing et al. (2012) identified a heterozygous 1-bp deletion in the OTX2 gene (c.316delC; 600037.0012) that segregated with disease. Included in the pedigree were 3 deceased offspring with otocephaly, from whom DNA was unavailable; however, a deceased male infant with an intermediate phenotype was also found to be heterozygous for the 1-bp deletion. In a 12-year-old girl with otocephaly, Chassaing et al. (2012) identified heterozygosity for a de novo 1-bp deletion in OTX2 (c.130delC). Because of the phenotypic variability observed in the 4-generation family, Chassaing et al. (2012) screened 5 additional candidate genes known to play a role in vertebrate otocephalic malformations, including PRRX1 (167420), but did not detect any likely pathogenic variants. The authors concluded that loss-of-function OTX2 mutations do not sufficiently explain the complex anatomic defects in patients with otocephaly/dysgnathia, suggesting the requirement for a second genetic hit. In a male fetus with agnathia-otocephaly complex, known to be negative for mutation in the PRRX1 gene, Patat et al. (2013) identified heterozygosity for a nonsense mutation in the OTX2 gene (R97X; 600037.0013) that was inherited from his mother, who exhibited only unilateral severe microphthalmia. The fetus also carried a heterozygous synonymous OTX2 variant (c.525C-G) that was inherited from his asymptomatic father; however, the authors stated that it was unlikely that the silent variant explained the intrafamilial phenotypic variability. In an unrelated male infant who died at birth of respiratory insufficiency due to absence of the mandible and severe microstomia, who was also negative for mutation in PRRX1, Patat et al. (2013) identified an approximately 400-kb de novo deletion at 14q23.1 that involved the entire OTX2 gene but did not include any other genes. Williamson and FitzPatrick (2014) reviewed the screening of the OTX2 gene in what they designated as cases of 'MAC' (microphthalmia-anophthalmia-coloboma) and stated that in over 1,000 MAC cases screened, a heterozygous OTX2 mutation was identified in 69 cases from 51 families. Forty-seven different variants were detected, including 9 nonsynonymous variants and 38 unequivocal loss-of-function alleles, 40% of which were de novo. Nonpenetrance and variable expressivity were observed; transmission of a heterozygous OTX2 mutation from an unaffected parent was reported on 10 occasions and from an affected parent on 8 occasions, and maternal gonosomal mosaicism was reported or suspected in 3 cases. Ocular phenotypes included various combinations of microphthalmia and/or clinical anophthalmia with or without coloboma, as well as 'atypical' eye defects, including optic nerve hypoplasia and early onset retinal dystrophy. Extraocular phenotypes included mild to severe learning disability in more than 40% of cases, pituitary abnormalities in 20% of cases, and motor delay in about 10% of cases. Williamson and FitzPatrick (2014) discussed the markedly variable expressivity of OTX2 haploinsufficiency, which has been associated with otocephaly-dysgnathia complex in some patients, as well as phenotypic and genotypic discordance of OTX2 mutations, illustrated by substitutions within the transactivation domain that have been associated with combined pituitary hormone deficiency without ocular defects (CPHD6; 613986) or optic nerve hypoplasia and pituitary dysfunction. Sergouniotis et al. (2015) reported a family in which a 9-year-old girl had a small mandible, normal ears, and velopharyngeal insufficiency due to a short hemi-palate. She was found to be heterozygous for a 3-bp duplication in the OTX2 gene (c.271_273dupCAG; Gln91dup); however, the mutation was also present in her unaffected father. Family history was significant for 2 pregnancies exhibiting apparent agnathia-otocephaly complex on prenatal ultrasonography; fetal DNA from 1 of the pregnancies revealed heterozygosity for the 3-bp duplication. ### Early-Onset Retinal Dystrophy with or without Pituitary Dysfunction Henderson et al. (2009) analyzed DNA samples from 142 patients with Leber congenital amaurosis (LCA; see 204000) or severe childhood-onset retinal dystrophy (RD; see 613341) using an 'LCA chip' involving 8 LCA- and RD-associated genes, as well as screening the OTX2 gene. In a 7-year-old boy with RD who was negative for all variants assayed by the LCA chip, they identified heterozygosity for a de novo nonsense mutation in the OTX2 gene (S138X; 600037.0008). The patient, who was noted to have poor vision and nyctalopia during his first year of life, also had failure to thrive and subsequent short stature, and growth hormone deficiency was suggested indirectly due to low levels of IGF1 (147440) and IGFBP3 (146732). Electroretinography (ERG) at 6 years of age was markedly electronegative with additional a-wave reduction, suggesting dysfunction at the photoreceptor level and also post-phototransduction, likely to involve both ON- and OFF-bipolar cells. In a 3-generation Caucasian Canadian family with pattern retinal dystrophy without pituitary dysfunction, Vincent et al. (2014) performed whole-genome SNP genotyping followed by exome sequencing and identified a heterozygous missense mutation in the OTX2 gene (E79K; 600037.0014) that was confirmed by Sanger sequencing to segregate with disease in the family. An affected father and son from a second Canadian family were also heterozygous for the E79K mutation. Haplotype analysis revealed a 19.68-cM shared haplotype between SNPs rs17107459 and rs710050; the number of generations between a common ancestor and affected individuals in the youngest generation in each family was estimated to be 5, making them fourth cousins. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (in some patients) HEAD & NECK Eyes \- Microphthalmia, unilateral or bilateral \- Anophthalmia, clinical, unilateral or bilateral \- Coloboma \- Microcornea \- Cataract \- Retinal dystrophy \- Optic nerve hypoplasia or agenesis Mouth \- Cleft palate (in some patients) \- Dysgnathia or agnathnia (in some patients) GENITOURINARY External Genitalia (Male) \- Small penis (rare) Internal Genitalia (Male) \- Cryptorchidism (rare) SKELETAL \- Joint laxity NEUROLOGIC Central Nervous System \- Developmental delay \- Hypotonia \- Seizures (rare) \- Corpus callosum, agenesis of (in some patients) \- Pituitary hypoplasia (in some patients) \- Ectopic posterior pituitary (in some patients) ENDOCRINE FEATURES \- Pituitary hypoplasia (in some patients) \- Pituitary hormone deficiencies (in some patients) MISCELLANEOUS \- Marked phenotypic variability in some families MOLECULAR BASIS \- Caused by mutation in the homolog of the drosophila orthodenticle 2 gene (OTX2, 600038.0001 ) ▲ 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	MICROPHTHALMIA, SYNDROMIC 5	c1864690	6,555	omim	https://www.omim.org/entry/610125	2019-09-22T16:05:06	{"doid": ["10629"], "mesh": ["C566441"], "omim": ["610125"], "orphanet": ["178364", "99001"], "genereviews": ["NBK1378"]}
Balamuthia infection SpecialtyDermatology Balamuthia infection is a cutaneous condition resulting from Balamuthia that may result in various skin lesions.[1]:422 Balamuthia mandrillarisis a free-living amoeba (a single-celled living organism) found in the environment. It is one of the causes of granulomatous amoebic encephalitis (GAE), a serious infection of the brain and spinal cord. Balamuthia is thought to enter the body when soil containing it comes in contact with skin wounds and cuts, or when dust containing it is breathed in or gets in the mouth. The Balamuthia amoebae can then travel to the brain through the bloodstream and cause GAE. GAE is a very rare disease that is usually fatal.[2] Scientists at the Centers for Disease Control and Prevention (CDC) first discovered Balamuthia mandrillaris in 1986. The amoeba was found in the brain of a dead mandrill. After extensive research, B. mandrillaris was declared a new species in 1993. Since then, more than 200 cases of Balamuthia infection have been diagnosed worldwide, with at least 70 cases reported in the United States. Little is known at this time about how a person becomes infected.[2] ## See also[edit] * Acanthamoeba infection ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 2. ^ a b "CDC - Balamuthia - General Information - Frequently Asked Questions (FAQs)". Archived from the original on 9 July 2011. ## External links[edit] * Centers for Disease Control and Prevention Balamuthia infection information, prevention, diagnosis, and treatment * v * t * e Amoebozoal diseases Lobosea (free-living) Centramoebida * Acanthamoeba * Acanthamoeba keratitis * Cutaneous acanthamoebiasis * Granulomatous amoebic encephalitis * Acanthamoeba infection * Balamuthia mandrillaris * Balamuthia amoebic encephalitis * Balamuthia infection Flabellinia * Sappinia diploidea/Sappinia pedata * Sappinia amoebic encephalitis Conosa/Archamoebae * Entamoeba histolytica * Amoebiasis * Amoebic dysentery * Amoebic liver abscess * Cutaneous amoebiasis * Amoebic brain abscess * Amebiasis cutis * Entamoeba gingivalis This infection-related cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Balamuthia infection	c2721655	6,556	wikipedia	https://en.wikipedia.org/wiki/Balamuthia_infection	2021-01-18T19:05:41	{"mesh": ["D000562"], "umls": ["C2721655"], "icd-9": ["136.2"], "wikidata": ["Q4849924"]}
Squamous cell carcinoma (SCC) of rectum is a rare epithelial tumor of the rectum, arising from squamous cells in the rectal epithelium, without the presence of squamous-lined fistulous tracts in the rectum or a proximal extension of SCC of anal or gynecological origin. The reported symptoms are often nonspecific, such as anorexia, weight loss, lower abdominal pain, rectal bleeding and changes of bowel habits. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Squamous cell carcinoma of the rectum	c1335690	6,557	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=424002	2021-01-23T17:20:16	{"umls": ["C1335690"], "icd-10": ["C20"], "synonyms": ["Rectal squamous cell carcinoma"]}
For a discussion of genetic heterogeneity of quantitative trait loci for stature (STQTL), see STQTL1 (606255). Mapping Hirschhorn et al. (2001) used genomewide scans in 4 populations (the Botnia region of Finland, other parts of Finland, southern Sweden, and a region of Quebec) for which genotyping, height, age, and gender data were available. They analyzed these populations using a variance-components method, using stature as a quantitative trait locus, and showed that 4 regions demonstrated strong evidence for linkage in at least 1 of the populations. In the Swedish population, the 7q31.3-q36 region showed strong evidence of linkage to stature (maximum lod = 3.40 at marker D7S195, p less than 0.02). Other regions showed evidence for linkage in other populations (see 606255). Perola et al. (2001) performed a quantitative trait locus analysis of body mass index (BMI) and stature. In a Finnish population they found suggestive evidence for linkage of stature to 7qter (maximum multipoint lod score = 2.91) and suggestive evidence for linkage to 9q. No evidence for QTLs affecting BMI were found. The abstract erroneously stated that the stature QTL was linked to 7pter (Peltonen, 2002). By linkage analysis of 2,508 families, Wu et al. (2003) replicated evidence for a QTL influencing adult height on chromosome 7q31 (maximum lod = 2.46). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	STATURE QUANTITATIVE TRAIT LOCUS 2	c1853476	6,558	omim	https://www.omim.org/entry/606256	2019-09-22T16:10:31	{"omim": ["606256"]}
Friedreich ataxia is a genetic condition that affects the nervous system and causes movement problems. People with this condition develop impaired muscle coordination (ataxia) that worsens over time. Other features of this condition include the gradual loss of strength and sensation in the arms and legs; muscle stiffness (spasticity); and impaired speech, hearing, and vision. Individuals with Friedreich ataxia often have a form of heart disease called hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle and can be life-threatening. Some affected individuals develop diabetes or an abnormal curvature of the spine (scoliosis). Most people with Friedreich ataxia begin to experience the signs and symptoms of the disorder between ages 5 and 15. Poor coordination and balance are often the first noticeable features. Affected individuals typically require the use of a wheelchair about 10 years after signs and symptoms appear. About 25 percent of people with Friedreich ataxia have an atypical form in which signs and symptoms begin after age 25. Affected individuals who develop Friedreich ataxia between ages 26 and 39 are considered to have late-onset Friedreich ataxia (LOFA). When the signs and symptoms begin after age 40 the condition is called very late-onset Friedreich ataxia (VLOFA). LOFA and VLOFA usually progress more slowly than typical Friedreich ataxia. ## Frequency Friedreich ataxia is estimated to affect 1 in 40,000 people in the United States. This condition is found in people with European, Middle Eastern, or North African ancestry. It is rarely identified in other ethnic groups. ## Causes Mutations in the FXN gene cause Friedreich ataxia. This gene provides instructions for making a protein called frataxin. Although its role is not fully understood, frataxin is important for the normal function of mitochondria, the energy-producing centers within cells. One region of the FXN gene contains a segment of DNA known as a GAA trinucleotide repeat. This segment is made up of a series of three DNA building blocks (one guanine and two adenines) that appear multiple times in a row. Normally, this segment is repeated 5 to 33 times within the FXN gene. In people with Friedreich ataxia, the GAA segment is repeated 66 to more than 1,000 times. The length of the GAA trinucleotide repeat appears to be related to the age at which the symptoms of Friedreich ataxia appear, how severe they are, and how quickly they progress. People with GAA segments repeated fewer than 300 times tend to have a later appearance of symptoms (after age 25) than those with larger GAA trinucleotide repeats. The abnormally long GAA trinucleotide repeat disrupts the production of frataxin, which severely reduces the amount of this protein in cells. Certain nerve and muscle cells cannot function properly with a shortage of frataxin, leading to the characteristic signs and symptoms of Friedreich ataxia. ### Learn more about the gene associated with Friedreich ataxia * FXN ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Friedreich ataxia	c1856689	6,559	medlineplus	https://medlineplus.gov/genetics/condition/friedreich-ataxia/	2021-01-27T08:25:41	{"gard": ["6468"], "mesh": ["C565561"], "omim": ["229300"], "synonyms": []}
A number sign (#) is used with this entry because autosomal recessive intermediate Charcot-Marie-Tooth disease C (CMTRIC) is caused by homozygous or compound heterozygous mutation in the PLEKHG5 gene (611101) on chromosome 1p36. Mutation in the PLEKHG5 gene can also cause autosomal recessive distal spinal muscular atrophy-4 (DSMA4; 611067). Description CMTRIC is an autosomal recessive peripheral neuropathy characterized by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. Electrophysiologic studies and sural nerve biopsy show mixed features of demyelinating and axonal neuropathy. The age at onset and the severity of the disease are variable (summary by Azzedine et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive intermediate CMT, see CMTRIA (608340). Clinical Features Azzedine et al. (2013) reported 2 unrelated consanguineous families of Portuguese and Moroccan origin, respectively, with onset of Charcot-Marie-Tooth disease mainly between the second and fifth decades of life, although 1 patient had onset at age 7 years. Affected individuals had distal muscle weakness and atrophy of the upper and lower limbs, foot deformities, areflexia, and distal sensory impairment. Some patients had mild proximal muscle involvement, one of whom was wheelchair-bound. Motor nerve conduction velocities were moderately decreased, and sural nerve biopsies showed a loss of large myelinated fibers and thin myelination, consistent with an intermediate form of the disorder. There were no signs of brain involvement. Kim et al. (2013) reported a 19-year-old Korean woman with Charcot-Marie-Tooth disease. She presented with distal muscle weakness in the lower limbs at age 8, and later had distal and proximal muscle weakness affecting the lower limbs and distal weakness of the upper limbs. Other features included distal muscle atrophy, sensory loss, areflexia, pes cavus, mildly increased serum creatine kinase, and fatty replacement of muscle tissue. Median motor nerve conduction velocities were decreased, suggesting a demyelinating process, and EMG showed a neurogenic pattern of muscle degeneration. Sural nerve biopsy showed a decrease in myelinated fibers and clusters of regenerating fibers, suggesting an axonal process. Inheritance The transmission pattern of CMTRIC in the families reported by Azzedine et al. (2013) was consistent with autosomal recessive inheritance. Mapping By homozygosity mapping of 2 unrelated consanguineous families with intermediate CMT, Azzedine et al. (2013) found linkage to a region on chromosome 1p36 (combined maximum lod score of 5.4 at the shared region of homozygosity). Molecular Genetics In affected members of 2 unrelated families with CMTRIC, Azzedine et al. (2013) identified 2 different homozygous truncating mutations in the PLEKHG5 gene (611101.0002 and 611101.0003, respectively). The mutations, which were found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the families and were not present in multiple controls. In a 19-year-old Korean woman with CMTRIC, Kim et al. (2013) identified compound heterozygous missense mutations in the PLEKHG5 gene (T663M, 611101.0004; G820R, 611101.0005). The mutations were found by whole-exome sequencing. Immunohistochemical analysis revealed that the patient had low levels of PLEKHG5 in the distal sural nerve, and an in vitro assay suggested that the mutant proteins had a defect in activating the NFKB (164011) signaling pathway. INHERITANCE \- Autosomal recessive SKELETAL Feet \- Pes cavus \- Hammertoes \- Foot deformities MUSCLE, SOFT TISSUES \- Neurogenic atrophy seen on muscle biopsy NEUROLOGIC Peripheral Nervous System \- Distal limb muscle weakness due to peripheral neuropathy \- Distal limb muscle atrophy due to peripheral neuropathy \- Lower limbs more severely affected than upper limbs \- Distal sensory impairment \- Areflexia \- Decreased motor nerve conduction velocities \- Sural nerve biopsy shows thin myelination \- Loss of large myelinated fibers LABORATORY ABNORMALITIES \- Mildly increased serum creatine kinase MISCELLANEOUS \- Variable age at onset (range childhood to adult) MOLECULAR BASIS \- Caused by mutation in the pleckstrin homology domain-containing protein, family G, member 5 gene (PLEKHG5, 611101.0002 ) ▲ 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	CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE C	c3809309	6,560	omim	https://www.omim.org/entry/615376	2019-09-22T15:52:25	{"doid": ["0110198"], "omim": ["615376"], "orphanet": ["369867"], "synonyms": ["CHARCOT-MARIE-TOOTH NEUROPATHY, RECESSIVE INTERMEDIATE C", "Alternative titles", "RI-CMT type C"]}
## Description Alt et al. (1986) identified the RMYC gene as a 12-kb cloned genomic EcoRI fragment that had homology to both the second and third exons of LMYC (164850); the authors considered it to be a member of the MYC (190080) gene family, along with NMYC (164840). Alt et al. (1986) and DePinho et al. (1987) stated that at least 1 pseudogene is known in this family and that functional activity of another gene, PMYC, had been suggested but was not confirmed. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	ONCOGENE RMYC	None	6,561	omim	https://www.omim.org/entry/165290	2019-09-22T16:37:07	{"omim": ["165290"]}
Sheehan syndrome is a rare, acquired, pituitary hormone deficiency disorder resulting from pituitary necrosis following peri- or postpartum hemorrhage characterized by various symptoms depending on resulting hormone decrease (e.g. failure or difficulty with lactation, oligo- or amenorrhea, hot flashes, decreased libido, weakness, fatigue, anorexia, nausea, vomiting, hypoglycemia, hyponatremia, dizziness, decreased muscle mass, adrenal crisis). Secondary hypothyroidism and secondary adrenal insufficiency may also be presenting signs. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Sheehan syndrome	c0242342	6,562	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=91355	2021-01-23T17:08:33	{"gard": ["7630"], "mesh": ["D007018"], "umls": ["C0242342"], "icd-10": ["E23.0"]}
Human disease that results in excess growth of certain parts of the body Acromegaly Pronunciation * /ˌækrəˈmɛɡəli, -roʊ-/[1][2] SpecialtyEndocrinology SymptomsEnlargement of the hands, feet, forehead, jaw, and nose, thicker skin, deepening of the voice[3] ComplicationsType 2 diabetes, sleep apnea, high blood pressure[3] Usual onsetMiddle age[3] CausesToo much growth hormone[3] Diagnostic methodBlood tests, medical imaging[3] Differential diagnosisPachydermoperiostosis[4] TreatmentSurgery, medications, radiation therapy[3] MedicationSomatostatin analogue, GH receptor antagonist[3] PrognosisUsually normal (with treatment), 10 year shorter life expectancy (no treatment)[5] Frequency6 per 100,000 people[3] Acromegaly is a disorder that results from excess growth hormone (GH) after the growth plates have closed.[3] The initial symptom is typically enlargement of the hands and feet.[3] There may also be an enlargement of the forehead, jaw, and nose.[3] Other symptoms may include joint pain, thicker skin, deepening of the voice, headaches, and problems with vision.[3] Complications of the disease may include type 2 diabetes, sleep apnea, and high blood pressure.[3] Acromegaly is usually caused by the pituitary gland producing excess growth hormone.[3] In more than 95% of cases the excess production is due to a benign tumor, known as a pituitary adenoma.[3] The condition is not inherited from a person's parents.[3] Acromegaly is rarely due to a tumor in another part of the body.[3] Diagnosis is by measuring growth hormone after a person has drunk a glucose solution, or by measuring insulin-like growth factor I in the blood.[3] After diagnosis, medical imaging of the pituitary is carried out to determine if an adenoma is present.[3] If excess growth hormone is produced during childhood, the result is the condition gigantism rather than acromegaly.[3] Treatment options include surgery to remove the tumor, medications, and radiation therapy.[3] Surgery is usually the preferred treatment; the smaller the tumor, the more likely surgery will be curative.[3] If surgery is contraindicated or not curative, somatostatin analogues or GH receptor antagonists may be used.[3] Radiation therapy may be used if neither surgery nor medications are completely effective.[3] Without treatment, life expectancy is reduced by 10 years; with treatment, life expectancy is not reduced.[5] Acromegaly affects about 6 per 100,000 people.[3] It is most commonly diagnosed in middle age.[3] Males and females are affected with equal frequency.[6] It was first described in the medical literature by Nicolas Saucerotte in 1772.[7][8] The term is from Greek ἄκρον akron meaning "extremity" and μέγα mega meaning "large".[3] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Causes * 2.1 Pituitary adenoma * 2.2 Other tumors * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 4.1 Medications * 4.1.1 Somatostatin analogues * 4.1.2 Dopamine agonists * 4.1.3 Growth hormone receptor antagonists * 4.2 Surgery * 4.3 Radiation therapy * 4.4 Selection of treatment * 5 Prognosis * 6 Notable people * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Compared with the hand of an unaffected person (left), the hand of a person with acromegaly (right) is enlarged, with fingers that are widened, thickened and stubby, and with thicker soft tissue Mandibular overgrowth leads to prognathism, maxillary widening, teeth spacing and malocclusion Brow ridge and forehead protrusion remaining after tumor removal and tissue swelling eliminated Lower jaw showing the classic spacing of teeth due to acromegaly Features that may result from a high level of GH or expanding tumor include: * Headaches – often severe and prolonged * Soft tissue swelling visibly resulting in enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin * Soft tissue swelling of internal organs, notably the heart with attendant weakening of its muscularity, and the kidneys, also the vocal cords resulting in a characteristic thick, deep voice and slowing of speech * Generalized expansion of the skull at the fontanelle * Pronounced brow protrusion, often with ocular distension (frontal bossing) * Pronounced lower jaw protrusion (prognathism) with attendant macroglossia (enlargement of the tongue) and teeth spacing * Hypertrichosis, hyperpigmentation and hyperhidrosis may occur in these people.[9]:499 * Skin tags * Carpal tunnel syndrome ### Complications[edit] * Problems with bones and joints, including osteoarthritis, nerve compression syndrome due to bony overgrowth, and carpal tunnel syndrome[10] * Hypertension[10][11] * Diabetes mellitus[12] * Cardiomyopathy, potentially leading to heart failure[10] * Colorectal cancer[13] * Sleep Apnea[10] * Thyroid nodules and thyroid cancer[14] * Hypogonadism[10] * Compression of the optic chiasm by the growth of pituitary adenoma leading to visual problems[15] ## Causes[edit] ### Pituitary adenoma[edit] About 98% of cases of acromegaly are due to the overproduction of growth hormone by a benign tumor of the pituitary gland called an adenoma.[16] These tumors produce excessive growth hormone and compress surrounding brain tissues as they grow larger. In some cases, they may compress the optic nerves. Expansion of the tumor may cause headaches and visual disturbances. In addition, compression of the surrounding normal pituitary tissue can alter production of other hormones, leading to changes in menstruation and breast discharge in women and impotence in men because of reduced testosterone production.[citation needed] A marked variation in rates of GH production and the aggressiveness of the tumor occurs. Some adenomas grow slowly and symptoms of GH excess are often not noticed for many years. Other adenomas grow rapidly and invade surrounding brain areas or the sinuses, which are located near the pituitary. In general, younger people tend to have more aggressive tumors.[citation needed] Most pituitary tumors arise spontaneously and are not genetically inherited. Many pituitary tumors arise from a genetic alteration in a single pituitary cell that leads to increased cell division and tumor formation. This genetic change, or mutation, is not present at birth but is acquired during life. The mutation occurs in a gene that regulates the transmission of chemical signals within pituitary cells; it permanently switches on the signal that tells the cell to divide and secrete growth hormones. The events within the cell that cause disordered pituitary cell growth and GH oversecretion currently are the subject of intensive research.[citation needed] Pituitary adenomas and diffuse somatomammotroph hyperplasia may result from somatic activating mutations GNAS, which may be acquired or associated with McCune-Albright syndrome.[17][18] ### Other tumors[edit] In a few people, acromegaly is caused not by pituitary tumors, but by tumors of the pancreas, lungs, and adrenal glands. These tumors also lead to an excess of GH, either because they produce GH themselves or, more frequently, because they produce GHRH (growth hormone releasing hormone), the hormone that stimulates the pituitary to make GH. In these people, the excess GHRH can be measured in the blood and establishes that the cause of the acromegaly is not due to a pituitary defect. When these nonpituitary tumors are surgically removed, GH levels fall and the symptoms of acromegaly improve.[citation needed] In people with GHRH-producing, non-pituitary tumors, the pituitary still may be enlarged and may be mistaken for a tumor. Therefore, it is important that physicians carefully analyze all "pituitary tumors" removed from people with acromegaly so as to not overlook the possibility that a tumor elsewhere in the body is causing the disorder.[citation needed] ## Diagnosis[edit] Frequent serum GH measurements in normal subjects (left panel) demonstrate that GH can fluctuate between undetectable levels most of the time intersperse with peaks of up to 30 μg/L (90 mIU/L); in acromegaly (right panel) GH hypersecretion is continuous with no undetectable levels. If acromegaly is suspected, medical laboratory investigations followed by medical imaging if the lab tests are positive confirms or rules out the presence of this condition.[citation needed] IGF1 provides the most sensitive lab test for the diagnosis of acromegaly, and a GH suppression test following an oral glucose load, which is a very specific lab test, will confirm the diagnosis following a positive screening test for IGF1. A single value of the GH is not useful in view of its pulsatality (levels in the blood vary greatly even in healthy individuals). Magnetic resonance image of a pituitary macroadenoma that caused acromegaly with compression of the optic chiasm GH levels taken 2 hours after a 75- or 100-gram glucose tolerance test are helpful in the diagnosis: GH levels are suppressed below 1 μg/L in normal people, and levels higher than this cutoff are confirmatory of acromegaly. Other pituitary hormones must be assessed to address the secretory effects of the tumor, as well as the mass effect of the tumor on the normal pituitary gland. They include thyroid stimulating hormone (TSH), gonadotropic hormones (FSH, LH), adrenocorticotropic hormone, and prolactin. An MRI of the brain focusing on the sella turcica after gadolinium administration allows for clear delineation of the pituitary and the hypothalamus and the location of the tumor. A number of other overgrowth syndromes can result in similar problems. ### Differential diagnosis[edit] Pseudoacromegaly is a condition with the usual acromegaloid features, but without an increase in growth hormone and IGF-1. It is frequently associated with insulin resistance.[19] Cases have been reported due to minoxidil at an unusually high dose.[20] It can also be caused by a selective post receptor defect of insulin signalling, leading to the impairment of metabolic, but preservation of mitogenic, signalling.[21] ## Treatment[edit] Site of action of the different therapeutic tools in acromegaly. Surgery, radiotherapy, somatostatin analogues and dopamine agonists act at the level of the pituitary adenoma, while GH receptor antagonists act in the periphery by blocking the growth hormone receptor and thus impairing the effects of GH on the different tissues. The goals of treatment are to reduce GH production to normal levels thereby reversing or ameliorating the signs and symptoms of acromegaly, to relieve the pressure that the growing pituitary tumor exerts on the surrounding brain areas, and to preserve normal pituitary function. Currently, treatment options include surgical removal of the tumor, drug therapy, and radiation therapy of the pituitary.[citation needed] ### Medications[edit] #### Somatostatin analogues[edit] The primary current medical treatment of acromegaly is to use somatostatin analogues – octreotide (Sandostatin) or lanreotide (Somatuline). These somatostatin analogues are synthetic forms of a brain hormone, somatostatin, which stops GH production. The long-acting forms of these drugs must be injected every 2 to 4 weeks for effective treatment. Most people with acromegaly respond to this medication. In many people with acromegaly, GH levels fall within one hour and headaches improve within minutes after the injection. Octreotide and lanreotide are effective for long-term treatment. Octreotide and lanreotide have also been used successfully to treat people with acromegaly caused by non-pituitary tumors.[citation needed] Somatostatin analogues are also sometimes used to shrink large tumors before surgery.[citation needed] Because octreotide inhibits gastrointestinal and pancreatic function, long-term use causes digestive problems such as loose stools, nausea, and gas in one third of people. In addition, approximately 25 percent of people with acromegaly develop gallstones, which are usually asymptomatic.[22] In some cases, octreotide treatment can cause diabetes due to the fact that somatostatin and its analogues can inhibit the release of insulin.[citation needed] #### Dopamine agonists[edit] For those who are unresponsive to somatostatin analogues, or for whom they are otherwise contraindicated, it is possible to treat using one of the dopamine agonists, bromocriptine or cabergoline. As tablets rather than injections, they cost considerably less. These drugs can also be used as an adjunct to somatostatin analogue therapy. They are most effective in those whose pituitary tumours cosecrete prolactin. Side effects of these dopamine agonists include gastrointestinal upset, nausea, vomiting, light-headedness when standing, and nasal congestion. These side effects can be reduced or eliminated if medication is started at a very low dose at bedtime, taken with food, and gradually increased to the full therapeutic dose. Bromocriptine lowers GH and IGF-1 levels and reduces tumor size in fewer than half of people with acromegaly. Some people report improvement in their symptoms although their GH and IGF-1 levels still are elevated.