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Pseudoepitheliomatous keratotic and micaceous balanitis SpecialtyDermatology Pseudoepitheliomatous keratotic and micaceous balanitis is a cutaneous condition characterized by skin lesions on the glans penis that are wart-like with scaling.[1]:657 It can present as a cutaneous horn.[2] ## See also[edit] * Balanitis * Balanitis plasmacellularis * Skin lesion ## 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. ^ Pai VV, Hanumanthayya K, Naveen KN, Rao R, Dinesh U (2010). "Pseudoepitheliomatous, keratotic, and micaceous balanitis presenting as cutaneous horn in an adult male". Indian J Dermatol Venereol Leprol. 76 (5): 547–9. doi:10.4103/0378-6323.69087. PMID 20826996. * v * t * e Male diseases of the pelvis and genitals Internal Testicular * Orchitis * Hydrocele testis * Testicular cancer * Testicular torsion * Male infertility * Aspermia * Asthenozoospermia * Azoospermia * Hyperspermia * Hypospermia * Oligospermia * Necrospermia * Teratospermia Epididymis * Epididymitis * Spermatocele * Hematocele Prostate * Prostatitis * Acute prostatitis * Chronic bacterial prostatitis * Chronic prostatitis/chronic pelvic pain syndrome * Asymptomatic inflammatory prostatitis * Benign prostatic hyperplasia * Prostate cancer Seminal vesicle * Seminal vesiculitis External Penis * Balanoposthitis / Balanitis * Balanitis plasmacellularis * Pseudoepitheliomatous keratotic and micaceous balanitis * Phimosis * Paraphimosis * Priapism * Sexual dysfunction * Erectile dysfunction * Peyronie's disease * Penile cancer * Penile fracture * Balanitis xerotica obliterans Other * Hematospermia * Retrograde ejaculation * Postorgasmic illness syndrome This Epidermal nevi, neoplasms, cysts article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Pseudoepitheliomatous keratotic and micaceous balanitis	c1274817	6,200	wikipedia	https://en.wikipedia.org/wiki/Pseudoepitheliomatous_keratotic_and_micaceous_balanitis	2021-01-18T18:42:30	{"umls": ["C1274817"], "wikidata": ["Q7254776"]}
Baroreflex failure is a rare disorder that causes fluctuations in blood pressure with episodes of severe hypertension (high blood pressure) and elevated heart rate in response to stress, exercise, and pain. Individuals may also have hypotension (low blood pressure) with normal or reduced heart rate during periods of rest. Symptoms of baroreflex failure may include headache, sweating, and a heart rate that does not respond to medications. The onset of baroreflex failure may be very abrupt or more gradual. In many cases, the cause of baroreflex failure is not known. However, baroreflex failure can result from surgery or radiation treatment for cancers of the neck, injury to the nerves involved in sensing blood pressure, or a degenerative neurologic disease. Treatment usually involves medications to control blood pressure and heart rate along with stress reduction techniques. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Baroreflex failure	None	6,201	gard	https://rarediseases.info.nih.gov/diseases/10664/baroreflex-failure	2021-01-18T18:01:52	{"synonyms": []}
Shell nail syndrome SpecialtyDermatology Shell nail syndrome is characterized by a nail that resembles a clubbed nail, but in which the nail bed is atrophic instead of being bulbous proliferation of the soft tissue, described in association with bronchiectasis.[1]:782 ## See also[edit] * Nail clubbing ## 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 condition of the skin appendages 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	Shell nail syndrome	None	6,202	wikipedia	https://en.wikipedia.org/wiki/Shell_nail_syndrome	2021-01-18T19:03:40	{"wikidata": ["Q7493720"]}
A number sign (#) is used with this entry because of evidence that Adams-Oliver syndrome-5 (AOS5) is caused by heterozygous mutation in the NOTCH1 gene (190198) on chromosome 9q34. Description Adams-Oliver syndrome (AOS) is a rare developmental disorder defined by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations, syndactyly, brachydactyly, or oligodactyly). In addition, vascular anomalies such as cutis marmorata telangiectatica congenita, pulmonary hypertension, portal hypertension, and retinal hypervascularization are recurrently seen. Congenital heart defects have been estimated to be present in 20% of AOS patients; reported malformations include ventricular septal defects, anomalies of the great arteries and their valves, and tetralogy of Fallot (summary by Stittrich et al., 2014). For a discussion of genetic heterogeneity of Adams-Oliver syndrome, see AOS1 (100300). Clinical Features Dallapiccola et al. (1992) observed aplasia cutis congenita and coarctation of the aorta in a mother and son. Both had coarctectomy, at age 14 years and 5 months, respectively. The aortic valve was bicuspid in the son. Vandersteen and Dixon (2011) described a father and 2 daughters from New Zealand with Adams-Oliver syndrome. The proband was a 24-year-old woman with congenital prominent scalp veins, cutis marmorata telangiectatica congenita (CMTC; 219250), and brachydactyly. She had mild motor delay with an in-toeing gait, and radiographs showed bilateral hip dysplasia. Brain MRI at age 7 years showed white matter abnormalities, with multiple high-signal intensities in the periventricular white matter and larger lesions at the gray/white matter junction. At age 24 years, she had short stature, no visible cutaneous vascular malformation of the scalp, and normal hair growth. Her more severely affected sister had cutis aplasia and prominent veins on the scalp, brachydactyly of all digits, and nail aplasia of all toes except the left hallux. She also exhibited extensive generalized CMTC and was diagnosed with pulmonary hypertension; she died of complications of right-sided heart failure at 3.5 years of age. Autopsy showed exudative crusted scalp lesions with a venous hemangiomatous border, right ventricular hypertrophy, dilated right atrium, and tricuspid valve incompetence. The cerebellum showed structural abnormalities with absent inferior medullary velum and tela choroidea. Histologic examination showed hypoplasia of the folia with loss of myelin and cells from Purkinje, granular, and molecular layers. There was also hypoplasia of the dentate nucleus. Lung pathology was consistent with grade 4 pulmonary hypertension. The girls' father had a congenital scalp defect, prominent scalp veins, and CMTC noted at birth. Skull x-ray was reported to show thin bone in the left parietal region. No limb abnormalities were reported, and there was no history of developmental delay or learning difficulties. He developed epilepsy at age 15 years, and insulin-dependent diabetes in his 20s. At age 34, he developed progressive proximal muscle weakness of the upper and lower limb girdles, with no sensory component and normal creatine phosphokinase level. Electromyography suggested a myopathic process, and he died of complications of myopathy at age 44 years. No autopsy was performed. Silva et al. (2012) reported a boy of Portuguese origin who at birth was noted to have extensive cutis aplasia of the scalp, cutis marmorata, bilateral brachydactyly and syndactyly of the toes with hypoplastic nails, and umbilical and right scrotal hernias. Evaluation of a systolic ejection murmur revealed mild pulmonary stenosis. Head CT showed partial agenesis of the wall with exposure of the dura mater and a necrotic area along the sagittal sinus and biparietal areas. MRI at 1.5 months of age showed absence of the middle portion of the parietal bones; however, by 6 years of age, the parietal bones had grown to cover the cranium completely. The patient also developed progressive splenomegaly and at 5 months of age had portal vein obstruction with esophageal varices and hypertensive gastropathy. After thrombosis of a mesenteric-portal shunt, a splenorenal shunt was inserted, which closed spontaneously by 3 years of age. He had an ischemic stroke at placement of the first shunt. He also had spastic diplegia, left frontal lobe epilepsy, hyperactivity and attention deficit disorder, and severe psychomotor retardation. At 11 years of age, he had chronic liver failure with hyperammonemia and coagulopathy, with multiple hospitalizations for decompensated ascites and/or encephalopathy. Silva et al. (2012) suggested that early embryonic vascular disruption might explain the vascular phenomena. Stittrich et al. (2014) restudied the 2 families with AOS reported by Vandersteen and Dixon (2011) and Silva et al. (2012), and described affected individuals from 3 more unrelated families. Patients had aplasia cutis congenita of the scalp, with or without an underlying bony defect, as well as variable transverse distal upper or lower extremity reduction deficits or hypoplasia, including isolated toenail hypoplasia without other findings. One patient exhibited distal vesicles of calcinosis cutis. Intracranial vascular lesions were present in 3 patients. Cardiovascular findings included narrow pulmonary arteries, pulmonary valve stenosis, hypoplastic portal venous tree, distal aortic arch narrowing, mitral annulus hypoplasia, dilated main pulmonary artery, and vascular thromboses. Cutis marmorata was present in 4 of the families. Southgate et al. (2015) studied 17 patients from 11 families with molecularly proven AOS5, including the family originally reported by Dallapiccola et al. (1992). The authors noted that the proportion of AOS probands with congenital heart abnormalities (5 of 11; 45%) was significantly higher than in previous reports of AOS cases (13-20%). Cardiovascular anomalies were identified in 8 (47%) of 17 affected mutation carriers, suggesting that NOTCH1 variants may represent a distinct subtype of AOS associated with cardiac malformations. Many vascular complications, including cutis marmorata telangiectatica congenita and portal vein abnormalities, were also seen in NOTCH1-positive cases. In addition, these patients predominantly exhibited mild terminal transverse limb defects, in contrast to reports of other AOS-associated genes. Molecular Genetics Stittrich et al. (2014) performed whole-exome sequencing in affected individuals from 11 families with Adams-Oliver syndrome who were negative for mutations in known AOS-associated genes. The authors identified heterozygous mutations in the NOTCH1 gene in 5 families, including the 2 families originally reported by Vandersteen and Dixon (2011) and Silva et al. (2012); the mutations included an 85-kb deletion spanning the NOTCH1 5-prime region (190198.0003), a splice site mutation (190198.0004), and 3 missense mutations (C429R, 190198.0005; C1496Y, 190198.0006; D1989N, 190198.0007). The mutations were confirmed to have occurred de novo in 3 probands, and none of the variants was found in more 10,000 control genomes or exomes. By exome sequencing in 12 unrelated AOS probands who were negative for mutation in the ARHGAP31 (610911) and RBPJ (147183) genes, Southgate et al. (2015) identified 2 probands with heterozygous mutations in the NOTCH1 gene: a nonsense mutation (Y550X; 190198.0008) in the proband of a 3-generation family segregating autosomal dominant AOS, and a 2-bp deletion (190198.0009) in the male proband originally reported by Dallapiccola et al. (1992). Southgate et al. (2015) performed mutation screening of NOTCH1 coding regions in 52 additional probands with a clear clinical diagnosis of AOS and identified 9 more patients with heterozygous mutations in NOTCH1. Cardiovascular evaluation of 2 apparently unaffected mutation carriers from 2 of the families did not reveal any cardiac abnormality (see, e.g., 190198.0010), demonstrating incomplete penetrance for mutations in NOTCH1. Noting that NOTCH1 mutations accounted for 17% of cases in their cohort, Southgate et al. (2015) concluded that NOTCH1 is the primary cause of Adams-Oliver syndrome. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Aplasia cutis congenita of the scalp \- Prominent veins of the scalp Neck \- Aplasia cutis congenita (rare) CARDIOVASCULAR Heart \- Tricuspid valve incompetence \- Pulmonary valve stenosis \- Mitral valve hypoplasia \- Multiperforated patent foramen ovale \- Dilated right atrium \- Right ventricular hypertrophy Vascular \- Pulmonary artery hypertension \- Portal vein thrombosis (rare) ABDOMEN External Features \- Umbilical hernia (rare) \- Inguinal hernia (rare) Spleen \- Splenomegaly (rare) \- Hypersplenism (rare) Gastrointestinal \- Esophageal varices (rare) \- Hypertensive gastropathy (rare) SKELETAL Skull \- Absent bone in areas of aplasia cutis congenita Hands \- Brachydactyly Feet \- Brachydactyly \- Syndactyly SKIN, NAILS, & HAIR Skin \- Cutis marmorata telangiectatica congenita \- Strawberry nevi \- Macular hemangioma \- Cavernous hemangioma Nails \- Hypoplastic or absent toenails \- Dystrophic toenails NEUROLOGIC Central Nervous System \- Ischemic infarct of brain \- Sagittal sinus thrombosis \- Cortical venous thromboses \- Structural abnormalities of cerebellum \- Hypoplasia of dentate nucleus \- High signal intensities in periventricular white matter \- High signal intensities at gray/white matter junction \- Seizures (rare) MISCELLANEOUS \- Variable phenotype MOLECULAR BASIS \- Caused by mutation in the notch receptor 1 gene (NOTCH1, 190198.0003 ) ▲ 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	ADAMS-OLIVER SYNDROME 5	c0265268	6,203	omim	https://www.omim.org/entry/616028	2019-09-22T15:50:08	{"doid": ["0060227"], "omim": ["616028"], "orphanet": ["974"], "genereviews": ["NBK355754"]}
Familial dyskinesia and facial myokymia is a rare paroxysmal movement disorder, with childhood or adolescent onset, characterized by paroxysmal choreiform, dystonic, and myoclonic movements involving the limbs (mostly distal upper limbs), neck and/or face, which can progressively increase in both frequency and severity until they become nearly constant. Patients may also present with delayed motor milestones, perioral and periorbital dyskinesias, dysarthria, hypotonia, and weakness. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 dyskinesia and facial myokymia	c1847627	6,204	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324588	2021-01-23T18:55:12	{"gard": ["12722"], "mesh": ["C564676"], "omim": ["606703"], "umls": ["C1847627"], "icd-10": ["G51.4"], "synonyms": ["FDFM"]}
This article relies too much on references to primary sources. Please improve this by adding secondary or tertiary sources. (December 2018) (Learn how and when to remove this template message) H syndrome Other namesHistiocytosis-lymphadenopathy plus syndrome This condition is inherited in an autosomal recessive manner H syndrome, also known as Histiocytosis-lymphadenopathy plus syndrome or PHID,[1] is a rare genetic condition caused by mutations in the SLC29A3 gene which encode the human equilibrative nucleoside transporter (hENT3) protein.[2] It is also known as Faisalabad histocytosis, familial Rosai-Dorfman disease, sinus histocytosis with massive lymphadenopathy and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome. ## Contents * 1 Presentation * 2 Genetics * 3 Pathogenesis * 4 Management * 5 History * 6 References * 7 External links ## Presentation[edit] This syndrome has a number of different clinical features many of which start with the letter 'H' giving rise to the name of the syndrome. These features include * Hyperpigmentation * Hypertrichosis * Hepatosplenomegaly * Hearing loss * Heart anomalies * Hypogonadism * Low height (short stature) * Hyperglycemia/diabetes mellitus * Hallux valgus/flexion contractures Exophthalmos, malabsorption and renal anomalies have also been reported. ## Genetics[edit] The SLC29A3 gene is located on the long arm of chromosome 10 (10q22). The causative gene was identified in 2010.[3] ## Pathogenesis[edit] This is not understood at present. ## Management[edit] There is no curative treatment for this condition at present. Management is directed to the clinical features. ## History[edit] This condition was first described in 1998.[4] ## References[edit] 1. ^ Virginia P. Sybert (2017). Genetic Skin Disorders. Oxford University Press. pp. 182–. ISBN 978-0-19-027648-5. 2. ^ Moynihan L M, Bundey SE, Heath D, Jones EL, McHale DP, Mueller RF, Markham, AF, Lench NJ (1998) Autozygosity mapping, to chromosome 11q25, of a rare autosomal recessive syndrome causing histiocytosis, joint contractures, and sensorineural deafness. Am J Hum Genet 62: 1123-1128 3. ^ Morgan NV, Morris MR, Cangul H, Gleeson D, Straatman-Iwanowska A, Davies N, Keenan S, Pasha S, Rahman F, Gentle D, Vreeswijk MPG, Devilee P, and 10 others. Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. PLoS Genet. 6: e1000833 4. ^ Moynihan L M, Bundey SE, Heath D, Jones EL, McHale DP, Mueller RF, Markham, AF, Lench NJ (1998) Autozygosity mapping, to chromosome 11q25, of a rare autosomal recessive syndrome causing histiocytosis, joint contractures, and sensorineural deafness. Am J Hum Genet 62: 1123-1128 ## External links[edit] Classification D * OMIM: 602782 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	H syndrome	c1864445	6,205	wikipedia	https://en.wikipedia.org/wiki/H_syndrome	2021-01-18T18:51:48	{"gard": ["10239"], "mesh": ["C538322"], "omim": ["602782"], "orphanet": ["168569"], "synonyms": [], "wikidata": ["Q31841284"]}
Multifocal fibrosclerosis Other namesIdiopathic fibrosclerosis Multifocal fibrosclerosis is inherited in an autosomal recessive manner Multifocal fibrosclerosis and idiopathic fibrosclerosis are disorders of unknown aetiology, characterised by fibrous lesions (co-)occurring at a variety of sites. Known manifestations include retroperitoneal fibrosis, mediastinal fibrosis and Riedel's thyroiditis.[1][2] They are now considered to be manifestations of IgG4-related disease.[3] ## References[edit] 1. ^ Brooks, MS; Robinson, JA (1985). "Idiopathic fibrosclerosis". The Journal of Rheumatology. 12 (3): 575–9. PMID 4045855. 2. ^ Kishimoto, M.; Okimura, Y.; Kimura, K.; Mizuno, I.; Iguchi, G.; Fumoto, M.; Takahashi, Y.; Kanda, F.; Kaji, H.; Abe, H.; Hanioka, K.; Chihara, K. (2000). "Multifocal fibrosclerosis as a possible cause of panhypopituitarism with central diabetes insipidus". Endocrine Journal. 47 (3): 335–342. doi:10.1507/endocrj.47.335. PMID 11036878. 3. ^ John H. Stone; Arezou Khosroshahi; Vikram Deshpande; et al. (October 2012). "Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations". Arthritis & Rheumatism. 64 (10): 3061–3067. doi:10.1002/art.34593. PMC 5963880. PMID 22736240. ## External links[edit] Classification D * ICD-10: N13.5 * OMIM: 228800 * MeSH: C537375 C537375, C537375 External resources * Orphanet: 49041 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Multifocal fibrosclerosis	c0494949	6,206	wikipedia	https://en.wikipedia.org/wiki/Multifocal_fibrosclerosis	2021-01-18T18:54:35	{"gard": ["5697"], "mesh": ["C537375"], "umls": ["C0494949"], "icd-10": ["M35.5"], "orphanet": ["49041"], "wikidata": ["Q6934687"]}