[citation needed] #### Growth hormone receptor antagonists[edit] The latest development in the medical treatment of acromegaly is the use of growth hormone receptor antagonists. The only available member of this family is pegvisomant (Somavert). By blocking the action of the endogenous growth hormone molecules, this compound is able to control disease activity of acromegaly in virtually everyone with acromegaly. Pegvisomant has to be administered subcutaneously by daily injections. Combinations of long-acting somatostatin analogues and weekly injections of pegvisomant seem to be equally effective as daily injections of pegvisomant.[citation needed] ### Surgery[edit] Surgical removal of the pituitary tumor is usually effective in lowering growth hormone levels. Two surgical procedures are available for use. The first is endonasal transphenoidal surgery, which involves the surgeon reaching the pituitary through an incision in the nasal cavity wall. The wall is reached by passing through the nostrils with microsurgical instruments. The second method is transphenoidal surgery during which an incision is made into the gum beneath the upper lip. Further incisions are made to cut through the septum to reach the nasal cavity, where the pituitary is located. Endonasal transphenoidal surgery is a less invasive procedure with a shorter recovery time than the older method of transphenoidal surgery, and the likelihood of removing the entire tumor is greater with reduced side effects. Consequently, endonasal transphenoidal surgery is the more common surgical choice.[citation needed] These procedures normally relieve the pressure on the surrounding brain regions and lead to a lowering of GH levels. Surgery is most successful in people with blood GH levels below 40 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter. Success depends on the skill and experience of the surgeon. The success rate also depends on what level of GH is defined as a cure. The best measure of surgical success is normalization of GH and IGF-1 levels. Ideally, GH should be less than 2 ng/ml after an oral glucose load. A review of GH levels in 1,360 people worldwide immediately after surgery revealed that 60% had random GH levels below 5 ng/ml. Complications of surgery may include cerebrospinal fluid leaks, meningitis, or damage to the surrounding normal pituitary tissue, requiring lifelong pituitary hormone replacement.[citation needed] Even when surgery is successful and hormone levels return to normal, people must be carefully monitored for years for possible recurrence. More commonly, hormone levels may improve, but not return completely to normal. These people may then require additional treatment, usually with medications. ### Radiation therapy[edit] Radiation therapy has been used both as a primary treatment and combined with surgery or drugs. It is usually reserved for people who have tumor remaining after surgery. These people often also receive medication to lower GH levels. Radiation therapy is given in divided doses over four to six weeks. This treatment lowers GH levels by about 50 percent over 2 to 5 years. People monitored for more than 5 years show significant further improvement. Radiation therapy causes a gradual loss of production of other pituitary hormones with time. Loss of vision and brain injury, which have been reported, are very rare complications of radiation treatments.[citation needed] ### Selection of treatment[edit] The initial treatment chosen should be individualized depending on the person's characteristics, such as age and tumor size. If the tumor has not yet invaded surrounding brain tissues, removal of the pituitary adenoma by an experienced neurosurgeon is usually the first choice. After surgery, a person must be monitored long-term for increasing GH levels.[citation needed] If surgery does not normalize hormone levels or a relapse occurs, a doctor will usually begin additional drug therapy. The current first choice is generally octreotide or lanreotide; however, bromocriptine and cabergoline are both cheaper and easier to administer. With all of these medications, long-term therapy is necessary, because their withdrawal can lead to rising GH levels and tumor re-expansion.[citation needed] Radiation therapy is generally used for people whose tumors are not completely removed by surgery, for people who are not good candidates for surgery because of other health problems, and for people who do not respond adequately to surgery and medication.[citation needed] ## Prognosis[edit] Life expectancy of people with acromegaly is dependent on how early the disease is detected.[23] Life expectancy after the successful treatment of early disease is equal to that of the general population.[24] Acromegaly can often go on for years before diagnosis, resulting in poorer outcome, and it is suggested that the better the growth hormone is controlled, the better the outcome.[23] Upon successful surgical treatment, headaches and visual symptoms tend to resolve.[11] One exception is sleep apnea, which is present in around 70% of cases, but does not tend to resolve with successful treatment of growth hormone level.[10] While hypertension is a complication of 40% of cases, it typically responds well to regular regimens of blood pressure medication.[10] Diabetes that occurs with acromegaly is treated with the typical medications, but successful lowering of growth hormone levels often alleviates symptoms of diabetes.[10] Hypogonadism without gonad destruction is reversible with treatment.[10] ## Notable people[edit] Famous people with acromegaly include: * André the Giant (born André Roussimoff, 1946-1993), French professional wrestler and actor[25][26] * Salvatore Baccaro (1932–1984), Italian character actor. Active in B-movies, Comedies and Horrors cause of its peculiar features and his spontaneous sympathy. * Paul Benedict (1938–2008), American actor. Best known for portraying Harry Bentley, The Jeffersons English next door neighbour[27] * Big Show (born Paul Wight; 1972), American professional wrestler and actor, currently working for the WWE, had his pituitary tumor removed in 1991.[28] * Eddie Carmel, born Oded Ha-Carmeili (1936–1972), Israeli-born entertainer with gigantism and acromegaly, popularly known as "The Jewish Giant" * Ted Cassidy (1932–1979), American actor. Best known for portraying Lurch in the TV sitcom The Addams Family.[29] * Rondo Hatton (1894–1946), American journalist and actor. A Hollywood favorite in B-movie horror films of the 1930s and 1940s. Hatton's disfigurement, due to acromegaly, developed over time, beginning during his service in World War I.[30] * Sultan Kösen, the world's tallest man. * Maximinus Thrax, Roman emperor (* c. 173, reigned 235 - 238). Descriptions as well as depictions indicate acromegaly, remains of his body are yet to be found. * The Great Khali (born Dalip Singh Rana), Indian professional wrestler, is best known for his tenure with WWE. He had his pituitary tumor removed in 2012, aged 39.[31] * Maurice Tillet (1903-1954), Russian-born French professional wrestler, is better known by his ring name, the French Angel.[32] * Richard Kiel (1939-2014), actor, "Jaws" from two James Bond movies and Mr. Larson in Happy Gilmore.[33] * Pío Pico, the last Mexican Governor of California (1801–1894), manifested acromegaly without gigantism between at least 1847 and 1858. Some time after 1858, signs of the growth hormone-producing tumor disappeared along with all the secondary effects the tumor had caused in him. He looked normal in his 90s.[34] His remarkable recovery is likely an example of spontaneous selective pituitary tumor apoplexy.[35] * Tony Robbins, motivational speaker.[36] * Carel Struycken, Dutch actor, 2.13 m (7 ft), is best known for playing Lurch in The Addams Family film trilogy, The Giant in Twin Peaks, and Lwaxana Troi's silent Servant Mr. Homn in Star Trek: The Next Generation, and The Moonlight Man in Gerald's Game, based on the Stephen King book.[37] * Irwin Keyes, American actor. Best known for portraying Hugo Mojoloweski, George's occasional bodyguard on The Jeffersons[38] * Morteza Mehrzad, Iranian Paralympian and medalist. Member of the Iranian sitting volleyball team. Top scorer in the 2016 gold medal match.[39] * Neil McCarthy, British actor. Known for roles in Zulu, Time Bandits, and many British television series.[40] * Nikolai Valuev, Russian politician and former professional boxer. * Antônio "Bigfoot" Silva, Brazilian kickboxer and mixed martial arts fighter.[41][42][43] Pianist and composer Sergei Rachmaninoff, noted for his very large hands, was never diagnosed with acromegaly in his lifetime, but a medical article from 2006 suggests that he might have had it.[44] ## See also[edit] * Hypothalamic–pituitary–somatic axis * Macrognathism ## References[edit] 1. ^ "Acromegaly". Oxford Dictionaries UK Dictionary. Oxford University Press. Retrieved 20 January 2016. 2. ^ "Acromegaly". Merriam-Webster Dictionary. 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 "Acromegaly". NIDDK. April 2012. Archived from the original on 27 August 2016. Retrieved 20 August 2016. 4. ^ Guglielmi G, Van Kuijk C (2001). Fundamentals of Hand and Wrist Imaging. Springer Science & Business Media. p. 205. ISBN 9783540678540. Archived from the original on 8 September 2017. 5. ^ a b Ho K (2011). Growth Hormone Related Diseases and Therapy: A Molecular and Physiological Perspective for the Clinician. Springer Science & Business Media. p. 400. ISBN 9781607613176. Archived from the original on 25 August 2016. 6. ^ Pack AI (2016). Sleep Apnea: Pathogenesis, Diagnosis and Treatment (2 ed.). CRC Press. p. 291. ISBN 9781420020885. Archived from the original on 25 August 2016. 7. ^ Pearce JM (2003). Fragments of Neurological History. World Scientific. p. 501. ISBN 9781783261109. Archived from the original on 25 August 2016. 8. ^ Pearce JM (September 2006). "Nicolas Saucerotte: Acromegaly before Pierre Marie". Journal of the History of the Neurosciences. 15 (3): 269–75. doi:10.1080/09647040500471764. PMID 16887764. S2CID 22801883. 9. ^ James W, Berger T, Elston D (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. ISBN 0-7216-2921-0. 10. ^ a b c d e f g h i Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW, et al. (September 2013). "A consensus on the diagnosis and treatment of acromegaly complications". Pituitary. 16 (3): 294–302. doi:10.1007/s11102-012-0420-x. PMC 3730092. PMID 22903574. 11. ^ a b Laws ER (March 2008). "Surgery for acromegaly: evolution of the techniques and outcomes". Reviews in Endocrine & Metabolic Disorders. 9 (1): 67–70. doi:10.1007/s11154-007-9064-y. PMID 18228147. S2CID 1365262. 12. ^ Fieffe S, Morange I, Petrossians P, Chanson P, Rohmer V, Cortet C, et al. (June 2011). "Diabetes in acromegaly, prevalence, risk factors, and evolution: data from the French Acromegaly Registry". European Journal of Endocrinology. 164 (6): 877–84. doi:10.1530/EJE-10-1050. PMID 21464140. 13. ^ Renehan AG, O'Connell J, O'Halloran D, Shanahan F, Potten CS, O'Dwyer ST, Shalet SM (2003). "Acromegaly and colorectal cancer: a comprehensive review of epidemiology, biological mechanisms, and clinical implications". Hormone and Metabolic Research. 35 (11–12): 712–25. doi:10.1055/s-2004-814150. PMID 14710350. 14. ^ Wolinski K, Czarnywojtek A, Ruchala M (14 February 2014). "Risk of thyroid nodular disease and thyroid cancer in patients with acromegaly--meta-analysis and systematic review". PLOS ONE. 9 (2): e88787. Bibcode:2014PLoSO...988787W. doi:10.1371/journal.pone.0088787. PMC 3925168. PMID 24551163. 15. ^ Melmed S, Jackson I, Kleinberg D, Klibanski A (August 1998). "Current treatment guidelines for acromegaly". The Journal of Clinical Endocrinology and Metabolism. 83 (8): 2646–52. doi:10.1210/jcem.83.8.4995. PMID 9709926. 16. ^ Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J (8 April 2015). Harrison's Principles of Internal Medicine (19th ed.). McGraw Hill. pp. 2269–2271. ISBN 978-0071802154. 17. ^ Vortmeyer AO, Gläsker S, Mehta GU, Abu-Asab MS, Smith JH, Zhuang Z, et al. (July 2012). "Somatic GNAS mutation causes widespread and diffuse pituitary disease in acromegalic patients with McCune-Albright syndrome". The Journal of Clinical Endocrinology and Metabolism. 97 (7): 2404–13. doi:10.1210/jc.2012-1274. PMC 3791436. PMID 22564667. 18. ^ Salenave S, Boyce AM, Collins MT, Chanson P (June 2014). "Acromegaly and McCune-Albright syndrome". The Journal of Clinical Endocrinology and Metabolism. 99 (6): 1955–69. doi:10.1210/jc.2013-3826. PMC 4037730. PMID 24517150. 19. ^ Yaqub A, Yaqub N (2008). "Insulin-mediated pseudoacromegaly: a case report and review of the literature". The West Virginia Medical Journal. 104 (5): 12–5. PMID 18846753. 20. ^ Nguyen KH, Marks JG (June 2003). "Pseudoacromegaly induced by the long-term use of minoxidil". Journal of the American Academy of Dermatology. 48 (6): 962–5. doi:10.1067/mjd.2003.325. PMID 12789195. 21. ^ Sam AH, Tan T, Meeran K (2011). "Insulin-mediated "pseudoacromegaly"". Hormones. 10 (2): 156–61. doi:10.14310/horm.2002.1306. PMID 21724541. 22. ^ "Octreotide Side Effects". Archived from the original on 22 April 2016. Retrieved 24 July 2019. 23. ^ a b Lugo G, Pena L, Cordido F (2012). "Clinical manifestations and diagnosis of acromegaly". International Journal of Endocrinology. 2012: 540398. doi:10.1155/2012/540398. PMC 3296170. PMID 22518126. 24. ^ Melmed S, Bronstein MD, Chanson P, Klibanski A, Casanueva FF, Wass JA, et al. (September 2018). "A Consensus Statement on acromegaly therapeutic outcomes". Nature Reviews. Endocrinology. 14 (9): 552–561. doi:10.1038/s41574-018-0058-5. PMC 7136157. PMID 30050156. 25. ^ "Andre the Giant: Bio". WWE.com. Archived from the original on 10 January 2008. Retrieved 16 October 2007. 26. ^ "André the Giant official website". Archived from the original on 4 July 2007. Retrieved 8 July 2007. 27. ^ Times Staff And Wire Reports (5 December 2008). "Paul Benedict dies at 70; actor from 'The Jeffersons' and 'Sesame Street'". The Los Angeles Times. Archived from the original on 26 August 2016. 28. ^ Baines T. "Big Show at home in current role". Ottawa Sun. Archived from the original on 6 October 2015. 29. ^ "Hope for Acromegaly Patients". 30 January 2015. Archived from the original on 9 February 2019. Retrieved 24 July 2019. 30. ^ Duryea B (27 June 1999). "Floridian: In love with a monster". St Petersburg Times. Archived from the original on 8 June 2016. 31. ^ Harish A. "WWE Star Great Khali's Growth-Inducing Tumor Removed". ABC News. Archived from the original on 4 March 2016. 32. ^ Oliver G. "The French Angel was more man than monster". SLAM! Wrestling. Archived from the original on 6 July 2015. 33. ^ "Richard "Jaws" Kiel, Famed Bond Movie Villain, Raises Awareness Oflife-Threatening Hormone Disorder". Prnewswire.com. Archived from the original on 10 July 2009. Retrieved 26 July 2010. 34. ^ Login IS, Login J (July 2008). "Governor Pio Pico, the monster of California...no more: lessons in neuroendocrinology". Pituitary. 13 (1): 80–6. doi:10.1007/s11102-008-0127-1. PMC 2807602. PMID 18597174. Open Access; https://doi.org/10.1007%2Fs11102-008-0127-1 35. ^ Nawar RN, AbdelMannan D, Selman WR, Arafah BM (2008). "Pituitary tumor apoplexy: a review". Journal of Intensive Care Medicine. 23 (2): 75–90. doi:10.1177/0885066607312992. PMID 18372348. S2CID 34782106. 36. ^ Plaskin G (13 August 2013). "Playboy Interview: Tony Robbins". Playboy. Archived from the original on 2 April 2015. Retrieved 5 March 2015. 37. ^ McLellan D (27 December 1992). "Shedding Light on a Rare Disease: Woman Hopes O.C. Group Will Increase Awareness of Life-Threatening Effects of Excessive-Growth Illness". The Los Angeles Times. Archived from the original on 7 March 2016. 38. ^ Dagan C (8 July 2015). "Irwin Keyes, Horror Movie Character Actor, Dies at 63". Variety. Archived from the original on 29 May 2016. 39. ^ Davies GA (13 September 2016). "Paralympics' tallest ever competitor: 'My life has changed playing sitting volleyball'". The Telegraph. Retrieved 4 May 2017. 40. ^ Stampede P. "Neil McCarthy". The Avengers Forever. Retrieved 29 January 2014. 41. ^ https://extra.globo.com/esporte/mma/ex-treinador-de-pezao-andre-benkei-explica-doenca-do-lutador-afirma-ele-jamais-colocaria-saude-em-risco-11143681.html 42. ^ https://mmajunkie.usatoday.com/2014/09/trt-ban-forces-ufc-headliner-bigfoot-silva-into-surgery 43. ^ https://www.usatoday.com/story/sports/ufc/2013/05/23/ufc-title-hopeful-bigfoot-silva-gigantism-ufc-160/2356405/ 44. ^ Manoj Ramachandran; Jeffrey K Aronson (October 2006). "The diagnosis of art: Rachmaninov's hand span". Journal of the Royal Society of Medicine. 99 (10): 529–30. doi:10.1258/jrsm.99.10.529. PMC 1592053. PMID 17066567. ## External links[edit] * Acromegaly at Curlie * 2011 American Association of Clinical Endocrinologists Guideline * Endocrine and Metabolic Diseases Information Service Classification D * ICD-10: E22.0inusl * ICD-9-CM: 253.0 * OMIM: 102200 * MeSH: D000172 * DiseasesDB: 114 External resources * MedlinePlus: 000321 * eMedicine: med/27 derm/593 * Patient UK: Acromegaly * Orphanet: 963 * v * t * e Pituitary disease Hyperpituitarism Anterior * Acromegaly * Hyperprolactinaemia * Pituitary ACTH hypersecretion Posterior * SIADH General * Nelson's syndrome * Hypophysitis Hypopituitarism Anterior * Kallmann syndrome * Growth hormone deficiency * Hypoprolactinemia * ACTH deficiency/Secondary adrenal insufficiency * GnRH insensitivity * FSH insensitivity * LH/hCG insensitivity Posterior Neurogenic diabetes insipidus General * Empty sella syndrome * Pituitary apoplexy * Sheehan's syndrome * Lymphocytic hypophysitis * Pituitary adenoma Authority control * NDL: 01150006 * NSK: 004898397 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Acromegaly	c0001206	6,563	wikipedia	https://en.wikipedia.org/wiki/Acromegaly	2021-01-18T18:41:02	{"gard": ["5725"], "mesh": ["D000172"], "umls": ["C0001206"], "icd-9": ["253.0"], "icd-10": ["E22.0"], "orphanet": ["963"], "wikidata": ["Q189580"]}
## Clinical Features Gorlin (1978) described 3 sons of 2 sisters who had multiple impacted teeth. The woman who mothered 2 of the boys was related to her husband as first cousin. Mercuri and O'Neill (1980) reported 2 sisters with multiple impacted and supernumerary teeth (a total of 27 in one of them) (see 187100), who had a history of the same in 2 brothers, the father, and a paternal grandparent. Babu et al. (1998) reported a mother and daughter with nonsyndromic multiple impacted normal and supernumerary teeth. The daughter presented at age 8 years with retained upper and lower primary teeth anteriorly. Intraoral examination showed a complete set of primary dentition in both the maxillary and mandibular arches, with a single conical supernumerary tooth between the left central and lateral incisors. Radiography confirmed the complete set of primary dentition and revealed 3 supernumerary teeth in the anterior mandibular region as well as the previously noted supernumerary tooth in the anterior maxillary region. There was lack of resorption of roots of the anterior teeth. Radiography of the mother, who reported a similar history of retained primary teeth, showed multiple impacted teeth in both the maxilla and mandible, with approximately 18 impacted teeth in the anterior mandible, including 8 supernumerary teeth. Inheritance \- X-linked Teeth \- Multiple impacted teeth \- Supernumerary teeth ▲ 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	IMPACTED TEETH, MULTIPLE	c1839965	6,564	omim	https://www.omim.org/entry/308280	2019-09-22T16:18:03	{"omim": ["308280"]}
A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 2 (MC1DN2) is caused by homozygous or compound heterozygous mutation in the NDUFS8 gene (602141) on chromosome 11q13. For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010. Clinical Features Loeffen et al. (1998) reported a patient with mitochondrial complex I deficiency manifesting as Leigh syndrome (see 256000). The patient presented at age 5 weeks with poor feeding and episodes of apnea and cyanosis. The symptoms, which had existed since the first day of life, escalated in the course of an acute gastroenteritis. The parents were nonconsanguineous. Cardiac examination revealed a moderate hypertrophic obstructive cardiomyopathy. CT scan of the brain showed extensive white matter hypodensity, mild ventricular enlargement, and hypodense symmetric lesions in putamen and mesencephalon. The disorder progressed, leading to death at the age of 11 weeks from cardiorespiratory failure. Procaccio and Wallace (2004) reported a patient with late onset of mitochondrial complex I deficiency manifesting as Leigh syndrome. The patient first developed walking difficulties at age 7 years, which progressed to balance impairment, dysarthria, mild dystonic posture, and nystagmus. Brain imaging showed bilateral symmetric lesions in the putamen. Complex I activity in the patient's skeletal muscle and lymphoblasts was reduced to 31% and 43% of controls, respectively. Haack et al. (2012) reported 3 patients, including 2 sibs, with complex I deficiency. The unrelated patient had mitochondrial encephalopathy, hypertrophic cardiomyopathy, hypotonia, and respiratory insufficiency. respectively. Both sibs had Leigh syndrome, hypotonia, and lactic acidosis; one had seizures and the other had hypertrophic cardiomyopathy. Molecular Genetics In a patient with mitochondrial complex I deficiency manifesting as Leigh syndrome, Loeffen et al. (1998) identified compound heterozygous mutations in the NDUFS8 gene (P79L, 602141.0001 and R102H, 602141.0002). These were the first mutations identified in a nuclear-encoded component of the respiratory chain complex I. In a patient with late onset of mitochondrial complex I deficiency manifesting as Leigh syndrome, Procaccio and Wallace (2004) identified compound heterozygous mutations in the NDUFS8 gene (P85L, 602141.0003 and R138H, 602141.0004). In a patient with complex I deficiency, Haack et al. (2012) identified compound heterozygous mutations in the NDUFS8 gene (R77W, 602141.0005 and A149D, 602141.0006). Each unaffected parent was heterozygous for 1 of the mutations. In 2 sibs with MC1DN2, Haack et al. (2012) identified a homozygous mutation in the NDUFS8 gene (E63Q; 602141.0007). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Nystagmus CARDIOVASCULAR Heart \- Hypertrophic cardiomyopathy RESPIRATORY \- Respiratory insufficiency \- Apnea, episodic ABDOMEN Gastrointestinal \- Poor feeding MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay (in some patients) \- Normal cognition (in some patients) \- Dystonia \- Difficulty walking \- Seizures \- Hyperreflexia \- Dyskinesia \- Dysarthria \- White matter abnormalities consistent with Leigh syndrome LABORATORY ABNORMALITIES \- Increased serum and CSF lactate \- Increased pyruvate \- Mitochondrial complex I deficiency in various tissues MISCELLANEOUS \- Onset in early infancy or childhood \- Variable severity MOLECULAR BASIS \- Caused by mutation in the NADH-ubiquinone oxidoreductase core subunit S8 gene (NDUFS8, 602141.0001 ) ▲ 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	MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 2	c2936907	6,565	omim	https://www.omim.org/entry/618222	2019-09-22T15:43:03	{"mesh": ["C537475"], "omim": ["618222"], "orphanet": ["2609", "255241"]}
Lutembacher's syndrome This condition affects the atrium SpecialtyMedical genetics Lutembacher's syndrome is a very rare[1] form of congenital heart disease that affects one of the chambers of the heart (commonly the atria) as well as a valve (commonly the mitral valve). It is commonly known as both congenital atrial septal defect (ASD) and acquired mitral stenosis (MS).[2] Congenital (at birth) atrial septal defect refers to a hole being in the septum or wall that separates the two atria; this condition is usually seen in fetuses and infants.[3] Mitral stenosis refers to mitral valve leaflets (or valve flaps) sticking to each other making the opening for blood to pass from the atrium to the ventricles very small.[4] With the valve being so small, blood has difficulty passing from the left atrium into the left ventricle. Septal defects that may occur with Lutembacher's syndrome include: Ostium primum atrial septal defect or ostium secundum which is more prevalent.[1] Lutembacher's syndrome affects females more often than males.[1] It can affect children or adults; the person can either be born with the disorder or develop it later in life. The syndrome was first described by René Lutembacher (1884–1968)[5] of Paris in 1916.[2] To correct Lutembacher's syndrome, surgery is often done. There are several types of surgeries depending on the cause of Lutembacher's syndrome(ASD Primium or ASD Ostium Secundum with Mitral Stenosis): 1. Suturing (stitching) or placing a patch of tissue (similar to skin grafting) over the hole to completely close the opening 2. Reconstructing of the mitral and tricuspid valve while patching any holes in the heart 3. Device closure of ASD (e.g. Amplatzer umbrella or CardioSEAL to seal the hole[2][citation needed] 4. Percutaneous transcatheter therapy[2] 5. Transcatheter therapy of balloon valvuloplasty to correct MS[2] ## Contents * 1 Symptoms and signs * 1.1 Major symptoms * 1.2 Minor symptoms * 1.3 Less common symptoms * 1.4 Related disorders * 2 Causes * 3 Mechanism * 3.1 Atrial Septal Defect Primium * 3.2 Atrial Septal Defect Ostium secundum * 3.3 Mitral Valve Stenosis * 4 Diagnosis * 4.1 Physical examinations * 4.2 Electrocardiograms * 4.3 Chest radiogram * 4.4 Transthoracic or Transesophageal echocardiography * 4.5 Color flow mapping and Doppler imaging * 4.6 Chest X-ray * 4.7 Cardiac catheterization * 5 Treatments * 5.1 Percutaneous transcatheter therapy * 5.1.1 Side effects * 5.2 Device closure * 5.2.1 Interventionally * 5.2.2 Surgically * 5.2.2.1 Side effects * 6 Recent research * 7 References * 7.1 Additional references * 8 External links ## Symptoms and signs[edit] As Lutembacher's syndrome is known for ASD and MS, most of the symptoms experienced will be associated with ASD and MS. For most people, they will remain asymptomatic (experience no symptoms) but when symptoms are shown, they are due mainly to ASD and will vary depending on the size of the hole in the atria. If the patient has a large ASD, pulmonary congestion (blood or fluid buildup in the lungs) will happen later but if the patient has a small ASD, symptoms will appear early in the disorder. In general, unless the ASD and mitral stenosis causing Lutembacher's syndrome is severe, symptoms may not appear until the second and third decade of the patient's life.[citation needed] As many of the patients are asymptomic and symptoms may not appear until later in life, the duration or frequency of the symptoms varies. For symptoms such as palipitations, ventricular overload, heart failure, and pulmonary congenstion, these symptoms may be sudden and not that frequent as they are very severe symptoms. For symptoms such as loud mitral S1, pulmonary S2, mid-diastolic murmur, fatigue, reduced exercise tolerance, weight gain, ankle edema, and right upper quadrant pain, and ascities, these symptoms may be less frequent and severe; their duration may be only a few seconds, minutes, or even months. ### Major symptoms[edit] Major symptoms of Lutembacher's syndrome as a result of ASD and MS can range from heart failure to pulmonary congestion. * Right ventricular overload and Right-sided heart failure: Both are caused by a large ASD and MS (moderate to severe). * Palpitations: This is caused by blood flowing from left atrium to the right atrium causing a higher left atrial pressure and leading to mitral stenosis. Both atria will be dilated (stretched or open)leading to future atrial arrhythmias or atrial fibrillation (Riaz). * Pulmonary congestion: When blood or fluid pools within the lungs; this is usually a symptom of mitral stenosis and a small ASD. * Loud mitral S1 and wide fixed split of pulmonary S2: The loud sound of the mitral S1 and the wide fixed split of pulmonary S2 is a symptoms of mitral stenosis. The sounds often are caused by a reduced pressure gradient in the mitral area that was caused from decompression of the left atrium from the ASD and a displacement (moving from normal position) of the left ventricular lower portion of the heart to the a large right ventricle. The second heart sound (S2) split is caused by the increase right heart blood flow through the ASD causing a late closing of the pulmonary component of the S2 as well as decreased left ventricular and aortic blood flow. * III/IV mid diastolic murmur, early systolic murmur: This heart murmur is caused by an increase blood flow through the tricuspid valve due to ASD; it is heard best in the left lower sternal area or the bottom of the heart (apex).[1][6] ### Minor symptoms[edit] * Fatigue: symptoms is caused by decreased systemic (oxygenated blood to the rest of the body)flow. When the patient suffers from MS and the blood flows from the left atrium to the right atrium causes the forward blood flow into the left ventricle to reduce leading to a reduction of systemic blood flow; this causes tiredness. * Reduced exercise tolerance: symptoms also caused by decreased systemic (oxygenated blood to the rest of the body) flow. Just as with fatigue, when the patient suffers from MS and the blood flows from the left atrium to the right atrium, the forward blood flow into the left ventricle is reduced leading to a reduction of systemic blood flow; this causes tiredness and hence a reduced exercise tolerance. * Weight gain: this is commonly found in patients with large ASD and can be a symptom of developing right-sided heart failure. As there is a chronically increased left-to-right blood flow through the atria, this will lead in the future to right-sided heart failure. * Ankle edema: This is also caused by a large ASD and has the same symptoms and causes as seen in weight gain and right upper quadrant pain. As blood flow is not happening correctly and the heart is pumping under strain, pooling of blood and fluid will happen in the ankles. * Right upper quadrant pain: Also caused by large ASD; has same symptoms and underlying causes as weight gain and ankle edema. * Ascites: Ascite is known as abnormal buildup of fluid in spaces between abdomen lining and abdominal organs. Same symptoms and causes as weight, gain, ankle edema, and right upper quadrant pain.[6] ### Less common symptoms[edit] * Paroxysmal nocturnal dyspnea, orthopnea, and hemoptysis (sign of pulmonary venous congestion): this symptoms are less frequent in Lutembacher's syndrome and are more associated with MS and small ASD or patients who develop reverse Lutembacher's syndrome. This symptom is caused by mitral stenosis.[6] ### Related disorders[edit] * Eisenmenger syndrome * Ventricular Septal Defect * Mitral regurgitation * Ebstein disease ## Causes[edit] Lutembacher is caused indirectly by heart damage or disorders. Lutembacher's syndrome is caused by either birth defects where the heart fails to close all holes in the walls between the atria or from an episode of rheumatic fever where damage is done to the heart valves such as the mitral valve and resultant in an opening of heart wall between atria. With Lutembacher's syndrome, a fetus or infant is usually seen to have a hole in their heart wall (interatrial) separating their right and left atria.[7] Normally during fetal development, blood bypasses the lungs and is oxygenated from the placenta. Blood passes from the umbilical cord and flows into the left atrium through an opening called the foramen ovale; the formaen ovale is a hole between the two atria.[7] Once a baby is born and the lungs begin to fill with air and the blood flow of the heart changes, a tissue flap (somewhat like a trap door) called the septum primium closes the foramen ovale or hole between the two atria and becomes part of the atrial wall. The failure of the hole between the two atria to close after birth leads to a disorder called ASD primium.[7] The most common problems with an opening found in the heart with Lutembacher's syndrome is Ostium Secundum. Ostium Secundum is a hole that is found within the flap of tissue (septum primium) that will eventually close the hole between the two atria after birth. With either type of ASD, ASD will usually cause the blood flow from the right atrium to skip going to the right ventricle and instead flow to the left atrium. If mitral stenosis (the hardening of flap of tissue known as a valve which opens and closes between the left atrium and ventricle to control blood flow) is also present, blood will flow into the right atrium through the hole between the atria wall instead of flowing into the left ventricle and systemic circulation.[1][7] Eventually this leads to other problems such as the right ventricle failing and a reduced blood flow to the left ventricle.[1] In addition to the ASD, MS can either be acquired (present either from an episode of rheumatic fever or the mother has or had rheumatic fever during the pregnancy) or congenital (the child being born with the disorder). With the combination of both ASD and MS, the heart can be under severe strain as it tries to move blood throughout the heart and lungs.[citation needed] ## Mechanism[edit] Atrial Septal Defect (ASD) Mitral Valve Stenosis (MS) There is no exact mechanism for Lutembacher's syndrome but instead a combination of disorders as the result of Atrial septal defect (ASD) and/or Mitral valve stenosis.[citation needed]It is thought ASD is caused by the failure to close the hole (foramen ovale) between the right and left atrium normally found within the heart during fetal development; the creation of a hole between the atrium may also be acquired. There are two types of ASD: Ostium secundum and ASD Primium.[citation needed] ### Atrial Septal Defect Primium[edit] The failure of the hole between the right and left atrium to close shortly after birth is the cause behind ASD primium. During fetal development blood will pass from the umbilical cord and flow into the left atrium through a hole between the two atria. Once a baby is born and the lungs begin to fill with air, the blood flow of the heart changes; a tissue flap (septum primium) normally closes the hole (foramen ovale) between the two atria and becomes part of the atrial wall.[7] During ASD primium, after birth the hole is not completely closed allowing deoxygenated blood to flow into the left atria from the right atria. With the failure of the blood to pass from the right atrium into the right ventricle and then into the pulmonary veins, blood will not obtain any oxygen before it is leaves the heart and goes to other parts of the body.[7] Due to the incorrect blood flow, symptoms such as fatigue (from decreased systemic blood flow), palpitations (from blood flowing from left atria to right atria), weight gain, edema, right upper chest pain (all caused from the left to right atria blood flow), and paroxysmal nocturnal dyspnea (shortness of breath during sleep), orthopnea (difficulty in breathing while lying down), and hemoptysis or coughing up blood (all caused by small ASD that cause blood flow from left to right atria).[6] ### Atrial Septal Defect Ostium secundum[edit] During the more common form of Lutembacher's syndrome, ASD Ostium secundum, a hole will form in the flap of tissue (septum primium) that should close between the two atria after birth. With the onset of a hole created in the tissue flap that closes the larger hole between the left and right atrium, blood can again flow from the right atrium to the left.[1][7] Ostium secundum causes many of the same symptoms seen in ASD primium. With either type of ASD, blood will flow from the right atrium skipping the right ventricle (or very little flowing into the ventricle) and instead flow to the left atrium introducing the possibility of blood lacking oxygen to go the rest of the body.[1][7] Sometimes, the direction of blood flow is largely determined by the left and right ventricle ability to squeeze (contract) and relax (compliance).[1] Apart from congential or birth defects causing ASD, ASD is thought to be also acquired. During pecutaneous interventional procedures such as mitral valvuloplasty (a surgical process done to repair a mitral valve), 11-12% of individuals will develop ASD allowing blood to flow from the left atrium to the right.[8] ### Mitral Valve Stenosis[edit] The second cause of Lutembacher's syndrome is mitral stenosis (MS). MS can be caused by birth defects, rheumatic fever, or just stress to the heart due to ASD; because MS can be caused by several things, there is no exact mechanism but many mechanisms or causes. If mitral valve stenosis is a result of birth defects during development stemming from rheumatic fever, several things may occur in the heart. Rheumatic fever causes the immune system to attack its own protein tissues leading to lesions forming on the mitral valve flaps. As the flaps heals over time, the flaps lose their filmy and floppiness resulting in solid, stiff flaps. The loss of proper flappy mitral valves makes it harder for the valves to open and allow blood to flow through. As a result of blood flow being stopped or slowed by the faulty valve, pressure begins to build in the heart. It was once thought an ASD is not already present, could form because of MS, but it is now thought the ASD is either a birth defect or acquired from surgical procedures.[8] Overall, Lutembacher's syndrome has no certain mechanism but a combination as the result of ASD and MS. ## Diagnosis[edit] Lutembacher's syndrome is diagnosis primarily by physical examinations for heart sounds, electrocardiograms, chest radiogram, transthoracic or transesophageal echocardiography, color flow mapping, and Doppler imaging. Use of the various test can help to differentiate other possible conditions such as mitral regurgitation, Ebstein disease, ventricular septal defect (VSD).[9] ### Physical examinations[edit] A physical examination will be done to check for abnormal heart sounds, condition of heart, blood pressure, lungs, palpitations, edema, weight gain, ascites, or any other abnormal symptoms. Blood may also be drawn to help determine the cause of fatigue, determination of ascites, other health problems that maybe closely related to cause the symptoms such as kidney, liver, immune (signs of rheumatic fever), abnormal glucose levels.[citation needed] ### Electrocardiograms[edit] Electrocardiogram (ECG) is used for determination of the location, size, direction of blood flow through the atrial hole, hemodynamic of the right ventricle (blood circulation), tricuspid valve, and functioning of left ventricle. The ECG can also be used to determine the rhythm of the heart to determine if there is an indication of sinus rhythm or atrial fibrillation. In the ECG, the p wave morphology will be study for any abnormalities. If during the ECG, the P-wave (atrial depolarization) is tall, broad, or split waves in lead II and accompanied with a deep negative force in V1, this would be considered to be abnormal; only one wave should be associated with the P-wave. Additionally, in an ECG the QRS morphology and axis will be examined for any abnormalities. If the ECG shows a right axis deviation which is abnormal or a right bundle-branch block (this would mean there was no signal going through the atrium to instruct the ventricle to contract or squeeze blood out of the ventricle).[9] ### Chest radiogram[edit] A chest radiogram can be given to a patient to determine: * Pulmonary plethora: the test will help to determine if there is a left-to-right shunt meaning the blood is flowing from the left atrium to the right through a hole between the two atria. * Mild left atrial enlargement: the test will help to determine if the left atrium is enlarged due to alternate blood flows * Right ventricular enlargement: the test will help to determine if the ventricle is enlarged due to a surge of blood above normal or if the ventricle is having to work harder than normal to pump blood out of the ventricle. * Pulmonary artery enlargement: the test will help to determine if there is a large volume of blood in the pulmonary veins and arteries than normal * Mitral Valve calcification late in life: the test will help to determine if the mitral valve or flaps are becoming hardened and losing their floppiness. * pulmonary vascular congestion, marked left atrial enlargement: the test will help to determine if there is a sign of MS and small ASD and how severe both are.[9] ### Transthoracic or Transesophageal echocardiography[edit] Transthoracic or Transesophageal echocardiography two dimensional images that can be made of the heart. They can be used to determine the stages of Lutembacher's syndrome. They are used to determine: * Large left atrium: the test can help to determine if the left atrium is enlarged to a large blood flow then unusually * Large right atrium and ventricle: the test will help to determine if the right atrium and ventricle are enlarged due to a greater blood flow * ASD: the test will help to determine if there is a hole between the two atria and if blood is flowing through both * Stenotic mital valve: the test will help to determine if the blood flow through the mitral valve is normal or if the mitral valve is stiff, has a reduced opening, and constricting blood flow through it.[9] ### Color flow mapping and Doppler imaging[edit] A color flow and doppler imaging is used to help confirm the presence as well as evaluate the severity of ASD and MS.[9] ### Chest X-ray[edit] A chest x-ray will be given to determine the size of the heart and the blood vessels supplying blood to the lungs.[10] ### Cardiac catheterization[edit] Cardiac catheterization is done to confirm a diagnosis; it is not routinely done prior. It can also be used to evaluate the severity of ASD and measure the mitral valve area. To determine the presence ASD, a catheter is passed through the suspected hole between the atrium into the left atrium.[citation needed] ## Treatments[edit] To treat Lutembacher's syndrome, the underlying causes of the disorder must first be treated: mitral stenosis and atrial septal defect. Lutembacher's syndrome is usually treated surgically with treatments such as: * percutaneous transcatheter therapy for MS * Device closure of ASD Percutaneous transcatheter treatment for the MS can include transcatheter therapies of such as balloon valvuloplasty. ### Percutaneous transcatheter therapy[edit] Percutaneous transcatheter therapy is used to repair the mitral valve and sometimes the septum. In percutaneous balloon mitral valvuloplasty, using a catheter, a ballon such as the Inoue ballon is placed into blood vessels in the groin area and the balloon guided to the heart. If a hole is not already present, a small hole may need to be inserted the atria and inserted into the mitral valve through the left atrium; the balloon is then inflated. The balloon inside the mitral valve will be inflated and deflated several times to wide the valve opening until the opening is satisfactory; the balloon will then be deflated and removed.[2][11] The advantage to using percutaneous procedures instead of open-heart surgery is not needing general anesthesia, blood transfusions, and the recovery time is quicker. The drawback to this procedure is the lack of repeating and transseptal procedures if they are needed later. Also if the patient later develops a relapse of MS, surgery will need to be performed where using more evasive techniques.[2] Additionally, if a hole is needed to be inserted into the atria to obtain access to the mitral valve, there is a risk of developing ASD secondarily.[2] #### Side effects[edit] Possible side effects from this non-invasive procedure could be: * fever * Chest pain * Shortness of breath * Unusual swelling or weight gain * Swelling, bleeding, change in skin color at site of initial catheterization in groin, or pain in the groin.[11] If any of the above symptoms occur, it is important to contact your doctor to prevent another lapse of mitral stenosis. To ensure good health, routine doctors visits, diet, weight loss, doctor-approved exercise, and use of antibiotics in dental and other procedures are recommended.[11] ### Device closure[edit] To treat ASD a device closure can be used. In fact an ASD closure is often recommended for certain cases such as with a patient who has significant left-to-right shunt with a pulmonary and/or systemic flow fraction of Qp/Qs >1.5. It is best to perform this procedure/surgery between the ages of 2–4 years.[citation needed] The closure is done by two methods: interventionally or surgically.[citation needed] #### Interventionally[edit] This procedure is done by placing a device such as Amplatzer "umbrella", CardioSEAL similar to percutaneous transcatheter therapy. A catheter is inserted in the vessels and threaded to the heart and inserted into the ASD closing the defect.[citation needed] Other closure device that have been used is the GORE HELEX Septal Occluder.[10] After the device has been inserted and covers the defect, over time tissue will grow over the implant device to make it become part of the heart. Anticoagulant medication will be given to the patient for the first six months following the surgery: aspirin, clopidogrel or warfarin (Coumadin).[10] #### Surgically[edit] This procedure is done through open heart surgery (sternotomy or thoracotomy) using an ECC where the heart is stopped to allow a system of special cannulas to be placed. The hole is closed by a direct suture (sewing) if the hole is small enough or if the hole is larger, suturing (sewing) a small patch of pericardium (heart tissue or skin) or fabric to close the hole.[citation needed] To increase quality life following ASD procedures/surgeries, patients should have a physical exam and ECG every 3, 6, and 12 months with their cardiologist.[10] For many patients with secundum ASD closure repair, they can return to their normal activities unless their procedure was heart catheterization which in this case they should rest for a few days.[10][12] All patients should remain on blood thinner medication for at least 6 months and up to a year unless the patient had a stroke in which they would always be on blood thinners.[10][12] Patients with coronary artery disease or pulmonary hypertension will take additional medicines described by their physician. For patients who had heart surgery to repair the defect or received a transcatheter closure device, they will need to take some form of antibiotics to prevent infections such as endocarditis for at least 6 months following the procedure.[10][12] Success with ASD closure is very high, 96% for percutaneous procedures and 100% of ASD surgeries as found by one research group.[12] No patient was found to have died from either interventional or surgical treatments and only 7.2% of patients who received a device and 24.0% of patients who had surgery had complications. The hospital stay for each group also varied, the surgical group was 3.4 ± 1.2 days and device group 1.0 ± 0.3 days.[12] As seen by this study, prognosis was good and quality of life could be excellent.[citation needed] ##### Side effects[edit] Side effects with interventional device closure have not been extensively supported as yet.[12] Possible side effects from the ASD device closure procedure could be: * fever * Chest pain * Swelling * Swelling, bleeding, change in skin color at site of initial catheterization in groin, or pain in the groin With surgically closure, the normal risk of infection, fevers, and blood clots are among the risks. If any signs of infection such as swelling, pain, or fever are present, the patient should seek medical attention. Patients who have ASD repaired later in life are also at a higher risk of developing atrial fibrillation especially if the device is not stable.[12] ## Recent research[edit] Through examining the benefits of using percutaneous treatment as an alternative to surgically means to correct MS and ASD, it was found that combined percutaneous treatment (including balloon valvuloplasty for MS and Amplatzer septal occluder for closure of the ASD) has improved the patient's planimetric mitral valve area to 2.1 cm (as compared to the previous 1.5 cm), maximum diastolic gradient to 9 mmHg (compared to previous 17 mmHg), and mean diastolic gradient to 4 mmHg (as compared to previous 9 mmHg).[13] In another study, surgeons developed a way to use percanteous therapy in difficult situations. In this study they developed a technique to use the Inoue balloon in valvuloplasty but to insert a wire into the left atrium prior to inserting the balloon. This enabled the surgeons to be more precise in treating the mitral valve and not have the balloon to slip out of place; the wire served as a guide to inserting the balloon.[14] Other Percutaneous procedures beside balloon valvuloplasty for MS have been looked into. Percutaneous Leaflet Plication (Edge-to-Edge Leaflet Repair) is being explored as a way to increase the opening of the mitral valve by clamping down mitral leaflets. The clamps are delivered to the mitral through a catheter as with the balloon, and then clamped onto the mitral valve. Of the patients that received this treatment, 74% patients achieved surgical success, and at 1-year, 68% were saved from dying, 90% from having to have surgery or dying from the lack thereof, a 76.3% prognosis at three years.[15] Given the many possible treatments that are to come, future research is continuing to find better methods of treating Lutembacher patients non-invasively as with percutaneous therapy. Without successfully treating Lutembacher's more serious complications can occur such as heart failure or even disorders such as Eisenmenger syndrome.[7] ## References[edit] 1. ^ a b c d e f g h i Kulkarni, Sandhya; Amit K. Sakaria; Sanket K. Mahajan; Kuldeep B. Shah (2012). "Lutembacher's syndrome". Journal of Cardiovascular Disease Research. 3 (2): 179–181. doi:10.4103/0975-3583.95381. PMC 3354470. PMID 22629045. 2. ^ a b c d e f g h Behjatiardakani, Mostafa; Mansour Rafiei; Hossein Nough; Reza Rafiei (2011). "Trans-Catheter Therapy of Lutembacher Syndrome: A Case Report". Acta Medica Iranica. 49 (5): 327–330. PMID 21713755. 3. ^ "Facts about Atrial Septal Defect". Centers for Disease Control and Prevention. Retrieved 2 May 2014. 4. ^ Hall, John (2011). Guyton and Hall Textbook of Medical Physiology. Philadelphia, PA: Saunders Elsevier. 5. ^ "René Lutembacher". www.whonamedit.com. Retrieved 2018-11-27. 6. ^ a b c d Riaz, Kamran. "Lutembacher Syndrome Clinical Presentation". 7. ^ a b c d e f g h i Marmur, Johnathan. "Atrial Septal Defects (ASD) and Patent Foramen Ovale (PFO)". 8. ^ a b Riaz, Kamran (February 2019). "Lutembacher Syndrome". Cite journal requires `\|journal=` (help) 9. ^ a b c d e Riaz, Kamran. "Lutembacher Syndrome Workup". 10. ^ a b c d e f g "Atrial Septal Defect (ASD)". Cleveland Clinic. Retrieved May 2, 2014. 11. ^ a b c "Diseases & Conditions". Cleveland Clinic. Retrieved 2 May 2014. 12. ^ a b c d e f g Krasuski, Richard A. (Feb 2007). "When and how to fix a 'hole in the heart': approach to ASD and PFO". Cleveland Clinic Journal of Medicine. 74 (2): 137–147. doi:10.3949/ccjm.74.2.137. ISSN 0891-1150. PMID 17333641. 13. ^ Ozdemir, Aydan Ongun; Kumbasar, Deniz; Dinçer, Irem; Atmaca, Yusuf (Jan 2010). "[Percutaneous treatment of Lutembacher syndrome: a case report]". Turk Kardiyoloji Dernegi Arsivi: Turk Kardiyoloji Derneginin Yayin Organidir. 38 (1): 47–49. ISSN 1016-5169. PMID 20215845. 14. ^ Bhambhani, Anupam; Somanath, H. S. (March 2012). "Percutaneous treatment of Lutembacher syndrome in a case with difficult mitral valve crossing". The Journal of Invasive Cardiology. 24 (3): E54–56. ISSN 1557-2501. PMID 22388316. 15. ^ Chiam, Paul T. L.; Ruiz, Carlos E. (Jan 2011). "Percutaneous transcatheter mitral valve repair: a classification of the technology". JACC. Cardiovascular Interventions. 4 (1): 1–13. doi:10.1016/j.jcin.2010.09.023. ISSN 1876-7605. PMID 21251623. ### Additional references[edit] * Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. ISBN 978-1437727883. ## External links[edit] * 00732 at CHORUS Classification D * ICD-10: Q21.1 (EUROCAT Q21.14) * ICD-9-CM: 745.5 * MeSH: D008185 * DiseasesDB: 7655 External resources * eMedicine: med/3424 * v * t * e Congenital heart defects Heart septal defect Aortopulmonary septal defect * Double outlet right ventricle * Taussig–Bing syndrome * Transposition of the great vessels * dextro * levo * Persistent truncus arteriosus * Aortopulmonary window Atrial septal defect * Sinus venosus atrial septal defect * Lutembacher's syndrome Ventricular septal defect * Tetralogy of Fallot Atrioventricular septal defect * Ostium primum Consequences * Cardiac shunt * Cyanotic heart disease * Eisenmenger syndrome Valvular heart disease Right * pulmonary valves * stenosis * insufficiency * absence * tricuspid valves * stenosis * atresia * Ebstein's anomaly Left * aortic valves * stenosis * insufficiency * bicuspid * mitral valves * stenosis * regurgitation Other * Underdeveloped heart chambers * right * left * Uhl anomaly * Dextrocardia * Levocardia * Cor triatriatum * Crisscross heart * Brugada syndrome * Coronary artery anomaly * Anomalous aortic origin of a coronary artery * Ventricular inversion [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Lutembacher's syndrome	c0024164	6,566	wikipedia	https://en.wikipedia.org/wiki/Lutembacher%27s_syndrome	2021-01-18T19:05:00	{"mesh": ["D008185"], "umls": ["C0024164"], "icd-9": ["745.5"], "icd-10": ["Q21.1"], "wikidata": ["Q6705425"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant striatal degeneration-2 (ADSD2) is caused by heterozygous mutation in the PDE10A gene (610652) on chromosome 6q27. Biallelic mutation in the PDE10A gene causes an autosomal recessive infantile-onset limb and orofacial dyskinesia (IOLOD; 616921), which shows some overlapping features. Description Autosomal dominant striatal degeneration-2 is a neurologic disorder characterized by hyperkinetic movements, mainly chorea, resulting from dysfunction of the basal ganglia. Although symptoms appear in the first decade, the disorder is not progressive (summary by Mencacci et al., 2016). For a discussion of genetic heterogeneity of ADSD, see ADSD1 (609161). Clinical Features Mencacci et al. (2016) reported 3 unrelated patients of European descent with onset of chorea between 5 and 10 years of age. The patients were 11, 22, and 60 years of age. All had normal developmental milestones and normal cognition. There was no progression of the disorder, and none had a family history of a similar phenotype. Brain imaging of all showed bilateral T2-weighted hyperintensities in the striatum; the 2 older individuals had striatal atrophy. The oldest patient developed levodopa-responsive parkinsonism in the fifth decade. Brain imaging of this patient showed reduced dopaminergic innervation, consistent with nigrostriatal degeneration. Molecular Genetics In 3 unrelated patients with ADSD2, Mencacci et al. (2016) identified de novo heterozygous missense mutations in the PDE10A gene (610652.0003 and 610652.0004). The mutations were found by whole-exome sequencing. Although 2 of the patients carried the same mutation, haplotype analysis did not show a founder effect. Structural modeling suggested that both mutations could alter the affinity for cAMP. In vitro functional expression studies showed that the mutations did not substantially affect basal PDE10A enzymatic activity, but that both severely disrupted the stimulatory effect on enzyme activity mediated by cAMP binding. The findings highlighted the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry and movement. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Chorea \- Striatal T2-weighted hyperintensities seen on MRI \- Striatal atrophy (later) \- Striatal swelling (early) MISCELLANEOUS \- De novo mutation \- Onset between 5 and 10 years of age \- Nonprogressive \- Three unrelated patients have been reported (last curated April 2016) MOLECULAR BASIS \- Caused by mutation in the phosphodiesterase 10A gene (PDE10A, 610652.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	STRIATAL DEGENERATION, AUTOSOMAL DOMINANT 2	c4310791	6,567	omim	https://www.omim.org/entry/616922	2019-09-22T15:47:28	{"omim": ["616922"], "orphanet": ["494541"], "synonyms": []}
A rare syndromic X-linked intellectual disability characterized by cognitive impairment, behavioral and psychiatric problems, obesity, recurrent infections, atopic diseases, and distinctive facial features in males. Females are clinically asymptomatic or mildly affected, presenting mild learning difficulties and facial dysmorphism. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Distal Xq28 microduplication syndrome	c2749007	6,568	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=293939	2021-01-23T18:09:10	{"mesh": ["C567580"], "omim": ["300815"], "icd-10": ["Q99.8"], "synonyms": ["Distal dup(X)q(28)", "Distal trisomy Xq28"]}
A number sign (#) is used with this entry because of evidence that susceptibility to otitis media may be conferred by variation in the A2ML1 gene (610627) on chromosome 12p13. Inheritance A genetic contribution to susceptibility to otitis media is suggested by racial variations; the frequency is unusually high in American Indians and Australian aborigines and comparatively low in blacks. Family studies have suggested familial aggregation for otitis media, mastoid size, and cholesteatoma. Todd (1987) studied otitis media in Apache Indians in Arizona. The findings suggested familial predisposition. Casselbrant et al. (1999) estimated the heritability of otitis media by means of a twin and triplet study. They recruited 168 healthy same-sex twin and 7 triplet sets within the first 2 months of life. They compared the time with middle ear effusion, the number of episodes of middle ear effusion, and the episodes of acute otitis media according to zygosity status. At the end of a 2-year period, the estimate of heritability of time with middle ear effusion was 0.73 (P less than 0.001). The estimates of discordance for 3 or more episodes of middle ear effusion were 0.04 for monozygotic twins and 0.37 for dizygotic twins (P = 0.01). The estimate of discordance of an episode of acute otitis media in monozygotic twins was 0.04 compared with 0.49 in dizygotic twins (P = 0.005). Ehrlich and Post (1999) editorialized the demonstration by Casselbrant et al. (1999) that otitis media in children has a strong heritable component, stating that, for primary care clinicians, the lesson is that once an otitis media-prone child is identified, closer observation of sibs is indicated. Mapping There is evidence that chronic/recurrent otitis media (COME/ROM) clusters in families and exhibits substantial heritability. Daly et al. (2004) studied probands who had tympanostomy tube surgery for COME/ROM and their families. Of these families, 121 had at least 2 individuals who had received the diagnosis of COME/ROM, of whom 238 affected and informative relative pairs were used for analyses. Single-point nonparametric linkage analysis provided evidence of linkage to marker D10S212 on 10q26.3 (lod = 3.78, p = 0.00003) and to marker D19S254 on 19q13.42-q13.43 (lod = 2.61, p = 0.00053). Analyses conditional on support for linkage at chromosomes 10q and 19q resulted in a significant increase in lod score support on chromosome 3p25.3 (between markers D3S4545 and D3S1259). Daly et al. (2004) concluded that risk of COME/ROM is determined by interactions between genes that reside in several candidate regions of the genome and are probably modulated by other environmental risk factors. Molecular Genetics In 134 individuals from an intermarried, indigenous Filipino population with high frequency of otitis media, Santos-Cortez et al. (2015) identified an 8-bp duplication in the A2ML1 gene (c.2478_2485dupGGCTAAAT; 610627.0004), resulting in a frameshift and premature termination (Ser829TrpfsTer9). The variant was predicted to result in nonsense-mediated mRNA decay and a loss of thiol-ester and receptor binding domains. The variant was found by exome sequencing and confirmed by Sanger sequencing. Assuming 95% penetrance and a 5% phenocopy rate, the lod score for the variant was 7.5. Direct sequencing of the A2ML1 gene identified the same intragenic duplication in 3 of 123 otitis-prone children from a different cohort. Two children, of European American and Hispanic origin, were homozygous for the duplication, whereas the third child of European American descent was heterozygous for the variant. The variant was absent in 118 children who were not prone to otitis media. Haplotype analysis indicated a founder effect for this variant. Seven additional heterozygous variants in the A2ML1 gene, including 3 nonsense and 4 missense, were identified in 7 patients of Hispanic or European American descent with chronic or recurrent otitis media. Five of these variants were not found in the ExAC database; familial segregation information was not available. Functional studies of any of the variants and studies of patient cells were not performed. Santos-Cortez et al. (2015) demonstrated that the A2ml1 gene is expressed in murine epithelial cells in the middle ear, and postulated that it may have a protective function within the middle ear. In a follow-up study analyzing genetic and environmental risk factors for otitis media in the Filipino population, Santos-Cortez et al. (2016) concluded that there was no association between otitis media and gender, body mass index, breastfeeding, tobacco exposure, or deep swimming. Multivariate analyses indicated that the A2ML1 genotype was the strongest predictor of otitis media, with an odds ratio of 3.7 (p = 0.005). In this group, otitis media was observed within the first year of life and chronic otitis media persisted to adulthood, particularly in carriers of the A2ML1 variant. There was a 48.7% prevalence of otitis media in this population. Animal Model Depreux et al. (2008) found that Eya4 (603550)-null mice had severe hearing deficits and developed otitis media with effusion. All 50 mutant mice showed hypervascularity of the tympanic membrane, marked retraction of the tympanic membrane, and middle ear effusions consistent with otitis media. Fifty control mice showed no such abnormalities. Anatomic studies of mutant mice showed an abnormal middle ear cavity and dysmorphology of the eustachian tube. The authors postulated that susceptibility to human otitis media may involve genetic variation in genes such as EYA4 that regulate middle ear and eustachian tube anatomy. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Otitis media MOLECULAR BASIS \- Susceptibility conferred by mutation in the alpha-2-macroglobulin-like 1 gene (A2ML1, 610627.0004 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	OTITIS MEDIA, SUSCEPTIBILITY TO	c1833692	6,569	omim	https://www.omim.org/entry/166760	2019-09-22T16:36:50	{"omim": ["166760"], "synonyms": ["Alternative titles", "OTITIS MEDIA, CHRONIC/RECURRENT", "COME/ROM"]}