This article is about the disorder. For the 2008 film, see Parasomnia (film). Category of sleep disorders Parasomnia SpecialtyPsychiatry, psychology Parasomnias are a category of sleep disorders that involve abnormal movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep. Parasomnias are dissociated sleep states which are partial arousals during the transitions between wakefulness, NREM sleep, and REM sleep, and their combinations. ## Contents * 1 Classification * 2 Non-rapid eye movement (NREM)-related parasomnias * 2.1 Differential diagnosis for NREM-related parasomnias[2] * 2.2 Confusional arousals * 2.2.1 Sleep-related abnormal sexual behavior * 2.3 Sleepwalking (somnambulism) * 2.4 Sleep terrors (night terrors/ pavor nocturnus) * 2.5 Sleep-related eating disorder (SRED) * 3 Rapid eye movement (REM)-related parasomnias * 3.1 REM sleep behavior disorder * 3.2 Recurrent isolated sleep paralysis * 3.3 Nightmare disorder * 3.4 Catathrenia * 3.5 Sleep-Related Painful Erections * 4 Other parasomnias * 4.1 Exploding head syndrome * 4.2 Sleep-related hallucinations * 4.3 Sleep enuresis * 4.4 Parasomnias due to medical disorder * 4.5 Parasomnias due to medication or substance * 4.6 Parasomnia, unspecific * 5 Isolated symptom/normal variant * 5.1 Sleep talking (somniloquy) * 6 Diagnosis * 7 Treatment * 8 Prognosis * 9 See also * 10 References * 11 Notes * 12 Further reading * 13 External links ## Classification[edit] The newest version of the International Classification of Sleep Disorders (ICSD, 3rd. Ed.) uses State Dissociation as the paradigm for parasomnias.[1][2] Unlike before, where wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were considered exclusive states, research has shown that combinations of these states are possible and thus, may result in unusual unstable states that could eventually manifest as parasomnias or as altered levels of awareness.[1][3][4][5][6][7] Although, the previous definition is technically correct, it contains flaws. The consideration of the State Dissociation paradigm facilitates the understanding of the sleep disorder and provides a classification of 10 core categories.[1][2] ## Non-rapid eye movement (NREM)-related parasomnias[edit] NREM parasomnias are arousal disorders that occur during stage 3 (or 4 by the R&K standardization) of NREM sleep—also known as slow wave sleep (SWS). They are caused by a physiological activation in which the patient's brain exits from SWS and is caught in between a sleeping and waking state. In particular, these disorders involve activation of the autonomic nervous system, motor system, or cognitive processes during sleep or sleep-wake transitions.[8] Some NREM parasomnias (sleep-walking, night-terrors, and confusional arousal) are common during childhood but decrease in frequency with increasing age. They can be triggered in certain individuals, by alcohol, sleep deprivation, physical activity, emotional stress, depression, medications, or a fevered illness. These disorders of arousal can range from confusional arousals, somnambulism, to night terrors. Other specific disorders include sleepeating, sleep sex, teeth grinding, rhythmic movement disorder, restless legs syndrome, and somniloquy. ### Differential diagnosis for NREM-related parasomnias[2][edit] * Sleep-disordered breathing * REM-related parasomnias * Nocturnal seizures * Psychogenic dissociative disorders ### Confusional arousals[edit] Main article: Confusional arousals Confusional arousal is a condition when an individual awakens from sleep and remains in a confused state. It is characterized by the individual's partial awakening and sitting up to look around. They usually remain in bed and then return to sleep. These episodes last anywhere from seconds to minutes and may not be reactive to stimuli.[9] Confusional arousal is more common in children than in adults. It has a lifetime prevalence of 18.5% in children and a lifetime prevalence of 2.9-4.2% in adults.[10][11][12][13] Infants and toddlers usually experience confusional arousals beginning with large amounts of movement and moaning, which can later progress to occasional thrashings or inconsolable crying. In rare cases, confusional arousals can cause injuries and drowsy driving accidents, thus it can also be considered dangerous.[14] Another sleeping disorder may be present triggering these incomplete arousals.[15] #### Sleep-related abnormal sexual behavior[edit] Main article: Sleep sex Sleep-related abnormal sexual behavior, Sleep sex, or sexsomnia, is a form of confusional arousal that may overlap with somnambulism.[1] Thereby, a person will engage in sexual acts while still asleep. It can include such acts as masturbation, inappropriate fondling themselves or others, having sex with another person; and in more extreme cases, sexual assault.[16] These behaviors are unconscious, occur frequently without dreaming, and bring along clinical, social, and legal implications.[17] It has a lifetime prevalence of 7.1% and an annual prevalence of 2.7%.[11] ### Sleepwalking (somnambulism)[edit] Main article: Sleepwalking Sleepwalking has a prevalence of 1–17% in childhood, with the most frequent occurrences around the age of eleven to twelve. About 4% of adults experience somnambulism.[18] Normal sleep cycles include states varying from drowsiness all the way to deep sleep. Every time an individual sleeps, he or she goes through various sequences of non-REM and REM sleep. Anxiety and fatigue are often connected with sleepwalking. For adults, alcohol, sedatives, medications, medical conditions and mental disorders are all associated with sleepwalking. Sleep walking may involve sitting up and looking awake when the individual is actually asleep, and getting up and walking around, moving items or undressing themselves. They will also be confused when waking up or opening their eyes during sleep. Sleep walking can be associated with sleeptalking.[19] ### Sleep terrors (night terrors/ pavor nocturnus)[edit] Main article: Night terror Sleep terror is the most disruptive arousal disorder since it may involve loud screams and panic; in extreme cases, it may result in bodily harm or property damage by running about or hitting walls. All attempts to console the individual are futile and may prolong or intensify the victim's confused state. Usually the victim experiences amnesia after the event but it may not be complete amnesia. Up to 3% of adults suffer from sleep terrors and exhibited behavior of this parasomnia can range from mild to extremely violent. This is very prevalent in those who suffer violent post-traumatic stress disorder (PTSD).[10] They typically occur in stage 3 sleep.[20] ### Sleep-related eating disorder (SRED)[edit] Main article: Nocturnal sleep related eating disorder The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) classifies sleep-related eating disorder under sleepwalking, while ICSD classifies it as NREM-related parasomnia.[1][21] It is conceptualized as a mixture of binge-eating behavior and arousal disorder.[1][21] Thereby, preferentially high-caloric food is consumed in an uncontrolled manner.[22] However, SRED should not be confused with nocturnal eating syndrome, which is characterized by an excessive consumption of food before or during sleep in full consciousness.[22][23] Since sleep-related eating disorders are associated with other sleep disorders, successful treatment of the latter can reduce symptoms of this parasomnia.[22] ## Rapid eye movement (REM)-related parasomnias[edit] ### REM sleep behavior disorder[edit] Unlike other parasomnias, rapid eye movement sleep behavior disorder (RBD) in which muscle atonia is absent is most common in older adults.[24] This allows the individual to act out their dreams and may result in repeated injury—bruises, lacerations, and fractures—to themselves or others. Patients may take self-protection measures by tethering themselves to bed, using pillow barricades, or sleeping in an empty room on a mattress.[10] Besides ensuring the sleep environment is a safe place, pharmacologic therapy using melatonin and clonazepam is also common as a treatment for RBD, even though might not eliminate all abnormal behaviours.[25] Before starting a treatment with clonazepam, a screening for obstructive sleep apnea should performed.[22] However, clonazepam needs to be manipulated carefully because of its significant side effects, i.e., morning confusion or memory impairment,[22] mainly in patients with neurodegenerative disorders with dementia.[26] Demographically, 90% of RBD patients are males, and most are older than 50 years of age.[10] However, this prevalence in males could be biased due to the fact that women tends to have a less violent type of RBD, which leads to lower reports at sleep centres and different clinical characteristics.[27][28] While men might have more aggressive behaviour during dreaming, women have presented more disturbance in their sleep.[27][28] RBD may be also influenced by a genetic compound, since primary relatives seem to have significantly more chance to develop RBD compared with non-relatives control group.[25][29] Typical clinical features of REM sleep behavior disorder are: * Male gender predilection * Mean age of onset 50–65 years (range 20–80 years) * Vocalisation, screaming, swearing that may be associated with dreams * Motor activity, simple or complex, that may result in injury to patient or bed-partner * Occurrence usually in latter half of sleep period (REM sleep) * May be associated with neurodegenerative disease [30] Acute RBD occurs mostly as a result of a side-effect in prescribed medication—usually antidepressants. Furthermore, substance abuse or withdrawal can result in RBD.[22] Chronic RBD is idiopathic, meaning of unknown origin, or associated with neurological disorders.[22] There is a growing association of chronic RBD with neurodegenerative disorders—Parkinson's disease, multiple system atrophy (MSA), or dementia—as an early indicator of these conditions by as much as 10 years. RBD associated with neurological disorders is frequently related to abnormal accumulation of alpha-synuclein, and more than 80% of patients with idiopathic RBD might develop Lewy body disease (LBD).[25] Patients with narcolepsy are also more likely to develop RBD. The diagnosis is based on clinical history, including partner's account and needs to be confirmed by polysomnography (PSG), mainly for its accuracy in differentiating RBD from other sleep disorders, since there is a loss of REM atonia with excessive muscle tone.[22] However, screening questionnaires, such as RBDSQ, are also very useful for diagnosing RBD.[25][27][28] ### Recurrent isolated sleep paralysis[edit] Recurrent isolated sleep paralysis is an inability to perform voluntary movements at sleep onset, or upon waking from sleep.[22] Although the affected individual is conscious and recall is present, the person is not able to speak or move. However, respiration remains unimpaired.[22] The episodes last seconds to minutes and diminish spontaneously.[22] The lifetime prevalence is 7%.[31] Sleep paralysis is associated with sleep-related hallucinations.[22] Predisposing factors for the development of recurrent isolated sleep paralysis are sleep deprivation, an irregular sleep-wake cycle, e.g. caused by shift work, or stress.[22] A possible cause could be the prolongation of REM sleep muscle atonia upon awakening.[32] ### Nightmare disorder[edit] Nightmares are like dreams primarily associated with REM sleep. Nightmare disorder is defined as recurrent nightmares associated with awakening dysphoria that impairs sleep or daytime functioning.[1][2] It is rare in children, however persists until adulthood.[11][33] About 2/3 of the adult population report experiencing nightmares at least once in their life.[11] ### Catathrenia[edit] Main article: Catathrenia Before the ICSD-3, Catathrenia was classified as a rapid-eye-movement sleep parasomnia, but is now classified as sleep-related breathing disorder.[1][34] It consists of breath holding and expiratory groaning during sleep, is distinct from both somniloquy and obstructive sleep apnea. The sound is produced during exhalation as opposed to snoring which occurs during inhalation. It is usually not noticed by the person producing the sound but can be extremely disturbing to sleep partners, although once aware of it, sufferers tend to be woken up by their own groaning as well. Bed partners generally report hearing the person take a deep breath, hold it, then slowly exhale; often with a high-pitched squeak or groaning sound. ### Sleep-Related Painful Erections[edit] Painful erections appear only during the sleep.[35] This condition is present during the REM sleep.[35] Sexual activity doesn't produce any pain.[35] There isn't any lesion or physical damage but an hypertonia of the pelvic floor could be one cause.[36] It affects men of all ages but especially from the middle-age.[36] Some pharmacologic treatment as propranolol, clozapine, clonazepam, baclofen and various antidepressants, seems to be effective.[35] ## Other parasomnias[edit] ### Exploding head syndrome[edit] Main article: Exploding head syndrome ### Sleep-related hallucinations[edit] Sleep-related hallucinations are brief episodes of dream-like imagery that can be of any sensory modality, i.e., auditory, visual, or tactile.[2] They are differentiated between hypnagogic hallucination, that occur at sleep onset, and hypnapompic hallucinations, which occur at the transition of sleep to awakening.[2] Although normal individuals have reported nocturnal hallucinations, they are more frequent in comorbidity with other sleep disorders, e.g. narcolepsy.[1][2][37] ### Sleep enuresis[edit] Main article: Nocturnal enuresis ### Parasomnias due to medical disorder[edit] ### Parasomnias due to medication or substance[edit] ### Parasomnia, unspecific[edit] * Sleep drunkenness, also known as confusional arousal, is the feeling of confusion or sudden action upon waking up from deep sleep. Severe sleep inertia, one cause of oversleeping, is considered to develop sleep drunkenness.[38] ## Isolated symptom/normal variant[edit] ### Sleep talking (somniloquy)[edit] According to ICSD-3 it is not defined a disorder in particular. It is rather an isolated symptom or normal variant and ranges from isolated speech to full conversations without recall.[1][2][22] With a lifetime prevalence of 69% it is considered fairly common.[11] Sleep talking is associated with REM-related parasomnias as well as with disorders or arousal.[1][2] It occurs in all sleep states. Until now, there is no specific treatment for sleeptalking available.[22] ## Diagnosis[edit] Parasomnias are most commonly diagnosed by means of questionnaires.[22] These questionnaires include a detailed analyses of the clinical history and contain questions to: 1. Rule out sleep deprivation 2. Rule out effects of intoxication or withdrawal 3. Rule out sleep disorders causing sleep instability 4. Rule out medical disorders or treatments associated with sleep instability 5. Confirm presence of NREM parasomnias in other family members and during the patient's childhood 6. Determine the timing of the events 7. Determine the morphology of the events.[22] Furthermore, a sleep diary is helpful to exclude that sleep deprivation could be a precipitating factor.[22] An additional tool could be the partner's log of the events.[22] The following questions should therefore be considered: 1. Do you or your bed partner believe that you move your arms, legs, or body too much, or have unusual behaviors during sleep? 2. Do you move while dreaming, as if you are simultaneously attempting to carry out the dream? l Have you ever hurt yourself or your bed partner during sleep? 3. Do you sleepwalk or have sleep terrors with loud screaming? 4. Do your legs feel restless or begin to twitch a lot or jump around when you are drowsy or sleepy, either at bedtime or during the day? 5. Do you eat food or drink fluids without full awareness during the night? Do you wake up in the morning feeling bloated and with no desire to eat breakfast?[39] In potentially harmful or disturbing cases a specialist in sleep disorders should be approached.[22] Video polysomnographic documentation is necessary only in REM sleep behavior disorder (RBD), since it is an essential diagnostic criteria in the ICSD to demonstrate the absence of muscle atonia and to exclude comorbid sleep disorders.[1][2][22] For most of the other parasomnias, polysomnographic monitoring is a costly, but still supportive tool in the clinical diagnosis.[2][22] The use of actigraphy can be promising in the diagnostical assessment of NREM-related parasomnias, for example to rule out sleep deprivation or other sleep disorders, like circadian sleep-wake rhythm disorder which often develops among shift workers.[22] However, there is currently no generally accepted standardized technique available of identifying and quantifying periodic limb movements in sleep (PLMS) that distinguishes movements resulting from parasomnias, nocturnal seizures, and other dyskinesias.[40] Eventually, using actigraphy for parasomnias in general is disputed.[41] ## Treatment[edit] Parasomnias can be considered as potentially harmful to oneself as well as to bed partners, and are associated with other disorders.[22] Children with parasomnias do not undergo medical intervention, because they tend to recover the NREM-related disorder with the process of growth.[32] In those cases, the parents receive education on sleep hygiene to reduce and eventually eliminate precipitating factors.[32] In adults psychoeducation about a proper sleep hygiene can reduce the risk to develop parasomnia.[22] Case studies have shown that pharmacological interventions can improve symptoms of parasomnia, however mostly they are accompanied by side-effects.[22][42] Behavioral treatments, i.e., relaxation therapy, biofeedback, hypnosis, and stress reduction, may also be helpful, but are not considered as universally effective.