A number sign (#) is used with this entry because of evidence that foveal hypoplasia-2 with or without optic nerve misrouting and/or anterior segment dysgenesis (FVH2) is caused by homozygous or compound heterozygous mutation in the SLC38A8 gene (615585) on chromosome 16q23. Description Foveal hypoplasia is defined as the lack of foveal depression with continuity of all neurosensory retinal layers in the presumed foveal area. Foveal hypoplasia as an isolated entity is a rare phenomenon; it is usually described in association with other ocular disorders, such as aniridia (106210), microphthalmia (see 251600), albinism (see 203100), or achromatopsia (see 216900). All reported cases of foveal hypoplasia have been accompanied by decreased visual acuity and nystagmus (summary by Perez et al., 2014). For a discussion of genetic heterogeneity of foveal hypoplasia, see FVH1 (136520). Clinical Features Pal et al. (2004) described foveal hypoplasia and anterior segment dysgenesis in a large consanguineous pedigree. Five members of the pedigree presented with nystagmus and poor vision. The parents were unaffected. The combination of developmental abnormalities in both anterior and posterior eye structures suggested a defect in early ocular development and morphogenesis. Van Genderen et al. (2006) reported 2 Afghan sisters and a Dutch girl with foveal hypoplasia and optic chiasm misrouting, but no albinism. The Dutch girl had previously been diagnosed with Kartagener syndrome (see 244400). All 3 patients exhibited nystagmus, and fundus examination showed absence of the usual foveal hyperpigmentation, foveal avascular zone, and macular and foveal reflexes, with small retinal vessels extending through the presumed macular area. The exit angles of the main temporal arteries were below the mean -2 SD of those seen in albino patients and well within the range of angles in controls. Optical coherence tomography (OCT) in the Dutch girl showed extension of all neurosensory retinal layers through the area in which the fovea would normally be located; no clivus, anticlivus, or foveal pit could be seen. Visual evoked potential (VEP) recordings yielded chiasmal coefficients significantly indicative of misrouting in all 3 patients. The affected girls were all dark haired with dark brown eyes and no iris transillumination; the Dutch girl tanned normally and the Afghan sisters had skin color similar to that of other family members. Parents and sibs in both families were unaffected. Vincent et al. (2009) described a father and 2 daughters with foveal hypoplasia from a highly consanguineous Indian family. All 3 patients had poor vision, horizontal pendular nystagmus, and alternating esotropia, with normal color vision. Fundus examination of the 40-year-old father showed a poorly defined foveal zone in both eyes and a large typical inferior chorioretinal coloboma in the right eye; in addition, the axial length in both eyes was less than 19 mm, consistent with microphthalmia. In his 9-year-old and 6-year-old daughters, fundus examination showed bilateral absence of foveal reflex, and OCT demonstrated absence of foveal pits bilaterally; electroretinographic recordings were normal in both. The older daughter was also diagnosed with bilateral microphthalmia, with axial lengths less than 20 mm in both eyes, whereas in the younger daughter, axial lengths were 20.70 mm and 20.54 mm in the right and left eyes, respectively. The father was born of a consanguineous marriage, and was married to his unaffected niece; there was 1 unaffected daughter. The father's older sister and a paternal aunt and uncle were reported to have poor vision, esotropia, and nystagmus. Perez et al. (2014) studied 9 patients from 3 apparently unrelated nonconsanguineous Israeli families of Jewish Indian (Mumbai region) ancestry with nystagmus and subnormal vision from infancy. Visual acuities ranged between 20/50 and 20/200; refractive errors were found in all patients and varied between moderate hypermetropia and high myopia. All patients had astigmatism, and 3 had strabismus. All had normal cutaneous and ocular pigmentation and no iris transillumination, and full-field electroretinography and flash VEP testing in 6 patients were within normal limits. Fundus examination in all patients revealed foveal hypoplasia; OCT, performed in 1 patient, showed absence of the normal foveal pit. The 3 affected sisters in 1 family also had mild developmental delay and pervasive developmental disorder-like features. Al-Araimi et al. (2013) restudied the Pakistani family with foveal hypoplasia and anterior segment dysgenesis originally reported by Pal et al. (2004). Flash VEP in 2 affected family members showed contralateral predominance, indicating increased crossover at optic chiasm. Reexamination of the 2 Afghan sisters who were originally described by van Genderen et al. (2006) revealed posterior embryotoxon in both. Al-Araimi et al. (2013) concluded that both families had the same clinical phenotype, which they designated 'FHONDA' syndrome, representing foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis in the absence of albinism. Inheritance The transmission pattern of foveal hypoplasia and anterior segment dysgenesis in the family reported by Pal et al. (2004) was consistent with autosomal recessive inheritance. Mapping By linkage analysis in a consanguineous family segregating foveal hypoplasia and anterior segment dysgenesis, Pal et al. (2004) identified a region on 16q23.2-q24.2 that showed highly significant cosegregation with the disease. Multipoint linkage analysis generated a lod score of 5.51 at D16S511. Recombination events defined a 22.1-cM/6.5-Mb interval between markers D16S3098 and D16S2621, which included the transcription factor FOXC2 (602402); however, sequencing of this single-exon gene in patients' DNA revealed no mutations. In an Israeli family of Jewish Indian ancestry in which 3 sisters had isolated foveal hypoplasia, Perez et al. (2014) performed homozygosity-by-descent analysis and identified a 3.4-Mb homozygous segment on chromosome 16q23.3-q24.1, between SNPs rs4888203 and rs6419428, that was common to the affected individuals. Fine mapping and haplotype reconstruction in this family and 2 additional families of similar ancestry with isolated foveal hypoplasia narrowed the region of shared homozygosity to an 830-kb interval between chr16:83,885 (GRCh37) and D16S2625, supporting a common ancestral origin for this locus. A maximum lod score of 3.5 was obtained for the 3 pedigrees combined at chr16:84,282. In 2 Afghan sisters with foveal hypoplasia and anterior segment defects who were originally described by van Genderen et al. (2006), Al-Araimi et al. (2013) genotyped 12 microsatellites spanning the locus on chromosome 16q23.2-q24.2 and found that the sisters shared a region of homozygosity from marker D16S402 to the end of the 16q telomere. A maximum lod score of 2.0 was obtained with the telomeric 7 markers. Whole-genome SNP analysis of DNA from 1 Afghan sister and 1 member of the Pakistani family with foveal hypoplasia and anterior segment defects originally studied by Pal et al. (2004) refined the locus to a 3.1-Mb interval at chr16:83,639,061-86,716,445 (GRCh37). Molecular Genetics In an Israeli family of Jewish Indian ancestry in which 3 sisters had isolated foveal hypoplasia mapping to chromosome 16q23, Perez et al. (2014) performed whole-exome sequencing and found no mutations in any genes previously associated with foveal hypoplasia. However, within the 830-kb mapped locus, they identified a homozygous missense mutation in the SLC38A8 gene (I32S; 615585.0001) that segregated with disease in each of the families. The mutation, which was not reported in the 1000 Genomes Project, was detected in heterozygosity in 5 of 50 unrelated Jews of Mumbai ancestry. In 2 unrelated individuals with foveal hypoplasia, optic nerve misrouting, and anterior segment dysgenesis mapping to chromosome 16q23.3-q24.1, 1 from a Pakistani family originally studied by Pal et al. (2004) and 1 from an Afghan family originally described by van Genderen et al. (2006), Poulter et al. (2013) performed Sanger sequencing of the 33 candidate genes within the 3.1-Mb locus and identified homozygosity for a missense mutation (V236D; 615585.0002) and a 1-bp deletion (615585.0003) in the SLC38A8 gene, respectively. Sequencing SLC38A8 in 12 additional probands with foveal hypoplasia with or without other eye defects revealed homozygous or compound heterozygous mutations in 5 more cases (see, e.g., 615585.0002-615585.0007), including a Dutch girl previously reported by van Genderen et al. (2006) and an Indian family reported by Vincent et al. (2009). All mutations segregated with disease in the respective families and were not found in ethnically matched controls. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Decreased visual acuity \- Nystagmus \- Alternating esotropia (in some patients) \- Foveal hypoplasia \- Absence of foveal hyperpigmentation \- Absence of foveal avascularity \- Absence of foveal and macular reflexes \- Absence of foveal pit on optical coherence tomography \- Optic nerve misrouting on visual evoked potential analysis \- Posterior embryotoxon (in some patients) \- Axenfeld anomaly (in some patients) \- Microphthalmia (in some patients) \- Coloboma, retinochoroidal (rare) MISCELLANEOUS \- Patients exhibit no signs of ocular or cutaneous albinism MOLECULAR BASIS \- Caused by mutation in the solute carrier family 38 (amino acid transporter), member 8 gene (SLC38A8, 615585.0001 ) ▲ 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	FOVEAL HYPOPLASIA 2	c3807873	6,570	omim	https://www.omim.org/entry/609218	2019-09-22T16:06:31	{"omim": ["609218"], "orphanet": ["397618"], "synonyms": ["FHONDA syndrome", "Alternative titles", "FOVEAL HYPOPLASIA 2 WITH OPTIC NERVE DECUSSATION DEFECTS AND ANTERIOR SEGMENT DYSGENESIS WITHOUT ALBINISM", "FOVEAL HYPOPLASIA 2 WITH OR WITHOUT OPTIC NERVE MISROUTING AND/OR ANTERIOR SEGMENT DYSGENESIS"]}
Sclerosing rhabdomyosarcoma SpecialtyOncology Sclerosing rhabdomyosarcoma is a rare subtype of rhabdomyosarcoma that was characterized by Folpe et al. in 2002.[citation needed] It is microscopically characterized by primitive round cells forming microalveoli, nests, and cords in a sclerotic background.[1] ## References[edit] 1. ^ "Sclerosing rhabdomyosarcoma". www.pathologyoutlines.com. Retrieved 17 November 2017. 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	Sclerosing rhabdomyosarcoma	c4048700	6,571	wikipedia	https://en.wikipedia.org/wiki/Sclerosing_rhabdomyosarcoma	2021-01-18T19:09:39	{"umls": ["C4048700"], "wikidata": ["Q7434193"]}
Schizoaffective disorder is a mental health condition that includes features of both schizophrenia and a mood disorder such as bipolar disorder or depression. The prefix "schizo-" refers to the psychotic symptoms of schizophrenia that affect a person's thinking, sense of self, and perceptions. The term "-affective" refers to extreme shifts in mood, energy, and behavior. Schizoaffective disorder has a wide range of signs and symptoms that make it challenging to diagnose. Its features overlap significantly with those of schizophrenia and bipolar disorder, and there is debate about whether schizoaffective disorder should be considered a separate diagnosis or a subtype of one of these other conditions. Signs and symptoms of psychosis in people with schizoaffective disorder include false perceptions called hallucinations, such as hearing voices no one else can hear or experiencing visions, smells, or tactile (touch) sensations. Strongly held false beliefs (delusions) are also a characteristic feature. For example, affected individuals may be certain that they are a particular historical figure or that they are being plotted against or controlled by others. There are two major types of schizoaffective disorder, based on which mood disorder is involved: the bipolar type and the depressive type. The bipolar type includes both dramatic "highs," called manic episodes, and "lows," called depressive episodes. The depressive type includes only depressive episodes. Manic episodes are characterized by increased energy and activity, irritability, restlessness, an inability to sleep, and reckless behavior. Depressive episodes are marked by low energy and activity, a feeling of hopelessness, and an inability to perform everyday tasks. The psychosis and mood problems associated with schizoaffective disorder usually become evident in adolescence or young adulthood. People with this condition often have difficulty functioning at school, at work, and in social settings. Disordered thinking and concentration, inappropriate emotional responses, erratic speech and behavior, and difficulty with personal hygiene and everyday tasks are also common. People with schizoaffective disorder have a higher risk of substance abuse problems and dying by suicide than the general population. ## Frequency Studies suggest that schizoaffective disorder is less common than schizophrenia, bipolar disorder, or depression alone. However, because schizoaffective disorder can be difficult to differentiate from these other conditions, its prevalence is unknown. One study from Finland estimated that schizoaffective disorder affects 3 in 1,000 people. ## Causes Very little is known for certain about the genetics of schizoaffective disorder. Studies suggest that variations in many genes, each with a small effect, combine to increase the risk of developing the condition. There may also be genetic variations with larger effects in some affected individuals or families, but these variants are rare in the general population, and it is unclear which particular genes are involved. The genes that have been studied as possible contributors to schizoaffective disorder have diverse functions in the brain. These genes include some that regulate the body's daily (circadian) rhythms, such as the sleep-wake cycle; others that help control the movement (migration) of nerve cells during brain development; and still others involved in sending and receiving chemical signals in the brain. In particular, several genes that have been associated with the risk of schizoaffective disorder provide instructions for making parts of a receptor for gamma-amino butyric acid (GABA), a chemical called a neurotransmitter that sends signals in the brain. GABA's primary role is to prevent the brain from being overloaded with too many signals. Many of the genetic variations associated with schizoaffective disorder appear also to be involved in schizophrenia or bipolar disorder. Other variations seem to be specific to schizoaffective disorder. However, it is challenging to study the genetics of schizoaffective disorder because the disorder has such significant overlap with these other mental health conditions. In some studies, people with schizoaffective disorder are analyzed in the same group as those with schizophrenia or bipolar disorder, so it can be difficult to determine which genetic variations influence each of these specific diagnoses. ## Inheritance Pattern The inheritance pattern of schizoaffective disorder is unclear. Overall, the risk of developing this condition is greater for first-degree relatives of affected individuals (such as siblings or children) as compared to the general public. Many individuals with schizoaffective disorder also have relatives with depression, bipolar disorder, schizophrenia, or other mental health conditions. These disorders may run in families in part because they share some genetic risk factors with schizoaffective disorder. Research with twins found that when a member of an identical twin pair has schizoaffective disorder, the risk that the co-twin will also develop the condition is about 40 percent. In nonidentical (fraternal) twins, the risk is lower, around 5 percent. Because identical twins are more genetically similar than nonidentical twins, this finding suggests that genetics plays an important role in schizoaffective disorder. However, the fact that the risk is much lower than 100 percent, even in identical twins, suggests that noninherited factors are also important causes of schizoaffective 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	Schizoaffective disorder	c0036341	6,572	medlineplus	https://medlineplus.gov/genetics/condition/schizoaffective-disorder/	2021-01-27T08:24:36	{"mesh": ["D012559"], "omim": ["181500"], "synonyms": []}
A rare, congenital, isolated hyperinsulinism disorder characterized by diazoxide unresponsive recurrent episodes of hyperinsulinemic hypoglycemia resulting from an excessive insulin secretion by the pancreatic bêta-cells due to SUR1 deficiency. Hypoglycemia may lead to variable clinical manifestations, ranging from asymptomatic hypoglycemia revealed by routine blood glucose monitoring to macrosomia at birth, mild to moderate hepatomegaly and life-threatening hypoglycemic coma or status epilepticus, further leading to poor neurological outcome. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency	c3888018	6,573	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=276598	2021-01-23T18:38:51	{"mesh": ["D044903"], "omim": ["256450"], "icd-10": ["E16.1"], "synonyms": ["Hyperinsulinemic hypoglycemia due to SUR1 deficiency, diazoxide-resistant focal form"]}
A number sign (#) is used with this entry because of evidence that geleophysic dysplasia-1 (GPHYSD1) is caused by homozygous or compound heterozygous mutation in the ADAMTSL2 gene (612277) on chromosome 9q34. Description Geleophysic dysplasia-1 is an autosomal recessive disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a 'happy' face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues (summary by Le Goff et al., 2011). ### Genetic Heterogeneity of Geleophysic Dysplasia Geleophysic dysplasia-2 (GPHYSD2; 614185) is an autosomal dominant form of the disorder caused by heterozygous mutation in the FBN1 gene (134797) on chromosome 15q21.1. Acromicric dysplasia (102370) and the autosomal dominant form of Weill-Marchesani syndrome (608328) are allelic to geleophysic dysplasia-2 and share overlapping skeletal and joint features. Geleophysic dysplasia-3 (GPHYSD3; 617809) is caused by heterozygous mutation in the LTBP3 gene (602090) on chromosome 11q13. Clinical Features Spranger et al. (1971) suggested the designation 'geleophysic' because of the happy-appearing faces of the affected children (gelios = happy, physis = nature); the typical facies includes upturned corners of the mouth. They further suggested that the disorder is a 'focal' mucopolysaccharidosis. In addition to the facial appearance, 2 unrelated children showed dysostosis multiplex-like changes, predominantly in the hands and feet, and an apparently focal accumulation of acid mucopolysaccharides in the liver and possibly the cardiovascular system. Small hands and feet were evident at birth. The upper lip was long and thick with 'ironing out' of the philtrum. The nasal bridge was depressed. Joint contractures affected particularly the fingers. Hepatomegaly and cardiomegaly were present. Urinary excretion of mucopolysaccharides was normal. Spranger et al. (1971) thought that the patient reported by Vanace et al. (1960) probably had this disorder. Spranger et al. (1984) gave a follow-up of the male patient described by Spranger et al. (1971) and described the same disorder in of his sibs. The original patient had progressive joint contractures; he walked on his toes and stood bent forward, flexed at the hips and knees. By age 12 he had extensive disease of the aortic and mitral valves. A sister developed heart failure soon after birth and was found to have right ventricular hypertrophy. She was found to have severe mitral stenosis with aortic regurgitation; she died at age 7.5 years during preparation for surgical repair of the valvular lesions. At autopsy all 4 heart valves were strikingly abnormal. The liver and heart as well as the growth plates showed cells with lysosomal inclusions with the staining properties of a neutral glycoprotein. Radiographic changes were most striking in the hands and feet where the tubular bones were short and plump. The other sib was stillborn and was probably affected. Legare et al. (2018) provided another follow-up on the male patient with GPHYSD1 described by Spranger et al. (1971). On physical examination at 48 years of age, he had a high-pitched voice, round face, low-set hairline, broad nasal bridge, prominent nasal spine, and small mandible. He had a wide mouth, upturned corners of his mouth, and normal teeth. He had thickening of his perioral skin and of the area above his vermilion, resulting in a smooth philtrum. Skin was thick and tight over his chest and joints. His chest was short and broad with pectus excavatum. Extremities were micromelic, with relative acromelia and brachydactyly. He had multiple joint contractures. His hands were short and broad, with short thumbs. He used a walker for balance because of his plantar flexion contractures. Deep tendon reflexes were increased, with clonus in his lower extremities. His clinical course had included slowly progressive decreased joint mobility at shoulders, elbows, wrists, fingers, hips, knees, and ankles, and he eventually developed arthritis in these joints. He had severe restrictive lung disease that had progressed over the past 2 decades, which was thought to be due to his small chest and pectus excavatum. Other comorbidities included irritable bowel syndrome, cholelithiasis, early cataracts, and moderate to severe hearing loss. Cognitive evaluation in childhood revealed an IQ of 74, but in adulthood, his cognitive function appeared close to normal. At age 48 years, he presented with chronic heart failure due to severe aortic regurgitation with severe left outflow tract obstruction and left ventricular dysfunction. He underwent a transcatheter aortic valve replacement, which resulted in resolution of his aortic regurgitation and improvement of his left ventricular outflow tract physiology. A year later, his heart failure symptoms had completely resolved. Koiffmann et al. (1984) reported the disorder in an 11-year-old Brazilian girl. At birth she was short with small hands and feet. At presentation she had 'tip-toe gait' because of bilateral talipes equinovarus, joint limitation at the elbows, and hepatomegaly to 4 cm below the right costal margin. Aortic systolic and diastolic murmurs were explained by 'important stenosis and mild insufficiency' of the aortic valve found at cardiac catheterization. A sister, who died of heart failure at age 3, was described by the mother as 'a tiny child with small hands.' Lipson et al. (1987) reported the clinical, radiologic, and pathologic findings in a patient with a typical picture of progressive growth delay, mild facial anomalies, small hands, hepatosplenomegaly, and progressive cardiac valvular lesions. Electron microscopy showed electron-dense, lysosomal-like bodies in hepatocytes, similar to those previously reported. A defect of glycoprotein metabolism had been proposed. A patient with an acrofacial dysplasia described by Spranger et al. (1984) had many features similar to those in patients with geleophysic dysplasia but the identity was imperfect. Lipson et al. (1987) and Rosser et al. (1995) noted phenotypic similarities to acromicric dysplasia (102370). Wraith et al. (1990) described 2 patients, one of whom was the offspring of consanguineous parents. One died of heart failure at the age of 5 months. A disturbance in the relations between cell membrane and extracellular matrix was suggested by histologic and ultrastructural changes. Shohat et al. (1990) described 5 patients, 2 of whom were sibs. The facies included long, thin upper lip with flat and long philtrum and inverted vermilion borders. Behavior, development, and intelligence were normal. Growth delay was noted during infancy; 2 patients who completed normal puberty had remarkably short stature (140 and 150 cm) with relatively lean body habitus. The hands and feet were small, with short, plump tubular bones and broad proximal phalanges, associated with marked limitation in motion of fingers and wrists. The liver was enlarged after the age of 3 years. Two patients had mild mitral and tricuspid valve stenosis and 1 had severe aortic stenosis. The most severely affected child died at the age of 3.5 years of airway obstruction resulting from progressive tracheal narrowing. Skin biopsy showed lysosomal storage vacuoles in epithelial cells, and autopsy in the child that died showed similar vacuoles in the cells of the tracheal mucosa, liver, cartilage, and macrophages. Rosser et al. (1995) reported 3 boys with geleophysic dysplasia, 2 of whom were brothers. Serial ultrasound scans, performed on 2 of the cases during pregnancy, failed to demonstrate short limbs until after 28 weeks of gestation. The facies and small hands with limitation of movement of interphalangeal joints were pictured. Both brothers had bicuspid aortic valve and 1 had aortic stenosis with mild poststenotic dilatation. Because of stiff joints, all 3 patients had a marked tiptoe gait. Pontz et al. (1996) described clinical and ultrastructural findings in 3 patients with geleophysic dysplasia. They presented electron microscopic evidence supporting the hypothesis that geleophysic dysplasia is indeed a lysosomal storage disease. Santolaya et al. (1997) suggested that geleophysic dysplasia may have a broader clinical spectrum than initially suspected. They reported the cases of 2 boys with facial anomalies, small hands and feet, joint contractures, thick skin, unusual tiptoe gait, and lysosome-like inclusions in the hepatocytes, compatible with the diagnosis of geleophysic dysplasia. One of them also had fibrosis and fatty degeneration of the liver. Neither had short stature nor progressive cardiac valvular disease. The facial appearance of the 2 cases was thought to be different. The second case had the same 'happy-natured' face as in the cases of Spranger et al. (1984). Titomanlio et al. (1999) reported a new case of geleophysic dysplasia. Born to consanguineous parents, the patient was first observed at age 8 months and was followed for 7 years. Ben-Salem et al. (2013) reported patients with geleophysic dysplasia from 2 unrelated consanguineous Arab families. The patient in family 1 was a 2-year-old girl with short stature, small hands and feet with stubby fingers and toes, and dysmorphic features including upslanting palpebral fissures, short nose, long smooth philtrum, and thin upper lip. She had limited movement of the elbow and ankle joints. Skeletal survey showed mild shortening of the long bones and small iliac wings. Echocardiography was normal. The proband in the second family was a 2-year-old boy with similar dysmorphic and skeletal features. He had respiratory difficulties from birth. Echocardiography showed severe pulmonary stenosis, mild aortic stenosis and tricuspid regurgitation, and thickened interventricular septum. He had 2 sibs with similar features who died at ages 4 months and 1 year. Mapping Le Goff et al. (2008) performed homozygosity mapping in 4 consanguineous geleophysic dysplasia families of French Polynesian, Moroccan, Algerian, and Pakistani origins and showed linkage of the underlying gene to chromosome 9q34.2-q34.3 in a 619-kb interval (Zmax = 4.52 at theta = 0.0 at the gt-AL590710 locus). A recombination event in family 4 defined the proximal boundary of the region (gt-AL593848), and a second recombinant in the same family defined the distal boundary (gt-AL593186). Molecular Genetics Because geleophysic dysplasia belongs to the group of acromelic dysplasias that also includes the autosomal recessive form of Weill-Marchesani syndrome (277600), which is caused by mutations in ADAMTS10 (608990), Le Goff et al. (2008) considered the ADAMTSL2 gene (612277) as the likely candidate among the 7 genes located within the critical interval. Among affected members of 6 families with geleophysic dysplasia, Le Goff et al. (2008) detected 5 different mutations in ADAMTSL2 (612277.0001-612277.0005). In 2 families the same mutation was found (R113H; 612277.0002). Allali et al. (2011) analyzed the ADAMTSL2 gene in an additional 33 GD patients from 30 families and identified mutations in 14 patients (see, e.g., 612277.0003 and 612277.0006-612277.0007). Comparison of the 20 patients with mutations in ADAMTSL2 (including 6 patients previously reported by Le Goff et al., 2008) and the 19 patients without ADAMTSL2 mutations revealed that while tiptoe walking was consistently reported in patients with ADAMTSL2 mutations, it was rarely reported in the patients without mutations in ADAMTSL2 (88% vs 18%). Facial dysmorphism was also more frequent in the patients with ADAMTSL2 mutations, whereas short stature was much more severe in the patients without mutation in ADAMTSL2. No differences were found regarding heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngotracheal stenosis, deafness, or radiologic features, and long-term follow-up did not reveal any differences in the course of the disease. Allali et al. (2011) concluded that GD is a genetically heterogeneous condition. In affected members of 2 unrelated consanguineous Arab families with geleophysic dysplasia-1, Ben-Salem et al. (2013) identified homozygous missense mutations (see, e.g., 612277.0008) that segregated with the disorder in the families. The mutations were not found in the NHLBI EVS database or in ethnically matched controls. In a 48-year-old man with GPHYSD1, originally described by Spranger et al. (1971), Legare et al. (2018) identified compound heterozygous mutations in the ADAMTSL2 gene (NM_014694.3): the previously identified D167N mutation and a 1-bp deletion (c.31delG) resulting in a frameshift and premature termination (Ala11ProfsTer10). The frameshift was predicted to be pathogenic based on ACMG criteria. The parents were not tested so there was a small possibility that the mutations occurred in cis; the authors considered this unlikely because the patient had 2 affected sibs. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature \- Normal upper/lower segment ratio Weight \- Normal birth weight HEAD & NECK Head \- Normal head circumference Face \- Round, full face \- Long, smooth philtrum \- 'Pleasant, happy-nature' appearance Ears \- Thickened helices Eyes \- Upward slanting palpebral fissures Nose \- Short nose \- Anteverted nares Mouth \- Wide mouth CARDIOVASCULAR Heart \- Cardiac failure \- Mitral stenosis \- Tricuspid stenosis Vascular \- Aortic stenosis RESPIRATORY Airways \- Tracheal stenosis \- Brainstem bronchi stenosis CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum ABDOMEN Liver \- Hepatomegaly SKELETAL \- Osteopenia Skull \- J-shaped sella turcica Pelvis \- Coxa valga Limbs \- Shortened long tubular bones \- Small, irregular capital femoral epiphyses Hands \- Short hands \- Wrist contractures \- Finger contractures \- Short metacarpals with rounded proximal ends Feet \- Short feet \- Short, plump tubular bones SKIN, NAILS, & HAIR Skin \- Thickened skin \- Tight skin Nails \- Small nails NEUROLOGIC Central Nervous System \- Developmental delay \- Seizures VOICE \- High-pitched voice MISCELLANEOUS \- Lysosomal storage vacuoles in trachea, liver, cartilage, and heart MOLECULAR BASIS \- Caused by mutation in the ADAMTS-like protein 2 gene (ADAMTSL2, 612277.0001 ) ▲ 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	GELEOPHYSIC DYSPLASIA 1	c3489726	6,574	omim	https://www.omim.org/entry/231050	2019-09-22T16:27:39	{"mesh": ["C535662"], "omim": ["231050"], "orphanet": ["2623"], "genereviews": ["NBK11168"]}
Charcot-Marie-Tooth disease type 4A (CMT4A) is a subtype of Charcot-Marie-Tooth disease type 4 characterized by early-onset (infancy to early childhood) of severe, rapidly progressing demyelinating, axonal, or intermediate sensorimotor neuropathy usually affecting first, and more severely, the distal lower extremities and later the proximal muscles and upper extremities. Nerve conduction velocities range from very slow to normal. Apart from the typical CMT phenotype (distal muscle weakness and atrophy, sensory loss, frequent pes cavus foot deformity), patients commonly present delayed motor development, vocal cord paresis, mild sensory loss, abolished deep tendon reflexes, and skeletal deformities. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Charcot-Marie-Tooth disease type 4A	c1859198	6,575	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99948	2021-01-23T18:07:43	{"gard": ["1252"], "mesh": ["C535419"], "omim": ["214400"], "umls": ["C1859198"], "icd-10": ["G60.0"], "synonyms": ["CMT4A"]}
## Description Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. CMT neuropathy is subdivided into CMT1 (see 118200) and CMT2 (see 118210) types on the basis of electrophysiologic and neuropathologic criteria. CMT1 is a demyelinating neuropathy, whereas CMT2 is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Davis et al. (1978) proposed that this form be designated 'intermediate' CMT. For a phenotypic description and a discussion of genetic heterogeneity of dominant intermediate CMT neuropathy, see CMTDIB (606482). Clinical Features Rossi et al. (1985) and Villanova et al. (1998) reported a large kinship in which 15 individuals, ranging in age from 7 to 72 years, had onset of slowly progressive CMT in the first or second decades of life. Patients presented with lower limb weakness, resulting in muscle cramps and difficulty walking and running. Later in life, they developed severe weakness and atrophy of distal leg and intrinsic hand muscles, steppage gait, pes cavus, areflexia, and mild distal sensory loss. However, none of the patients became wheelchair-bound. Sural nerve biopsy showed chronic axonal degeneration with regeneration, secondary segmental de- and remyelination, and occasional onion bulbs. Electrophysiologic studies of the median motor nerve showed intermediate values between 25 and 45 m/s. Inheritance The transmission pattern of CMTDIA in the family reported by Rossi et al. (1985) was consistent with autosomal dominant inheritance. Mapping In an Italian family with dominant intermediate CMT, described earlier by Rossi et al. (1985) and Villanova et al. (1998), Verhoeven et al. (2001) demonstrated linkage to chromosome 10q24.1-q25.1. Sural nerve biopsy in affected members of this family showed axonal degeneration, loss of large diameter fibers, rare segmental demyelination, and remyelination with onion bulb formation. INHERITANCE \- Autosomal dominant SKELETAL Feet \- Pes cavus NEUROLOGIC Peripheral Nervous System \- Distal limb muscle weakness due to peripheral neuropathy \- Distal limb muscle atrophy due to peripheral neuropathy \- Muscles cramps \- 'Steppage' gait \- Foot drop \- Hyporeflexia \- Areflexia \- Distal sensory impairment \- Low to normal range of motor nerve conduction velocity (NCV) (25-45 m/s) \- Axonal degeneration/regeneration on nerve biopsy \- Segmental demyelination/remyelination \- Rare 'onion bulb' formations MISCELLANEOUS \- Onset in second decade \- Begins in feet and legs (peroneal distribution) \- Upper limb involvement occurs later \- Rapid disease progression from ages 40 to 50 years \- Features intermediate between demyelinating CMT and axonal CMT \- Genetic heterogeneity (see, e.g., CMTDIB 606482 , CMTDID 607791 ) ▲ 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	CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE A	c1847896	6,576	omim	https://www.omim.org/entry/606483	2019-09-22T16:10:22	{"doid": ["0110202"], "mesh": ["C564702"], "omim": ["606483"], "orphanet": ["100043"], "synonyms": ["Alternative titles", "CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE A", "DI-CMTA"]}
Distal renal tubular acidosis (dRTA) is a disorder of impaired net acid secretion by the distal tubule characterized by hyperchloremic metabolic acidosis. The classic form is often associated with hypokalemia whereas other forms of acquired dRTA may be associated with hypokalemia, hyperkalemia or normokalemia. ## Epidemiology Prevalence of dRTA is unknown but is often underreported. The hereditary forms of dRTA are more prevalent in areas of high consanguinity (Arabic peninsula and North Africa) whereas acquired dRTA has been reported more frequently in Western countries. ## Clinical description Disease onset can occur at any age, depending on cause. Hereditary dRTA subtypes include autosomal dominant (AD) and autosomal recessive (AR) dRTA (see these terms). A recessive subtype of dRTA associated with anemia has also been described in Southeast Asia. AR forms are frequently diagnosed in infants and young children. AD dRTA is mostly diagnosed in adolescents and young adults. Patients with dRTA can be asymptomatic or can present with polyuria, polydipsia, weakness and fatigue (symptoms associated with hypokalemia). Failure to thrive, rickets, stunting of growth (seen in children) and osteomalacia or osteopenia (seen in adults) are a result of urinary calcium wastage and a loss of calcium salts from the bones. Hypercalciuria, nephrolithiasis and nephrocalcinosis usually occur. Low plasma potassium levels in those with the classic form of dRTA can also cause cardiac arrhythmias, paralysis and even death. In the recessive forms of dRTA, progressive and irreversible deafness often occurs. ## Etiology dRTA can be acquired or inherited. AD dRTA is usually due to mutations in the SLC4A1 gene (17q21.31). Mutations in the ATP6V1B1 gene (2p13) or ATP6V0A4 gene (7q34) are responsible for AR dRTA with deafness. AR dRTA without deafness or late onset deafness has been mainly described in patients with mutations in the ATP6V0A4 gene but overlap does exist in that some patients with this mutation develop deafness and others do not. Acquired forms of dRTA are thought to be caused by autoimmune diseases such as Sjögren syndrome (see this term) or secondary to other conditions like sickle cell anemia, systemic lupus erythematosus (see these terms), chronic obstructive uropathy, or post-renal transplantation. ## Diagnostic methods The disease is characterized by hyperchloremic metabolic acidosis. The inability to lower urine pH below 5.5 and a positive urine anion gap during spontaneous metabolic acidosis is indicative of dRTA. Provocative tests for further diagnosis include the NH4Cl acidifying test and the furosemide test. Patients with dRTA also show renal potassium wasting except in the hyperkalemic type of dRTA. Molecular genetic testing for one of the causal genetic mutations can also confirm diagnosis. ## Differential diagnosis The main differential diagnosis is proximal RTA (see this term) along with other causes of chronic metabolic acidosis (i.e. diarrhea). ## Antenatal diagnosis Antenatal diagnosis is rarely performed. ## Genetic counseling The inherited forms of dRTA are inherited autosomal dominantly or recessively and genetic counseling is possible. ## Management and treatment Alkali therapy is the standard treatment (to achieve normal serum bicarbonate levels). Patients are usually given sodium bicarbonate or sodium citrate. Children require very high doses (4-8 meq/kg/day) whereas adults need much lower doses (1-2 meq/kg/day). Potassium replacement is also necessary in hypokalemic patients and potassium citrate is usually recommended. The dose depends on the severity of hypokalemia. Hyperkalemic types require low dietary potassium intake and other therapies. ## Prognosis All forms of dRTA are chronic and may have significant effects on growth and development. With treatment there is no decrease in life expectancy and renal failure is uncommon but progressive chronic kidney disease may sometimes occur if there are recurrent kidney stones and when nephrocalcinosis is very severe. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Distal renal tubular acidosis	c1704380	6,577	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=18	2021-01-23T18:55:32	{"gard": ["4667"], "mesh": ["D000141"], "omim": ["179800", "267300", "602722", "611590"], "umls": ["C0259810", "C1704380"], "icd-10": ["N25.8"], "synonyms": ["Classic RTA", "Familial distal primary acidosis", "Renal tubular acidosis type 1", "dRTA"]}
Renal nutcracker syndrome (NCS) is a condition that occurs when the left renal vein (the vein that carries blood purified by the left kidney) becomes compressed. Signs and symptoms can vary from person to person. Some people may not have symptoms, while others develop severe and persistent symptoms. Symptoms may include blood in the urine (hematuria), orthostatic proteinuria, flank pain and/or abdominal pain. Some cases of mild NCS in children may be due to changes in body proportions associated with growth. It is less clear why NCS occurs or causes symptoms in adults. Treatment ranges from surveillance (in less severe cases) to various types of surgery. The surgical technique depends upon each person's anatomy and how likely it is to relieve 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	Renal nutcracker syndrome	c3178770	6,578	gard	https://rarediseases.info.nih.gov/diseases/11971/renal-nutcracker-syndrome	2021-01-18T17:57:58	{"mesh": ["D059228"], "orphanet": ["71273"], "synonyms": ["Nutcracker syndrome", "Left renal vein entrapment syndrome", "RNS"]}
Blue cone monochromatism (BCM) is a recessive X-linked disease characterized by severely impaired color discrimination, low visual acuity, nystagmus, and photophobia, due to dysfunction of the red (L) and green (M) cone photoreceptors. BCM is as an incomplete form of achromatopsia (see this term). ## Epidemiology The prevalence is estimated to be 1/100,000 worldwide. ## Clinical description BCM manifests in early infancy and predominantly affects males, with severely impaired color vision and low visual acuity (only rod and blue cone function is preserved). Additionally, photophobia, myopia, and pendular nystagmus are commonly observed. Nystagmus may wane with time. ## Etiology The disorder is caused by mutations in the red and green opsin gene cluster OPN1LW and OPN1MW (Xq28) and thus affect the corresponding cones. These mutations include deletions of the locus control region that is critical for expression of both genes. These deletions may also extend to parts of or the whole opsin gene cluster. Genomic rearrangements (unequal crossing-over) can result in single red and/or red/green hybrid genes carrying deleterious point mutations. The c.607T>C p.C203R missense mutation is commonly observed, but other missense and nonsense mutations have also been reported. ## Diagnostic methods The diagnosis of BCM is achieved by clinical ophthalmological examination, electrophysiological (i.e. electroretinography/ ERG) and psychophysical testing (i.e. color vision, dark adaptometry), where BCM patients show no response to red and green light but normal response to blue light. Mutation screening can confirm the diagnosis. ## Differential diagnosis Differential diagnosis includes achromatopsia, Leber congenital amaurosis, various types of cone dystrophies (see these terms) and cerebral achromatopsia. ## Antenatal diagnosis Prenatal diagnosis may be offered by specialized laboratories for at-risk couples. The use of prenatal diagnostic testing in BCM will vary depending on national customs and ethics. ## Genetic counseling BCM is inherited in an X-linked manner. Genetic counseling is mandatory. A carrier female has a 50% risk of transmitting the mutated allele to her offspring. Penetrance is complete with little variability in disease expression. ## Management and treatment There is no specific therapy available. Management is symptomatic and includes regular ophthalmological follow-up examinations. Patients should be informed about the possibility of using filtering glasses or contact lenses (red tinted or brown) to reduce photophobia and to improve contrast sensitivity. Low-vision aids include high-powered magnifiers for reading. ## Prognosis BCM is usually a stationary disease, yet in rare cases, macular degeneration can occur in older patients. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Blue cone monochromatism	c0339537	6,579	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=16	2021-01-23T18:46:55	{"gard": ["917"], "mesh": ["C536238", "C538165"], "omim": ["303700"], "umls": ["C0339537", "C2931753"], "icd-10": ["H53.5"], "synonyms": ["Atypical X-linked achromatopsia", "Blue cone monochromacy", "Color blindness, blue monocone monochromatic type", "S cone monochromacy", "S cone monochromatism", "X-linked incomplete achromatopsia"]}
Congenital shortness of the costocoracoid ligament is a rare anomaly characterized by fixation of the scapula to the first rib, resulting in a cosmetic deformity with rounding of the shoulders and loss of the anterior clavicular contour. ## Epidemiology It has been described only once, in several members of a single family from Canada. ## Clinical description The abnormality resulted in a strong pectoral girdle with lack of mobility. Movements requiring rotation or retraction of the scapula were limited, but this does not normally interfere with daily activities. ## Management and treatment Surgical treatment, which revealed a short costocoracoid ligament and sometimes ossification, consists of excision of the ligament and results in some cosmetic correction. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Congenitally short costocoracoid ligament	c1852523	6,580	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2391	2021-01-23T17:03:35	{"gard": ["1551"], "mesh": ["C536448"], "omim": ["122580"], "umls": ["C1852523"], "icd-10": ["Q68.8"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant nonsyndromic thrombocytopenia-4 (THC4) is caused by heterozygous mutation in the CYCS gene (123970) on chromosome 7p15. For a phenotypic description and a discussion of genetic heterogeneity of thrombocytopenia, see 313900. Clinical Features Morison et al. (2008) described a 6-generation pedigree segregating autosomal dominant thrombocytopenia. Affected individuals had platelet counts ranging from 73 to 167 with a reference interval of 150 to 430. Clinical manifestations of thrombocytopenia were absent or mild. Affected individuals had normal longevity, fertility, and fitness with no evidence of neurodegenerative, muscular, eye, or kidney disease, or diabetes. De Rocco et al. (2014) reported a 3-generation Italian family in which 4 individuals had thrombocytopenia. The proband was a 3-year-old boy ascertained though routine bloodwork. In all affected family members, peripheral blood smear showed normal platelet size and morphology. None of the individuals had bleeding abnormalities or hematologic or extra-hematologic defects associated with the thrombocytopenia. Uchiyama et al. (2018) reported 6 family members with mild nonsyndromic thrombocytopenia in a family that was also segregating for hemophilia A (306700). Affected individuals had platelet counts ranging from 70-80 x 10(9)/L. Platelet morphology and other complete blood count results were normal. Inheritance The transmission pattern of thrombocytopenia in the families reported by Morison et al. (2008) and De Rocco et al. (2014) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of a family with thrombocytopenia, Morison et al. (2008) identified a G-to-A transition at nucleotide 132 in exon 2 of the CYCS gene that caused a gly42-to-ser (G42S; 123970.0001) substitution. (Morison et al. (2008) reported the substitution as G41S based on a numbering system that does not count the initiator methionine.) Cytochrome c is a highly conserved protein, and glycine-42 is invariant among 113 eukaryotic species. Peripheral blood from affected family members contained the same proportion of immature platelets as controls, indicating no reduction of platelet life span. However, the absolute number of immature platelets was lower, suggesting reduced production. Bone marrow from a 76-year-old affected individual showed intramedullary naked megakaryocyte nuclei and platelets, suggesting dysregulated megakaryopoiesis with premature release of platelets into the marrow space rather than into sinusoids. In 4 affected members of an Italian family with thrombocytopenia, De Rocco et al. (2014) identified a heterozygous missense mutation in the CYCS gene (Y48H; 123970.0002). In vitro studies in yeast and murine knockout cells showed that both the Y48H and G42S mutations reduced the mitochondrial respiratory rate and increased apoptosis. Using whole-exome sequencing, Uchiyama et al. (2018) identified heterozygosity for a 3-bp deletion in the CYCS gene (c.301_303del; 123970.0003) in a 64-year-old Japanese woman with autosomal dominant nonsyndromic thrombocytopenia, within a pedigree with X-linked transmission of hemophilia A. All 5 family members with thrombocytopenia tested had the variant, whereas 4 unaffected family members did not. Sanger sequencing confirmed the variant and its segregation. Using a yeast model system, the variant was shown to result in reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain. INHERITANCE \- Autosomal dominant HEMATOLOGY \- Thrombocytopenia, mild \- Normal platelet size and morphology \- No increased bleeding tendency MISCELLANEOUS \- Two unrelated families have been reported (last curated February 2015) MOLECULAR BASIS \- Caused by mutation in the somatic cytochrome c gene (CYCS, 123970.0001 ) ▲ 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	THROMBOCYTOPENIA 4	c2677608	6,581	omim	https://www.omim.org/entry/612004	2019-09-22T16:02:33	{"doid": ["1588"], "mesh": ["C567438"], "omim": ["612004"], "orphanet": ["168629", "268322"], "synonyms": ["Alternative titles", "THROMBOCYTOPENIA, AUTOSOMAL DOMINANT, 4"]}
## Summary ### Clinical characteristics. Arts syndrome, which is part of the spectrum of PRPS1-related disorders, is characterized by profound congenital sensorineural hearing impairment, early-onset hypotonia, delayed motor development, mild to moderate intellectual disability, ataxia, and increased risk of infection, all of which – with the exception of optic atrophy – present before age two years. Signs of peripheral neuropathy develop during early childhood. Twelve of 15 boys from the two Dutch families reported with Arts syndrome died before age six years of complications of infection. Carrier females can show late-onset (age >20 years) hearing impairment and other findings. ### Diagnosis/testing. The diagnosis of Arts syndrome can be established in a male proband with absent ribose-phosphate pyrophosphokinase 1 (PRS-I) enzyme activity in erythrocytes, or significantly lower PRS-1 enzyme activity in fibroblasts than in controls, or identification of a hemizygous pathogenic variant in PRPS1 by molecular genetic testing. The diagnosis of Arts syndrome can be established in a female proband with suggestive clinical features and identification of a heterozygous pathogenic variant in PRPS1 by molecular genetic testing. ### Management. Treatment of manifestations: Educational program tailored to individual needs. Sensorineural hearing loss has been treated with cochlear implantation with good results. Ataxia and visual impairment from optic atrophy are treated in a routine manner. Prevention of secondary complications: Routine immunizations against common childhood infections and annual influenza immunization. Surveillance: Regular neuropsychological, audiologic, and ophthalmologic examinations. ### Genetic counseling. Arts syndrome is inherited in an X-linked manner. If the mother is a carrier, the chance of transmitting the PRPS1 pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and may or may not be mildly affected. Males with Arts syndrome have not reproduced. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known. ## Diagnosis Formal diagnostic criteria for Arts syndrome have not been established. ### Suggestive Findings Arts syndrome, part of the spectrum of PRPS1-related disorders, should be suspected in a male proband with the following clinical and laboratory features. Clinical features * Intellectual disability * Profound congenital sensorineural hearing impairment * Early-onset hypotonia * Delayed motor development * Ataxia * Optic atrophy * Liability to infections, especially of the upper respiratory tract Laboratory features * Serum uric acid concentration lower than average (0.13-0.16 mmol/L), although still within the normal range (i.e., 0.12-0.35 mmol/L) [de Brouwer et al 2007] Note: (1) Serum uric acid concentration is not zero because PRS-II, which has the same enzyme activity as PRS-I, is active in tissues such as liver, which consequently will result in purine nucleotide synthesis and uric acid production. (2) However, a low/normal serum uric acid concentration may be helpful in ruling out a diagnosis of PRS superactivity, in which serum uric acid concentration is usually high. * Purine analysis in urine * Absent/low hypoxanthine on analysis of purines in the urine * When individuals with Arts syndrome are on a low-purine diet, the uric acid to creatinine ratio in urine may also tend to be at the lower end of normal, but not zero. * Concentrations of other purines in urine within the normal range Arts syndrome should be suspected in a female proband with late-onset (age >20 years) sensorineural hearing impairment. ### Establishing the Diagnosis Male proband. The diagnosis of Arts syndrome is established in a male proband with ANY of the following: * Absent ribose-phosphate pyrophosphokinase 1 (PRS-I) enzyme activity in erythrocytes (because PRS-I is the only isoform present) * Significantly lower ribose-phosphate pyrophosphokinase 1 (PRS-I) enzyme activity in fibroblasts than in controls [de Brouwer et al 2007] * A hemizygous pathogenic variant in PRPS1 identified by molecular genetic testing (see Table 1) Female proband. The diagnosis of Arts syndrome is usually established in a female proband with late-onset (age >20 years) sensorineural hearing impairment and identification of a heterozygous pathogenic variant in PRPS1 by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Arts syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Arts syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Arts syndrome molecular genetic testing approaches can include single-gene testing or use of a multigene panel: * Single-gene testing. Sequence analysis of PRPS1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * A multigene panel that includes PRPS1 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the diagnosis of Arts syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Arts Syndrome View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method PRPS1Sequence analysis 3, 44 families 5 Gene-targeted deletion/duplication analysis 6Unknown 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. 5\. Four families reported to date [de Brouwer et al 2007, Synofzik et al 2014, Maruyama et al 2016] 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics ### Clinical Description Arts syndrome is characterized by intellectual disability, early-onset hypotonia, ataxia, delayed motor development, profound congenital sensorineural hearing impairment, and progressive optic atrophy [Arts et al 1993, de Brouwer et al 2007]. At birth these symptoms can be present in various combinations. All symptoms except for the visual impairment become apparent in the first two years of life. Visual impairment usually becomes obvious after age two years. Delayed motor nerve conduction velocities and an electromyography suggestive of denervation develop during early childhood and are consistent with clinical findings that suggest peripheral neuropathy. Affected males usually have mild to moderate intellectual disability; however, cognitive abilities can be difficult to assess in the presence of combined visual and hearing impairment. Liability to infections, especially upper-respiratory tract infections, resulted in death before age six years in 12 of 15 boys from the two Dutch families reported with Arts syndrome. During infection, the slowly progressive muscle weakness is punctuated by acute deterioration in muscle strength, which may result in respiratory failure requiring mechanical ventilation. Heterozygous females can show isolated and/or milder manifestations, most notably late-onset (age >20 years) hearing impairment. Ataxia (in 2 females), hypotonia (1 female), and hyperreflexia (1 female) have been reported as well [Arts et al 1993]. MRI shows no recognizable abnormalities (e.g., reduction of white matter in the brain, which would indicate demyelination) [de Brouwer et al 2007]. Sural nerve biopsy in a boy age five years with Arts syndrome from the original Dutch family showed a loss of myelinated fibers, but no signs of demyelination or axonal degeneration [Arts et al 1993]. Sural nerve biopsy of a boy age two years from the Australian family, who had absent lower-limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy, showed mild paranodal demyelination indicative of peripheral neuropathy [de Brouwer et al 2007]. Autopsy of one individual who died at age five and a half years revealed complete absence of myelinated axons in the posterior columns of the spinal cord, although their number and appearance were normal in the other tracts [Arts et al 1993]. A number of dorsal root nerves showed the same abnormalities as posterior columns. No abnormalities were seen in the brain stem or in the gray and white matter of the cerebral and cerebellar hemispheres. ### Genotype-Phenotype Correlations Computer-assisted molecular modeling showed that pathogenic variants causing Arts syndrome and CMTX5 disturb the ATP binding site of PRS-I. Pathogenic variants that result in PRS superactivity disturb either one or both allosteric sites that are involved in the inhibition of PRS-I enzyme activity. Pathogenic variants that lead to DFNX1 nonsyndromic hearing loss and deafness (DFN2) either disturb local stability of PRS-I or moderately affect interactions in the trimer interface. ### Penetrance Penetrance in males is complete. ### Prevalence Four kindreds with Arts syndrome have been identified worldwide [de Brouwer et al 2007, Synofzik et al 2014, Maruyama et al 2016]. ## Differential Diagnosis See Genetically Related Disorders. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Arts syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Neurologic evaluation for manifestations of hypotonia, ataxia, presence/absence of tendon reflexes * Audiometry for evidence of hearing loss * Eye examination for evidence of optic atrophy * Assessment of intellectual abilities * Analysis of the family pedigree for other possible affected individuals and carrier females * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Intellectual disability. An individualized educational support program tailored to the individual’s needs and based on assessment of cognitive abilities should be provided. Ataxia. See Hereditary Ataxias, Management. Sensorineural hearing loss. See Hereditary Hearing Loss and Deafness Overview, Management. Cochlear implantation in the two affected Australian males was associated with improved communication skills. Optic atrophy. No treatment is available. ### Prevention of Secondary Complications Because of immune system compromise in males with Arts syndrome, the following are recommended: * An annual influenza immunization * Routine immunizations against other common childhood infections (e.g., measles, mumps) ### Surveillance Cognitive impairment appears to be non-progressive, but repeat neuropsychologic assessments are recommended to help guide educational support programs. Although the sensorineural deafness appears to be static (albeit very severe), regular audiologic assessment is recommended so that educational support can be optimized. Visual impairment appears to be progressive; thus, regular evaluation by an ophthalmologist is recommended. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Dietary S-adenosylmethionine (SAM) supplementation could theoretically alleviate some of the symptoms of Arts syndrome by providing an oral source of purine nucleotide precursor that is not phosphoribosyl pyrophosphate dependent. Furthermore, SAM is known to cross the blood-brain barrier. An adult with HPRT deficiency has been reported to benefit neurologically from SAM administration without untoward side effects [Glick 2006]. In an open-label clinical trial of SAM in two Australian brothers (ages 14 and 13 in 2010) with Arts syndrome [J Christodoulou et al, unpublished data; approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia], oral SAM supplementation was set at 30 mg/kg/day. The brothers appear to have had significant benefit from this therapy based on decreased number of hospitalizations and stabilization of nocturnal BIPAP requirements; however, slight deterioration in their vision was noted. Eventually, they died at ages 19 and 18 years of respiratory failure associated with a severe lower respiratory tract infection. Mildly affected carrier females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Arts Syndrome	c0796028	6,582	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK2591/	2021-01-18T21:42:43	{"mesh": ["C535388"], "synonyms": []}
A rare bone development disorder characterized by mostly anterolateral bowing of the tibia usually evident at birth, with subsequent non-healing fractures and formation of a false joint (pseudoarthrosis), and instability and angulation at the pseudoarthrosis site. In the vast majority of patients the defect is unilateral, and more than half of the cases are associated with neurofibromatosis type 1. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 pseudoarthrosis of the tibia	c0265661	6,583	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=295018	2021-01-23T17:01:19	{"umls": ["C0265661"], "icd-10": ["Q74.2"], "synonyms": ["Congenital pseudarthrosis of the tibia"]}
Aerobic vaginitis Aerobic vaginitis (in a 14-week pregnant woman): parabasal cells, absent lactobacilli and overgrowth of other bacilli, inflammation SpecialtyGynecology Aerobic vaginitis (AV) is a form of vaginitis first described by Donders et al. in 2002.[1][2] It is characterized by a more or less severe disruption of the lactobacillary flora, along with inflammation, atrophy, and the presence of a predominantly aerobic microflora, composed of enteric commensals or pathogens.[3] It can be considered the aerobic counterpart of bacterial vaginosis. The lack of acknowledgement of the difference between the two conditions might have led to inaccurate conclusions in several studies in the past.[4] The entity that has been described as "desquamative inflammatory vaginitis" probably corresponds to the more severe forms of aerobic vaginitis.[5] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Diagnosis * 3 Treatment * 4 Epidemiology * 5 References * 6 External links ## Signs and symptoms[edit] Women with aerobic vaginitis usually present with a thinned reddish vaginal mucosa, sometimes with extensive erosions or ulcerations and abundant yellowish discharge (without the fishy amine odour, typical of bacterial vaginosis). The pH is usually high. Symptoms can include burning, stinging and dyspareunia. The symptoms can last for long periods of time—sometimes even years. Typically, patients have been treated several times with antimycotic and antibiotic drugs without relief.[3] In asymptomatic cases, there is microscopic evidence but no symptoms. The prevalence of asymptomatic cases is unknown.[3] ### Complications[edit] Aerobic vaginitis has been associated with several gynecological and obstetrical complications, including: * Premature rupture of membranes * Preterm labour * Ascending chorioamnionitis.[6] * Increased risk to acquire sexually transmitted infections (including HIV)[7] * Abnormal Pap test results[8] ## Diagnosis[edit] The diagnosis is based on microscopic criteria. Ideally, phase-contrast microscopy is used with a magnification of 400x (high-power field).[9] For scoring purposes, along with relative number of leucocytes, percentage of toxic leucocytes, background flora and proportion of epitheliocytes, lactobacillary grade must be evaluated: grade I numerous pleiomorphic lactobacilli; no other bacteria grade IIa mixed flora, but predominantly lactobacilli grade IIb mixed flora, but proportion of lactobacilli severely decreased because of an increased number of other bacteria grade III lactobacilli severely depressed or absent because of overgrowth of other bacteria AV score Lactobacillary grades Number of leukocytes Proportion of toxic leucocytes Background flora Proportion of parabasal epitheliocytes 0 I and IIa <10/hpf None or sporadic Unremarkable or cytolysis None or <1% 1 IIb >10/hpf and; <10/epithelial cell <50% of leukocytes Small coliform bacilli ≤10% 2 III >10/epithelial cell >50% of leukocytes Cocci or chains >10% The "AV score" is calculated according to what is described in the table. * AV score <3: no signs of AV * AV score 3 or 4: light AV * AV score 5 or 6: moderate AV * AV score ≥7:severe AV. pH measurement alone is not enough for the diagnosis. ## Treatment[edit] Treatment is not always easy and aims at correcting the three key changes encountered in aerobic vaginitis: the presence of atrophy, inflammation and abnormal flora. The treatment can include topical steroids to diminish the inflammation and topical estrogen to reduce the atrophy. The use and choice of antibiotics to diminish the load/proportion of aerobic bacteria is still a matter of debate. The use of local antibiotics, preferably local non-absorbed and broad spectrum, covering enteric gram-positive and gram-negative aerobes, like kanamycin can be an option. In some cases, systemic antibiotics can be helpful, such as amoxyclav or moxifloxacin.[10] Vaginal rinsing with povidone iodine can provide rapid relief of symptoms but does not provide long-term reduction of bacterial loads.[11] Dequalinium chloride can also be an option for treatment.[12] ## Epidemiology[edit] About 5 to 10% of women are affected by aerobic vaginitis.[13] Reports in pregnant women point to a prevalence of 8.3–10.8%.[14][15] When considering symptomatic women, the prevalence of AV can be as high as 23%.[16][17][18] ## References[edit] 1. ^ Donders, Gilbert G.G.; Vereecken, Annie; Bosmans, Eugene; Dekeersmaecker, Alfons; Salembier, Geert; Spitz, Bernard (2002). "Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis". BJOG. 109 (1): 34–43. doi:10.1111/j.1471-0528.2002.00432.x. hdl:10067/1033820151162165141. PMID 11845812. S2CID 8304009. 2. ^ Donders, Gilbert G. G.; Bellen, Gert; Grinceviciene, Svitrigaile; Ruban, Kateryna; Vieira-Baptista, Pedro (2017-05-11). "Aerobic vaginitis: no longer a stranger". Research in Microbiology. 168 (9–10): 845–858. doi:10.1016/j.resmic.2017.04.004. ISSN 1769-7123. PMID 28502874. 3. ^ a b c Donders, G; Bellen, G; Rezeberga, D (2011). "Aerobic vaginitis in pregnancy". BJOG. 118 (10): 1163–70. doi:10.1111/j.1471-0528.2011.03020.x. PMID 21668769. S2CID 7789770. 4. ^ Han, Cha; Wu, Wenjuan; Fan, Aiping; Wang, Yingmei; Zhang, Huiying; Chu, Zanjun; Wang, Chen; Xue, Fengxia (2015). "Diagnostic and therapeutic advancements for aerobic vaginitis". Archives of Gynecology and Obstetrics. 291 (2): 251–7. doi:10.1007/s00404-014-3525-9. PMID 25367602. S2CID 9753771. 5. ^ Newbern, EC; Foxman, B; Leaman, D; Sobel, JD (2002). "Desquamative Inflammatory Vaginitis An Exploratory Case-Control Study". Annals of Epidemiology. 12 (5): 346–52. doi:10.1016/S1047-2797(01)00316-7. PMID 12062923. 6. ^ Donders, G. G. G.; Moerman, P.; De Wet, G. H.; Hooft, P.; Goubau, P. (1991). "The association between Chlamydia cervicitis, chorioamnionitis and neonatal complications". Archives of Gynecology and Obstetrics. 249 (2): 79–85. doi:10.1007/BF02390366. PMID 1953055. S2CID 32669309. 7. ^ Donders, Gilbert; De Wet, Henry; Hooft, Peter; Desmyter, Jan (1993). "Lactobacilli in Papanicolaou Smears, Genital Infections, and Pregnancy". American Journal of Perinatology. 10 (5): 358–61. doi:10.1055/s-2007-994761. PMID 8240593. 8. ^ Vieira-Baptista, P.; Lima-Silva, J.; Pinto, C.; Saldanha, C.; Beires, J.; Martinez-de-Oliveira, J.; Donders, G. (2016). "Bacterial vaginosis, aerobic vaginitis, vaginal inflammation and major Pap smear abnormalities". European Journal of Clinical Microbiology & Infectious Diseases. 35 (4): 657–64. doi:10.1007/s10096-016-2584-1. hdl:10067/1332670151162165141. PMID 26810061. S2CID 17963709. 9. ^ Donders, G.G.G.; Larsson, P.G.; Platz-Christensen, J.J.; Hallén, A.; van der Meijden, W.; Wölner-Hanssen, P. (2009). "Variability in diagnosis of clue cells, lactobacillary grading and white blood cells in vaginal wet smears with conventional bright light and phase contrast microscopy". European Journal of Obstetrics & Gynecology and Reproductive Biology. 145 (1): 109–12. doi:10.1016/j.ejogrb.2009.04.012. PMID 19481329. 10. ^ Wang, C.; Han, C.; Geng, N.; Fan, A.; Wang, Y.; Yue, Y.; Zhang, H.; Xue, F. (2016). "Efficacy of oral moxifloxacin for aerobic vaginitis". European Journal of Clinical Microbiology & Infectious Diseases. 35 (1): 95–101. doi:10.1007/s10096-015-2513-8. PMID 26526787. S2CID 15238909. 11. ^ Donders, Gilbert G. G.; Ruban, Katerina; Bellen, Gert (2015). "Selecting Anti-Microbial Treatment of Aerobic Vaginitis". Current Infectious Disease Reports. 17 (5): 477. doi:10.1007/s11908-015-0477-6. PMID 25896749. S2CID 34979527. 12. ^ Mendling, Werner; Weissenbacher, Ernst Rainer; Gerber, Stefan; Prasauskas, Valdas; Grob, Philipp (2016). "Use of locally delivered dequalinium chloride in the treatment of vaginal infections: a review". Archives of Gynecology and Obstetrics. 293 (3): 469–84. doi:10.1007/s00404-015-3914-8. PMC 4757629. PMID 26506926. 13. ^ Tansarli, G. S.; Kostaras, E. K.; Athanasiou, S.; Falagas, M. E. (2013). "Prevalence and treatment of aerobic vaginitis among non-pregnant women: evaluation of the evidence for an underestimated clinical entity". European Journal of Clinical Microbiology & Infectious Diseases. 32 (8): 977–84. doi:10.1007/s10096-013-1846-4. PMID 23443475. S2CID 14514975. 14. ^ Donders, GG; Van Calsteren, K; Bellen, G; Reybrouck, R; Van den Bosch, T; Riphagen, I; Van Lierde, S (2009). "Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the first trimester of pregnancy". BJOG. 116 (10): 1315–24. doi:10.1111/j.1471-0528.2009.02237.x. PMID 19538417. S2CID 31922934. 15. ^ Zodzika, Jana; Rezeberga, Dace; Jermakova, Irina; Vasina, Olga; Vedmedovska, Natalija; Donders, Gilbert (2011). "Factors related to elevated vaginal pH in the first trimester of pregnancy". Acta Obstetricia et Gynecologica Scandinavica. 90 (1): 41–6. doi:10.1111/j.1600-0412.2010.01011.x. PMID 21275914. S2CID 10508510. 16. ^ Fan, Aiping; Yue, Yingli; Geng, Nv; Zhang, Huiying; Wang, Yingmei; Xue, Fengxia (2013). "Aerobic vaginitis and mixed infections: comparison of clinical and laboratory findings". Archives of Gynecology and Obstetrics. 287 (2): 329–35. doi:10.1007/s00404-012-2571-4. PMID 23015152. S2CID 30442929. 17. ^ Bologno, Romina; Díaz, Yanina M.; Giraudo, María C.; Fernández, Rosa; Menéndez, Viviana; Brizuela, Juan C.; Gallardo, Adriana A.; Álvarez, Laura A.; Estevao Belchior, Silvia G. (2011). "Importancia del estudio del balance del contenido vaginal (BACOVA) en el control preventivo de las trabajadoras sexuales" [Importance of studying the balance of vaginal content (BAVACO) in the preventive control of sex workers]. Revista Argentina de Microbiología (in Spanish). 43 (4): 246–50. doi:10.1590/S0325-75412011000400002 (inactive 2021-01-17). PMID 22274820.CS1 maint: DOI inactive as of January 2021 (link) 18. ^ Marconi, C.; Donders, G.G.G.; Bellen, G.; Brown, D.R.; Parada, C.M.G.L.; Silva, M.G. (2013). "Sialidase activity in aerobic vaginitis is equal to levels during bacterial vaginosis". European Journal of Obstetrics & Gynecology and Reproductive Biology. 167 (2): 205–9. doi:10.1016/j.ejogrb.2012.12.003. hdl:11449/74921. PMID 23375395. ## External links[edit] Classification D [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Aerobic vaginitis	None	6,584	wikipedia	https://en.wikipedia.org/wiki/Aerobic_vaginitis	2021-01-18T18:50:08	{"wikidata": ["Q23844400"]}