[42] ## Prognosis[edit] NREM-related parasomnias which are common in childhood show a good prognosis, since severity decreases with age, the symptoms tend to resolve during puberty.[32][33] Adults suffering from NREM-related parasomnias, however, are faced with a stronger persistence of the symptoms, therefore, full remission is quite unlikely and is also associated with violent complications, including homicide.[1][33] The variant sleep-related eating disorders is chronic, without remission, but treatable.[33] REM sleep behavior disorder (RBD) can mostly be handled well with the use of melatonin or clonazepam.[25][33] However, there is high comorbidity with neurodegenerative disorders, that is in up to 93% of cases.[33] The underlying psychopathology of nightmare disorder complicates a clear prognosis.[33] The prognosis for other parasomnias seems promising. While exploding head syndrome usually resolves spontaneously, the symptoms for sleep-related hallucinations tend to diminish over time.[33] ## See also[edit] * Dyssomnia * Insomnia * Rhythmic movement disorder * Sleep medicine * Sleep paralysis ## References[edit] * Mahowald & Schenck. Insights from studying human sleep disorders. Nature (2005); 437(7063):1279-85. * Bassetti et al., Lancet (2000); 356: 484–485 * Boeve et al. Journal of Geriatr Psychiatry Neurol 2004; 17:146-157 * Aurora RN et al. Journal of Clinical Sleep Medicine 2010; 6(1):85-95. * Aurora RN et al. Journal of Clinical Sleep Medicine 2010; 6(4):398-401. * https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001811/ ## Notes[edit] 1. ^ a b c d e f g h i j k l m International Classification of Sleep Disorders. Darien, IL: American Academy of Sleep Medicine. 2014. 2. ^ a b c d e f g h i j k Kazaglis, Louis; Bornemann, Michel A. Cramer (2016). "Classification of Parasomnias". Current Sleep Medicine Reports. 2 (2): 45–52. doi:10.1007/s40675-016-0039-y. ISSN 2198-6401. 3. ^ Mahowald MW, Schenk CH. Dissociated states of wakefulness and sleep. In: Lydic R, Baghdoyan HA, editors. Handbook of behavioral state control: cellular and molecular mechanisms. Boca Raton: CRC Press; 1999. p. 143-58. 4. ^ Mahowald MW, Schenk CH. dissociated states of wakefulness and sleep. Neurology. 1992; 42(7 Suppl 6):44-51. 5. ^ Nobili, Lino; De Gennaro, Luigi; Proserpio, Paola; Moroni, Fabio; Sarasso, Simone; Pigorini, Andrea; De Carli, Fabrizio; Ferrara, Michele (2012), "Local aspects of sleep", Progress in Brain Research, Elsevier, 199: 219–232, doi:10.1016/b978-0-444-59427-3.00013-7, ISBN 9780444594273, PMID 22877668 6. ^ Nobili, Lino; Ferrara, Michele; Moroni, Fabio; De Gennaro, Luigi; Russo, Giorgio Lo; Campus, Claudio; Cardinale, Francesco; De Carli, Fabrizio (2011). "Dissociated wake-like and sleep-like electro-cortical activity during sleep". NeuroImage. 58 (2): 612–619. doi:10.1016/j.neuroimage.2011.06.032. PMID 21718789. 7. ^ Peter-Derex, Laure; Magnin, Michel; Bastuji, Hélène (2015). "Heterogeneity of arousals in human sleep: A stereo-electroencephalographic study". NeuroImage. 123: 229–244. doi:10.1016/j.neuroimage.2015.07.057. PMID 26220744. 8. ^ Bassetti, Claudio; Vella, Silvano; Donati, Filippo; Wielepp, Peter; Weder, Bruno (August 2000). "SPECT during sleepwalking". The Lancet. 356 (9228): 484–485. doi:10.1016/S0140-6736(00)02561-7. PMID 10981896. 9. ^ Peters, Brandon R. (2014-12-01). "Irregular Bedtimes and Awakenings". Sleep Medicine Clinics. 9 (4): 481–489. doi:10.1016/j.jsmc.2014.08.001. ISSN 1556-407X. 10. ^ a b c d Mahowald, Mark W.; Schenck, Carlos H. (October 2005). "Insights from studying human sleep disorders". Nature. 437 (7063): 1279–1285. Bibcode:2005Natur.437.1279M. doi:10.1038/nature04287. ISSN 0028-0836. PMID 16251953. 11. ^ a b c d e Bjorvatn, Bjørn; Grønli, Janne; Pallesen, Ståle (2010). "Prevalence of different parasomnias in the general population". Sleep Medicine. 11 (10): 1031–1034. doi:10.1016/j.sleep.2010.07.011. PMID 21093361. 12. ^ Ohayon MM, Priest RG, Zulley J, Smirne S. The place of confusional arousals in sleep and mental disorders: findings in a general population sample of 13,057 subjects. J Nerv Ment Dis. 2000;188(6):340-8. 13. ^ Ohayon MM, Guilleminault C, Priest RG. Night terrors, sleepwalking, and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry. 1999;60(4):268-76. 14. ^ "Sleep education". 15. ^ Durmer, Jeffrey S.; Chervin, Ronald D. (June 2007). "PEDIATRIC SLEEP MEDICINE". CONTINUUM: Lifelong Learning in Neurology. 13: 153–200. doi:10.1212/01.CON.0000275610.56077.ee. ISSN 1080-2371. 16. ^ "R. v. Luedecke, 2008 ONCA 716". CanLII.org. 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The Journal of Sexual Medicine, 15(1), 5‑19. https://doi.org/10.1016/j.jsxm.2017.11.006 37. ^ Ivanenko, Anna; Relia, Sachin (2013), Kothare, Sanjeev V.; Ivanenko, Anna (eds.), "Sleep-Related Hallucinations", Parasomnias, Springer New York, pp. 207–220, doi:10.1007/978-1-4614-7627-6_14, ISBN 9781461476269 38. ^ Hilditch, Cassie J.; McHill, Andrew W. (2019-08-22). "Sleep inertia: current insights". Nature and Science of Sleep. doi:10.2147/nss.s188911. PMC 6710480. PMID 31692489. Retrieved 2020-11-29. 39. ^ Mahowald, Mark W.; Schenck, Carlos H. (2000-01-01). "Diagnosis and management of parasomnias". Clinical Cornerstone. 2 (5): 48–54. doi:10.1016/S1098-3597(00)90040-1. ISSN 1098-3597. 40. ^ Chokroverty, Sudhansu; Thomas, Robert J. (2014), "Specialized Techniques", Atlas of Sleep Medicine, Elsevier, pp. 255–299, doi:10.1016/b978-1-4557-1267-0.00014-x, ISBN 9781455712670 41. ^ Louter, Maartje; Arends, Johan BAM; Bloem, Bastiaan R; Overeem, Sebastiaan (2014). "Actigraphy as a diagnostic aid for REM sleep behavior disorder in Parkinson's disease". BMC Neurology. 14 (1): 76. doi:10.1186/1471-2377-14-76. ISSN 1471-2377. PMC 3986453. PMID 24708629. 42. ^ a b "Disorders That Disrupt Sleep: Parasomnia Causes & Types". eMedicineHealth. Retrieved 2019-06-23. ## Further reading[edit] * Siegel, Ronald (1992). Fire in the Brain: Clinical Tales of Hallucination. * Warren, Jeff (2007). The Head Trip: Adventures on the Wheel of Consciousness. ISBN 978-0-679-31408-0. ## External links[edit] Classification D * ICD-10: F51.3-F51.4 * ICD-10-CM: G47.5 * ICD-9-CM: 307.47, 327.4, 780.59 * MeSH: D020447 External resources * eMedicine: med/3131 * v * t * e Mental and behavioral disorders Adult personality and behavior Gender dysphoria * Ego-dystonic sexual orientation * Paraphilia * Fetishism * Voyeurism * Sexual maturation disorder * Sexual relationship disorder Other * Factitious disorder * Munchausen syndrome * Intermittent explosive disorder * Dermatillomania * Kleptomania * Pyromania * Trichotillomania * Personality disorder Childhood and learning Emotional and behavioral * ADHD * Conduct disorder * ODD * Emotional and behavioral disorders * Separation anxiety disorder * Movement disorders * Stereotypic * Social functioning * DAD * RAD * Selective mutism * Speech * Stuttering * Cluttering * Tic disorder * Tourette syndrome Intellectual disability * X-linked intellectual disability * Lujan–Fryns syndrome Psychological development (developmental disabilities) * Pervasive * Specific Mood (affective) * Bipolar * Bipolar I * Bipolar II * Bipolar NOS * Cyclothymia * Depression * Atypical depression * Dysthymia * Major depressive disorder * Melancholic depression * Seasonal affective disorder * Mania Neurological and symptomatic Autism spectrum * Autism * Asperger syndrome * High-functioning autism * PDD-NOS * Savant syndrome Dementia * AIDS dementia complex * Alzheimer's disease * Creutzfeldt–Jakob disease * Frontotemporal dementia * Huntington's disease * Mild cognitive impairment * Parkinson's disease * Pick's disease * Sundowning * Vascular dementia * Wandering Other * Delirium * Organic brain syndrome * Post-concussion syndrome Neurotic, stress-related and somatoform Adjustment * Adjustment disorder with depressed mood Anxiety Phobia * Agoraphobia * Social anxiety * Social phobia * Anthropophobia * Specific social phobia * Specific phobia * Claustrophobia Other * Generalized anxiety disorder * OCD * Panic attack * Panic disorder * Stress * Acute stress reaction * PTSD Dissociative * Depersonalization disorder * Dissociative identity disorder * Fugue state * Psychogenic amnesia Somatic symptom * Body dysmorphic disorder * Conversion disorder * Ganser syndrome * Globus pharyngis * Psychogenic non-epileptic seizures * False pregnancy * Hypochondriasis * Mass psychogenic illness * Nosophobia * Psychogenic pain * Somatization disorder Physiological and physical behavior Eating * Anorexia nervosa * Bulimia nervosa * Rumination syndrome * Other specified feeding or eating disorder Nonorganic sleep * Hypersomnia * Insomnia * Parasomnia * Night terror * Nightmare * REM sleep behavior disorder Postnatal * Postpartum depression * Postpartum psychosis Sexual dysfunction Arousal * Erectile dysfunction * Female sexual arousal disorder Desire * Hypersexuality * Hypoactive sexual desire disorder Orgasm * Anorgasmia * Delayed ejaculation * Premature ejaculation * Sexual anhedonia Pain * Nonorganic dyspareunia * Nonorganic vaginismus Psychoactive substances, substance abuse and substance-related * Drug overdose * Intoxication * Physical dependence * Rebound effect * Stimulant psychosis * Substance dependence * Withdrawal Schizophrenia, schizotypal and delusional Delusional * Delusional disorder * Folie à deux Psychosis and schizophrenia-like * Brief reactive psychosis * Schizoaffective disorder * Schizophreniform disorder Schizophrenia * Childhood schizophrenia * Disorganized (hebephrenic) schizophrenia * Paranoid schizophrenia * Pseudoneurotic schizophrenia * Simple-type schizophrenia Other * Catatonia Symptoms and uncategorized * Impulse control disorder * Klüver–Bucy syndrome * Psychomotor agitation * Stereotypy * v * t * e Sleep and sleep disorders Stages of sleep cycles * Rapid eye movement (REM) * Non-rapid eye movement * Slow-wave Brain waves * Alpha wave * Beta wave * Delta wave * Gamma wave * K-complex * Mu rhythm * PGO waves * Sensorimotor rhythm * Sleep spindle * Theta wave Sleep disorders Dyssomnia * Excessive daytime sleepiness * Hypersomnia * Insomnia * Kleine–Levin syndrome * Narcolepsy * Night eating syndrome * Nocturia * Sleep apnea * Catathrenia * Central hypoventilation syndrome * Obesity hypoventilation syndrome * Obstructive sleep apnea * Periodic breathing * Sleep state misperception Circadian rhythm disorders * Advanced sleep phase disorder * Cyclic alternating pattern * Delayed sleep phase disorder * Irregular sleep–wake rhythm * Jet lag * Non-24-hour sleep–wake disorder * Shift work sleep disorder Parasomnia * Bruxism * Nightmare disorder * Night terror * Periodic limb movement disorder * Rapid eye movement sleep behavior disorder * Sleepwalking * Somniloquy Benign phenomena * Dreams * Exploding head syndrome * Hypnic jerk * Hypnagogia / Sleep onset * Hypnopompic state * Sleep paralysis * Sleep inertia * Somnolence * Nocturnal clitoral tumescence * Nocturnal penile tumescence * Nocturnal emission Treatment * Sleep diary * Sleep hygiene * Sleep induction * Hypnosis * Lullaby * Somnology * Polysomnography Other * Sleep medicine * Behavioral sleep medicine * Sleep study Daily life * Bed * Bunk bed * Daybed * Four-poster bed * Futon * Hammock * Mattress * Sleeping bag * Bed bug * Bedding * Bedroom * Bedtime * Bedtime story * Bedtime toy * Biphasic and polyphasic sleep * Chronotype * Dream diary * Microsleep * Mouth breathing * Nap * Nightwear * Power nap * Second wind * Siesta * Sleep and creativity * Sleep and learning * Sleep deprivation / Sleep debt * Sleeping while on duty * Sleepover * Snoring [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Parasomnia	c0030508	6,207	wikipedia	https://en.wikipedia.org/wiki/Parasomnia	2021-01-18T18:28:10	{"mesh": ["D020447"], "icd-9": ["327.4", "780.59", "307.47"], "icd-10": ["F51.3-F51.5"], "wikidata": ["Q559869"]}
A rare disorder of proline metabolism characterized biochemically by markedly elevated levels of proline in plasma and urine due to deficiency of proline oxidase. The reported clinical phenotype ranges from asymptomatic to variable neurologic and psychiatric manifestations (including global developmental delay, seizures, autistic features, and hyperactivity). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Hyperprolinemia type 1	c0268529	6,208	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=419	2021-01-23T17:17:13	{"gard": ["2847"], "omim": ["239500"], "umls": ["C0268529"], "icd-10": ["E72.5"], "synonyms": ["Proline oxidase deficiency"]}
Severe neurodegenerative syndrome with lipodystrophy is a rare, genetic, neurodegenerative disorder characterized by progressive psychomotor and cognitive regression (manifesting with gait ataxia, spasticity, loss of language, mild to severe intellectual disability, pyramidal and extrapyramidal signs and, frequently, development of tretraplegia or tetraparesis) associated with variable degrees of lipodystrophy, hepatomegaly, hypertriglyceridemia and muscular hypertorphy. Hyperactivity, tremor and development of seizures may also be associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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 neurodegenerative syndrome with lipodystrophy	c4014700	6,209	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=363400	2021-01-23T17:09:51	{"omim": ["615924"], "icd-10": ["G31.8"], "synonyms": ["Severe neurodegenerative syndrome due to BSCL2 deficiency"]}
A number sign (#) is used with this entry because familial paragangliomas-4 (PGL4) is caused by heterozygous mutation in the SDHB gene (185470), which encodes the iron sulfur subunit of succinate dehydrogenase, on chromosome 1p36. For a general phenotypic description and a discussion of genetic heterogeneity of familial paragangliomas, see PGL1 (168000). Clinical Features Bogdasarian and Lotz (1979) reported a family in which affected individuals had multiple catecholamine-secreting head and neck paragangliomas and retroperitoneal pheochromocytomas. Glowniak et al. (1985) reported a family in which 3 individuals spanning 3 generations had pheochromocytoma of the right renal hilum; 1 of these patients had metastatic disease. In the 2 previous generations, pheochromocytoma was suspected in 3 persons, including a hypertensive girl who died suddenly at age 16 years. The pedigree had an obligatory carrier, according to the hypothesis of autosomal dominant inheritance, who at age 52 years showed no signs of pheochromocytoma by any test including CT scans and scintigraphy with radioiodine-tagged metaiodobenzylguanidine. Glowniak et al. (1985) referred to reports by Cook et al. (1960), who described a brother and sister with pheochromocytoma of the organs of Zuckerkandl, which are masses of chromaffin tissue found at the aortic bifurcation, and Spring and Palubinskas (1977), who described a mother and son with pheochromocytoma involving the lower urinary tract. Glowniak et al. (1985) suggested that primary extraadrenal pheochromocytoma was a distinct genetic entity. Pritchett (1982) and Jensen et al. (1991) reported familial concurrence of carotid body tumors and adrenal and extraadrenal pheochromocytomas. Skoldberg et al. (1998) reported a Swedish family in which members of 3 successive generations had extramedullary pheochromocytomas (familial chromaffin paragangliomas). An affected woman in the first generation had paragangliomas in the thyroid gland and bladder. Thyrotoxicosis was diagnosed at the age of 59; she died at the age of 69 of acute heart failure associated with thyrotoxicosis. This woman's daughter had paragangliomas retroperitoneally and in the neck, and her grandson had 2 retroperitoneal paragangliomas. The transmission from 2 females differentiated the condition from PLG1, which shows imprinting with inheritance only from the father. No mutations were found in the VHL gene (608537) or the RET gene (164761). Young et al. (2002) reported a man diagnosed with metastatic catecholamine-secreting paragangliomas in 1972. He presented with signs of catecholamine excess, including recurrent throbbing headache, palpitations, diaphoresis, and anxiety. He had hypertension and increased excretion of urinary catecholamines and total metanephrines. Laparotomy identified 3 paragangliomas: 2 periaortic and 1 adjacent to the adrenal gland. He was later found to have paragangliomas behind the head of the pancreas, beneath the diaphragm, within the liver, in the femur, and in the thorax. He was well in 2002. His 27-year-old son also developed extraadrenal catecholamine-secreting paragangliomas. Vanharanta et al. (2004) reported a family in which the proband was diagnosed with metastatic renal clear cell carcinoma (RCC; 144700) at age 28 years. The patient's mother had a malignant PGL within the heart. The patient and his mother both had a heterozygous germline mutation in the SDHB gene (185470.0006); tumor tissue from both patients showed loss of heterozygosity (LOH) of the wildtype SDHB allele. In an unrelated family, 2 sibs had PGL and developed RCC in their twenties. Both sibs had a heterozygous germline mutation in the SDHB gene (185470.0005); PGL tissue from 1 patient and both RCC tumor tissue showed somatic LOH of the wildtype allele. No SDHB mutations were identified in 35 renal cell carcinomas diagnosed before age 50 years. Timmers et al. (2007) reviewed the findings in 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. PGL often presented as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consisted of hypersecretion of norepinephrine and/or dopamine, but 10% of tumors were biochemically silent. The clinical expression of the tumors could not be predicted by the genotype. Timmers et al. (2007) studied 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. Mean +/- SD age at diagnosis was 33.7 +/- 15.7 years. Tumor-related pain was among the presenting symptoms in 54% of patients and was the sole symptom in 14%. Seventy-six percent had hypertension, and 90% lacked a family history of PGL. All primary tumors but one originated from extraadrenal locations. Mean +/- SD tumor size was 7.8 +/- 3.7 cm. In this referral-based study, 28% presented with metastatic disease and all but one eventually developed metastases after 2.7 +/- 4.1 years. Ten percent had additional head and neck PGLs. The biochemical phenotype was consistent with hypersecretion of both norepinephrine and dopamine in 46%, norepinephrine only in 41%, and dopamine only in 3%. SDHB-related PGL often presents as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consists