Nickel allergy SpecialtyAllergology, immunology Nickel allergy or nickel allergic contact dermatitis (Ni-ACD) is a form of allergic contact dermatitis (ACD) caused by exposure to the chemical element nickel. ## Contents * 1 Physiology * 2 Syndromes * 3 History * 4 Sources of Ni-ACD * 4.1 Foods * 4.2 Workplace * 5 Effects * 6 Prevention * 7 Diagnosis * 8 Treatment * 9 Regulation * 10 References * 11 Further reading ## Physiology[edit] Nickel allergy results in a skin response after the skin comes in contact with an item that releases a large amount of nickel from its surface. It is commonly associated with nickel-containing belt buckles coming into prolonged contact with the skin.[1][2][3] The skin reaction can occur at the site of contact, or sometimes spread beyond to the rest of the body. Free (released) nickel that is able to penetrate the skin is taken up by scavenger (dendritic) cells and then presented to the immune system T-Cells. With each subsequent exposure to nickel these T cells become stimulated and duplicate themselves. With enough exposure to nickel, the amassing clones of T-cells reach “threshold” and the skin develops a rash. The rash can appear as acute, subacute, or chronic eczema-like skin patches, primarily at the site of contact with the nickel (e.g., earlobe from nickel earrings). From the time of exposure, the rash usually appears within 12–120 hours and can last for 3–4 weeks or for the continued duration of nickel contact/exposure.[1] Three simultaneous conditions must occur to trigger Ni-ACD: 1. Direct skin contact with nickel-releasing item 2. Prolonged skin contact with nickel-releasing item 3. A sufficient amount of nickel is released and absorbed into the skin to cause a reaction[4] The pathophysiology is divided into induction elicitation phases. Induction is the critical phase (immunological event) when skin contact to nickel results in antigen presentation to the T cells, and T cell duplication (cloning) occurs. The metal cation Ni++ is a low molecular weight hapten that easily penetrates the stratum corneum (top layer of skin). Nickel then binds to skin protein carriers creating an antigenic epitope.[5] The determining factor in sensitization is exposure of significant amounts of “free nickel”.[6] This is important because different metal alloys release different amounts of free nickel. The antigenic epitope is collected by dermal dendritic cells and Langerhans cells, the antigen-presenting cells (APC) of the skin, and undergo maturation and migration to regional lymph nodes. The complex is predominantly expressed on major histocompatibility complex (MHC) II, which activates and clonally expands naive CD4+ T cells.[7] Upon re-exposure these now primed T cells will be activated and massively recruited to the skin, resulting in the elicitation phase and the clinical presentation of Ni-ACD. Although ACD has been considered a Th1 predominate process, recent studies highlight a more complex picture. In Ni-ACD other cells are involved including: Th17, Th22, Th1/IFN and the innate immune responses consistent with toll-like receptor 4.[8] [9] ## Syndromes[edit] Josef Jadassohn described the first case of metal contact dermatitis in 1895, to a mercurial-based therapeutic cream, and confirmed the cause by epi-cutaneous patch testing.[10] Systemic contact dermatitis (SCD) is defined as a dermatitis occurring in an epi-cutaneously contact-sensitized person when exposed to haptens systemically such as orally, per rectum, intravesically, transcutaneously, intrauterinely, intravenously, or by inhalation.[11] Systemic nickel allergy syndrome (SNAS) pathophysiology is extremely complex and not well understood. The clinical course is determined by an immunological interplay between two diverse types of T cells (Th1 and Th2 responses). SCD is often considered a subset of SNAS, but with only skin manifestations.[12] SNAS presents with an array of symptoms ranging from respiratory to generalized skin rash to gastrointestinal symptoms[13] A meta review evaluating SNAS found that 1% of patients sensitized to nickel reacted to the nickel content of a 'normal' diet, and with increasing doses of nickel more individuals reacted[14] SNAS is a multilayered immunologic response demonstrating variance between individuals and doses of nickel exposure. ## History[edit] In the 17th century, copper miners in Saxony, Germany, began to experience irritation caused by a "dark red ore". Since the substance, which would later be called nickel, led to many ailments, they believed it to be protected by "goblins", and called it "Goblin's Copper".[15] In the next century nickel began to be mass-produced for jewelry worldwide due to its cheap cost, resistance to corrosion and high supply. In 1979 a large comprehensive study of healthy US volunteers found that 9% had been unknowingly sensitized to nickel.[16] As of 2008[update], that number has tripled.[17] Most importantly, nickel allergy among children is increasing, with an estimated 250,000 children sensitized to nickel.[18] Published literature shows an exponential increase in reported nickel allergy cases.[19] The North American Contact Dermatitis Group (NACDG) patch tested 5,085 adults, presenting with eczema-like symptoms, showing 19.5% had a positive reaction to nickel.[20] Nickel allergy is also more prevalent in women (17.1%) than men (3%), possibly due to cultural norms related to jewelry and ear piercings and therefore increased exposure to nickel.[21] In order to investigate the current prevalence of nickel, Loma Linda University, Nickel Allergy Alliance, and Dermatitis Academy,[22] are conducting a self-reporting nickel allergy-dermatitis survey.[23] ## Sources of Ni-ACD[edit] Nickel is a widely utilized metal. It can be found in a wide variety of items including jewelry, zippers, buttons, belt buckles, coins, cell phones, guitar strings, tablets, surgical implants, and certain foods. ### Foods[edit] Nickel is present in a wide range of foods, in varying concentrations. Adults with ongoing nickel allergic contact dermatitis that does not respond to clinical treatments are recommended to follow a low-nickel diet and avoid foods such as chocolate, granola, oatmeal, and beans.[24] While systemic elicitation of ACD in individuals sensitized by direct skin contact is well documented for a small proportion of nickel-sensitized individuals, there exists some controversy about the ability to sensitize individuals when nickel exposure is oral, intravenous, or inhaled. Only about 1–10% of dietary nickel is absorbed by the body. Average daily-ingested intake of nickel is about 200 micrograms. A few studies have shown that nickel-sensitive individuals given greater than 5,000 micrograms nickel (as NiSO4) as a single oral dose had a nickel ACD response. While such exposures are in excess of those encountered in normal diets, some researchers suggest that dietary control of nickel intake may help in the ongoing treatment of nickel ACD caused by other sources. These researchers have correctly identified foods high in nickel content (e.g., nuts, chocolate, beans), but they have sometimes incorrectly advocated the avoidance of cutlery, bowls, etc. made from stainless steel, which do not release significant amounts of nickel.[25] ### Workplace[edit] Within the workplace, individuals may be exposed to significant amounts of nickel, airborne from the combustion of fossil fuels or from contact with tools that are nickel plated.[26] Historically, workplaces where prolonged contact with soluble nickel has been high have shown high risks for allergic contact nickel dermatitis. For example, nickel dermatitis was common in the past among nickel platers. Due to improved industrial and personal hygiene practices, however, over the past several decades, reports of nickel sensitivity in workplaces, such as the electroplating industry, have been sparse. In the workplace, exposure reduction includes personal protection equipment and other risk management measures.[27] ## Effects[edit] Nickel allergy results in a skin response (rash) after the skin comes in direct and sustained contact with any item that releases a large amount of free nickel from its surface. The skin reaction can occur at the site of contact, or sometimes spread beyond to the rest of the body. Cutaneous exposure can cause localized erythematous, pruritic, vesicular, and scaly patches. Ingestion of nickel may cause a systemic reaction, which will affect a larger skin surface. Examples of systemic reactions can include hand dermatitis, baboon syndrome, or generalized eczematous reactions.[28] ## Prevention[edit] Nickel has a wide utility of application in manufactured metals because it is both strong and malleable, leading to ubiquitous presence and the potential for consumers to be in contact with it daily. However, for those who have the rash of allergic contact dermatitis (ACD) due to a nickel allergy, it can be a challenge to avoid. Foods, common kitchen utensils, cell phones, jewelry, and many other items may contain nickel and be a source of irritation due to the allergic reaction caused by the absorption of free released nickel through direct and prolonged contact. The most appropriate measure for nickel-allergic persons is to prevent contact with the allergen. In 2011, researchers showed that applying a thin layer of glycerine emollient containing nanoparticles of either calcium carbonate or calcium phosphate on an isolated piece of pig skin (in vitro) and on the skin of mice (in vivo) prevents the penetration of nickel ions into the skin. The nanoparticles capture nickel ions by cation exchange, and remain on the surface of the skin, allowing them to be removed by simple washing with water. Approximately 11-fold fewer nanoparticles by mass are required to achieve the same efficacy as the chelating agent ethylenediamine tetraacetic acid. Using nanoparticles with diameters smaller than 500 nm in topical creams may be an effective way to limit the exposure to metal ions that can cause skin irritation'.[29] Pre-emptive avoidance strategies (PEAS) might ultimately lower the sensitization rates of children who would suffer from ACD[30] It is theorized that prevention of exposure to nickel early on could reduce the number of those that are sensitive to nickel by one-quarter to one-third. Identification of the many sources of nickel is vital to understanding the nickel sensitization story, food like chocolate and fish, zippers, buttons, cell phones and even orthodontic braces and eyeglass frames might contain nickel. Items that contain sentimental value (heirlooms, wedding rings) could be treated with an enamel or rhodium plating.[31] Sensitized individuals may check product labels or contact the manufacturer or retailer regarding possible nickel content.[32] The Dermatitis Academy has created an educational website to provide more information about nickel, including information about prevention, exposure, sources, and general information about nickel allergy. These resources provide guidance in a prevention initiative for children worldwide. ## Diagnosis[edit] Nickel allergy can be confirmed by a properly trained health care provider based on a patient's medical history, a physical exam, and a painless specialized patch test—when necessary. A significant number of people may self-diagnose, and not contact medical professionals, which could result in massive underreporting of the problem by scientific researchers. Confirming the diagnosis of Ni-ACD specifically involves inducing the skin to demonstrate a rash where the chemicals are applied (a delayed type hypersensitivity reaction), evidence that the patient is exposed to nickel, and establishing that the reaction and the exposure explain the current rash/symptoms under question.[33] The patch test plays a significant role in diagnosing ACD. The epicutaneous patch test evokes a delayed, Type IV hypersensitivity reaction, which is a cell-mediated, antibody-independent, immune response. Patch testing is the "gold standard" diagnostic tool for Ni-ACD.[34] In this sense, a positive patch test to nickel establishes that the subject has been previously exposed and is therefore sensitized to nickel. It does not necessarily indicate that the patch reaction is the cause of the current clinical disease. A negative test demonstrates that the patient is sub-threshold, either minimally or not sensitized. Cumulatively, clinical reasoning and a patch test help determine if nickel could be the cause of a current dermatitis reaction. ## Treatment[edit] Once a nickel allergy is detected, the best treatment is avoidance of nickel-releasing items. The top 13 categories that contain nickel include beauty accessories, eyeglasses, money, cigarettes, clothes, kitchen and household, electronics and office equipment, metal utensils, aliment, jewelry, batteries, orthodontic and dental appliances, and medical equipment.[35] Other than strict avoidance of items that release free nickel, there are other treatment options for reduction of exposure. The first step is to limit friction between skin and metallic items. Susceptible people may try to limit sweating while wearing nickel items, to reduce nickel release and thus decrease chances for developing sensitization or allergy. Another option is to shield electronics, metal devices, and tools with fabric, plastic, or acrylic coverings.[35] There are dimethylglyoxime test kits that can be very helpful to check for nickel release from items prior to purchasing. [36] The American Contact Dermatitis Society find a provider resource can help identify clinicians with training in providing guidance lists of safe items.[37] In addition to avoidance, healthcare providers may prescribe additional creams or medications to help relieve the skin reaction. ## Regulation[edit] As nickel can be harmful to skin, its use in daily products must be regulated. A safety directive has been in place in Europe since 2004. Denmark in 1980, and then shortly after the European Union (EU), enacted legislation that limited the amount of free nickel in consumer products that come in contact with the skin. This resulted in significantly decreased rates of sensitization among Danish children 0 to 18 years of age from 24.8% to 9.2% between 1985 and 1998, with similar reductions in sensitization throughout the EU.[38][39] No such directive exists in the United States, but efforts are under way to mandate safe use guidelines for nickel. In August 2015, the American Academy of Dermatology (AAD) adopted a nickel safety position paper.[40] The exact prevalence of Ni-ACD in the general population in the US is largely unknown. However, current estimates gauge that roughly 2.5 million US adults and 250,000 children suffer from nickel allergy, which costs an estimated $5.7 billion per year for treatment of symptoms.[41] Loma Linda University, Nickel Allergy Alliance, and Dermatitis Academy created the first open access self-reported patient registry to record nickel allergy prevalence data in the US.[ref 23] ## References[edit] 1. ^ a b Usatine R (May 2001). "A belt buckle allergy?". The Western Journal of Medicine. 174 (5): 307–8. doi:10.1136/ewjm.174.5.307. PMC 1071380. PMID 11342499. 2. ^ "Nickel allergy - Symptoms and causes". 3. ^ "Nickel Contact Dermatitis Picture Image on MedicineNet.com". 4. ^ "What Do You Need To Know About Nickel Allergy?" (PDF). 5. ^ Lu L, Vollmer J, Moulon C, Weltzien HU, Marrack P, Kappler J (March 2003). "Components of the ligand for a Ni++ reactive human T cell clone". The Journal of Experimental Medicine. 197 (5): 567–74. doi:10.1084/jem.20021762. PMC 2193829. PMID 12615898. 6. ^ Silverberg NB, Licht J, Friedler S, Sethi S, Laude TA (2002). "Nickel contact hypersensitivity in children". Pediatric Dermatology. 19 (2): 110–3. doi:10.1046/j.1525-1470.2002.00057.x. PMID 11994170. 7. ^ Girolomoni G, Gisondi P, Ottaviani C, Cavani A (April 2004). "Immunoregulation of allergic contact dermatitis". The Journal of Dermatology. 31 (4): 264–70. doi:10.1111/j.1346-8138.2004.tb00671.x. PMID 15187320. 8. ^ Peana M, Zdyb K, Medici S, Pelucelli A, Simula G, Gumienna-Kontecka E, Zoroddu MA (December 2017). "Ni(II) interaction with a peptide model of the human TLR4 ectodomain". Journal of Trace Elements in Medicine and Biology. 44: 151–160. doi:10.1016/j.jtemb.2017.07.006. PMID 28965571. 9. ^ Dhingra N, Shemer A, Correa da Rosa J, Rozenblit M, Fuentes-Duculan J, Gittler JK, Finney R, Czarnowicki T, Zheng X, Xu H, Estrada YD, Cardinale I, Suárez-Fariñas M, Krueger JG, Guttman-Yassky E (August 2014). "Molecular profiling of contact dermatitis skin identifies allergen-dependent differences in immune response". The Journal of Allergy and Clinical Immunology. 134 (2): 362–72. doi:10.1016/j.jaci.2014.03.009. PMID 24768652. 10. ^ Jadassohn J (1895). "Zur kenntnis der medikamentössen dermatosen". Verhandlungen der Deutschen Dermatologischen Gesellschaft. Fünfter Kongress, Raz (in German). Berlin: Julius Springer. pp. 103–129. 11. ^ Veien NK (December 2011). "Systemic contact dermatitis". International Journal of Dermatology. 50 (12): 1445–56. doi:10.1111/j.1365-4632.2011.05104.x. PMID 22097987. 12. ^ Di Gioacchino M, Ricciardi L, De Pità O, Minelli M, Patella V, Voltolini S, Di Rienzo V, Braga M, Ballone E, Mangifesta R, Schiavino D (February 2014). "Nickel oral hyposensitization in patients with systemic nickel allergy syndrome". Annals of Medicine. 46 (1): 31–7. doi:10.3109/07853890.2013.861158. PMC 4673509. PMID 24256166. 13. ^ Matiz C, Jacob SE (2011). "Systemic contact dermatitis in children: how an avoidance diet can make a difference". Pediatric Dermatology. 28 (4): 368–74. doi:10.1111/j.1525-1470.2010.01130.x. PMID 20807367. 14. ^ Jensen CS, Menné T, Johansen JD (February 2006). "Systemic contact dermatitis after oral exposure to nickel: a review with a modified meta-analysis". Contact Dermatitis. 54 (2): 79–86. doi:10.1111/j.0105-1873.2006.00773.x. PMID 16487279. 15. ^ Baldwin WH (1931). "The story of nickel. How "old nick's" gnomes were outwitted". Journal of Chemical Education. 8 (9): 1749. Bibcode:1931JChEd...8.1749B. doi:10.1021/ed008p1749. 16. ^ Prystowsky SD, Allen AM, Smith RW, Nonomura JH, Odom RB, Akers WA (August 1979). "Allergic contact hypersensitivity to nickel, neomycin, ethylenediamine, and benzocaine. Relationships between age, sex, history of exposure, and reactivity to standard patch tests and use tests in a general population". Archives of Dermatology. 115 (8): 959–62. doi:10.1001/archderm.1979.04010080023015. PMID 157103. 17. ^ Rietschel RL, Fowler JF, Warshaw EM, Belsito D, DeLeo VA, Maibach HI, Marks JG, Mathias CG, Pratt M, Sasseville D, Storrs FJ, Taylor JS, Zug KA (2008). "Detection of nickel sensitivity has increased in North American patch-test patients". Dermatitis. 19 (1): 16–9. doi:10.2310/6620.2008.06062. PMID 18346391. 18. ^ Jacob SE, Goldenberg A, Pelletier JL, Fonacier LS, Usatine R, Silverberg N (2015). "Nickel Allergy and Our Children's Health: A Review of Indexed Cases and a View of Future Prevention". Pediatric Dermatology. 32 (6): 779–85. doi:10.1111/pde.12639. PMID 26212605. 19. ^ Goldenberg A, Vassantachart J, Lin EJ, Lampel HP, Jacob SE (2015). "Nickel Allergy in Adults in the U.S.: 1962 to 2015". Dermatitis. 26 (5): 216–23. doi:10.1097/der.0000000000000130. PMID 26177034. 20. ^ Fransway AF, Zug KA, Belsito DV, Deleo VA, Fowler JF, Maibach HI, Marks JG, Mathias CG, Pratt MD, Rietschel RL, Sasseville D, Storrs FJ, Taylor JS, Warshaw EM, Dekoven J, Zirwas M (2013). "North American Contact Dermatitis Group patch test results for 2007-2008". Dermatitis. 24 (1): 10–21. doi:10.1097/der.0b013e318277ca50. PMID 23340394. 21. ^ Thyssen JP, Menné T (February 2010). "Metal allergy--a review on exposures, penetration, genetics, prevalence, and clinical implications". Chemical Research in Toxicology. 23 (2): 309–18. doi:10.1021/tx9002726. PMID 19831422. 22. ^ http://www.dermatitisacademy.com 23. ^ https://emg.wufoo.com/forms/zmnl51i1unpoj3/ 24. ^ "Nickel Contact Dermatitis". Dermatitis Academy. 25. ^ "Fact Sheet: Nickel and Human Health". nickelinstitute.org. 26. ^ Grandjean P (1984). "Human exposure to nickel". IARC Scientific Publications (53): 469–85. PMID 6241927. 27. ^ "Knowledge of properties and safe use of substances \| Nickel Institute". www.nickelinstitute.org. 28. ^ Zirwas MJ, Molenda MA (June 2009). "Dietary nickel as a cause of systemic contact dermatitis". The Journal of Clinical and Aesthetic Dermatology. 2 (6): 39–43. PMC 2923958. PMID 20729949. 29. ^ Vemula PK, Anderson RR, Karp JM (2011). "Nanoparticles reduce nickel allergy by capturing metal ions". Nature Nanotechnology. 6 (5): 291–5. Bibcode:2011NatNa...6..291V. doi:10.1038/nnano.2011.37. PMID 21460828. 30. ^ Hill H, Goldenberg A, Golkar L, Beck K, Williams J, Jacob SE (2016). "Pre-Emptive Avoidance Strategy (P.E.A.S.) - addressing allergic contact dermatitis in pediatric populations". Expert Review of Clinical Immunology. 12 (5): 551–61. doi:10.1586/1744666X.2016.1142373. PMID 26764601. 31. ^ Hill H, Goldenberg A, Sheehan MP, Patel A, Jacob SE (2015). "Nickel-Free Alternatives Raise Awareness". Dermatitis : Contact, Atopic, Occupational, Drug. 26 (6): 245–53. doi:10.1097/DER.0000000000000135. PMID 26551602. 32. ^ Kerr M, Cafasso J (11 January 2016). Weatherspoon D (ed.). "Nickel Allergies Symptoms, Tests, and Treatment". Healthline. 33. ^ Ale IS, Maibacht HA (March 2010). "Diagnostic approach in allergic and irritant contact dermatitis". Expert Review of Clinical Immunology. 6 (2): 291–310. doi:10.1586/eci.10.4. PMID 20402391. 34. ^ Schalock PC, Menné T, Johansen JD, Taylor JS, Maibach HI, Lidén C, Bruze M, Thyssen JP (January 2012). "Hypersensitivity reactions to metallic implants - diagnostic algorithm and suggested patch test series for clinical use". Contact Dermatitis. 66 (1): 4–19. doi:10.1111/j.1600-0536.2011.01971.x. PMID 21957996. 35. ^ a b "Be Nickel Aware" (PDF). Dermatitis Academy. Retrieved 2018-06-05. 36. ^ https://www.dermatitisacademy.com/nickel-sources/ 37. ^ https://www.contactderm.org/find/ 38. ^ Johansen JD, Menné T, Christophersen J, Kaaber K, Veien N (March 2000). "Changes in the pattern of sensitization to common contact allergens in denmark between 1985-86 and 1997-98, with a special view to the effect of preventive strategies". The British Journal of Dermatology. 142 (3): 490–5. doi:10.1046/j.1365-2133.2000.03362.x. PMID 10735956. 39. ^ Thyssen JP, Uter W, McFadden J, Menné T, Spiewak R, Vigan M, Gimenez-Arnau A, Lidén C (March 2011). "The EU Nickel Directive revisited--future steps towards better protection against nickel allergy". Contact Dermatitis. 64 (3): 121–5. doi:10.1111/j.1600-0536.2010.01852.x. PMID 21226718. 40. ^ "Position Statement on Nickel Sensitivity" (PDF). American Academy of Dermatology. 41. ^ Jacob SE, Goldenberg A, Pelletier JL, Fonacier LS, Usatine R, Silverberg N (2015). "Nickel Allergy and Our Children's Health: A Review of Indexed Cases and a View of Future Prevention". Pediatric Dermatology. 32 (6): 779–785. doi:10.1111/pde.12639. PMID 26212605. ## Further reading[edit] * "Woman's metal allergy causes severe symptoms after knee replacement". ScienceDaily. December 16, 2014. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Nickel allergy	None	6,585	wikipedia	https://en.wikipedia.org/wiki/Nickel_allergy	2021-01-18T18:46:26	{"icd-9": ["995.3"], "icd-10": ["L23.0"], "wikidata": ["Q16606544"]}
A number sign (#) is used with this entry because of evidence that congenital cataract-45 (CTRCT45) is caused by homozygous mutation in the SIPA1L3 gene (616655) on chromosome 19q13. One such family has been reported. Clinical Features Evers et al. (2015) studied a German family in which 2 of 3 sisters, born of fourth-cousin parents, had bilateral dense white cataracts diagnosed soon after birth. Both affected sisters had normal psychomotor development, normal growth, and no dysmorphic features. Ophthalmologic examination of their parents did not show any ocular abnormalities. Mapping In a German family segregating autosomal recessive congenital cataract, Evers et al. (2015) performed genomewide parametric linkage analysis with SNP genotypes and found significant evidence of linkage to a locus on chromosome 19p13-q13.2, obtaining a maximal lod score of 3.3 between SNP markers rs12461484 and rs7351086 (chr19:16,743,209-39,150,199; GRCh37). Molecular Genetics In a German family segregating autosomal recessive congenital cataract mapping to chromosome 19p13-q13.2, Evers et al. (2015) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the SIPA1L3 gene (R1497X; 616655.0001) in 2 affected sisters. Their unaffected parents were heterozygous for the mutation, which was not found in the 1000 Genomes Project or Exome Variant Server databases. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Congenital cataract, dense white MISCELLANEOUS \- Cataract evident at birth \- Based on report of 2 affected sisters (last curated March 2016) MOLECULAR BASIS \- Caused by mutation in the SIPA1-like protein-3 gene (SIPA1L3, 616655.0002 ) ▲ 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	CATARACT 45	c4225182	6,586	omim	https://www.omim.org/entry/616851	2019-09-22T15:47:44	{"doid": ["0110262"], "omim": ["616851"], "icd-10": ["Q12.0"], "orphanet": ["91492"], "synonyms": []}
This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Idioventricular rhythm" – news · newspapers · books · scholar · JSTOR (May 2020) (Learn how and when to remove this template message) An idioventricular rhythm is a cardiac rhythm characterized by a rate of <50 beats per minute (bpm), absence of P waves and widening of the QRS complex.[1] In cases where the heart rate is between 50 and 110 bpm, it is known as accelerated idioventricular rhythm and ventricular tachycardia if the rate exceeds 120 bpm. Causes of idioventricular rhythms are varied and can include drugs or a heart defect at birth. It is typically benign and not life-threatening. ## Contents * 1 Aetiology * 2 Pathophysiology * 3 Diagnosis and treatment * 4 References ## Aetiology[edit] Various aetiologies may contribute to the formation of an idioventricular rhythm, and include:[1] * Heart block * Reperfusion after myocardial infarction * Electrolyte abnormalities * Heart diseases present at birth * Certain drugs (eg. digoxin, β-agonists, anaesthetics) ## Pathophysiology[edit] The physiological pacemaker of the heart is the sinoatrial node.[2] If the sinoatrial node is rendered dysfunctional, the AV node may act as the pacemaker.[3] If both of these fail, the ventricles begin to act as the dominant pacemaker in the heart.[1] The ventricles acting as their own pacemaker gives rise to an idioventricular rhythm. ## Diagnosis and treatment[edit] An ECG trace is required for diagnosis. As this rhythm is not life-threatening, treatment has limited value for the patient. If underlying pathologies are identified, they should be treated appropriately. Antidysrhythmics may be utilised if the patient suffers from dysrhythmias. ## References[edit] 1. ^ a b c Gangwani, Manesh Kumar (31 January 2020). Idioventricular Rhythm. 2. ^ Kashou, Anthony H.; Basit, Hajira; Chhabra, Lovely (23 June 2019). Physiology, Sinoatrial Node (SA Node). StatPearls Publishing. 3. ^ Guyton, Arthur C.; Hall, John E. Textbook of Medical Physiology (11 ed.). pp. 120–121. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Idioventricular rhythm	c0700363	6,587	wikipedia	https://en.wikipedia.org/wiki/Idioventricular_rhythm	2021-01-18T18:55:53	{"umls": ["C0700363"], "wikidata": ["Q5989048"]}
A rare genetic neurological disorder characterized by pediatric onset of calcifying leukoencephalopathy and skeletal dysplasia. Reported structural brain abnormalities include agenesis of corpus callosum, ventriculomegaly, congenital hydrocephalus, pontocerebellar hypoplasia, periventricular calcifications, Dandy-Walker malformation and absence of microglia. Characteristic skeletal features include increased bone mineral density (reported in skull, pelvic bone and vertebrae), platyspondyly, and under-modeling of tubular bones with widened/radiolucent metaphysis and constricted/sclerotic diaphysis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Early-onset calcifying leukoencephalopathy-skeletal dysplasia	None	6,588	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=556985	2021-01-23T19:06:26	{}
Noma neonatorum SpecialtyDermatology Noma neonatorum is a cutaneous condition, a manifestation of infection, usually Pseudomonas aeruginosa sepsis, and has been reported almost exclusively in developing countries.[1] Despite the similarity of facial lesions, noma neonatorum is not related to noma.[2] ## See also[edit] * Green nail syndrome * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ T.B. Parikh; R.N. Nanavati; R.H. Udani. Noma Neonatorum Indian Journal of Pediatrics, Volume 73—May, 2006 This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Noma neonatorum	c2930832	6,589	wikipedia	https://en.wikipedia.org/wiki/Noma_neonatorum	2021-01-18T18:39:29	{"mesh": ["C531760"], "umls": ["C2930832"], "wikidata": ["Q7048374"]}
Arthrogryposis Other namesArthrogryposis multiplex congenita (AMC) Drawing of an infant with arthrogryposis SpecialtyMedical genetics Arthrogryposis, describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning "curving of joints" (arthron, "joint"; grȳpōsis, late Latin form of late Greek grūpōsis, "hooking").[1] Children born with one or more joint contractures have abnormal fibrosis of the muscle tissue causing muscle shortening, and therefore are unable to perform active extension and flexion in the affected joint or joints.[2] AMC has been divided into three groups: amyoplasia, distal arthrogryposis, and syndromic. Amyoplasia is characterized by severe joint contractures and muscle weakness.[3] Distal arthrogryposis mainly involves the hands and feet. Types of arthrogryposis with a primary neurological or muscle disease belong to the syndromic group.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Extrinsic factors * 2.2 Intrinsic factors * 2.3 Molecular basis * 2.4 Muscle and connective tissue development disorders * 2.5 Neurological abnormalities * 3 Diagnosis * 3.1 Classification * 4 Treatment * 4.1 Passive enhancement * 4.2 Wrist surgery * 4.3 Thumb surgery * 4.4 Foot surgeries * 5 Prognosis * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Often, every joint in a patient with arthrogryposis is affected; in 84% all limbs are involved, in 11% only the legs, and in 4% only the arms are involved.[4] Every joint in the body, when affected, displays typical signs and symptoms: for example, the shoulder (internal rotation); wrist (volar and ulnar); hand (fingers in fixed flexion and thumb in palm); hip (flexed, abducted and externally rotated, frequently dislocated); elbow (extension and pronation) and foot clubfoot and less commonly congenital vertical talus.[2][5] Range of motion can be different between joints because of the different deviations.[6] Some types of arthrogryposis like amyoplasia have a symmetrical joint/limb involvement, with normal sensations.[4][6] The contractures in the joints can result in delayed walking development in the first 5 years, but severity of contractures do not necessarily predict eventual walking ability or inability.[6] Intelligence is normal to above normal in children with amyoplasia,[4] but it is not known how many of these children have an above normal intelligence, and there is no literature available about the cause of this syndrome. There are a few syndromes like the Freeman-Sheldon and Gordon syndrome, which have craniofacial involvement.[4] The amyoplasia form of arthrogryposis is sometimes accompanied with a midline facial hemangioma.[4] Arthrogryposis is not a diagnosis but a clinical finding, so this disease is often accompanied with other syndromes or diseases. These other diagnoses could affect any organ in a patient. There are a few slightly more common diagnoses such as pulmonary hypoplasia, cryptorchidism, congenital heart defects, tracheoesophageal fistulas, inguinal hernias, cleft palate, and eye abnormalities.[7] ## Causes[edit] Research of arthrogryposis has shown that anything that inhibits normal joint movement before birth can result in joint contractures.[3] Arthrogryposis could be caused by genetic and environmental factors. In principle: any factor that curtails fetal movement can result in congenital contractures.[4] The exact causes of arthrogryposis are unknown. ### Extrinsic factors[edit] The malformations of arthrogryposis can be secondary to environmental factors such as: decreased intrauterine movement, oligohydramnios (low volume or abnormal distribution of intrauterine fluid), and defects in the fetal blood supply. Other causes could be: hyperthermia, limb immobilization and viral infections. Myasthenia gravis of the mother leads also in rare cases to arthrogryposis. The major cause in humans is fetal akinesia.[2] However, this is disputed lately.[2] ### Intrinsic factors[edit] Arthrogryposis could also be caused by intrinsic factors. This includes molecular, muscle- and connective tissue development disorders or neurological abnormalities.[citation needed] ### Molecular basis[edit] Research has shown that there are more than 35 specific genetic disorders associated with arthrogryposis. Most of those mutations are missense, which means the mutation results in a different amino acid. Other mutations that could cause arthrogryposis are: single gene defects (X-linked recessive, autosomal recessive and autosomal dominant), mitochondrial defects and chromosomal disorders (for example: trisomy 18).[4] This is mostly seen in distal arthrogryposis. Mutations in at least five genes (TNN12, TNNT3, TPM2, MYH3 and MYH8) could cause distal arthrogryposis.[3] There could be also connective tissue, neurological or muscle development disorders.[3] ### Muscle and connective tissue development disorders[edit] Loss of muscle mass with an imbalance of muscle power at the joint can lead to connective tissue abnormality.[2] This leads to joint fixation and reduced fetal movement.[2] Also muscle abnormalities could lead to a reduction of fetal movement. Those could be: dystrophy, myopathy and mitochondrial disorders. This is mostly the result of abnormal function of the dystrophin-glycoprotein-associated complex in the sarcolemma of skeletal muscles.[2] ### Neurological abnormalities[edit] Seventy to eighty percent of cases of the most severe forms of arthrogryposis are caused by neurological abnormalities, which can be either genetic or environmental.[3] The underlying aetiology and pathogenesis of congenital contractures, particularly arthrogryposis and the mechanism of the mutations remains an active area of investigation, because identifying these factors could help to develop treatment and congenital finding of arthrogryposis.[3][8] ## Diagnosis[edit] Research on prenatal diagnosis has shown that a diagnosis can be made prenatally in approximately 50% of fetuses presenting arthrogryposis.[9] It could be found during routine ultrasound scanning showing a lack of mobility and abnormal position of the foetus.[2] There are other options for visualization of details and structures using techniques such as 4D ultrasound.[2] In clinic a child can be diagnosed with arthrogryposis with physical examination, confirmed by ultrasound, MRI,[3][9] or muscle biopsy.[9] ### Classification[edit] Some of the different types of AMC include: * Arthrogryposis multiplex due to muscular dystrophy.[10][11] * Arthrogryposis ectodermal dysplasia other anomalies, also known as Cote Adamopoulos Pantelakis syndrome, Trichooculodermovertebral syndrome, TODV syndrome and Alves syndrome.[12][13] * Arthrogryposis epileptic seizures migrational brain disorder.[14] * Arthrogryposis IUGR thoracic dystrophy, also known as Van Bervliet syndrome.[15][16] * Arthrogryposis like disorder, also known as Kuskokwim disease.[17] * Arthrogryposis-like hand anomaly and sensorineural deafness.[18][19] * Arthrogryposis multiplex congenita CNS calcification.[20] * Arthrogryposis multiplex congenita distal (AMCD), also known as X-linked spinal muscular atrophy type 2[21][22][23] * Gordon syndrome, also known as distal arthrogryposis type 3.[24] * Arthrogryposis multiplex congenita, distal type 2A, also known as Freeman–Sheldon syndrome.[25] * Arthrogryposis multiplex congenita, distal type 2B, also known as Sheldon–Hall syndrome.[26] * Arthrogryposis multiplex congenita neurogenic type (AMCN).[27] This particular type of AMC has been linked to the AMCN gene on locus 5q35.[28][29] * Arthrogryposis multiplex congenita pulmonary hypoplasia, also with a large number of synonyms.[30][31] * Arthrogryposis multiplex congenita whistling face, also known as Illum syndrome.[32][33][34][35] * Arthrogryposis multiplex congenita, distal type 1 (AMCD1).[36] * Arthrogryposis ophthalmoplegia retinopathy, also known as Oculomelic amyoplasia.[37][38][39] * Arthrogryposis renal dysfunction cholestasis syndrome, also known as ARC Syndrome.[40][41] Another form has been related to mutations in the leucine-rich glioma-inactivated 4 (LGI4) gene.[42] ## Treatment[edit] The treatment of arthrogryposis includes occupational therapy, physical therapy, splinting and surgery.[3] The primary long-term goals of these treatments are increasing joint mobility and muscle strength and the development of adaptive use patterns that allow for walking and independence with activities of daily living. Since arthrogryposis has many different types, the treatment varies between patients depending on the symptoms.[3] Only a few good articles exist in which a surgical technique that is used to treat arthrogryposis is described. These surgeries are explained below.[citation needed] ### Passive enhancement[edit] There are a number of passive devices for enhancing limb movement, intended to be worn to aid movement and encourage muscular development. For example, the Wilmington Robotic Exoskeleton is a potential assistive device built on a back brace, shadowing the upper arm and forearm. It can be difficult to fit and heavy and awkward to wear.[43][44][45] Researchers at the University of Delaware are developing a light and unobtrusive therapeutic garment, suitable for babies and children, called the Playskin Lift. The garment looks like normal clothing but contains bundled steel wires under the arms, which help to push the arms toward a lifted position while allowing the wearer to move freely from that position.[45][46][47][48] ### Wrist surgery[edit] Dorsal carpal wedge osteotomy Children with the amyoplasia type of arthrogryposis usually have flexion and ulnar deviation of the wrists.[2] Dorsal carpal wedge osteotomy is indicated for wrists with excessive flexion contracture deformity when non-surgical interventions such as occupational therapy and splinting have failed to improve function. On the dorsal side, at the level of the midcarpus, a wedge osteotomy is made. Sufficient bone is resected to at least be able to put the wrist in a neutral position. If the wrist also has ulnar deviation, more bone can be taken from the radial side to correct this abnormality. This position is held into place with two cross K-wires. In addition, a tendon transfer of the extensor carpi ulnaris to the extensor carpi radialis brevis may be performed to correct ulnar deviation or wrist extension weakness, or both. This tendon transfer is only used if the extensor carpi ulnaris appears to be functional enough.[49] ### Thumb surgery[edit] Index rotation flap The soft tissue envelope in congenital contractual conditions such as clasped or arthrogrypotic thumbs is often deficient in two planes, the thumb-index web and the flexor aspect of the thumb. There is often an appearance of increased skin at the base of the index finger that is part of the deformity. This tissue can be used to resurface the thumb-index web after a comprehensive release of all the tight structures to allow for a larger range of motion of the thumb. This technique is called the index rotation flap.[citation needed] The flap is taken from the radial side of the index finger. It is proximally based at the distal edge of the thumb-index web. The flap is made as wide as possible, but still small enough to close with the excessive skin on the palmar side of the index finger. The flap is rotated around the tightest part of the thumb to the metacarpophalangeal joint of the thumb, allowing for a larger range of motion.[50] ### Foot surgeries[edit] Generally, foot surgery is usually reserved for patients with a walking or ambulatory potential. Foot surgery may also be indicated to assist brace and orthosis fitting and hence promote supported standing. The most common foot deformity in arthrogryposis is club feet or talipes equinovarus. In the early years of life the serial casting according to the Ponseti method usually yields good results. The Ponseti method can also be used as a first line treatment in older and more resistant cases.[51] In such severe and neglected cases bony surgery in the form of foot osteotomies and arthrodesis is usually indicated. It is usually be accompanied by soft tissue surgery in the form of release of contracted tendon and capsular structures. In older patients near skeletal maturity joint fusion or arthrodesis may be indicated as well.[52] Less frequent patients with arthrogryposis may develop congenital vertical talus also known as rocker bottom foot. Similarly, congenital vertical talus is classically managed by serial casting according to the reversed Ponseti method. Resistant or recurrent cases may be offered an extensive soft tissue release. However this is fraught with risk of foot stiffness and pain in the long term. Talectomy or excision of the talus to give room for creation of plantigrade foot has been practiced. Naviculectomy or midtarsal resection arthroplasty represents a less invasive option with satisfactory short-term results.[53] Lee Pearson, a ten-time Paralympic Games gold medallist born with arthrogryposis ## Prognosis[edit] AMC is considered non-progressive, so with proper medical treatment, things can improve. The joint contractures that are present will not get worse than they are at the time of birth. There is no way to completely resolve or cure AMC. But with proper treatment, most children make significant improvements in their range of motion and ability to move their limbs which enables them to do activities of daily life, and live relatively normal lives.[citation needed] Therapeutic interventions that are cornerstones in the treatment of AMC include: stretching and range of motion exercises, physical, occupational, and speech therapy, splinting and serial casting. Surgical intervention may also improve joint mobility and function.[54] Other positive prognostic factors for independent walking were active hips and knees, hip flexion contractures of less than 20 degrees and knee flexion contractures of less than 15 degrees without severe scoliosis.[6] ## Epidemiology[edit] Arthrogryposis is a rare condition. Some authors say the overall prevalence is one in 3,000[3] and others say it is one in 11,000–12,000 among European live births.[55] Congenital clubfoot is the most common single contracture and its prevalence is one in 500 live births.[3] ## See also[edit] * X-linked spinal muscular atrophy type 2 ## References[edit] 1. ^ "The Free Dictionary: Arthrogryposis". Retrieved 11 July 2013. 2. ^ a b c d e f g h i j Kalampokas, Emmanouil; Kalampokas, Theodoros; Sofoudis, Chrisostomos; Deligeoroglou, Efthymios; Botsis, Dimitrios (2012). "Diagnosing Arthrogryposis Multiplex Congenita: A Review". ISRN Obstetrics and Gynecology. 2012: 1–6. doi:10.5402/2012/264918. PMC 3461621. PMID 23050160. 3. ^ a b c d e f g h i j k l Bamshad, Michael; Van Heest, AE; Pleasure, D (2009). "Arthrogryposis: A Review and Update". The Journal of Bone and Joint Surgery. American Volume. 91 (Suppl 4): 40–6. doi:10.2106/JBJS.I.00281. PMC 2698792. PMID 19571066. 4. ^ a b c d e f g Bevan, Wesley P.; Hall, Judith G.; Bamshad, Micheal; Staheli, Lynn T.; Jaffe, Kenneth M.; Song, Kit (2007). "Arthrogryposis Multiplex Congenita (Amyoplasia)". Journal of Pediatric Orthopaedics. 27 (5): 594–600. doi:10.1097/BPO.0b013e318070cc76. PMID 17585274. 5. ^ Miller, Mark; Dobbs, Matthew B. (October 2015). "Congenital Vertical Talus". Journal of the American Academy of Orthopaedic Surgeons. 23 (10): 604–611. doi:10.5435/JAAOS-D-14-00034. PMID 26337950. S2CID 2282828. 6. ^ a b c d Fassier, Alice; Wicart, Philippe; Dubousset, Jean; Seringe, Raphaël (2009). "Arthrogryposis multiplex congenita. Long-term follow-up from birth until skeletal maturity". Journal of Children's Orthopaedics. 3 (5): 383–90. doi:10.1007/s11832-009-0187-4. PMC 2758174. PMID 19669823. 7. ^ Brooks, James G; Coster, Douglas J (1994). "Arthrogryposis multiplex congenita: A report of two cases". Australian and New Zealand Journal of Ophthalmology. 22 (2): 127–32. doi:10.1111/j.1442-9071.1994.tb00780.x. PMID 7917267. 8. ^ Wynne-Davies, R; Williams, PF; O'Connor, JC (1981). "The 1960s epidemic of arthrogryposis multiplex congenita: A survey from the United Kingdom, Australia and the United States of America". The Journal of Bone and Joint Surgery. British Volume. 63-B (1): 76–82. doi:10.1302/0301-620X.63B1.7204479. PMID 7204479. 9. ^ a b c Rink, Britton D. (2011). "Arthrogryposis: A Review and Approach to Prenatal Diagnosis". Obstetrical & Gynecological Survey. 66 (6): 369–77. doi:10.1097/OGX.0b013e31822bf5bb. PMID 21851751. S2CID 34468857. 10. ^ Smit, L. M. E.; Earth, P. G. (2008). "Arthrogryposis Multiplex Congenita due to Congenital Myasthenia". Developmental Medicine & Child Neurology. 22 (3): 371–4. doi:10.1111/j.1469-8749.1980.tb03718.x. PMID 6446471. 11. ^ Banker, Betty Q.; Victor, Maurice; Adams, Raymond D. (1957). "Arthrogryposis Multiplex Due to Congenital Muscular Dystrophy". Brain. 80 (3): 319–34. doi:10.1093/brain/80.3.319. PMID 13471804. 12. ^ Arthrogryposis and ectodermal dysplasia at NIH's Office of Rare Diseases 13. ^ Stoll, C; Alembik, Y; Finck, S; Janser, B (1992). "Arthrogryposis, ectodermal dysplasia and other anomalies in two sisters". Genetic Counseling. 3 (1): 35–9. PMID 1590979. 14. ^ "ORPHA1139 Arthrogryposis - epileptic seizures - migrational brain disorder". Orphanet.ORPHANET - About rare diseases - About orphan drugs 15. ^ "ORPHANET - About rare diseases - About orphan drugs". Archived from the original on 2005-11-04. Retrieved 2007-04-25. 16. ^ Arthrogryposis IUGR thoracic dystrophy at NIH's Office of Rare Diseases 17. ^ CTD: Disease Not Found[permanent dead link] 18. ^ CTD: Disease Not Found[permanent dead link] 19. ^ Arthrogryposis-like hand anomaly and sensorineural deafness at NIH's Office of Rare Diseases 20. ^ Arthrogryposis multiplex congenita CNS calcification at NIH's Office of Rare Diseases 21. ^ Online Mendelian Inheritance in Man (OMIM): 301830 22. ^ ORPHANET - About rare diseases - About orphan drugs Archived December 26, 2004, at the Wayback Machine 23. ^ Kizilates, Sevim Ünal; Talim, Beril; Sel, Kutay; Köse, Gulsen; Caglar, Melda (2005). "Severe lethal spinal muscular atrophy variant with arthrogryposis". Pediatric Neurology. 32 (3): 201–4. doi:10.1016/j.pediatrneurol.2004.10.003. PMID 15730903. INIST:16634238. 24. ^ Gordon Syndrome Archived September 27, 2007, at the Wayback Machine 25. ^ "Archived copy". Archived from the original on 2007-09-27. Retrieved 2007-04-25.CS1 maint: archived copy as title (link) 26. ^ Reference, Genetics Home. "Sheldon-Hall syndrome". Genetics Home Reference. Retrieved 2019-09-12. 27. ^ Arthrogryposis Multiplex Congenita, Neurogenic Type - What does AMCN stand for? Acronyms and abbreviations by the Free Online Dictionary 28. ^ CTD: Disease Not Found 29. ^ CTD: Disease Not Found 30. ^ ORPHANET - About rare diseases - About orphan drugs 31. ^ Leichtman, Lawrence G.; Say, Burhan; Barber, Nancy (1980). "Primary pulmonary hypoplasia and arthrogryposis multiplex congenita". The Journal of Pediatrics. 96 (5): 950–1. doi:10.1016/S0022-3476(80)80591-9. PMID 7365612. 32. ^ Illum, N.; Reske-Nielsen, Edith; Skovby, F.; Askjaer, S.; Bernsen, Alice (2008). "Lethal Autosomal Recessive Arthrogryposis Multiplex Congenita with Whistling Face and Calcifications of the Nervous System". Neuropediatrics. 19 (4): 186–92. doi:10.1055/s-2008-1052443. PMID 3205375. 33. ^ CTD: Disease Not Found[permanent dead link] 34. ^ ORPHANET - About rare diseases - About orphan drugs 35. ^ Arthrogryposis multiplex congenita whistling face at NIH's Office of Rare Diseases 36. ^ Arthrogryposis multiplex congenita at NIH's Office of Rare Diseases 37. ^ ORPHANET - About rare diseases - About orphan drugs 38. ^ Arthrogryposis ophthalmoplegia retinopathy at NIH's Office of Rare Diseases 39. ^ Schrander-Stumpel, C T; Höweler, C J; Reekers, A D; De Smet, N M; Hall, J G; Fryns, J P (1993). "Arthrogryposis, ophthalmoplegia, and retinopathy: Confirmation of a new type of arthrogryposis". Journal of Medical Genetics. 30 (1): 78–80. doi:10.1136/jmg.30.1.78. PMC 1016242. PMID 8423615. 40. ^ Rocco, M.; Callea, F.; Pollice, B.; Faraci, M.; Campiani, F.; Borrone, C. (1995). "Arthrogryposis, renal dysfunction and cholestasis syndrome: Report of five patients from three Italian families". European Journal of Pediatrics. 154 (10): 835–9. doi:10.1007/BF01959793. PMID 8529684. S2CID 32845371. 41. ^ Arthrogryposis renal dysfunction cholestasis syndrome at NIH's Office of Rare Diseases 42. ^ Mishra S, Rai A, Srivastava P, Phadke SR (2019) A mild phenotype of LGI4-Related arthrogryposis multiplex congenita with intrafamilial variability. Eur J Med Genet 43. ^ Rahman, Tariq; Sample, Whitney; Jayakumar, Shanmuga; King, Marilyn Marnie; Wee, Jin Yong; Seliktar, Rahamim; Alexander, Michael; Scavina, Mena; Clark, Alisa (2006). "Passive exoskeletons for assisting limb movement". The Journal of Rehabilitation Research and Development. 43 (5): 583–90. doi:10.1682/JRRD.2005.04.0070. PMID 17123200. Retrieved 10 May 2017. 44. ^ Jean-Francois, Edvige (April 2, 2014). "Robot exoskeleton lets girl lift her arms, reach for the stars". CNN. Retrieved 10 May 2017. 45. ^ a b Chen, Eli (27 January 2016). "Building functional, fashionable exoskeletons for babies". NewsWorks The Pulse. Archived from the original on 4 August 2017. Retrieved 10 May 2017. 46. ^ Maguire, Gillian (April 21, 2017). "Learning to Move with Move to Learn". Distillations Blog. Archived from the original on 23 March 2018. Retrieved 22 March 2018. 47. ^ "Researchers combat developmental delays with 'super suits'". Science Daily. May 17, 2016. Retrieved 10 May 2017. 48. ^ Fishman, Margie (January 19, 2015). "Wearable tech: Supporting limbs, easing Parkinson's". Delaware Online. Retrieved 10 May 2017. 49. ^ Van Heest, Ann E.; Rodriguez, Rudy (2013). "Dorsal Carpal Wedge Osteotomy in the Arthrogrypotic Wrist". The Journal of Hand Surgery. 38 (2): 265–70. doi:10.1016/j.jhsa.2012.10.034. PMID 23267756. 50. ^ Ezaki, Marybeth; Oishi, Scott N. (2010). "Index Rotation Flap for Palmar Thumb Release in Arthrogryposis". Techniques in Hand & Upper Extremity Surgery. 14 (1): 38–40. doi:10.1097/BTH.0b013e3181d44583. PMID 20216051. 51. ^ Matar, Hosam E.; Beirne, Peter; Garg, Neeraj (February 2016). "The effectiveness of the Ponseti method for treating clubfoot associated with arthrogryposis: up to 8 years follow-up". Journal of Children's Orthopaedics. 10 (1): 15–18. doi:10.1007/s11832-016-0712-1. PMC 4763152. PMID 26833334. 52. ^ Machida, Jiro; Inaba, Yutaka; Nakamura, Naoyuki (March 2017). "Management of foot deformity in children". Journal of Orthopaedic Science. 22 (2): 175–183. doi:10.1016/j.jos.2016.12.009. PMID 28081930. 53. ^ EL-Sobky, Tamer A.; Samir, Shady; Mahmoud, Shady (July 2019). "Naviculectomy for two ambulatory children with intractable congenital vertical talus". Journal of Pediatric Orthopaedics B. 29 (4): 387–391. doi:10.1097/BPB.0000000000000663. PMC 7255489. PMID 31356503. 54. ^ http://www.amcsupport.org 55. ^ Hoff, Jana Midelfart; Loane, Maria; Gilhus, Nils Erik; Rasmussen, Svein; Daltveit, Anne Kjersti (2011). "Arthrogryposis multiplexa congenita: An epidemiologic study of nearly 9 million births in 24 EUROCAT registers". European Journal of Obstetrics & Gynecology and Reproductive Biology. 159 (2): 347–50. doi:10.1016/j.ejogrb.2011.09.027. PMID 22005589. ## External links[edit] Classification D * ICD-10: Q74.3 * ICD-9-CM: 728.3, 754.89 * OMIM: 108110 108120 208100 301830 601701 208200 108200 301830 208155 601680 108145 208085 * MeSH: D001176 * DiseasesDB: 31688 External resources * eMedicine: ped/142 * v * t * e Diseases of joints General * Arthritis * Monoarthritis * Oligoarthritis * Polyarthritis Symptoms * Joint pain * Joint stiffness Inflammatory Infectious * Septic arthritis * Tuberculosis arthritis Crystal * Chondrocalcinosis * CPPD (Psudogout) * Gout Seronegative * Reactive arthritis * Psoriatic arthritis * Ankylosing spondylitis Other * Juvenile idiopathic arthritis * Rheumatoid arthritis * Felty's syndrome * Palindromic rheumatism * Adult-onset Still's disease Noninflammatory * Hemarthrosis * Osteoarthritis * Heberden's node * Bouchard's nodes * Osteophyte * v * t * e 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	Arthrogryposis	c1859721	6,590	wikipedia	https://en.wikipedia.org/wiki/Arthrogryposis	2021-01-18T18:36:00	{"gard": ["790"], "mesh": ["C536614"], "umls": ["C1859721"], "icd-9": ["754.89", "728.3"], "orphanet": ["1143"], "wikidata": ["Q708165"]}
## Clinical Features Weisdorf and Krivit (1982) and McKinley et al. (1987) described a syndrome of massive splenomegaly with reduced circulating T helper cells and splenic germinal center hypoplasia. The first patient of McKinley et al. (1987) was a 33-year-old male in whom splenomegaly was detected at birth, after his older brother was noted to have an enlarged spleen during infancy. In general he had been quite well except for 1 episode of pneumonia requiring hospitalization. The spleen was massively enlarged 17 cm below the costal margin. Because he complained of left hypochondrial pain, splenectomy was performed for symptomatic relief. The spleen weighed 1750 g. The blood count returned to normal after the operation, suggesting that the preoperative pancytopenia was due to hypersplenism. The older brother had a spleen that measured 9 cm below the costal margin, and the father of the 2 boys had 8 cm splenomegaly. The spleen and lymph nodes in the proband were shown to have germinal center hypoplasia with T helper cells being present in normal numbers and distribution in these tissues; however, there was a reduction in circulating T helper cells, a reversed T4/T8 ratio and cutaneous anergy. Inheritance \- Autosomal dominant Immunology \- Cutaneous anergy Lab \- Reduced circulating T-helper cells \- Splenic and lymph node germinal center hypoplasia \- Pancytopenia \- Reversed T4/T8 ratio GI \- Splenomegaly Heme \- Hypersplenism ▲ 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	SPLENOMEGALY SYNDROME WITH SPLENIC GERMINAL CENTER HYPOPLASIA AND REDUCED CIRCULATING T HELPER CELLS	c1866744	6,591	omim	https://www.omim.org/entry/183350	2019-09-22T16:34:29	{"mesh": ["C566666"], "omim": ["183350"]}
A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 13 (NPHS13) is caused by homozygous mutation in the NUP205 gene (614352) on chromosome 7q33. One such family has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300). Clinical Features Braun et al. (2016) reported 2 sibs, born of unrelated Turkish parents (family A1733), with early-onset steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FSGS). The patients had onset of renal dysfunction at ages 2 and 3 years, respectively; 1 had end-stage renal disease at age 7 years and underwent renal transplant. The other had aortic abnormalities and showed a partial response to steroid treatment. Inheritance The transmission pattern of NPHS13 in the family reported by Braun et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 Turkish sibs with NPHS13, Braun et al. (2016) identified a homozygous missense mutation in the NUP205 gene (F1995S; 614352.0001). The mutation, which was found by genetic mapping and whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the mutation abrogated the interaction of NUP205 with NUP93 (614351). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	NEPHROTIC SYNDROME, TYPE 13	c1868672	6,592	omim	https://www.omim.org/entry/616893	2019-09-22T15:47:31	{"doid": ["0080381"], "mesh": ["C536404"], "omim": ["616893"], "orphanet": ["656"]}
Histidinemia is an inherited condition characterized by elevated blood levels of the amino acid histidine, a building block of most proteins. Histidinemia is caused by the shortage (deficiency) of the enzyme that breaks down histidine. Histidinemia typically causes no health problems, and most people with elevated histidine levels are unaware that they have this condition. The combination of histidinemia and a medical complication during or soon after birth (such as a temporary lack of oxygen) might increase a person's chances of developing intellectual disability, behavioral problems, or learning disorders. ## Frequency Estimates of the incidence of histidinemia vary widely, ranging between 1 in 8,600 to 1 in 90,000 people. ## Causes Histidinemia is caused by mutations in the HAL gene, which provides instructions for making an enzyme called histidase. Histidase breaks down histidine to a molecule called urocanic acid. Histidase is active (expressed) primarily in the liver and the skin. HAL gene mutations lead to the production of a histidase enzyme that cannot break down histidine, which results in elevated levels of histidine in the blood and urine. These increased levels of histidine do not appear to have any negative effects on the body. ### Learn more about the gene associated with Histidinemia * HAL ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Histidinemia	c0220992	6,593	medlineplus	https://medlineplus.gov/genetics/condition/histidinemia/	2021-01-27T08:25:26	{"gard": ["6661"], "mesh": ["C538320"], "omim": ["235800"], "synonyms": []}
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. (April 2015) (Learn how and when to remove this template message) Propofol infusion syndrome Propofol Propofol infusion syndrome (PRIS) is a rare syndrome which affects patients undergoing long-term treatment with high doses of the anaesthetic and sedative drug propofol. It can lead to cardiac failure, rhabdomyolysis, metabolic acidosis, and kidney failure, and is often fatal.[1][2][3] High blood potassium, high blood triglycerides, and liver enlargement, proposed to be caused by either "a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism"[4] are also key features. It is associated with high doses and long-term use of propofol (> 4 mg/kg/h for more than 24 hours). It occurs more commonly in children, and critically ill patients receiving catecholamines and glucocorticoids are at high risk. Treatment is supportive. Early recognition of the syndrome and discontinuation of the propofol infusion reduces morbidity and mortality. ## Contents * 1 Presentation * 2 Mechanism of Action * 3 Risk Factors * 4 Treatment * 5 References ## Presentation[edit] The syndrome clinically presents as acute refractory bradycardia that leads to asystole, in the presence of one or more of the following conditions; metabolic acidosis, rhabdomyolysis, hyperlipidemia, and enlarged liver. The association between PRIS and propofol infusions is generally noted at infusions higher than 4 mg.kg for greater than 48 hours.[4] ## Mechanism of Action[edit] The mechanism of action is poorly understood but may involve the impairment of mitochondrial fatty acid metabolism by propofol.[4] ## Risk Factors[edit] Predisposing factors seem to include young age, severe critical illness of central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake and subclinical mitochondrial disease.[4] ## Treatment[edit] Treatment options are limited and are usually supportive, including hemodialysis with cardiorespiratory support.[4] ## References[edit] 1. ^ Vasile, Vasile B; Rasulo F; Candiani A; Latronico N. (September 2003). "The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome". Intensive Care Medicine. 29 (9): 1417–25. doi:10.1007/s00134-003-1905-x. PMID 12904852. 2. ^ Zaccheo, Melissa M; Bucher, Donald H. (June 2008). "Propofol Infusion Syndrome: A Rare Complication With Potentially Fatal Results". Critical Care Nurse. 28 (3): 18–25. PMID 18515605. 3. ^ Sharshar, T. (2008). "[ICU-acquired neuromyopathy, delirium and sedation in intensive care unit]". Ann Fr Anesth Reanim. 27 (7–8): 617–22. doi:10.1016/j.annfar.2008.05.010. PMID 18584998. 4. ^ a b c d e Kam, PC; Cardone D. (July 2007). "Propofol infusion syndrome". Anaesthesia. 62 (7): 690–701. doi:10.1111/j.1365-2044.2007.05055.x. PMID 17567345. 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	Propofol infusion syndrome	c1328409	6,594	wikipedia	https://en.wikipedia.org/wiki/Propofol_infusion_syndrome	2021-01-18T19:01:18	{"mesh": ["D000072736"], "umls": ["C1328409"], "wikidata": ["Q7250346"]}
A number sign (#) is used with this entry because of evidence that hereditary motor and sensory neuropathy type VIC with optic atrophy (HMSN6C) is caused by homozygous mutation in the PDXK gene (179020) on chromosome 21q22. Description Hereditary motor and sensory neuropathy type VIC with optic atrophy (HMSN6C) is an autosomal recessive axonal sensorimotor peripheral neuropathy characterized by progressive distal muscle weakness and atrophy primarily affecting the lower limbs. Onset of neuropathy is in the first decade, manifest by difficulty walking and running and followed by similar involvement of the upper limbs and hands. The disorder is associated with distal sensory impairment, particularly of position and vibration sense, as well as areflexia; individuals usually have pes cavus, hammertoes, and atrophy of the intrinsic hand muscles. In addition, progressive optic atrophy and visual impairment occur during adulthood. Treatment with pyridoxal 5-prime phosphate supplementation (vitamin B6) may result in amelioration of symptoms and slow progression of the disease (summary by Chelban et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (601152). Clinical Features Chelban et al. (2019) reported 4 patients from 2 unrelated families with a similar peripheral neuropathy associated with optic atrophy. In family 1, of Cypriot origin, the affected sibs were 80 and 75 years old at the time of the report; a third affected sib had died of other causes at age 71. These patients had presented with difficulty running due to muscle weakness and atrophy in the lower limbs before age 10, with similar upper limb involvement by age 12. They also had onset of progressive visual loss and optic atrophy in their forties. The disorder was progressive: by late-adulthood, the surviving patients had distal wasting from the mid-forearm and below the knee, atrophy of the intrinsic hand muscles, clawing of the hands, and pes cavus. One sib was wheelchair-bound, whereas the other could only walk short distances with assistant. They also had distal sensory impairment, particularly of position and vibration, areflexia, and neurogenic pain. Vision, including color vision, was reduced, and funduscopy confirmed optic atrophy. Two affected sisters from a second family of Scottish/Italian origin, who were 31 and 29 years of age, had childhood onset of progressive weakness of the lower and upper limbs. Features included difficulty running and mild hand weakness. At the time of the report, both were ambulatory and had no visual loss, but color vision was reduced and funduscopy confirmed optic atrophy. Nerve conduction studies in all patients showed a progressive, length-dependent axonal neuropathy with decreased compound muscle action potentials (CMAPs) and absent sensory responses. EMG was consistent with chronic denervation. Sural nerve biopsy of 1 patient from family 1 showed diffuse and severe depletion of both small and large myelinated axons with regenerating clusters and no evidence of demyelination. Clinical Management In 2 patients, one 75 and the other 80 years of age, with long-standing HMSN6C, Chelban et al. (2019) found that oral supplementation with pyridoxal 5-prime phosphate (PLP) resulted in increased plasma levels of PLP and improvement in neurogenic pain, weakness, and fatigue. During the first year of treatment, walking improved significantly and there appeared to be no further disease progression. Treatment was also associated with a decrease in plasma neurofilament light chain (NFL; 162280) protein levels, which reflects axonal damage. Inheritance The transmission pattern of HMSN6C in the families reported by Chelban et al. (2019) was consistent with autosomal recessive inheritance. Molecular Genetics In 4 patients from 2 unrelated families with HMSN6C, Chelban et al. (2019) identified homozygous missense mutations in the PDXK gene (A228T, 179020.0001 and R220Q, 179020.0002), encoding pyridoxal (PL) kinase. The mutations, which were found by a combination of whole-genome or whole-exome sequencing and homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro conformational analysis indicated that the A228T mutation induced changes around the catalytic pocket, hindering the enzyme's ability to bind ATP. Studies of cells derived from patients of both families showed decreased PL kinase activity compared to controls, and patients had decreased plasma PLP levels compared to controls. The findings were consistent with a loss-of-function effect. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Optic atrophy, adult-onset \- Visual impairment, progressive \- Impaired color vision SKELETAL Hands \- Atrophy of the intrinsic hand muscles \- Clawed hands Feet \- Pes cavus \- Hammertoes MUSCLE, SOFT TISSUES \- Distal muscle weakness due to peripheral neuropathy \- Distal muscle atrophy due to peripheral neuropathy \- Lower limbs affected earlier than upper limbs \- Upper limb involvement occurs later \- Neurogenic pattern seen on EMG NEUROLOGIC Peripheral Nervous System \- Impaired walking and running due to peripheral neuropathy \- Axonal sensorimotor peripheral neuropathy \- Impaired distal sensation of all modalities \- Areflexia \- Neurogenic pain \- Reduced compound action motor potentials (CMAP) \- Absent sensory responses seen on electrophysiologic testing MISCELLANEOUS \- Onset of peripheral neuropathy in the first decade \- Onset of optic atrophy in adulthood \- Progressive disorder \- Two unrelated families have been reported (last curated July 2019) \- Treatment with pyridoxal 5-prime phosphate supplementation may result in amelioration of symptoms MOLECULAR BASIS \- Caused by mutation in the pyridoxal kinase gene (PDXK, 179020.0001 ) ▲ 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	NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIC, WITH OPTIC ATROPHY	None	6,595	omim	https://www.omim.org/entry/618511	2019-09-22T15:41:37	{"omim": ["618511"], "synonyms": ["Alternative titles", "HMSN VIC", "CHARCOT-MARIE-TOOTH DISEASE, TYPE 6C"]}