of hypersecretion of norepinephrine and/or dopamine, whereas 10% of tumors are biochemically silent. Timmers et al. (2007) concluded that the clinical expression of these tumors cannot be predicted by the genotype. Armstrong et al. (2009) reported a 13-year-old girl with a composite paraganglioma/neuroblastoma (256700) who had a heterozygous germline deletion of the SDHB gene. She was initially found to have a paravertebral extraadrenal pheochromocytoma with features of a paraganglioma on histologic examination of the resected tumor, but further analysis showed an area with morphology of a differentiating neuroblastoma. The authors referred to a patient reported by Cascon et al. (2008) who had an adrenal neuroblastoma and partial deletion of the SDHB gene (185470.0017). Armstrong et al. (2009) noted that both paragangliomas and neuroblastomas show common embryogenesis from the neural crest, which may explain the composite histologic tumor identified in their patient. Schimke et al. (2010) reported 2 adult sibs with paraspinal paragangliomas. The family was of note because a deceased sib, previously reported by Fairchild et al. (1979), had neuroblastoma as an infant, metastatic extraadrenal sympathetic paragangliomas consistent with pheochromocytoma as a young adult, and renal cell carcinoma as an adult. Fairchild et al. (1979) noted that occurrence of these cancers in the same patient was unique. In addition, a first cousin of these sibs had died from metastatic renal cell carcinoma and had a history of a benign paraaortic PGL. Genetic analysis identified a heterozygous mutation in the SDHB gene (V140F; 185470.0016). There were 2 unaffected family members, suggesting decreased penetrance or a 'leaky' mutation. Schimke et al. (2010) noted the importance of family history in elucidating the etiology of this inherited disorder. Heesterman et al. (2013) found that 2 (11.8%) of 17 asymptomatic SDHB mutation carriers screened with MRI had an occult paraganglioma, both of which were vagal body tumors. One SDHB mutation carrier had a sympathetic paraganglioma. Rijken et al. (2016) reported a large multigenerational Dutch family in which 6 individuals had PGL4. Three patients had a pheochromocytoma, 2 of which were malignant; 1 patient had a carotid body PGL, 1 had a jugulotympanic PGL, and another had an extraadrenal PGL. There was evidence of incomplete penetrance. Inheritance PGL4 is transmitted in an autosomal dominant pattern with incomplete penetrance. Reports of penetrance have varied, but have been generally high: e.g., 77% by age 50 years, 100% by 80 years (Neumann et al., 2004). Schiavi et al. (2010) studied 437 individuals from 24 families with PGL4, including 135 SDHB mutation carriers. Individuals were followed from birth to the last follow-up or to age 80 years. Penetrance was estimated to be 13% at age 50, and 30% for lifetime. These figures were substantially lower than previous reports, which Schiavi et al. (2010) attributed to ascertainment bias. Diagnosis Gill et al. (2011) found that SDHB immunostaining was completely negative in renal cell carcinoma specimens from 3 kindreds with germline SDHB mutations. In contrast, SDHB immunostaining was positive in 70 unselected renal tumor specimens, including clear cell carcinomas, papillary renal carcinomas, and other forms of renal cancer. Gill et al. (2011) concluded that immunostaining for SDHB in renal cell carcinomas can direct genetic testing for paraganglioma-related disorders. Molecular Genetics In affected members of 3 families with pheochromocytoma and paragangliomas, Astuti et al. (2001) identified a mutation in the SDHB gene (185470.0001). One of the families had been reported by Skoldberg et al. (1998). In the second family, the proband presented with extraadrenal pheochromocytoma at age 10 years and her mother had a cervical paraganglioma (glomus jugulare tumor) removed at age 45 years; in the third family, 2 sibs developed early-onset pheochromocytoma before age 30 years. Genotype/Phenotype Correlations In a population-based genetic study of 334 unrelated patients with adrenal or extraadrenal pheochromocytomas and 83 patients with head and neck paragangliomas, Neumann et al. (2004) found that 12% of patients had a mutation in either the SDHB or SDHD (602690) gene, with equal distribution between the 2 genes (25 and 24 patients with mutations in the SDHB and SDHD genes, respectively). Mean age at diagnosis was similar between the 2 groups (approximately 30 years). Inheritance of SDHD mutations was consistent with maternal imprinting. Examination of relatives yielded a total of 32 and 34 manifesting carriers of SDHB and SDHD mutations, respectively. Multiple tumors occurred in 28% of SDHB carriers and 74% of SDHD carriers; adrenal pheochromocytomas occurred in 28% of SDHB carriers and 53% of SDHD carriers, whereas extraadrenal pheochromocytomas were identified in 48% of SDHB carriers and 21% of SDHD carriers; head and neck paragangliomas occurred in 31% of SDHB carriers and 79% of SDHD carriers; and malignancy occurred in 34% of SDHB carriers but no SDHD carriers. Two related SDHB carriers had renal cell carcinoma, and 1 SDHB and 1 SDHD carrier each had papillary thyroid carcinoma. Age-related penetrance for carriers of the 2 mutations were similar: SDHB and SDHD carriers showed 77% and 86% penetrance by age 50 years, respectively. Benn et al. (2006) determined genotype/phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs 28 years, respectively; p = 0.3). However, when all 112 mutation carriers were included, the estimated age-related penetrance was different for SDHB versus SDHD mutation carriers (p = 0.008). Amar et al. (2007) studied a total of 54 patients with malignant pheochromocytomas and paragangliomas, of whom 23 were found to have a germline mutation in the SDHB gene. The presence of SDHB mutations was significantly and independently associated with mortality (relative risk, 2.7; 95% CI, 1.2, 6.4; p = 0.021). In northern Spain, where cervical paraganglioma is particularly frequent, Lima et al. (2007) screened 48 patients for mutations in the SDHB, SDHC (602413), and SDHD genes. Eight sporadic cases (22.2%) carried pathogenic germline mutations, 6 of which were in SDHB and 2 in SDHD. Three families had mutations in SDHD and 1 in SDHB; 7 of 11 different pathogenic mutations (64%) affected SDHB. Ten mutations were novel. Missense mutations were primarily found in SDHB and frameshift mutations in SDHD. The authors concluded that a significant proportion of sporadic cervical PGLs arise as a consequence of intrinsic genetic factors. In patients with germline SDHB mutations, they found no evidence for distant metastases or extraparaganglial malignancies after 7 years' follow-up. Lima et al. (2007) concluded that occult familial cases and familial cases with a proven disease history have a common clinicopathologic signature that distinguishes them from truly sporadic cervical paraganglioma patients without germline mutations. Population Genetics Hensen et al. (2012) determined the mutation frequency of 4 succinate dehydrogenase genes in a total of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. Mutations were identified in 690 cases from 239 families. The most commonly affected gene in mutation carriers was SDHD (602690) (87.1%), followed by SDHAF2 (613019) (6.7%), SDHB (5.9%), and SDHC (602413) (0.3%). Almost 70% of all carriers had the founder mutation D92Y (602690.0004) in SDHD; approximately 89% of all SDH mutation carriers had 1 of 6 Dutch founder mutations. The most common mutation in SDHB was a splice site mutation (185470.0019), which was found in 22 patients from 9 families. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. In 9 apparently unrelated Dutch patients with PGL4, Bayley et al. (2009) identified a heterozygous 7.9-kb deletion (c.201-4429_287-933del) in the SDHB gene (185470.0021), predicted to result in a frameshift and premature termination (Cys68HisfsTer21). The deletion was found by multiplex ligation-dependent probe amplification (MLPA) analysis of 126 patients who did not carry point mutations in SDH genes, and all patients had the same breakpoints. Haplotype analysis indicated a founder effect. Only 1 patient had a family history of PGL, 5 patients had no family history, and family information from 3 patients was not available. The patients presented with head and neck PGL, extraadrenal PGL, and pheochromocytoma. Bayley et al. (2009) suggested incomplete penetrance associated with this mutation. Functional studies of the variant and studies of patient cells were not performed. Rijken et al. (2016) reported a large multigenerational Dutch family with PGL4 due to the Dutch founder 7.9-kb deletion in the SDGB gene. There were 17 family members who carried the mutation, but only 6 had clinical manifestations; 11 patients were disease-free, indicating incomplete penetrance. The age-dependent penetrance of this mutation in this family was estimated to be 9% at age 50 years. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Pulsatile tinnitus (tympanic paraganglioma) CARDIOVASCULAR Heart \- Palpitations (with pheochromocytoma) \- Tachycardia (with pheochromocytoma) Vascular \- Hypertension (with pheochromocytoma) SKIN, NAILS, & HAIR Skin \- Diaphoresis (with pheochromocytoma) NEUROLOGIC Central Nervous System \- Headache (with pheochromocytoma) \- Cranial nerve palsies can arise with head and neck paragangliomas Behavioral Psychiatric Manifestations \- Anxiety (with pheochromocytoma) NEOPLASIA \- Paragangliomas \- Multiple tumors in 28% of patients \- Paragangliomas, head and neck (31%) \- Chemodectomas \- Carotid body tumors \- Glomus jugular tumors \- Pheochromocytomas, adrenal (28%) \- Pheochromocytomas, extraadrenal (48%) \- Malignancy (34%) \- Gastrointestinal stromal tumors (less common) \- Renal cell carcinoma (less common) \- Neuroblastoma (less common) LABORATORY ABNORMALITIES \- Increased urinary catecholamines (with pheochromocytoma) MISCELLANEOUS \- Adult onset (mean 30 years, range 10-65 years) \- Incomplete penetrance (range 13% to 77% by 50 years of age) \- Signs and symptoms depend on tumor location and activity \- Patients may have head and neck paragangliomas only, adrenal or extraadrenal pheochromocytomas only, or both \- See also PGL1 ( 168000 ) MOLECULAR BASIS \- Caused by mutation in the succinate dehydrogenase complex subunit B gene (SDHB, 185470.0001 ) ▲ 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	PARAGANGLIOMAS 4	c1861848	6,210	omim	https://www.omim.org/entry/115310	2019-09-22T16:43:41	{"doid": ["0050773"], "mesh": ["C565335"], "omim": ["115310"], "orphanet": ["29072"], "synonyms": ["PHEOCHROMOCYTOMA, FAMILIAL EXTRAADRENAL", "Alternative titles", "PHEOCHROMOCYTOMA, EXTRAADRENAL, AND CERVICAL PARAGANGLIOMA", "Familial pheochromocytoma-paraganglioma", "PARAGANGLIOMAS, HEREDITARY EXTRAADRENAL", "CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS", "PARAGANGLIOMA, FAMILIAL MALIGNANT"], "genereviews": ["NBK1548"]}
Hereditary palmoplantar keratoderma, Gamborg-Nielsen type is characterised by the presence of diffuse palmoplantar keratoderma without associated symptoms. The syndrome has been described in multiple families from the northernmost county of Sweden (Norrbotten). The palmoplantar keratoderma found in the Gamborg-Nielsen type disease is milder than that found in Mal de Meleda but more severe than that found in Thost-Unna palmoplantar keratoderma (see these terms). Transmission is autosomal recessive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Hereditary palmoplantar keratoderma, Gamborg-Nielsen type	c1855644	6,211	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86923	2021-01-23T17:52:47	{"mesh": ["C565454"], "omim": ["244850"], "umls": ["C1855644"], "icd-10": ["Q82.8"], "synonyms": ["Hereditary palmoplantar hyperkeratosis, Gamborg-Nielsen type", "PPK, Gamborg-Nielsen type"]}
Not to be confused with syphilis. Nonvenereal endemic syphilis Other namesnonvenereal syphilis, endemic syphilis, bejel Disfiguring infiltration of the nose, glabella, and forehead with clustered nodules in left interciliary region of boy with endemic syphilis, Iran, 2010. Pronunciation * /ˈbɛdʒəl/ SpecialtyInfectious disease Bejel, or endemic syphilis, is a chronic skin and tissue disease caused by infection by the endemicum subspecies of the spirochete Treponema pallidum. Bejel is one of the "endemic trepanematoses" (endemic infections caused by spiral-shaped bacteria called treponemes), a group that also includes yaws and pinta. Typically, endemic trepanematoses begin with localized lesions on the skin or mucous membranes. Pinta is limited to affecting the skin, whereas bejel and yaws are considered to be invasive because they can also cause disease in bone and other internal tissues.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Bejel usually begins in childhood as a small patch on the mucosa, often on the interior of the mouth, followed by the appearance of raised, eroding lesions on the limbs and trunk. Periostitis (inflammation) of the leg bones is commonly seen, and gummas of the nose and soft palate develop in later stages.[citation needed] ## Causes[edit] Although the organism that causes bejel, Treponema pallidum endemicum,[2] is morphologically and serologically indistinguishable from Treponema pallidum pallidum, which causes venereal syphilis, transmission of bejel is not venereal in nature,[3] generally resulting from mouth-to-mouth contact or sharing of domestic utensils, and the courses of the two diseases are somewhat different.[citation needed] ## Diagnosis[edit] The diagnosis of bejel is based on the geographic history of the patient as well as laboratory testing of material from the lesions (dark-field microscopy). The responsible spirochaete is readily identifiable on sight in a microscope as a treponema.[4] ## Treatment[edit] It is treatable with penicillin or other antibiotics, resulting in a complete recovery.[citation needed] ## Epidemiology[edit] Bejel is mainly found in arid countries of the eastern Mediterranean region and in West Africa, where it is known as sahel. (Sahel disease should be distinguished from "Sahel", the geographical band between the Northern Sahara and Southern Sudan.)[citation needed] ## See also[edit] * Pinta (disease) * Syphilis * Yaws ## References[edit] 1. ^ Mitjà O, Šmajs D, Bassat Q (2013). "Advances in the diagnosis of endemic treponematoses: yaws, bejel, and pinta". PLOS Neglected Tropical Diseases. 7 (10): e2283. doi:10.1371/journal.pntd.0002283. PMC 3812090. PMID 24205410. 2. ^ Antal GM, Lukehart SA, Meheus AZ (January 2002). "The endemic treponematoses". Microbes and Infection. 4 (1): 83–94. doi:10.1016/S1286-4579(01)01513-1. PMID 11825779. 3. ^ Pace JL, Csonka GW (October 1984). "Endemic non-venereal syphilis (bejel) in Saudi Arabia". The British Journal of Venereal Diseases. 60 (5): 293–7. doi:10.1136/sti.60.5.293. PMC 1046341. PMID 6487985. 4. ^ Marks M, Solomon AW, Mabey DC (October 2014). "Endemic treponemal diseases". Transactions of the Royal Society of Tropical Medicine and Hygiene. 108 (10): 601–7. doi:10.1093/trstmh/tru128. PMC 4162659. PMID 25157125. ## External links[edit] Classification D * ICD-10: A65 * ICD-9-CM: 104 * MeSH: D014211 * DiseasesDB: 30090 * v * t * e Bacterial diseases due to gram negative non-proteobacteria (BV4) Spirochaete Spirochaetaceae Treponema * Treponema pallidum * Syphilis/bejel * Yaws * Treponema carateum (Pinta) * Treponema denticola Borrelia * Borrelia burgdorferi/Borrelia afzelii * Lyme disease * Erythema migrans * Neuroborreliosis * Borrelia recurrentis (Louse borne relapsing fever) * Borrelia hermsii/Borrelia duttoni/Borrelia parkeri (Tick borne relapsing fever) Leptospiraceae Leptospira * Leptospira interrogans (Leptospirosis) Chlamydiaceae Chlamydia * Chlamydia psittaci (Psittacosis) * Chlamydia pneumoniae * Chlamydia trachomatis * Chlamydia * Lymphogranuloma venereum * Trachoma Bacteroidetes * Bacteroides fragilis * Tannerella forsythia * Capnocytophaga canimorsus * Porphyromonas gingivalis * Prevotella intermedia Fusobacteria * Fusobacterium necrophorum (Lemierre's syndrome) * Fusobacterium nucleatum * Fusobacterium polymorphum * Streptobacillus moniliformis (Rat-bite fever/Haverhill fever) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Nonvenereal endemic syphilis	c0004945	6,212	wikipedia	https://en.wikipedia.org/wiki/Nonvenereal_endemic_syphilis	2021-01-18T18:42:31	{"gard": ["5905"], "mesh": ["D014211"], "umls": ["C0004945"], "icd-10": ["A65"], "wikidata": ["Q682798"]}
Sharony et al. (2002) described 3 sibs (2 females, 1 male), born of Arabic-Muslim consanguineous healthy parents, with an apparently 'new' lethal familial short-limb bone dysplasia associated with multiple congenital anomalies (MCA). Clinical abnormalities included short limbs and short hands, cloverleaf skull, frontal bossing, wide anterior fontanel, hypertelorism, bilateral microphthalmia, cataract, low-set ears, narrow chest, ambiguous genitalia, cardiac ventricular septal defect, and agenesis of the corpus callosum. Radiologic abnormalities included cloverleaf skull, hypoplastic clavicles and scapulas, thin and wavy cupped ribs, flat vertebral bodies with coronal clefting and several unossified vertebral pedicles, and hypoossification of the pubic bone. Long bones were short and bowed with abnormal metaphyses and unossified epiphyses. Degenerating chondrocytes with disorganization of the hypertrophied cartilage and short disorganized columns of hypertrophied areas were found. Sharony et al. (2002) postulated an autosomal recessive mode of inheritance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 CONGENITAL ANOMALIES SYNDROME WITH CLOVERLEAF SKULL	c1846671	6,213	omim	https://www.omim.org/entry/607161	2019-09-22T16:09:33	{"mesh": ["C564611"], "omim": ["607161"], "orphanet": ["93267"]}
Postinflammatory lymphedema SpecialtyDermatology Postinflammatory lymphedema is a condition characterized by swelling of the soft tissues in which an excessive amount of lymph has accumulated, and is caused by repeated bacterial infections.[1]:849 ## See also[edit] * Lymphedema * Skin lesion ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Postinflammatory lymphedema	c3697842	6,214	wikipedia	https://en.wikipedia.org/wiki/Postinflammatory_lymphedema	2021-01-18T18:32:15	{"umls": ["C3697842"], "wikidata": ["Q7234336"]}
A rare heart defect characterized by complete lack of anatomical continuity between the transverse aortic arch and the descending thoracic aorta. AAI should be distinguished anatomically from atresia of the aortic arch where continuity between these segments is achieved by an imperforate fibrous strand of various lengths. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Aortic arch interruption	c0152419	6,215	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2299	2021-01-23T17:25:36	{"gard": ["740"], "umls": ["C0152419"], "icd-10": ["Q25.4"]}
Feline acne Advanced feline acne SpecialtyVeterinary medicine Feline acne is a problem seen in cats primarily involving the formation of blackheads accompanied by inflammation on the cat's chin and surrounding areas that can cause lesions, alopecia, and crusty sores.[1][2][3] In many cases symptoms are mild and the disease does not require treatment.[1] Mild cases will look like dirt on the cat's chin, but the dirt will not brush off. More severe cases, however, may respond slowly to treatment and seriously detract from the health and appearance of the cat. Feline acne can affect cats of any age, sex or breed, although Persian cats are also likely to develop acne on the face and in the skin folds.[1][4] This problem can happen once, be reoccurring, or even persistent throughout the cat's life.[5] Sebaceous glands are skin glands that produce oil and are mostly found in the skin of the chin, at the base of the tail, and in the eyelids, lips, prepuce, and scrotum. They are connected to hair follicles. In acne, the follicles become clogged with black sebaceous material, forming comedones (also known as blackheads). Comedones can become irritated, swollen, infected, and ultimately pustules. These may elicit itching and discomfort due to swelling and bacterial growth inside infected glands.[2] Bacterial folliculitis occurs when follicules become infected with Staphylococcus aureus, and commonly associated with moderate-to-severe feline acne.[6] Secondary fungal infections (species malassezia) may also occur.[2] Other conditions that can cause similar-appearing conditions include skin mites, ringworm, yeast infection, or autoimmune diseases such as eosinophilic granuloma complex ("rodent ulcers"). These can be ruled out by a simple biopsy of affected cells.[citation needed] Feline acne is one of the top five most common skin conditions that veterinarians treat.[5][6] ## Contents * 1 Causes * 2 Treatment * 3 Prevention * 4 References * 5 External links ## Causes[edit] Although the exact cause of feline acne is unknown, some causes include: * Hyperactive sebaceous glands * Poor hygiene * Stress * Developing secondary to fungal, viral, and bacterial infections * Reaction to medication * Eating or drinking from plastic containers. While it has commonly been suggested that cats are "allergic" to these containers, recent research suggests that plastic containers harbour bacteria due to irregular surfaces. * Demodicosis or mange, causing itchiness and hair loss * Suppressed immune system * Hair follicles that don't function properly * Rubbing the chin (to display affection or mark territory) on non-sanitized household items * Hormonal imbalance * Contracting the infection from other cats in the same household Obese cats which have difficulty grooming themselves are predisposed to dry, flaky skin and feline acne.[7] ## Treatment[edit] Topical treatments such as warm compresses to the chin area may be sufficient for mild cases.[8] Veterinary intervention may be required for treatment if secondary infection occurs. [2] In this case, treatment may begin with clinical drainage of the pustules and a course of oral antibiotics.[2] Clearing the acne can be accomplished using an extra-soft bristled toothbrush or flea comb (one designated for this purpose) to brush the cat's chin. This will loosen debris and remove dried scabs. Epsom-salt compresses applied twice daily dry the affected area to relieve the inflammation and itchiness.[5] ## Prevention[edit] Placing the cat's water in a shallow dish may prevent the chin from absorbing the bacteria in the water while the cat is drinking. If the cat is allergic to plastics or dyes, using a stainless-steel or glass dish is recommended .[4] Cats may also have food allergies that make the development of acne more likely, so that switching kibble, or changing to a hydrolysed diet may be effective.[citation needed] Maintaining good hygiene and grooming habits make the development of feline acne less likely. Washing and exfoliating the chin with a gentle benzoyl-peroxide solution also may be preventive of further outbreaks.[5] ## References[edit] 1. ^ a b c Gross, Thelma Lee; Ihrke, Peter J.; Walder, Emily J.; K. Affolter, Verena (2005). Skin Diseases of the Dog and Cat: Clinical and Histopathologic Diagnosis. Ames, Iowa: Oxford. pp. 437–439. ISBN 978-0-632-06452-6. 2. ^ a b c d e Muller, George H.; Kirk, Robert Warren; Scott, Danny W.; Miller, William L.; Griffin, Craig E. (2001). Muller and Kirk's Small animal dermatology. Philadelphia (Pa.): Saunders. pp. 1042–1043. ISBN 978-0-7216-7618-0. 3. ^ Jazic, E.; Coyner, K. S.; Loeffler, D. G.; Lewis, T. P. (2005). "An Evaluation of the clinical, cytological, infectious and histopathological features of feline acne". European Society of Veterinary Dermatology. pp. 134–140. 4. ^ a b Foster; Smith. "Feline Acne: Signs, Diagnosis, and Treatment of Chin 'Blackheads' in Cats". peteducation.com. 5. ^ a b c d Moore, Arden (2002). "Cats Can Get Acne Too". Prevention. pp. 170–174. 6. ^ a b Scott, D. W.; Miller, W. H.; Erb, H. N. (2012). "Feline dermatology at Cornell University: 1407 cases (1988-2003)". Journal of Feline Medicine and Surgery. pp. 307–316. 7. ^ Lappin, MR, ed. (2001). "Obesity and polyphagia". Feline internal medicine secrets. Philadelphia: Hanley & Belfus. pp. 311–315. ISBN 9781560534617. 8. ^ D. Norsworthy, Gary; Crystal, Mitchell; Grace, Sharon; Patrick Tilley, Larry (2006). The feline patient. Ames, Iowa: Blackwell Publishing. p. 339. 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A number sign (#) is used with this entry because of evidence that Meier-Gorlin syndrome-1 (MGORS1) is caused by homozygous or compound heterozygous mutation in the ORC1 gene (601902) on chromosome 1p32. Description The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (summary by Shalev and Hall, 2003). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al., 2011). ### Genetic Heterogeneity of Meier-Gorlin Syndrome Most forms of Meier-Gorlin syndrome are autosomal recessive disorders, including Meier-Gorlin syndrome-1; Meier-Gorlin syndrome-2 (613800), caused by mutation in the ORC4 gene (603056) on chromosome 2q23; Meier-Gorlin syndrome-3 (613803), caused by mutation in the ORC6 gene (607213) on chromosome 16q11; Meier-Gorlin syndrome-4 (613804), caused by mutation in the CDT1 gene (605525) on chromosome 16q24; Meier-Gorlin syndrome-5 (613805), caused by mutation in the CDC6 gene (602627) on chromosome 17q21; Meier-Gorlin syndrome-7 (617063), caused by mutation in the CDC45L gene (603465) on chromosome 22q11; and Meier-Gorlin syndrome-8 (617564), caused by mutation in the MCM5 gene (602696) on chromosome 22q12. An autosomal dominant form of the disorder, Meier-Gorlin syndrome-6 (616835), is caused by mutation in the GMNN gene (602842) on chromosome 6p22. Clinical Features Gorlin et al. (1975) described this condition in a teenaged male in whom microtia, absent patellae, and micrognathia were the significant features. Camptodactyly of the fingers was noted, as well as Blount osteochondritis dissecans and bilateral aseptic necrosis of the lateral femoral condyles. The family history was unremarkable and parental consanguinity was denied. Gorlin et al. (1975) pointed to a single case report by Meier and Rothschild (1959) of what appeared to be the same disorder; the parents were consanguineous. Cohen et al. (1991) used the designation ear, patella, short stature syndrome (EPS) for a condition they observed in 2 sisters who had bilateral microtia, absent patellae, short stature, poor weight gain, and characteristic facial features. Other skeletal anomalies included complete habitual dislocation of the elbow, slender ribs and long bones, abnormal modeling of the glenoid fossas with hooked clavicles, and clinodactyly. Bone age was significantly delayed and there was flattening of the epiphyses. Similarities to the findings in the 2 unrelated males reported by Hurst et al. (1988) were noted. Bongers et al. (2005) presented pictures indicating the change in facial appearance of the Meier-Gorlin syndrome during aging. Pictures at ages 14 years and 20 years of the same individual reported by Cohen et al. (1991) were presented. Boles et al. (1994) described this disorder in 2 daughters of phenotypically normal, African American parents who showed severe proportional dwarfism with microcephaly, peculiar craniofacial anomalies (maxillary and mandibular hypoplasia, full lips, small mouth), microtia, absent patellae, and joint hyperextensibility. Lacombe et al. (1994) provided follow-up on the male patient originally reported by Gorlin et al. (1975). Family history was unremarkable, and the patient had 3 healthy sibs. As an infant he was observed to have bilateral microtia, micrognathia, bilateral talipes equinovarus, an arthrogryposis-like condition, and unilateral cryptorchidism. Absent patellae were later noted, together with short stature, mild scoliosis, and fifth-finger camptodactyly. On examination as an adult, he had degeneration of the knees due to absent patellae, with bilateral aseptic necrosis of the lateral femoral condyles. He had normal mental status. Loeys et al. (1999) reported 2 brothers with Meier-Gorlin syndrome, the younger of whom was more severely affected. Both patients had severe deafness and congenital labyrinthine anomalies, which had not previously been described as features of this syndrome. Unusual craniofacial appearance and hypoplastic genitalia were demonstrated by photographs. The neuromotor and mental development of these patients was adversely affected by late diagnosis, deafness, and their sociocultural environment, but their cognitive ability fell within the range observed in other Meier-Gorlin patients. Loeys et al. (1999) recommended neuroradiographic imaging and functional inner ear investigations in the diagnostic workup of this rather specific, probably autosomal recessive mental retardation syndrome with multiple congenital anomalies. Bongers et al. (2001) reported 6 female and 2 male patients from 7 families with Meier-Gorlin syndrome and reviewed the literature on this condition. Most of their patients had bilateral small ears, patellar aplasia/hypoplasia, and short stature, except for monozygotic twins who had normal patellae on physical examination. Radiographic studies of the patellae were recommended in patients with this condition to understand the patellar abnormality better. Bongers et al. (2001) also described differences in facial features between patients reported in early infancy (micrognathia, microstomia, and full lips) and those described at older age (high vertical forehead, narrow nose, and high nasal bridge). One of their male patients had hypoplasia of the corpora cavernosa and the medial segment of the urethra, which had not previously been reported in this condition. Bongers et al. (2005) presented pictures of the Meier-Gorlin syndrome in a 5-year-old boy with small and simply formed ears and full lips. Terhal et al. (2000) reported 2 patients who had disproportionate short stature and breast hypoplasia in addition to the typical features of EPS. Cohen et al. (2002) described an Italian boy with the triad of microtia, absent patellae, and growth retardation of prenatal onset. At the age of 18.5 years, he was 44 cm tall. Recombinant growth hormone therapy had no beneficial effect. At the age of 15 years, the patient had urgent surgery for acute torsion of the left spermatic cord, a condition related to a congenital defect of the tunica vaginalis. Shalev and Hall (2003) reported a 25-year-old woman with Meier-Gorlin syndrome. Her phenotypic evolution was characterized by severe growth retardation with decelerated growth of the head and subsequently a relatively small head, normal intelligence, alteration of the facial features to a more proportionate appearance, improvement of joint function, and incomplete breast development. Other characteristics of her phenotype in adulthood included a cheerful personality, a high forehead and accentuated nasolabial folds, very small ears, hypoplastic breasts, and normal menstruation. Faqeih et al. (2005) reported a girl, born of nonconsanguineous parents belonging to an endogamous tribe in Saudi Arabia, who exhibited the classic Meier-Gorlin triad of bilateral small ears, patellar aplasia, and short stature, as well as delayed bone age. At birth, she was diagnosed with congenital left upper lobe emphysema (see 130710) and underwent left upper lobectomy and subsequent right middle lobectomy; a chest x-ray also showed a soft tissue density posterior to the distal sternum, suggestive of Morgagni hernia. She was found to have growth hormone (GH) deficiency and was started on recombinant GH at age 6, but at age 10 she was still below the fifth percentile for height and weight. Inheritance Parental consanguinity and the occurrence of affected sibs of normal parents indicate autosomal recessive inheritance (Cohen et al., 1991; Boles et al., 1994). Mapping In a consanguineous Saudi Arabian family in which 2 children had a form of microcephalic primordial dwarfism resembling Meier-Gorlin syndrome, Bicknell et al. (2011) performed genomewide homozygosity mapping and identified a single homozygous region on chromosome 1p32 that was refined by microsatellite genotyping to a 15.6-cM region. Molecular Genetics In 2 affected sibs from a consanguineous Saudi Arabian family with a form of microcephalic primordial dwarfism resembling Meier-Gorlin syndrome mapping to chromosome 1p32, Bicknell et al. (2011) identified homozygosity for a missense mutation in the candidate gene ORC1 (601902.0001). Screening of 204 additional individuals with microcephalic primordial dwarfism identified a further 3 probands with biallelic missense mutations in ORC1 (601902.0002-601902.0004). All 5 mutation-positive individuals had very marked growth retardation with proportionate microcephaly and 3 had relatively small ears; however, in the 3 patients who underwent skeletal analysis, patellae were present, although 1 patient had hyperextended dislocated knees at birth. In a follow-up study, Bicknell et al. (2011) analyzed the ORC1 gene in 2 brothers with a complex lethal developmental syndrome involving profound growth retardation and microcephaly and identified compound heterozygosity for a missense (R105Q; 601902.0003) and a frameshift mutation (601902.0005). Both brothers also had microtia, and 1 had absent patellae. Subsequent sequencing of ORC1 in 33 individuals with an established diagnosis of Meier-Gorlin syndrome revealed 2 probands who were compound heterozygous for R105Q and a splice site mutation (601902.0006) in the ORC1 gene, 1 of whom was the male patient originally described by Gorlin et al. (1975) and the other, a 23-year-old English woman previously reported by Bongers et al. (2001). In a woman with Meier-Gorlin syndrome who was previously reported by Shalev and Hall (2003), Guernsey et al. (2011) independently identified compound heterozygosity for missense mutations in the ORC1 gene (601902.0003 and 601902.0007). ### Exclusion Studies Because the Meier-Gorlin syndrome had been suggested as the human equivalent of the 'short ear' mouse (Lacombe et al., 1994), Cohen et al. (2002) performed a mutation analysis of the BMP5 (112265) gene, which is mutant in the mouse disorder, in a patient with Meier-Gorlin syndrome; no mutation was found. The LMX1B (602575) and the SHOX (312865) genes were evaluated because of the absent patellae and short stature, respectively, and were found to be normal as well. Genotype/Phenotype Correlations De Munnik et al. (2012) studied 45 patients from 35 families with Meier-Gorlin syndrome, including 27 females and 18 males with ages ranging from 3 months to 47 years, most of whom had previously been reported (Bongers et al., 2001; Bicknell et al., 2011; Bicknell et al., 2011; Guernsey et al., 2011). Thirty-five patients from 26 families had mutations in 1 of the 5 known pre-replication complex genes, including 10 (29%) with mutations in ORC1, 7 (20%) in ORC4, 7 (20%) in ORC6, 10 (29%) in CDT1, and 1 (3%) in CDC6; 10 patients from 9 families did not have a definitive molecular diagnosis. The classic triad of microtia, absent or hypoplastic patellae, and short stature was observed in 82% of these patients. Additional manifestations included mammary hypoplasia, which was present in all 13 postpubertal females (10 mutation-positive and 3 without molecular diagnosis) and abnormal genitalia, which was present in 42% and consisted predominantly of cryptorchidism and hypoplastic labia majora/minora. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumference than individuals with mutations in the 4 other genes and individuals without definitive molecular diagnosis. No other clear genotype/phenotype correlation was detected, although compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation with mutations in ORC4 and more frequent pulmonary emphysema with mutations in CDT1, and a lethal phenotype was observed in 4 compound heterozygous individuals, 2 with mutations in ORC1 and 2 with mutations in CDT1. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature \- Birth length less than 3rd percentile Weight \- Birth weight less than 3rd percentile Other \- Failure to thrive \- Intrauterine growth retardation HEAD & NECK Head \- Microcephaly \- Small anterior fontanel Face \- Micrognathia \- Maxillary hypoplasia \- Mandibular hypoplasia \- Frontal bossing Ears \- Bilateral microtia \- Hearing loss \- Mondini malformation \- Low-set ears \- Atretic auditory canal Eyes \- Strabismus \- Long eyelashes \- Short palpebral fissures Mouth \- Small mouth \- Full lips \- Cleft palate \- High-arched palate Teeth \- Small teeth RESPIRATORY \- Respiratory distress (neonate) Lung \- Emphysema, congenital (in some patients) CHEST External Features \- Chest asymmetry Ribs Sternum Clavicles & Scapulae \- Pectus carinatum \- Lack of sternal ossification \- Slender ribs \- Flat or absent glenoid fossae \- Hooked clavicles \- Short ribs Breasts \- Breast hypoplasia ABDOMEN Gastrointestinal \- Feeding problems \- Gastroesophageal reflux GENITOURINARY External Genitalia (Male) \- Shawl scrotum \- Micropenis External Genitalia (Female) \- Clitoromegaly \- Hypoplastic labia minora \- Hypoplastic labia majora Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Delayed bone age \- Joint laxity \- Joint contractures Spine \- Hemivertebrae Pelvis \- Blount osteochondritis dissecans \- Aseptic femoral necrosis \- Coxa valga/vara Limbs \- Aplastic or hypoplastic patellae \- Elbow dislocation \- Epiphyseal flattening \- Slender long bones \- Genu valgum \- Genu varum Hands \- Fifth finger clinodactyly \- Small hands \- Camptodactyly Feet \- Cutaneous syndactyly (2nd-3rd, 4th-5th) \- Talipes equinovarus SKIN, NAILS, & HAIR Skin \- Thin skin \- Prominent vasculature (nose and forehead) Nails \- Hyperconvex nails Hair \- Long eyelashes NEUROLOGIC Central Nervous System \- Mental retardation PRENATAL MANIFESTATIONS Delivery \- Breech presentation MISCELLANEOUS \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the origin recognition complex, subunit 1, gene (ORC1, 601902.0001 ) ▲ 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	MEIER-GORLIN SYNDROME 1	c1868684	6,217	omim	https://www.omim.org/entry/224690	2019-09-22T16:28:28	{"doid": ["0080512"], "mesh": ["C538012"], "omim": ["224690"], "orphanet": ["2554"], "synonyms": ["Alternative titles", "EAR, PATELLA, SHORT STATURE SYNDROME", "MICROTIA, ABSENT PATELLAE, MICROGNATHIA SYNDROME", "MEIER-GORLIN SYNDROME"]}