Chorangioma Micrograph of a chorangioma (right of image). H&E stain. SpecialtyGynecology A chorangioma is a non-neoplastic, hamartoma-like growth in the placenta consisting of blood vessels.[1] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Treatment * 4 See also * 5 References * 6 External links ## Signs and symptoms[edit] Most chorangiomas are not clinically significant, i.e. they do not have an adverse effect on placental function. The significance of a chorangioma is determined by its size and whether it is found together with other chorangiomas. Chorangiomas are significant if multiple or "large", i.e. greater than 4 cm[1] or 5 cm.[2] ## Diagnosis[edit] Large chorangiomas are diagnosed by ultrasound or MRI,[1] and confirmed by histologic examination of the placenta. Histologically, chorangioma consist of abundant vascular channels and may be cellular. * Micrograph of a chorangioma (right of image) and normal placenta (left of image). H&E stain. ## Treatment[edit] Small chorangiomas are not treated. Large chorangioma can be treated several ways, including chemical ablation and laser coagulation.[1] ## See also[edit] * Hemangioma * Chorangiosis ## References[edit] 1. ^ a b c d Amer HZ, Heller DS (2010). "Chorangioma and related vascular lesions of the placenta--a review". Fetal Pediatr Pathol. 29 (4): 199–206. doi:10.3109/15513815.2010.487009. PMID 20594143. 2. ^ Lež C, Fures R, Hrgovic Z, Belina S, Fajdic J, Münstedt K (2010). "Chorangioma placentae". Rare Tumors. 2 (4): e67. doi:10.4081/rt.2010.e67. PMC 3019602. PMID 21234259. ## External links[edit] Classification D * MeSH: D006391 * Chorangioma (pathweb.uchc.edu) * Chorangioma (humpath.com) * v * t * e Tumors of the female urogenital system Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: * Ovarian serous cystadenoma * Mucinous cystadenoma * Cystadenocarcinoma * Papillary serous cystadenocarcinoma * Krukenberg tumor * Endometrioid tumor * Clear-cell ovarian carcinoma * Brenner tumour Sex cord–gonadal stromal * Leydig cell tumour * Sertoli cell tumour * Sertoli–Leydig cell tumour * Thecoma * Granulosa cell tumour * Luteoma * Sex cord tumour with annular tubules Germ cell * Dysgerminoma * Nongerminomatous * Embryonal carcinoma * Endodermal sinus tumor * Gonadoblastoma * Teratoma/Struma ovarii * Choriocarcinoma Fibroma * Meigs' syndrome Fallopian tube * Adenomatoid tumor Uterus Myometrium * Uterine fibroids/leiomyoma * Leiomyosarcoma * Adenomyoma Endometrium * Endometrioid tumor * Uterine papillary serous carcinoma * Endometrial intraepithelial neoplasia * Uterine clear-cell carcinoma Cervix * Cervical intraepithelial neoplasia * Clear-cell carcinoma * SCC * Glassy cell carcinoma * Villoglandular adenocarcinoma Placenta * Choriocarcinoma * Gestational trophoblastic disease General * Uterine sarcoma * Mixed Müllerian tumor Vagina * Squamous-cell carcinoma of the vagina * Botryoid rhabdomyosarcoma * Clear-cell adenocarcinoma of the vagina * Vaginal intraepithelial neoplasia * Vaginal cysts Vulva * SCC * Melanoma * Papillary hidradenoma * Extramammary Paget's disease * Vulvar intraepithelial neoplasia * Bartholin gland carcinoma * v * t * e Tumours of blood vessels Blood vessel * Hemangiosarcoma * Blue rubber bleb nevus syndrome * Hemangioendothelioma * Composite * Endovascular papillary * Epithelioid * Kaposiform * Infantile * Retiform) * Spindle cell * Proliferating angioendotheliomatosis * Hemangiopericytoma * Venous lake * Kaposi's sarcoma * African cutaneous * African lymphadenopathic * AIDS-associated * Classic * Immunosuppression-associated * Hemangioblastoma * Hemangioma * Capillary * Cavernous * Glomeruloid * Microvenular * Targeted hemosiderotic * Angioma * Cherry * Seriginosum * Spider * Tufted * Universal angiomatosis * Angiokeratoma * of Mibelli * Angiolipoma * Pyogenic granuloma Lymphatic * Lymphangioma/lymphangiosarcoma * Lymphangioma circumscriptum * Acquired progressive lymphangioma * PEComa * Lymphangioleiomyomatosis * Cystic hygroma * Multifocal lymphangioendotheliomatosis * Lymphangiomatosis Either * Angioma/angiosarcoma * Angiofibroma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Chorangioma	c0677608	6,596	wikipedia	https://en.wikipedia.org/wiki/Chorangioma	2021-01-18T18:31:42	{"mesh": ["D006391"], "umls": ["C0677608"], "wikidata": ["Q5104959"]}
A group of rare immunodeficiency-associated lymphoproliferative disorders characterized by lymphoid or plasmacytic proliferations developing in the context of immunosuppression in a recipient of a solid organ or stem cell allograft. The group includes non-destructive post-transplant lymphoproliferative disorders (PTLDs), polymorphic PTLD, monomorphic PTLDs, and classic Hodgkin lymphoma PTLD. Patients may have more than one type of PTLD in a single or in different locations. The most commonly involved sites are lymph nodes, gastrointestinal tract, lungs, and liver, although the disease may occur almost anywhere in the body. In solid organ transplant recipients, PTLD may also involve the allograft. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Post-transplant lymphoproliferative disease	c0432487	6,597	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=70568	2021-01-23T17:02:24	{"gard": ["9553"], "umls": ["C0432487"], "icd-10": ["D47.9"], "synonyms": ["PTLD"]}
A number sign (#) is used with this entry because it represents a phenotype that may be related to variation in the mitochondrial genome. Lin et al. (1992) concluded that a specific mtDNA point mutation was associated with Alzheimer disease in 10 of 19 patients studied. Two types of mutations were found, both at mtDNA position 5460 in codon 331 of ND2 (subunit 2 of NADH dehydrogenase-ubiquinone oxidoreductase, or complex I of the respiratory chain; 516001): a G-to-A transition converting ala (GCC) to thr (ACC) in 3 AD patients, and a G-to-T transversion converting ala (GCC) to ser (TCC) in 5 other AD patients; both mutations coexisted in yet 2 other AD patients. The mutation was heteroplasmic in 2 of the 3 patients in the first group and in 4 of the 5 patients in the second group; no wildtype mtDNA was found in the last 2 patients. No mutations were detected in 11 normal brains studied, but the G-to-A mutation was found in homoplasmic state in 2 of 6 patients with amyotrophic lateral sclerosis. Petruzzella et al. (1992) found none of the above nucleotide changes in 14 sporadic AD patients, 1 familial AD patient, and 5 controls. In a second survey, Shoffner et al. (1993) reported that the G-to-A variant was present in 4.4% (3 of 68) of patients with Alzheimer disease and Parkinson disease but in 8.6% (3 of 35) of Caucasian controls. The G-to-T mutation was not detected in 67 patients and 41 controls. This led them to conclude that the G to A substitution at the first position of codon 331 of the ND2 gene may be a polymorphism not related to Alzheimer disease. Shoffner et al. (1993) surveyed an additional 71 late-onset Caucasian patients, 33 with AD, 30 with AD and PD, and 8 with PD for novel restriction fragment length polymorphisms (RFLPs) that correlated with the diseases. Interesting RFLPs were then tested against a panel of patient and control samples. An mtRNA(Gln) gene (590030) variant of position 4336, which altered a moderately conserved nucleotide, was present in 5.2% (9 of 173) of patients but in only 0.7% (12 of 1,691) of Caucasian controls. A second variant in ND1 (516000) at position 3397 converted a highly conserved methionine to valine. This was found in 2.7% (2 of 73) of AD and PD families, 0% (0 of 248) in Caucasian controls, and 0.7% (7 of 1,051) in global controls. A 5 nucleotide insertion in the 12S rRNA gene at position 956-965 was found in 1 patient and an heteroplasmic base substitution at np 3196 in the 16S rRNA gene was found in another. The tRNA(Gln) np 4336 mutation defined an mtDNA lineage prone to AD and PD and 1 of the np 3397 families as well as the 12S rRNA insertion mutation individual were also included in this lineage. These observations support the hypothesis that the np 4336, 3397, and 12S rRNA insertion mutations may be risk factors for AD and PD. Hutchin and Cortopassi (1995) pursued the suggestion that the 4336 mutation leads to increased risk of AD by using a case-control study design of 72 AD autopsies and 296 race- and age-matched controls. The 4336G mutation occurred at higher frequency in AD autopsies than age-matched controls, a statistically significant difference. Evolutionary analysis of mtDNAs bearing the 4336G mutation indicated that they were more closely related to each other than to other mtDNAs, consistent with the model of a single origin for this mutation. The tight evolutionary relatedness and homoplasmy of mtDNAs that confer elevated risk for a late-onset disease contrasts strikingly with the distant relatedness and heteroplasmy of mitochondrial genomes that cause early-onset disease. The dichotomy can be explained by a lack of selection against mutations that confer a phenotype at advanced age during most of the evolution of humans. Hutchin and Cortopassi (1995) estimated that approximately 1.5 million Caucasians in the United States bear the 4336 gene mutation and are at significantly increased risk of developing mitochondrial AD in their lifetime. In a note added in proof, they indicated that further studies showed that the 4336G mutation is not evenly distributed throughout the Caucasian AD population, with only 2 instances in 122 cases being found in the National Neurological Research Specimen Bank and the Boston Brain Bank. Tysoe et al. (1996) followed up on the suggestion that the 4336 mutation in the tRNA(Gln) gene is a risk factor for AD. They investigated the frequency of this mutation in 2 community-based elderly cohorts in Cambridgeshire who had participated in longitudinal studies of cognitive function. The 4336 mitochondrial mutation was detected in 8 of 443 people examined. These people were found to be nondemented at ages 74, 81, 84, 86, 89, 90, 91, and 102 years, in contrast to the previously described cases whose onset of dementia occurred between 60 and 76 years (mean = 68). Accordingly, Tysoe et al. (1996) concluded that this mitochondrial variant is not a high penetrance mutation that predisposes to dementia before the age of 76 years. Davis et al. (1997) found that specific missense mutations in MTCO1 (516030) and MTCO2 (516040) but not in MTCO3 (516050) appeared to be associated with late-onset Alzheimer disease. However, Hirano et al. (1997) provided evidence that the DNA isolation method employed by Davis et al. (1997) resulted in the coamplification of authentic mtDNA-encoded COX genes together with highly similar COX-like sequences embedded in nuclear DNA (mtDNA pseudogenes). Hirano et al. (1997) concluded that the heteroplasmy observed by Davis et al. (1997) was an artifact. To test the hypothesis that nucleus-localized mtDNA pseudogenes might explain the findings of Davis et al. (1997), Wallace et al. (1997) used the PCR primers utilized in the Davis report to amplify CO1 and CO2 sequences from 2 independent mtDNA-less cell lines. CO1 and CO2 sequences were amplified from both cell lines, demonstrating that these sequences are present in human nuclear DNA. The nuclear pseudogene CO1 and CO2 sequences were then tested for each of the 5 'Alzheimer disease' mutations described by Davis et al. (1997), using restriction endonuclease site variant assays. All 5 mutations were found in the nuclear CO1 and CO2 PCR products from mtDNA-less cells, but none was found in the PCR products obtained from cells with normal mtDNA. Unlike the findings in the report by Davis et al. (1997), Wallace et al. (1997) found an additional 32 single-base substitutions, including 2 in adjacent tRNAs and a 2-bp deletion in the CO2 gene. Phylogenetic analysis of the nuclear CO1 and CO2 sequences revealed that they diverged from modern human mtDNAs early in hominid evolution about 770,000 years before the present. These data would be consistent with the interpretation that the missense mutation proposed to cause AD may be the product of ancient mtDNA variants preserved as nuclear pseudogenes. As pointed out by Wallace et al. (1997), nuclear copies of mtDNA sequences appear to be a common phenomenon, having been documented in sea urchin, birds, rodents, and nonhuman primates. Indeed, this transfer over evolutionary time undoubtedly accounts for the current nuclear location of most of the genes that encode mitochondrion-specific polypeptides, including most of those required for oxidative phosphorylation and mitochondrial biogenesis. This genetic transfer is a continuing process, as shown by the recent integration of mtDNA CO3 gene sequences into one of the 2 nuclear c-MYC gene alleles in HeLa cells (Shay et al., 1991). By using mtDNA-depleted NT2 cells, Davis and Parker (1998) came to the conclusion that the presumed mitochondrial DNA mutations identified by Davis et al. (1997) in Alzheimer disease subjects were the consequence of confusion with nuclear DNA pseudogenes. Davis et al. (1997) later retracted their conclusions. In their retraction, they stated that the presence of the nuclear pseudomitochondrial DNA was an unlikely cause of the CO defects in cells or in humans. However, they believed that the elevation of the ratio of the pseudogene to authentic mtDNA in the blood of AD patients was a true finding, possibly reflecting decreased mtDNA content in AD blood relative to control blood. Misc \- Late onset. Neuro \- Presenile and senile dementia. Parkinsonism. Long tract signs. Lab \- Neurofibrillary tangles composed of disordered microtubules in neurons. Inheritance \- ? Mitochondrial form \- multiple autosomal dominant forms. ▲ 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	ALZHEIMER DISEASE, SUSCEPTIBILITY TO, MITOCHONDRIAL	c1838990	6,598	omim	https://www.omim.org/entry/502500	2019-09-22T16:16:49	{"omim": ["502500"]}
See also: Musculoskeletal injury Musculoskeletal disorders Carpal tunnel syndrome is a common musculoskeletal disorder, and is often treated with a splint. SpecialtyRheumatology Musculoskeletal disorders (MSDs) are injuries or pain in the human musculoskeletal system, including the joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck and back.[1] MSDs can arise from a sudden exertion (e.g., lifting a heavy object),[2] or they can arise from making the same motions repeatedly repetitive strain, or from repeated exposure to force, vibration, or awkward posture.[3] Injuries and pain in the musculoskeletal system caused by acute traumatic events like a car accident or fall are not considered musculoskeletal disorders.[4] MSDs can affect many different parts of the body including upper and lower back, neck, shoulders and extremities (arms, legs, feet, and hands).[5] Examples of MSDs include carpal tunnel syndrome, epicondylitis, tendinitis, back pain, tension neck syndrome, and hand-arm vibration syndrome.[3] ## Contents * 1 Causes * 1.1 Biomechanical * 1.2 Individual differences * 1.3 Psychosocial * 1.4 Occupational * 2 Diagnosis * 3 Prevention * 3.1 Workplace controls * 3.2 Ergonomics * 4 Epidemiology * 4.1 General population * 4.2 Workplace * 5 See also * 6 References * 7 External links ## Causes[edit] MSDs can arise from the interaction of physical factors with ergonomic, psychological, social, and occupational factors.[6] ### Biomechanical[edit] MSDs are caused by biomechanical load which is the force that must be applied to do tasks, the duration of the force applied, and the frequency with which tasks are performed.[7] Activities involving heavy loads can result in acute injury, but most occupation-related MSDs are from motions that are repetitive, or from maintaining a static position.[8] Even activities that do not require a lot of force can result in muscle damage if the activity is repeated often enough at short intervals.[8] MSD risk factors involve doing tasks with heavy force, repetition, or maintaining a nonneutral posture.[8] Of particular concern is the combination of heavy load with repetition.[8] Although poor posture is often blamed for lower back pain, a systematic review of the literature failed to find a consistent connection.[9] ### Individual differences[edit] People vary in their tendency to get MSDs. Gender is a factor, with women having a higher incidence of MSDs than men.[8] Obesity is also a factor, with overweight individuals having a higher risk of some MSDs, specifically of the lower back.[10] ### Psychosocial[edit] There is a growing consensus that psychosocial factors are another cause of some MSDs.[11] Some theories for this causal relationship found by many researchers include increased muscle tension, increased blood and fluid pressure, reduction of growth functions, pain sensitivity reduction, pupil dilation, body remaining at heightened state of sensitivity. Although there is no consensus at this time,[12] some of the workplace stressors found to be associated with MSDs in the workplace include high job demands, low social support, and overall job strain.[11][13][14] Researchers have consistently identified causal relationships between job dissatisfaction and MSDs. For example, improving job satisfaction can reduce 17-69 per cent of work-related back disorders and improving job control can reduce 37-84 per cent of work-related wrist disorders.[15] ### Occupational[edit] Because workers maintain the same posture over long work days and often several years, even natural postures like standing can lead to MSDs like low back pain. Postures which are less natural, such as twisting of or tension in the upper body, are typically contributors to the development of MSDs due to the unnatural biomechanical load of these postures.[3][16] There is evidence that posture contributes to MSDs of the neck, shoulder, and back.[3] Repeated motion is another risk factor for MSDs of occupational origin because workers can perform the same movements repeatedly over long periods of time (e.g. typing leading to carpal tunnel syndrome, lifting heavy objects leading to herniated discs/slipped discs), which can wear on the joints and muscles involved in the motion in question.[3] [17] Workers doing repetitive motions at a high pace of work with little recovery time and workers with little to no control over the timing of motions (e.g. workers on assembly lines) are also prone to MSDs due to the motion of their work.[16] Force needed to perform actions on the job can also be associated with higher MSD risk in workers, because movements which require more force can fatigue muscles quicker which can lead to injury and/or pain.[3] Additionally, exposure to vibration (experienced by truck drivers or construction workers, for example) and extreme hot or cold temperatures can affect a worker's ability to judge force and strength, which can lead to development of MSDs.[16] Vibration exposure is also associated with hand-arm vibration syndrome, which has symptoms of lack of blood circulation to the fingers, nerve compression, tingling, and/or numbness.[18] ## Diagnosis[edit] Assessment of MSDs is based on self-reports of symptoms and pain as well as physical examination by a doctor.[3] Doctors rely on medical history, recreational and occupational hazards, intensity of pain, a physical exam to locate the source of the pain, and sometimes lab tests, X-rays, or an MRI[19] Doctors look for specific criteria to diagnose each different musculoskeletal disorder, based on location, type, and intensity of pain, as well as what kind of restricted or painful movement a patient is experiencing.[3] A popular measure of MSDs is the Nordic Questionnaire that has a picture of the body with various areas labeled and asks the individual to indicate in which areas they have experienced pain, and in which areas has the pain interfered with normal activity.[5] ## Prevention[edit] Prevention of MSDs relies upon identification of risk factors, either by self-report, observation on the job, or measurement of posture which could lead to MSDs.[20] Once risk factors have been determined, there are several intervention methods which could be used to prevent the development of MSDs. The target of MSD prevention efforts is often the workplace in order to identify incidence rates of both disorders and exposure to unsafe conditions.[21] ### Workplace controls[edit] Groups who are at particular risk can be identified, and modifications to the physical and psychosocial environment can be made.[21] Approaches to prevention in workplace settings include matching the person's physical abilities to the tasks, increasing the person's capabilities, changing how tasks are performed, or changing the tasks.[22] Employers can also utilize engineering controls and administrative controls to prevent injury happening on the job.[4] Implementation of engineering controls is the process of designing or redesigning the workplace to account for strengths, weaknesses, and needs of the working population- examples would be workstation layout changes to be more efficient or reducing bending over, or moving necessary tools within shorter reach of the worker's station.[4] Employers may also utilize administrative controls like reducing number of hours in a certain position, limiting overtime, or including more breaks during shifts in order to reduce amount of time at risk for each worker.[4] ### Ergonomics[edit] Encouraging the use of proper ergonomics not only includes matching the physical ability of the worker with the correct job, but it deals with designing equipment that is correct for the task.[23] Limiting heavy lifting, training, and reporting early signs of injury are examples that can prevent MSD.[24] Employers can provide support for employees in order to prevent MSD in the workplace by involving the employees in planning, assessing, and developing standards of procedures that will support proper ergonomics and prevent injury.[24] One focus of ergonomic principles is maintaining neutral postures, which are postures in which muscles are at their normal length and able to generate the most force, while reducing stress and possible injury to muscles, tendons, nerves, and bones- therefore, in the workplace or in everyday life, it is ideal for muscles and joints to maintain neutral positions.[25] Additionally, to prevent hand, wrist, and finger injuries, understanding when to use pinch grips (best for fine motor control and precise movements with low force) and power grips (best for high-force movements done repeatedly) is important for employees and general tasks outside the workplace.[25] The choice of tools should match that of the proper grip and be conducive to neutral postures, which is important for employers to consider when purchasing equipment.[25] In order to reduce injuries to the low back and spine, it is recommended to reduce weight and frequency of lifting cycles as well as decreasing the distance between the body and the load to reduce the torque force on the back for workers and individuals doing repeated lifting to avoid fatigue failure of the spine.[25] The shape of objects being lifted should also be considered, especially by employers, because objects which are easier to grip, lift, and access present less stress on the spine and back muscles than objects which are awkwardly shaped and difficult to access.[25] The National Institute of Occupational Safety and Health (NIOSH) has published ergonomic recommendations for several industries, including construction, mining, agriculture, healthcare, and retail, among others.[26] ## Epidemiology[edit] Deaths from musculoskeletal diseases per million persons in 2012 0-7 8-11 12-15 16-20 21-24 25-30 31-36 37-46 47-54 55-104 ### General population[edit] MSDs are an increasing healthcare issue globally, being the second leading cause of disability.[8] For example, in the U.S. there were more than 16 million strains and sprains treated in 2004, and the total cost for treating MSDs is estimated to be more than $125 billion per year.[27] In 2006 approximately 14.3% of the Canadian population was living with a disability, with nearly half due to MSDs.[28] Neck pain is one of the most common complaints, with about one fifth of adults worldwide reporting pain annually.[29] ### Workplace[edit] Most workplace MSD episodes involve multiple parts of the body.[30] MSDs are the most frequent health complaint by European, United States and Asian Pacific workers.[31] and the third leading reason for disability and early retirement in the U.S.[13] The incidence rate for MSDs among the working population in 2014 was 31.9 newly diagnosed MSDs per 10,000 full-time workers.[32] In 2014, the median days away from work due to MSDs was 13, and there were 10.4 cases per 10,000 full-time workers in which an MSD caused a worker to be away from work for 31 or more days.[32] MSDs are widespread in many occupations, including those with heavy biomechanical load like construction and factory work, and those with lighter loads like office work.[13] The transportation and warehousing industries have the highest incidence rate of musculoskeletal disorders, with an incidence rate of 89.9 cases per 10,000 full-time workers.[32] Healthcare, manufacturing, agriculture, wholesale trade, retail, and recreation industries all have incidence rates above 35 per 10,000 full-time workers.[32] For example, a national survey of U.S. nurses found that 38% reported an MSD in the prior year, mainly lower back injury.[33] The neck and back are the most common sites of MSDs in workers, followed by the upper limbs and lower limbs.[32] The Bureau of Labor Statistics reports that 31.8 new cases of MSDs per 10,000 full-time workers per year are due to overexertion, bodily reaction, or repetitive motions.[32] In 2013, members of the United States Army Medical Command Band (now the 323rd Army Band) were the center of a study which concluded that musicians have a high rate of MSDs and that it exceeds percentages in the general population.[34] ## See also[edit] * Carpal Tunnel * Human factors and ergonomics * Human musculoskeletal system * Low back pain * Sprain * Repetitive strain injury * Ischemia-repurfusion injuries of the appendicular musculoskeletal system ## References[edit] 1. ^ "CDC - NIOSH Program Portfolio : Musculoskeletal Disorders : Program Description". www.cdc.gov. Retrieved 2016-03-24. 2. ^ Kumaraveloo, K Sakthiaseelan; Lunner Kolstrup, Christina (2018-07-03). "Agriculture and musculoskeletal disorders in low- and middle-income countries". Journal of Agromedicine. 23 (3): 227–248. doi:10.1080/1059924x.2018.1458671. ISSN 1059-924X. PMID 30047854. 3. ^ a b c d e f g h "CDC - NIOSH Publications and Products - Musculoskeletal Disorders and Workplace Factors (97-141)". www.cdc.gov. 1997. doi:10.26616/NIOSHPUB97141. hdl:2027/coo.31924078629387. Retrieved 2016-03-24. 4. ^ a b c d Prevention, Centers for Disease Control and. "CDC - Workplace Health - Implementation - Work-Related Musculoskeletal Disorders (WMSD) Prevention". www.cdc.gov. Retrieved 2016-03-24. 5. ^ a b Kuorinka, I.; Jonsson, B.; Kilbom, A.; Vinterberg, H.; Biering-Sørensen, F.; Andersson, G.; Jørgensen, K. (1987). "Standardised Nordic questionnaires for the analysis of musculoskeletal symptoms". Applied Ergonomics. 18 (3): 233–7. doi:10.1016/0003-6870(87)90010-x. PMID 15676628. 6. ^ Gatchel, R. J., & Kishino, N. (2011). Pain, musculoskeletal injuries, and return to work. In J. C. Quick & L. E. Tetrick (Eds.), Handbook of occupational health psychology (2nd ed.). Washington, DC: American Psychological Association. 7. ^ Barriera-Viruet H.; Sobeih T. M.; Daraiseh N.; Salem S. (2006). "Questionnaires vs observational and direct measurements: A systematic review". Theoretical Issues in Ergonomics Science. 7 (3): 261–284. doi:10.1080/14639220500090661. 8. ^ a b c d e f Barbe, Mary F; Gallagher, Sean; Massicotte, Vicky S; Tytell, Michael; Popoff, Steven N; Barr-Gillespie, Ann E (2013). "The interaction of force and repetition on musculoskeletal and neural tissue responses and sensorimotor behavior in a rat model of work-related musculoskeletal disorders". BMC Musculoskeletal Disorders. 14: 303. doi:10.1186/1471-2474-14-303. PMC 3924406. PMID 24156755. 9. ^ Roffey DM, Wai EK, Bishop P, Kwon BK, Dagenais S (January 2010). "Causal assessment of awkward occupational postures and low back pain: results of a systematic review". The Spine Journal. 10 (1): 89–99. doi:10.1016/j.spinee.2009.09.003. PMID 19910263. 10. ^ Kerr MS, Frank JW, Shannon HS, Norman RW, Wells RP, Neumann WP, Bombardier C (July 2001). "Biomechanical and psychosocial risk factors for low back pain at work". American Journal of Public Health. 91 (7): 1069–75. doi:10.2105/AJPH.91.7.1069. PMC 1446725. PMID 11441733. 11. ^ a b Safety, Government of Canada, Canadian Centre for Occupational Health and. "Musculoskeletal Disorders - Psychosocial Factors : OSH Answers". www.ccohs.ca. Retrieved 2016-04-07. 12. ^ Courvoisier DS, Genevay S, Cedraschi C, Bessire N, Griesser-Delacretaz AC, Monnin D, Perneger TV (July 2011). "Job strain, work characteristics and back pain: a study in a university hospital". European Journal of Pain. 15 (6): 634–40. doi:10.1016/j.ejpain.2010.11.012. PMID 21186129. 13. ^ a b c Sprigg C. A.; Stride C. B.; Wall T. D.; Holman D. J.; Smith P. R. (2007). "Work characteristics, musculoskeletal disorders, and the mediating role of psychological strain: A study of call center employees". Journal of Applied Psychology. 92 (5): 1456–1466. doi:10.1037/0021-9010.92.5.1456. PMID 17845098. 14. ^ Hauke A.; Flintrop J.; Brun E.; Rugulies R. (2011). "The impact of work-related psychosocial stressors on the onset of musculoskeletal disorders in specific body regions: A review and meta-analysis of 54 longitudinal studies". Work & Stress. 25 (3): 243–256. doi:10.1080/02678373.2011.614069. 15. ^ Punnett (2004). "Work-related Musculoskeletal Disorders: The Epidemiologic Evidence and the Debate". Journal of Electromyography and Kinesiology. 14 (1): 13–23. doi:10.1016/j.jelekin.2003.09.015. PMID 14759746. 16. ^ a b c Safety, Government of Canada, Canadian Centre for Occupational Health and. "Work-related Musculoskeletal Disorders (WMSDs) - Risk Factors : OSH Answers". www.ccohs.ca. Retrieved 2016-03-25. 17. ^ "Herniated Disc and Social Security Disability"". CitizensDisability.com. Retrieved 9 October 2019. 18. ^ "CDC - NIOSH Publications and Products - Criteria for a Recommended Standard: Occupational Exposure to Hand-Arm Vibration (89-106)". www.cdc.gov. 1989. doi:10.26616/NIOSHPUB89106. Retrieved 2016-03-25. 19. ^ "Musculoskeletal Pain: Tendonitis, Myalgia & More \| Cleveland Clinic". my.clevelandclinic.org. Retrieved 2016-03-24. 20. ^ NIOSH [2014]. Observation-based posture assessment: review of current practice and recommendations for improvement. By Lowe BD, Weir PL, Andrews DM. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2014–131. 21. ^ a b Côté, Julie N.; Ngomo, Suzy; Stock, Susan; Messing, Karen; Vézina, Nicole; Antle, David; Delisle, Alain; Bellemare, Marie; Laberge, Marie; St-Vincent, Marie (2013). "Quebec Research on Work-related Musculoskeletal Disorders". Relations Industrielles. 68 (4): 643. doi:10.7202/1023009ar. 22. ^ Rostykus W.; Ip W.; Mallon J. (2013). "Musculoskeletal disorders". Professional Safety. 58 (12): 35–42. 23. ^ "Hospital eTool: Healthcare Wide Hazards - Ergonomics". www.osha.gov. Retrieved 2016-04-07. 24. ^ a b "Safety and Health Topics \| Ergonomics". www.osha.gov. Retrieved 2016-04-07. 25. ^ a b c d e Moore, S.M., Torma-Krajewski, J., & Steiner, L.J. (2011). Practical Demonstrations of Ergonomic Principles. Report of Investigations 9684. NIOSH. Retrieved 24 March 2016. 26. ^ "CDC - Ergonomics and Musculoskeletal Disorders - NIOSH Workplace Safety and Health Topic". www.cdc.gov. Retrieved 2016-03-25. 27. ^ Gallagher, Sean; Heberger, John R. (2013-02-01). "Examining the Interaction of Force and Repetition on Musculoskeletal Disorder Risk A Systematic Literature Review". Human Factors: The Journal of the Human Factors and Ergonomics Society. 55 (1): 108–124. doi:10.1177/0018720812449648. ISSN 0018-7208. PMC 4495348. PMID 23516797. 28. ^ Goodridge, Donna; Lawson, Josh; Marciniuk, Darcy; Rennie, Donna (2011-09-20). "A population-based profile of adult Canadians living with participation and activity limitations". Canadian Medical Association Journal. 183 (13): E1017–E1024. doi:10.1503/cmaj.110153. ISSN 0820-3946. PMC 3176864. PMID 21825051. 29. ^ McLean SM, May S, Klaber-Moffett J, Sharp DM, Gardiner E (July 2010). "Risk factors for the onset of non-specific neck pain: a systematic review". Journal of Epidemiology and Community Health. 64 (7): 565–72. doi:10.1136/jech.2009.090720. PMID 20466711. 30. ^ Haukkal, Eija; Leino-Arjasl, Päivi; Ojajärvil, Anneli; Takalal, Esa-Pekka; Viikari-Juntural, Eira; Riihimäkil, Hilkka (2011). "Mental stress and psychosocial factors at work in relation to multiple-site musculoskeletal pain: A longitudinal study of kitchen workers". European Journal of Pain. 15 (4): 432–8. doi:10.1016/j.ejpain.2010.09.005. PMID 20932789. 31. ^ Hauke, Angelika; Flintrop, Julia; Brun, Emmanuelle; Rugulies, Reiner (July 1, 2011). "The impact of work-related psychosocial stressors on the onset of musculoskeletal disorders in specific body regions: A review and meta-analysis of 54 longitudinal studies". Work & Stress. 25 (3): 243–256. doi:10.1080/02678373.2011.614069. ISSN 0267-8373. 32. ^ a b c d e f "Occupational Injuries/Illnesses and Fatal Injuries Profiles". Bureau of Labor Statistics. United States Department of Labor. 2014. Retrieved 25 March 2016. 33. ^ American Nurses Association. (2001). Nursingworld organizational health & safety survey. Silver Spring, MD. 34. ^ https://www.ncbi.nlm.nih.gov/m/pubmed/24337029/ ## External links[edit] Classification D * MeSH: D009140 * SNOMED CT: 928000 * Musculoskeletal disorders Single Entry Point European Agency for Safety and Health at Work (OSHA) * Good Practices to prevent Musculoskeletal disorders European Agency for Safety and Health at Work (OSHA) * Musculoskeletal disorders homepage Health and Safety Executive (HSE) * Hazards and risks associated with manual handling of loads in the workplace European Agency for Safety and Health at Work (OSHA) * National Institute for Occupational Safety and Health Musculoskeletal Health Program [1] * v * t * e Diseases of joints General * Arthritis * Monoarthritis * Oligoarthritis * Polyarthritis Symptoms * Joint pain * Joint stiffness Inflammatory Infectious * Septic arthritis * Tuberculosis arthritis Crystal * Chondrocalcinosis * CPPD (Psudogout) * Gout Seronegative * Reactive arthritis * Psoriatic arthritis * Ankylosing spondylitis Other * Juvenile idiopathic arthritis * Rheumatoid arthritis * Felty's syndrome * Palindromic rheumatism * Adult-onset Still's disease Noninflammatory * Hemarthrosis * Osteoarthritis * Heberden's node * Bouchard's nodes * Osteophyte [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Musculoskeletal disorder	c0026857	6,599	wikipedia	https://en.wikipedia.org/wiki/Musculoskeletal_disorder	2021-01-18T18:48:48	{"mesh": ["D009140"], "umls": ["C0026857"], "wikidata": ["Q4116663"]}

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