Blue rubber bleb nevus syndrome Other namesBRBNS, or Blue rubber bleb syndrome, or Blue rubber-bleb nevus or Bean syndrome The cutaneous vascular malformations of blue rubber bleb nevus syndrome. SpecialtyOncology Blue rubber bleb nevus syndrome is a rare disorder that consists mainly of abnormal blood vessels affecting the skin or internal organs – usually the gastrointestinal tract.[1] The disease is characterized by the presence of fluid-filled blisters (blebs) as visible, circumscribed, chronic lesions (nevus). It was described by William Bean in 1958.[2][3][4] BRBNS is caused by somatic mutations in the TEK (TIE2) gene.[5] ## Contents * 1 Presentation * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Incidence * 6 See also * 7 References * 8 External links ## Presentation[edit] Cutaneous manifestation of blue rubber bleb nevus syndrome. BRBNS is a venous malformation,[6] formerly, though incorrectly, thought to be related to the hemangioma. It carries significant potential for serious bleeding.[7] Lesions are most commonly found on the skin and in the small intestine and distal large bowel. Other organs with the lesions can also be found on the central nervous system, liver, and muscles.[8] It usually presents soon after birth or during early infancy.[8][9] ## Causes[edit] The cause as to why blue rubber bleb nevus syndrome occurs is currently unknown. The syndrome is considered sporadic. Someone who is diagnosed with BRBNS likely has a family relative that has other multifocal venous malformations[10] which is a symptom of the disease. Autosomal inheritance of BRBNS has been found in familial cases associated with chromosome 9p, but the majority of cases are sporadic.[8] The disease correlates with an onset of GI complications. It is reported that GI bleeding is the most common cause of death in most cases.[11] ## Diagnosis[edit] Visceral venous malformations seen in blue rubber bleb nevus syndrome. Lesions chiefly affect the gut (image above), are fragile, and bleed easily. Blue rubber bleb nevus syndrome is difficult to diagnose because of how rare the disease is. Diagnosing BRBNS is usually based on the presence of cutaneous lesions with or without gastrointestinal bleeding and/or involvement of other organs.[8] Cutaneous angiomas are found on the surface of the skin and from the scalp to the soles of feet.[8] The characteristics of the cutaneous lesions are rubbery, soft, tender and hemorrhagic, easily compressible and promptly refill after compression.[8] A physical examination is mostly used to diagnosis cutaneous angiomas on the surface of the skin. Endoscopy has been the leading diagnostic tool for diagnosing BRBNS for those who suffer from lesions in the gastrointestinal tract. The GI tract is illuminated and visualized in endoscopy. [10] Endoscopy also allows immediate therapeutic measures like argon plasma, coagulation, laser photocoagulation, sclerotherapy, or band ligation.[12] Besides physical examination and endoscopy, ultrasonography, radiographic images, CT and magnetic resonance imaging are helpful for detection of affected visceral organs.[8] ## Treatment[edit] There are several methods to treat BRBNS as it is not a curable disease. Treatment for BRBNS depends on the severity and location of affected areas.[13] The cutaneous lesions can be effectively treated by laser, surgical removal, electrodesiccation, cryotherapy, and sclerotherapy.[14] In other cases, iron therapy (such as iron supplementation) and blood transfusions are used to conservatively manage BRBNS because of the amount of blood that is lost from the GI bleeding.[10] It is not necessary to remove the lesions in the gastrointestinal system unless the bleeding leads to anemia and repeatedly have blood transfusions.[10] It is safe to remove GI lesions surgically, but one or more lengthy operations may be required.[10] If there is a recurrence with new angioma in the gastrointestinal tract, laser-steroid therapy is needed.[15] Treatment is not required for those with skin spots, but some individuals with BRBNS may want treatment for cosmetic reasons or if the affected location causes discomfort or affects normal function.[13] ## Incidence[edit] Blue Rubber Bleb Nevus Syndrome affects males and females in equal numbers.[10] According to a review of literature, 20% of patients with BRBNS were from the United States, 15% from Japan, 9% from Spain, 9% from Germany, 6% from China, and 6% from France; and a lower number of cases from other countries.[8] This indicates that any race can be affected by BRBNS.[citation needed] ## See also[edit] * Bart syndrome * List of cutaneous conditions ## References[edit] 1. ^ Lybecker, MB; Stawowy, M; Clausen, N (20 December 2016). "Blue rubber bleb naevus syndrome: a rare cause of chronic occult blood loss and iron deficiency anaemia". BMJ Case Reports. 2016: bcr2016216963. doi:10.1136/bcr-2016-216963. PMC 5174816. PMID 27999128. 2. ^ synd/740 at Who Named It? 3. ^ Bean WB (1958). Vascular spiders and related lesions of the skin. Springfield, Illinois: Charles C.Thomas. pp. 178–85. 4. ^ Walshe MM, Evans CD, Warin RP (October 1966). "Blue rubber bleb naevus". British Medical Journal. 2 (5519): 931–2. doi:10.1136/bmj.2.5519.931. PMC 1944156. PMID 5920397. 5. ^ Soblet J, Kangas J, Nätynki M, Mendola A, Helaers R, Uebelhoer M, et al. (January 2017). "Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations". The Journal of Investigative Dermatology. 137 (1): 207–216. doi:10.1016/j.jid.2016.07.034. PMID 27519652. 6. ^ Dobru D, Seuchea N, Dorin M, Careianu V (September 2004). "Blue rubber bleb nevus syndrome: case report and literature review". Romanian Journal of Gastroenterology. 13 (3): 237–40. PMID 15470538. 7. ^ Ertem D, Acar Y, Kotiloglu E, Yucelten D, Pehlivanoglu E (February 2001). "Blue rubber bleb nevus syndrome". Pediatrics. 107 (2): 418–20. doi:10.1542/peds.107.2.418. PMID 11158481. 8. ^ a b c d e f g h Jin XL, Wang ZH, Xiao XB, Huang LS, Zhao XY (December 2014). "Blue rubber bleb nevus syndrome: a case report and literature review". World Journal of Gastroenterology. 20 (45): 17254–9. doi:10.3748/wjg.v20.i45.17254. PMC 4258599. PMID 25493043. 9. ^ Kassarjian A, Fishman SJ, Fox VL, Burrows PE (October 2003). "Imaging characteristics of blue rubber bleb nevus syndrome". AJR. American Journal of Roentgenology. 181 (4): 1041–8. doi:10.2214/ajr.181.4.1811041. PMID 14500226. 10. ^ a b c d e f "Blue Rubber Bleb Nevus syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2018-10-08. 11. ^ "Blue rubber bleb nevus syndrome (Bean syndrome)". www.dermatologyadvisor.com. Retrieved 2018-10-08. 12. ^ Agnese M, Cipolletta L, Bianco MA, Quitadamo P, Miele E, Staiano A (April 2010). "Blue rubber bleb nevus syndrome". Acta Paediatrica. 99 (4): 632–5. doi:10.1111/j.1651-2227.2009.01608.x. PMID 19958301. S2CID 5722981. 13. ^ a b "Blue rubber bleb nevus syndrome \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-10-08. 14. ^ Chen W, Chen H, Shan G, Yang M, Hu F, Li Q, Chen L, Xu G (August 2017). "Blue rubber bleb nevus syndrome: our experience and new endoscopic management". Medicine. 96 (33): e7792. doi:10.1097/md.0000000000007792. PMC 5571702. PMID 28816965. 15. ^ Deng ZH, Xu CD, Chen SN (February 2008). "Diagnosis and treatment of blue rubber bleb nevus syndrome in children". World Journal of Pediatrics. 4 (1): 70–3. doi:10.1007/s12519-008-0015-9. PMID 18402258. S2CID 42702922. ## External links[edit] Classification D * ICD-10: D18 * ICD-9-CM: 228.0 * ICD-O: 9121/0 * OMIM: 112200 * MeSH: C536240 External resources * eMedicine: derm/56 * Blue rubber bleb nevus; Bean syndrome at NIH's Office of Rare Diseases * 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	Blue rubber bleb nevus syndrome	c0346072	6,218	wikipedia	https://en.wikipedia.org/wiki/Blue_rubber_bleb_nevus_syndrome	2021-01-18T18:50:11	{"gard": ["5940"], "mesh": ["C536240"], "umls": ["C0346072"], "icd-9": ["228.0"], "icd-10": ["D18"], "orphanet": ["1059"], "wikidata": ["Q885574"]}
Joubert syndrome with ocular defect is, along with pure JS, the most frequent subtype of Joubert syndrome and related disorders (JSRD, see these terms) characterized by the neurological features of JS associated with retinal dystrophy. ## Epidemiology Prevalence is unknown. ## Clinical description Age of onset and severity of retinal involvement are variable, ranging from congenital blindness in patients with Leber congenital amaurosis (LCA, see this term) to progressive retinopathy with partial conservation of vision. ## Etiology To date, the most frequently mutated gene in this subtype is AHI1 (6q23.2), which accounts for about 20% of cases, following autosomal recessive inheritance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 with ocular defect	c1837713	6,219	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=220493	2021-01-23T18:28:58	{"gard": ["10168"], "mesh": ["C536295"], "omim": ["608629", "614424", "614464", "614970", "617121"], "icd-10": ["H35.5", "Q04.3"], "synonyms": ["JS-O", "Joubert syndrome with retinopathy"]}
A number sign (#) is used with this entry because chondrocalcinosis-2 (CCAL2) is caused by heterozygous mutation in the ANKH gene (605145) on chromosome 5p15. Description Chondrocalcinosis, or cartilage calcification, is a common condition that usually results from deposition of crystals of calcium pyrophosphate dihydrate (CPPD) in articular hyaline and fibro-cartilage. CPPD crystal deposition may be asymptomatic or associated with characteristic acute attacks ('pseudogout') or chronic arthritis. It can be detected radiographically. Chondrocalcinosis occurs in 3 forms: a primary hereditary form (e.g., CCAL2); a form associated with metabolic disorders (e.g., hyperparathyroidism, hemochromatosis, and hypomagnesemia), and a sporadic form, which may in some cases represent the hereditary form (summary by Hughes et al., 1995 and Richette et al., 2009). ### Genetic Heterogeneity of Chondrocalcinosis Another form of chondrocalcinosis (CCAL1; 600668) has been mapped to chromosome 8q. Clinical Features Under the designation of chondrocalcinosis articularis, Aschoff et al. (1966) described a family with 4 affected persons in 2 generations. The disorder was manifested clinically by episodic inflammatory involvement, acute or subacute, of one or more joints. Calcified hyaline and fibrous cartilage is demonstrable by x-ray, particularly in large joints. In articular cartilage a dense narrow band follows the contour of the epiphysis. Reginato et al. (1970) observed an unusually high frequency among natives of the Chiloe Island group. Twenty-eight patients were observed of whom 19 were aggregated in 6 kindreds. Parent-child involvement with no male-to-male transmission was observed in 3 of the families. In the other 3 families one or both parents were not screened. Since the Chiloe group lives in an isolated area and is presumably inbred, recessive inheritance remains a possibility. In these cases involvement was polyarticular. Ankylosing of joints was a new feature observed in this study. Rodriguez-Valverde et al. (1980) studied the first-degree relatives of 46 cases in northern Spain and found that 5 cases were familial. In these 5 families, a total of 17 persons showed calcified cartilage radiographically. All were in the same generation, although not always in the same sibship. Inbreeding (type unspecified) was stated for 4 of the 5 kindreds. In a further study, Rodriguez-Valverde et al. (1988) identified 13 pedigrees through a systematic radiologic survey of the first-degree relatives of 76 probands. Thirty women and 11 men in 25 sibships were affected. The disease was of early onset in only 4 pedigrees. The clinical manifestations in these 4 pedigrees were similar to those found in the kindreds with late onset. Autosomal dominant inheritance was supported. In Spain, Fernandez Dapica and Gomez-Reino (1986) found a 28.1% prevalence of chondrocalcinosis in 149 relatives of 32 patients with calcium pyrophosphate dihydrate deposition disease. No clinical or radiologic differences between sporadic and familial cases were found. The features were similar to those of the Chiloe islanders with familial chondrocalcinosis as reported by Reginato (1976). Fernandez Dapica and Gomez-Reino (1986) concluded that the findings support the idea that the disorder was carried to Chile by Spanish immigrants. Depressed activity of synovial pyrophosphohydrolase was suggested by the findings of Good and Starkweather (1969). This was not pursued further (Good, 1974). Van der Korst et al. (1974) reported a family with chondrocalcinosis in which father-to-son transmission was noted, supporting autosomal dominant inheritance. Twenty-two cases in 2 generations were observed. Acute attacks occurred in only 14 of the 22 and 6 of the 14 had not yet sought medical care. Gaudreau et al. (1981) described articular chondrocalcinosis in 9 persons in 3 generations of a Quebec family (presumably French Canadian). Extensive calcification of the cartilage of the pinnae and of intervertebral discs was demonstrated. In 12 affected members of a single kindred (Gaucher et al., 1977), Lust et al. (1981) found that cultured fibroblasts and lymphocytes had a concentration of intracellular inorganic pyrophosphate 2 times greater than that in cells from unaffected family members and normal, unrelated volunteers. Bjelle et al. (1982) studied 2 extensive, affected Swedish kindreds that supported autosomal dominant inheritance. Of persons over 50 years of age, 47% had experienced acute attacks of arthritis and/or had joint calcifications. Back pain was frequent, but no ankylosis or deformity was observed. As compared with 50 sporadic cases observed in the same area of Sweden, the familial cases had an earlier onset, a greater number of involved joints, and more frequent peripheral joint involvement. Back pain was more frequent, and calcification of intervertebral discs was found only in the hereditary cases. Bjelle et al. (1982) demonstrated a genealogic link between 3 Swedish families, thus showing probable founder effect similar to that found in Slovakia, France, and Chile. No connection to other European families was found. In an Ashkenazi Jewish kindred, Eshel et al. (1990) found 7 members with a medical history of this disorder and in the most recent generations 5 members with direct evidence of the disorder. Symptoms started in the third decade and radiologic evidence developed by the fourth decade. The joints commonly affected were knees, wrists, and elbows. The course was chronic with acute, exercise-induced exacerbations. Doherty et al. (1991) reported 5 unrelated English kindreds with familial chondrocalcinosis due to CPPD crystal deposition. The largest pedigree was unique in that affected family members also suffered recurrent benign fits in childhood, permitting clear delineation of phenotype at a young age--a major advantage in a condition that usually shows late onset. The pattern of inheritance in this extended pedigree was consistent with autosomal dominant transmission with 100% penetrance. Hughes et al. (1995) described the clinical phenotype in this large English family, which included recurrent benign seizures that developed in the second half of the first year of life, occurred with a frequency of 3-9 per year, ceased around age 6 years, and were not associated with physical or mental retardation. Acute attacks of pseudogout associated with radiographic polyarticular chondrocalcinosis developed in the late third and early fourth decades. These attacks continued against a subsequent background of chronic or intermittent arthralgia. Chronic inflammatory arthritis or deformity did not develop and functional outcome was good in general. Inheritance An autosomal dominant mode of inheritance of chondrocalcinosis was suggested in several reports (e.g., van der Korst et al., 1974; Bjelle et al., 1982; Rodriguez-Valverde et al., 1988). In a study of 35 patients with chondrocalcinosis in Spain, Balsa et al. (1990) found a prevalence of familial disease of 26%. They suggested autosomal dominant inheritance with incomplete penetrance and more severe involvement in homozygotes. Autosomal dominant inheritance was demonstrated by Hughes et al. (1995). Mapping By a genomewide screen using highly informative microsatellite polymorphisms in a large English family with affected members with chondrocalcinosis in 4 generations, Hughes et al. (1995) mapped the mutant gene in this kindred to chromosome 5p. A maximum multipoint lod score of 4.6 was obtained for the region between D5S810 and D5S416. In a study of 2 families, an Argentinian kindred of northern Italian ancestry and a French kindred from the Alsace region, Andrew et al. (1999) found evidence of linkage consistent with the mapping to 5p15 previously reported by Hughes et al. (1995). Andrew et al. (1999) stated that recombinants in the Argentinian kindred enabled them to designate a region of less than 1 cM between markers D5D416 and D5S2114 for the CPPDD locus. Hughes (2001) pointed out that these 2 regions do not overlap. They stated that the likely reason for the discrepancy is misdiagnosis or mistyping in a family studied by Andrew et al. (1999) since phenocopies and nonpenetrant individuals had been shown in early versions of one of their pedigrees. Molecular Genetics Pendleton et al. (2002) showed that affected members of the families with chondrocalcinosis-2 reported by Hughes et al. (1995) and Andrew et al. (1999) had mutations in the ANKH gene; see 605145.0006-605145.0007. Williams et al. (2003) screened for mutations in the ANKH gene in 2 U.S. families with autosomal dominant CPPDD and found that all affected members were heterozygous for a pro5-to-thr mutation (605145.0010). The 2 families displayed distinct haplotypes. Williams et al. (2003) noted that the family described by Williams et al. (2002) had a different mutation at the same codon (see 605145.0009) and also displayed a distinct haplotype. They concluded that the evolutionarily conserved pro5 position of ANKH may represent a hotspot for mutation in families with autosomal dominant CCAL2. Baynam et al. (2009) restudied a large 4-generation Australian family with craniometaphyseal dysplasia (CMDD; 123000), originally described by Taylor and Sprague (1989) and in which affected individuals were found to have a heterozygous missense mutation in the ANKH gene (G389R; 605145.0002) by Nurnberg et al. (2001). A 57-year-old female family member with CMDD also reported episodic unilateral shoulder pain beginning in her twenties, with radiographically confirmed ectopic calcification treated by surgical excision at 22 years of age. In addition, she had episodic pain of the small joints of her hands and feet (second and third metacarpals and metatarsals, respectively) and of her knees, and underwent excision of an exostosis of the left knee in her thirties. Technetium bone scan was consistent with marked focal arthropathy and mild synovitis of the affected small joints. A sister and half sister, both mutation-positive and aged 53 and 68 years, respectively, similarly reported episodic excruciating joint pain typically lasting 48 hours, with onset in their twenties; 1 of the sisters had calcium hydroxyapatite crystals identified in synovial fluid from an affected joint. Their affected mother was described as having episodic joint pain that was occasionally debilitating, predominantly affecting the hands and feet. The 57-year-old woman had 3 mutation-positive sons, 2 of whom were asymptomatic; the third, who was 30 years old, manifested a slowly progressive unilateral facial palsy but no discrete episodes of pain, and he had a 22-month-old son with choanal stenosis and radiographic evidence of CMDD. Although a chance association of chondrocalcinosis with CMDD could not be excluded, Baynam et al. (2009) suggested that the lack of joint symptoms in affected male family members might be due to involvement of sex-dependent mechanisms or to the fact that only mutation-positive women in the pedigree had reached the age at which the chondrocalcinosis phenotype typically expresses. INHERITANCE \- Autosomal dominant SKELETAL Limbs \- Polyarticular chondrocalcinosis (cartilage calcification) \- Calcium pyrophosphate dihydrate (CPPD) crystal deposition (knee, symphysis pubis, wrist) \- Pseudoosteoarthritis \- Pseudogout \- Arthropathy \- Osteoarthritis MISCELLANEOUS \- Age of onset third decade \- Allelic to craniometaphyseal dysplasia ( 123000 ) MOLECULAR BASIS \- Caused by mutation in the ANKH inorganic pyrophosphate transport regulator gene (ANKH, 605145.0006 ) ▲ 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	CHONDROCALCINOSIS 2	c0553730	6,220	omim	https://www.omim.org/entry/118600	2019-09-22T16:43:22	{"doid": ["1156"], "mesh": ["D002805"], "omim": ["118600"], "orphanet": ["1416"], "synonyms": ["Alternative titles", "CHONDROCALCINOSIS, FAMILIAL ARTICULAR", "CALCIUM GOUT", "CALCIUM PYROPHOSPHATE ARTHROPATHY", "CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE"]}
A number sign (#) is used with this entry because of evidence that X-linked neurodevelopmental disorder with craniofacial abnormalities (NEDXCF) is caused by heterozygous or hemizygous mutation in the STAG2 gene (300826) on chromosome Xq25. Description X-linked neurodevelopmental disorder with craniofacial abnormalities is characterized by global developmental delay with impaired intellectual development and poor speech. Ear abnormalities and hearing loss are common, as are dysmorphic facial features such as microcephaly and cleft palate. Other features may include short stature, scoliosis, vertebral abnormalities, and mild limb abnormalities such as fifth finger clinodactyly. Clinical manifestations depend on the type of mutation: female carriers with missense mutations may be unaffected, and conversely, males with nonsense or truncating mutations may have a severe phenotype with early death (summary by Aoi et al., 2019). Clinical Features ### Female Patients Mullegama et al. (2017) reported an 8-year-old girl of Latino/Hispanic descent (patient 1) with global developmental delay, progressive microcephaly, microtia with hearing loss, speech and language delay, attention deficit-hyperactivity disorder, and poor overall growth. She walked and spoke her first words at 18 months. Dysmorphic features included borderline microcephaly, low anterior hairline, sloping forehead, left preauricular pit and tag, small left eye, asymmetric facial movements, and submucous cleft palate with bifid uvula. CT of the temporal bones showed several abnormalities on both sides, including left external auditory canal atresia with a fused ossicular mass, bilateral absent stapes, stenosis or absence of the oval windows, and abnormal placement of the facial nerves. Other features included fifth finger clinodactyly, scoliosis, vertebral body abnormalities, and dysgenesis of the splenium of the corpus callosum. Two additional unrelated girls with a similar phenotype were subsequently identified in the DECIPHER database. Clinical details were limited, but the girls were noted to have developmental delay, craniofacial, and limb or skeletal abnormalities. Yuan et al. (2019) reported 4 unrelated girls with NEDXCF who had developmental delay with impaired intellectual development, speech delay, hypotonia, microcephaly, and short stature. Variable dysmorphic features included micrognathia, long curly eyelashes, depressed or broad nasal bridge, bulbous nasal tip, dysmorphic ears, thin upper lip, and long smooth philtrum. Only 1 had conductive hearing loss. Two patients had congenital diaphragmatic hernia and 1 had hypoplastic left heart with ventricular septal defect and coarctation of the aorta. Other variable features included scoliosis, vertebral abnormalities, and fifth finger clinodactyly. Aoi et al. (2019) reported a 7-year-old Japanese girl (patient 2) with global developmental delay, impaired intellectual development, sensorineural hearing loss, and white matter hypoplasia. Dysmorphic features included cleft palate and long philtrum. She developed seizures at 8 months, which were responsive to medication. At age 7, she had only a few words and attended a school for hearing-impaired children. ### Male Patients Soardi et al. (2017) reported a large Brazilian family in which 5 males had a similar neurodevelopmental disorder. The proband was first seen at age 29 years. He had moderately impaired intellectual development, short stature, cleft palate, unilateral sensorineural deafness, and dysmorphic features, including large nose, prominent eyes, and frontal baldness. The other 4 affected males had a similar phenotype. Obligate female mutation carriers in the family were unaffected. Yuan et al. (2019) reported a 5-year-old male (patient 11) with failure to thrive, short stature, microcephaly, and developmental delay. He also had dysmorphic craniofacial features with cleft lip and palate and scoliosis. He had dysmorphic low-set ears, but did not have hearing loss. Mullegama et al. (2019) reported a 4-year-old boy, born of unrelated parents, with developmental delay, failure to thrive, short stature, foot polydactyly, and pes planus. He walked at 16 months, used small phrases at 17 months, and later showed an unsteady gait with lower limb hypotonia, as well as speech difficulties. Dysmorphic features included microcephaly (less than first percentile), high anterior hairline, mild frontal bossing, prominent cheeks, triangular face, and fifth finger clinodactyly. Brain imaging and audiology testing were normal. Aoi et al. (2019) reported a male fetus (patient 1), conceived of unrelated Japanese parents, who was noted on prenatal ultrasound at 15 weeks' gestation to have holoprosencephaly, blepharophimosis, cleft lip and palate, absence of the nasal bone, and hypoplastic left heart. The pregnancy was terminated due to multiple fetal abnormalities. Inheritance The transmission pattern of NEDXCF in the family reported by Soardi et al. (2017) was consistent with X-linked recessive inheritance. Molecular Genetics In an 8-year-old girl (patient 1) with NEDXCF, Mullegama et al. (2017) identified a de novo heterozygous nonsense mutation in the STAG2 gene (R69X; 300826.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to encode a protein lacking 3 essential protein domains. Western blot analysis of patient cells showed decreased amounts of STAG2 protein compared to controls, and the authors noted that the mutation may trigger nonsense-mediated mRNA decay. Analysis of metaphase in patient cells showed a reduction in premature sister chromatid separation compared to controls, although karyotypes were normal and there were no significant aneuploidies. Mullegama et al. (2017) postulated a loss-of-function mechanism causing haploinsufficiency, and noted that some of STAG2's other functions, such as the regulation of gene expression, may also be disrupted by the mutation. Subsequent searching of the DECIPHER database identified 2 additional girls with overlapping clinical features who had de novo heterozygous variants in the STAG2 gene (R604Q and c.1913_1922del). None of the variants were present in the 1000 Genomes Project or ExAC databases, but functional studies of the latter 2 mutations were not performed. In 5 affected males from a large Brazilian family with NEDXCF, Soardi et al. (2017) identified a hemizygous missense mutation in the STAG2 gene (S327N; 300826.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There were at least 2 confirmed healthy females carriers of the mutation. Analysis of patient fibroblasts showed that the mutant protein was expressed in normal amounts and localized properly to the nucleus, similar to wildtype, and there were no defects in sister chromatid cohesion. However, patient cells showed cell cycle abnormalities, including increased percentage of G2/M cells and upregulation of genes involved in cell division, mitotic regulation, and DNA replication compared to controls. These findings were consistent with a defect in transcriptional regulation. Expression of the mutation in HeLa cells showed decreased binding of the mutant protein to SCC1 and other cohesin regulators. In a 4-year-old boy with NEDXCF, Mullegama et al. (2019) identified a de novo hemizygous missense mutation in the STAG2 gene (K1009N; 300826.0003). The mutation was found by exome sequencing; functional studies of the variant and studies of patient cells were not performed. Mullegama et al. (2019) postulated that females, who carry 2 copies of the STAG2 gene, are able to survive with deleterious de novo variants, but show severe phenotypes. In contrast, males, who have only 1 copy of the gene, are unable to survive with similar variants due to early embryonic lethality. Males can survive with less damaging variants, such as missense mutations, and usually present with a milder phenotype. Yuan et al. (2019) reported 5 unrelated patients, including 4 females and 1 male, with NEDXCF who had de novo heterozygous or hemizygous mutations in the STAG2 gene (see, e.g., 300826.0004-300826.0006). Three of the 4 females had truncating mutations, whereas the male had a missense mutation; none of the mutations were found in the ExAC or Exome Sequencing Project databases. Yuan et al. (2019) postulated loss of function as the presumed mechanism, although functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a large cohort of over 10,000 patients referred for exome sequencing. Aoi et al. (2019) identified 2 nonsense mutations in the STAG2 gene in 2 unrelated Japanese patients with NEDXCF. A male fetus (patient 1) was hemizygous for R1033X (300826.0007) and a 7-year-old girl (patient 2) was heterozygous for W743X (300826.0008). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants were not performed, but the female patient showed skewed X-inactivation with expression of STAG2 only from the wildtype allele. Aoi et al. (2019) noted that no males with nonsense or frameshift STAG2 mutations had previously been reported, consistent with the hypothesis that hemizygous truncating mutations cause a severe fetal phenotype and/or embryonic lethality in males. INHERITANCE \- X-linked GROWTH Height \- Short stature Other \- Failure to thrive \- Poor overall growth HEAD & NECK Head \- Microcephaly \- Sloping forehead \- Frontal bossing Face \- Dysmorphic facial features, variable \- Asymmetric facial movements \- Triangular face \- Long philtrum \- Short philtrum \- Smooth philtrum \- Full cheeks \- Micrognathia Ears \- Microtia \- Dysmorphic ears \- Low-set ears \- Preauricular tag \- Preauricular pit \- Sensorineural hearing loss (in most patients) \- Abnormalities of the temporal bones and inner ear bones (in some patients) Eyes \- Small eyes \- Prominent eyes \- Long curly eyelashes Nose \- Depressed nasal bridge \- Broad nasal bridge \- Bulbous nasal tip \- Large nose Mouth \- Thin upper lip \- Cleft lip \- Cleft palate CARDIOVASCULAR Heart \- Hypoplastic left heart (in some patients) \- Septal defects (in some patients) \- Coarctation of the aorta (in some patients) CHEST Diaphragm \- Diaphragmatic hernia (in some patients) SKELETAL Spine \- Scoliosis \- Vertebral body abnormalities Hands \- Fifth finger clinodactyly Feet \- Pes planus \- Polydactyly SKIN, NAILS, & HAIR Hair \- Low anterior hairline \- High anterior hairline \- Frontal baldness (in males) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Impaired intellectual development \- Delayed walking \- Unsteady gait \- Speech and language delay \- Abnormalities of the corpus callosum (in some patients) \- White matter abnormalities, nonspecific Behavioral Psychiatric Manifestations \- Attention deficit-hyperactivity disorder (in some patients) MISCELLANEOUS \- Variable phenotype \- Manifestations may differ between female and male patients MOLECULAR BASIS \- Caused by mutation in the stromal antigen 2 gene (STAG2, 300826.0001 ) ▲ 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	NEURODEVELOPMENTAL DISORDER, X-LINKED, WITH CRANIOFACIAL ABNORMALITIES	None	6,221	omim	https://www.omim.org/entry/301022	2019-09-22T16:18:57	{"omim": ["301022"]}
Dermatopathia pigmentosa reticularis Other namesDermatopathic pigmentosa reticularis[1]:511 Dermatopathia pigmentosa reticularis has an autosomal dominant pattern of inheritance SpecialtyMedical genetics Dermatopathia pigmentosa reticularis is a rare, autosomal dominant[2] congenital disorder that is a form of ectodermal dysplasia. Dermatopathia pigmentosa reticularis is composed of the triad of generalized reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy.[3]:856 ## Contents * 1 Presentation * 2 Cause * 3 Treatment * 4 See also * 5 References * 6 External links ## Presentation[edit] Symptoms include lack of sweat glands, thin hair, brittle nails, mottled skin, and lack of fingerprints.[4] DPR is very similar to the related Naegeli-Franceschetti-Jadassohn syndrome. Both cause an affected person to lack fingerprints, have a lace-like pattern of hyperpigmentation and hyperkeratosis of the palms of the hands and soles of the feet. DPR is distinguished from NFJS by the duration of hyperpigmentation and lack of dental abnormalities.[5] ## Cause[edit] DPR is caused by a mutation in the keratin 14 gene.[6] ## Treatment[edit] This section is empty. You can help by adding to it. (April 2017) ## See also[edit] * List of cutaneous conditions caused by mutations in keratins ## References[edit] 1. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. 2. ^ Heimer WL II, Brauner G, James WD (1992). "Dermatopathia pigmentosa reticularis: a report of a family demonstrating autosomal dominant inheritance". J Am Acad Dermatol. 26 (2 pt. 2): 298–301. doi:10.1016/0190-9622(92)70039-I. PMID 1303619. 3. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 4. ^ "OMIM Clinical Synopsis - #125595 - DERMATOPATHIA PIGMENTOSA RETICULARIS; DPR". www.omim.org. Retrieved 13 October 2018. 5. ^ "OMIM Entry - # 125595 - DERMATOPATHIA PIGMENTOSA RETICULARIS; DPR". www.omim.org. Retrieved 13 October 2018. 6. ^ Lugassy J, Itin P, Ishida-Yamamoto A, et al. (October 2006). "Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14". Am. J. Hum. Genet. 79 (4): 724–30. doi:10.1086/507792. PMC 1592572. PMID 16960809. ## External links[edit] Classification D * ICD-10: Q82.4 * OMIM: 125595 * MeSH: C535374 * 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 This article about a congenital malformation is a stub. You can help Wikipedia by expanding it. * v * t * e This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e This genetic disorder article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Dermatopathia pigmentosa reticularis	c0406778	6,222	wikipedia	https://en.wikipedia.org/wiki/Dermatopathia_pigmentosa_reticularis	2021-01-18T19:04:21	{"gard": ["8550"], "mesh": ["C535374"], "umls": ["C0406778"], "icd-10": ["Q82.4"], "orphanet": ["86920"], "wikidata": ["Q5262702"]}
Seckel syndrome is a type of microcephalic primordial dwarfism that is characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly, a typical dysmorphic face (bird-like), and mild to severe intellectual disability. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Seckel syndrome	c0265202	6,223	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=808	2021-01-23T17:19:26	{"gard": ["8562"], "mesh": ["C537533"], "omim": ["210600", "600546", "606744", "613676", "613823", "615807", "616051", "616171", "616777"], "umls": ["C0265202"], "icd-10": ["Q87.1"]}
## Description Rupture of an intracranial aneurysm, an outpouching or sac-like widening of a cerebral artery, leads to a subarachnoid hemorrhage, a sudden-onset disease that can lead to severe disability and death. Several risk factors such as smoking, hypertension, and excessive alcohol intake are associated with subarachnoid hemorrhage (summary by Krischek and Inoue, 2006). For a discussion of genetic heterogeneity of intracranial berry aneurysms, see ANIB1 (105800). Mapping Kim et al. (2011) performed genomewide linkage analysis of 5 Korean families from the Chonbuk province in Korea who had autosomal dominant inheritance of intracranial aneurysm. DNA samples were available from 9 affected and 22 unaffected individuals. The study identified a locus on chromosome 8p22.2 (maximum 2-point lod score of 3.61 at marker D8S552). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	ANEURYSM, INTRACRANIAL BERRY, 11	c1862932	6,224	omim	https://www.omim.org/entry/614252	2019-09-22T15:55:56	{"doid": ["0060228"], "mesh": ["C566284"], "omim": ["105800", "614252"], "orphanet": ["231160"], "synonyms": ["Familial berry aneurysm", "Familial intracranial saccular aneurysm"]}
Abortion in Belarus has been legal since November 23, 1955, when Belarus was a republic of the Soviet Union.[1] The current abortion legislation dates from December 31, 1987, and is one of the most liberal abortion laws in Europe. Abortion is allowed on request up to 12 weeks, and in specific circumstances, on a variety of grounds, until 28 weeks.[2] The 1987 law allows abortion for the traditional reasons of harm or death to the fetus and/or mother, rape and incest, as well as: * the death of the husband during pregnancy, * a jail sentence for either the mother or father, * a court order stripping the pregnant woman of parental rights, * if a household already exceeds five children, * if the relationship between mother and father ends in divorce, * or a family history which includes mental or physical disabilities.[1] Once a popular method of birth control, abortions exceeded live births two-to-one in 1995.[3] The rate had fallen by over 75%, with abortions numbering 42,000 (or 39% of the live birth rate) in 2008.[3] As of 2010[update], the abortion rate was 14.7 abortions per 1000 women aged 15–44 years.[4] ## References[edit] 1. ^ a b Belarus - ABORTION POLICY - United Nations 2. ^ http://www.womenonwaves.org/en/page/4757/belarus--abortion-law 3. ^ a b Fewer Abortions In Belarus, But More Single Mothers 4. ^ "World Abortion Policies 2013". United Nations. 2013. Retrieved 3 March 2014. * v * t * e Abortion in Europe Sovereign states * Albania * Andorra * Armenia * Austria * Azerbaijan * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Cyprus * Czech Republic * Denmark * Estonia * Finland * France * Georgia * Germany * Greece * Hungary * Iceland * Ireland * * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Turkey * Ukraine * United Kingdom * England * Northern Ireland * Scotland * Wales * Vatican City States with limited recognition * Abkhazia * Artsakh * Kosovo * Northern Cyprus * South Ossetia * Transnistria * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category This abortion-related article is a stub. You can help Wikipedia by expanding it. * v * t * e This Belarus-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	Abortion in Belarus	None	6,225	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Belarus	2021-01-18T18:42:24	{"wikidata": ["Q625851"]}
Mendelian susceptibility to mycobacterial diseases (MSMD) due to partial STAT1 (signal transducer and activator of transcription 1) deficiency is a genetic variant of MSMD (see this term) characterized by a partial defect in the interferon (IFN)-gamma pathway, leading to mild mycobacterial infections. ## Epidemiology The prevalence is unknown. In 2001, two patients from unrelated kindreds were described and they suffered only mild MSMD. Since 2001, up to six other kindreds have been described to have a partial dominant STAT1 deficiency associated with MSMD. ## Clinical description First infections occur after the age of 3, most commonly with weakly virulent Mycobacterium bovis BCG and Mycobacterium avium complex or with the more virulent Mycobacterium tuberculosis. Clinical penetrance is incomplete and some patients are asymptomatic while others have very mild clinical manifestations. None of the patients identified to date developed severe viral illness. ## Etiology MSMD due to partial STAT1 deficiency is due to heterozygous mutations in the STAT1 gene on chromosome 2q32.2-q32.3 encoding the signal transducer and activator of transcription 1. Two distinct forms have been described: one affecting phosphorylation and the other impairing DNA-binding activity. ## Genetic counseling Transmission is autosomal dominant and genetic counseling is possible. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency	c4013950	6,226	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319595	2021-01-23T17:44:16	{"omim": ["614892"], "icd-10": ["D84.8"], "synonyms": ["MSMD due to partial STAT1 deficiency", "MSMD due to partial signal transducer and activator of transcription 1 deficiency", "Mendelian susceptibility to mycobacterial diseases due to partial signal transducer and activator of transcription 1 deficiency"]}
ANOTHER syndrome Other namesHypohidrotic ectodermal dysplasia-hypothyroidism-ciliary dyskinesia syndrome This condition is inherited in an autosomal recessive manner SpecialtyDermatology ANOTHER syndrome consists of alopecia, nail dystrophy, ophthalmic complications, thyroid dysfunction, hypohidrosis, ephelides and enteropathy, and respiratory tract infections.[1]:502 This is an autosomal recessive variant of ectodermal dysplasia.[1]:502 ## See also[edit] * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ a b James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. ## External links[edit] Classification D * ICD-10: Q82.4 * OMIM: 225050 * MeSH: C565604 External resources * Orphanet: 1882 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	ANOTHER syndrome	c1857052	6,227	wikipedia	https://en.wikipedia.org/wiki/ANOTHER_syndrome	2021-01-18T18:37:41	{"gard": ["2049"], "mesh": ["C565604"], "umls": ["C1857052"], "orphanet": ["1882"], "wikidata": ["Q4653007"]}
Aggressive NK-cell leukemia Other namesNK-cell large granular lymphocyte leukemia NK cell SpecialtyHematology and oncology Aggressive NK-cell leukemia is a disease with an aggressive, systemic proliferation of natural killer cells (NK cells) and a rapidly declining clinical course.[1] [2] [3] It is also called aggressive NK-cell lymphoma.[4] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Sites of involvement * 3 Diagnosis * 3.1 Peripheral blood * 3.2 Bone marrow * 3.3 Other organs * 3.4 Immunophenotype * 3.5 Genetic findings * 4 Treatment * 5 Epidemiology * 6 Research directions * 7 References * 8 External links ## Signs and symptoms[edit] Patients usually present with constitutional symptoms (malaise, weight loss, fatigue), and hepatosplenomegaly is commonly found on physical exam. Lymphadenopathy is also found to a lesser extent. Due to the aggressive nature of the disease, patients may initially present at a more advanced stage, with coagulopathies, hemophagocytic syndrome, and multi-organ failure.[1][2][5][6][7] Rarely, individuals who have an aggressive NK cell lymphoma that is associated with latent infection with the Epstein-Barr virus (see next section) present with or develop extensive allergic reactions to mosquito bites. The symptoms of these reactions range from a greatly enlarged bite site that may be painful and involve necrosis to systemic symptoms (e.g. fever, swollen lymph nodes, abdominal pain, and diarrhea), or, in extremely rare cases, to life-threatening anaphylaxis.[8] ## Cause[edit] This disease has a strong association with the Epstein-Barr virus (EBV),[9] but the true pathogenesis of this disease has yet to be described. The cell of origin is believed to be an NK cell.[4] Blastoid NK cell lymphoma appears to be a different entity and shows no association with EBV.[1] ### Sites of involvement[edit] This disease is typically found and diagnosed in peripheral blood, and while it can involve any organ, it is usually found in the spleen, liver, and bone marrow.[4] ## Diagnosis[edit] Leukemic cells are invariably present in samples of peripheral blood to a variable extent. Pancytopenia (anemia, neutropenia, thrombocytopenia) is commonly seen as well.[4] ### Peripheral blood[edit] The leukemic cells have a diameter mildly greater than a large granular lymphocyte (LGL) and have azurophilic granules and nucleoli of varying prominence. Nuclei may be irregular and hyperchromatic.[4] ### Bone marrow[edit] Bone marrow involvement runs the spectrum between an inconspicuous infiltrate to extensive marrow replacement by leukemic cells. Reactive histiocytes displaying hemophagocytosis can be seen interspersed in the neoplastic infiltrate.[4] ### Other organs[edit] Leukemic involvement of organs is typically destructive on tissue sections with necrosis and possibly angioinvasion, and the monotonous infiltrate may be diffuse or patchy.[4] ### Immunophenotype[edit] The immunophenotype of this disease is the same as extranodal NK/T-cell lymphoma, nasal type and is shown in the table below. CD11b and CD16 show variable expression.[1][10] Status Antigens Positive CD2, CD3ε, CD56, perforin, granzyme B, TIA-1, CCR5 Negative CD57 ### Genetic findings[edit] Due to the NK lineage, clonal rearrangements of lymphoid (T cell receptor; B cell receptor) genes are not seen.[4] The genome of the Epstein Barr virus (EBV) is detected in many cases,[9] along with a variety of chromosomal abnormalities.[11] ## Treatment[edit] Currently Aggressive NK-cell leukemia, being a subtype of PTCL, is treated similarly to B-cell lymphomas. However, in recent years, scientists have developed techniques to better recognize the different types of lymphomas, such as PTCL. It is now understood that PTCL behaves differently from B-cell lymphomas and therapies are being developed that specifically target these types of lymphoma. Currently, however, there are no therapies approved by the U.S. Food and Drug Administration (FDA) specifically for PTCL. Anthracycline-containing chemotherapy regimens are commonly offered as the initial therapy. Some patients may receive a stem cell transplant.[12][13][14][15][16] Novel approaches to the treatment of PTCL in the relapsed or refractory setting are under investigation. ## Epidemiology[edit] This rare form of leukemia is more common among Asians in comparison to other ethnic groups. It is typically diagnosed in adolescents and young adults, with a slight predominance in males.[1][2][3][5][17][9][10] ## Research directions[edit] Pralatrexate is one compound currently under investigations for the treatment of PTCL. ## References[edit] 1. ^ a b c d e Chan JK, Sin VC, Wong KF, et al. (June 1997). "Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm". Blood. 89 (12): 4501–13. doi:10.1182/blood.V89.12.4501. PMID 9192774. 2. ^ a b c Imamura N, Kusunoki Y, Kawa-Ha K, et al. (May 1990). "Aggressive natural killer cell leukaemia/lymphoma: report of four cases and review of the literature. Possible existence of a new clinical entity originating from the third lineage of lymphoid cells". Br. J. Haematol. 75 (1): 49–59. doi:10.1111/j.1365-2141.1990.tb02615.x. PMID 2375924. 3. ^ a b Chan JK (1998). "Natural killer cell neoplasms". Anat Pathol. 3: 77–145. PMID 10389582. 4. ^ a b c d e f g h Elaine Sarkin Jaffe; Nancy Lee Harris; World Health Organization, International Agency for Research on Cancer; Harald Stein; J.W. Vardiman (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumors. 3. Lyon: IARC Press. ISBN 978-92-832-2411-2. 5. ^ a b Kwong YL, Wong KF, Chan LC, et al. (January 1995). "Large granular lymphocyte leukemia. A study of nine cases in a Chinese population". Am. J. Clin. Pathol. 103 (1): 76–81. doi:10.1093/ajcp/103.1.76. PMID 7817949. 6. ^ Kobayashi Y, Uehara S, Inamori K, et al. (August 1996). "Hemophagocytosis as a para-neoplastic syndrome in NK cell leukemia". Int. J. Hematol. 64 (2): 135–42. doi:10.1016/0925-5710(96)00477-X. PMID 8854571. 7. ^ Okuda T, Sakamoto S, Deguchi T, et al. (December 1991). "Hemophagocytic syndrome associated with aggressive natural killer cell leukemia". Am. J. Hematol. 38 (4): 321–3. doi:10.1002/ajh.2830380412. PMID 1746541. 8. ^ Park S, Ko YH (January 2014). "Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders". The Journal of Dermatology. 41 (1): 29–39. doi:10.1111/1346-8138.12322. PMID 24438142. 9. ^ a b c Gelb AB, van de Rijn M, Regula DP, et al. (September 1994). "Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia". Hum. Pathol. 25 (9): 953–60. doi:10.1016/0046-8177(94)90018-3. PMID 8088773. 10. ^ a b Oshimi K (June 1996). "Lymphoproliferative disorders of natural killer cells". Int. J. Hematol. 63 (4): 279–90. doi:10.1016/0925-5710(96)00450-1. PMID 8762811. 11. ^ Wong KF, Zhang YM, Chan JK (July 1999). "Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia—is there a consistent pattern?". Leuk. Lymphoma. 34 (3–4): 241–50. doi:10.3109/10428199909050949. PMID 10439361. 12. ^ Reimer P, Rüdiger T, Geissinger E, et al. (January 2009). "Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study". J. Clin. Oncol. 27 (1): 106–13. doi:10.1200/JCO.2008.17.4870. PMID 19029417. Archived from the original on 2012-08-03. 13. ^ Mercadal S, Briones J, Xicoy B, et al. (May 2008). "Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma". Ann. Oncol. 19 (5): 958–63. doi:10.1093/annonc/mdn022. PMID 18303032. 14. ^ Rodríguez J, Conde E, Gutiérrez A, et al. (July 2007). "Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from The Gel-Tamo Study Group". Eur. J. Haematol. 79 (1): 32–8. doi:10.1111/j.1600-0609.2007.00856.x. PMID 17598836. 15. ^ Corradini P, Tarella C, Zallio F, et al. (September 2006). "Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation". Leukemia. 20 (9): 1533–8. doi:10.1038/sj.leu.2404306. PMID 16871285. 16. ^ d’Amore F, et al. Blood. 2006;108:A401 17. ^ Kwong YL, Chan AC, Liang RH (May 1997). "Natural killer cell lymphoma/leukemia: pathology and treatment". Hematol Oncol. 15 (2): 71–9. doi:10.1002/(SICI)1099-1069(199705)15:2<71::AID-HON601>3.0.CO;2-U. PMID 9375032. ## External links[edit] Classification D * ICD-10: C94.7 * ICD-O: M9948/3 External resources * eMedicine: ent/776 * Orphanet: 86873 * v * t * e Leukaemias, lymphomas and related disease B cell (lymphoma, leukemia) (most CD19 * CD20) By development/ marker TdT+ * ALL (Precursor B acute lymphoblastic leukemia/lymphoma) CD5+ * naive B cell (CLL/SLL) * mantle zone (Mantle cell) CD22+ * Prolymphocytic * CD11c+ (Hairy cell leukemia) CD79a+ * germinal center/follicular B cell (Follicular * Burkitt's * GCB DLBCL * Primary cutaneous follicle center lymphoma) * marginal zone/marginal zone B-cell (Splenic marginal zone * MALT * Nodal marginal zone * Primary cutaneous marginal zone lymphoma) RS (CD15+, CD30+) * Classic Hodgkin lymphoma (Nodular sclerosis) * CD20+ (Nodular lymphocyte predominant Hodgkin lymphoma) PCDs/PP (CD38+/CD138+) * see immunoproliferative immunoglobulin disorders By infection * KSHV (Primary effusion) * EBV * Lymphomatoid granulomatosis * Post-transplant lymphoproliferative disorder * Classic Hodgkin lymphoma * Burkitt's lymphoma * HCV * Splenic marginal zone lymphoma * HIV (AIDS-related lymphoma) * Helicobacter pylori (MALT lymphoma) Cutaneous * Diffuse large B-cell lymphoma * Intravascular large B-cell lymphoma * Primary cutaneous marginal zone lymphoma * Primary cutaneous immunocytoma * Plasmacytoma * Plasmacytosis * Primary cutaneous follicle center lymphoma T/NK T cell (lymphoma, leukemia) (most CD3 * CD4 * CD8) By development/ marker * TdT+: ALL (Precursor T acute lymphoblastic leukemia/lymphoma) * prolymphocyte (Prolymphocytic) * CD30+ (Anaplastic large-cell lymphoma * Lymphomatoid papulosis type A) Cutaneous MF+variants * indolent: Mycosis fungoides * Pagetoid reticulosis * Granulomatous slack skin aggressive: Sézary disease * Adult T-cell leukemia/lymphoma Non-MF * CD30-: Non-mycosis fungoides CD30− cutaneous large T-cell lymphoma * Pleomorphic T-cell lymphoma * Lymphomatoid papulosis type B * CD30+: CD30+ cutaneous T-cell lymphoma * Secondary cutaneous CD30+ large-cell lymphoma * Lymphomatoid papulosis type A Other peripheral * Hepatosplenic * Angioimmunoblastic * Enteropathy-associated T-cell lymphoma * Peripheral T-cell lymphoma not otherwise specified (Lennert lymphoma) * Subcutaneous T-cell lymphoma By infection * HTLV-1 (Adult T-cell leukemia/lymphoma) NK cell/ (most CD56) * Aggressive NK-cell leukemia * Blastic NK cell lymphoma T or NK * EBV (Extranodal NK-T-cell lymphoma/Angiocentric lymphoma) * Large granular lymphocytic leukemia Lymphoid+ myeloid * Acute biphenotypic leukaemia Lymphocytosis * Lymphoproliferative disorders (X-linked lymphoproliferative disease * Autoimmune lymphoproliferative syndrome) * Leukemoid reaction * Diffuse infiltrative lymphocytosis syndrome Cutaneous lymphoid hyperplasia * Cutaneous lymphoid hyperplasia * with bandlike and perivascular patterns * with nodular pattern * Jessner lymphocytic infiltrate of the skin General * Hematological malignancy * leukemia * Lymphoproliferative disorders * Lymphoid leukemias [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Aggressive NK-cell leukemia	c1522378	6,228	wikipedia	https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia	2021-01-18T18:51:33	{"gard": ["10493"], "mesh": ["D054066"], "umls": ["C1522378"], "orphanet": ["86873"], "wikidata": ["Q4692280"]}
Atypical pneumonia Other namesWalking pneumonia SpecialtyInfectious disease, pulmonology Atypical pneumonia, also known as walking pneumonia,[1] is any type of pneumonia not caused by one of the pathogens most commonly associated with the disease. Its clinical presentation contrasts to that of "typical" pneumonia. A variety of microorganisms can cause it. When it develops independently from another disease, it is called primary atypical pneumonia (PAP). The term was introduced in the 1930s[2][3] and was contrasted with the bacterial pneumonia caused by Streptococcus pneumoniae, at that time the best known and most commonly occurring form of pneumonia. The distinction was historically considered important, as it differentiated those more likely to present with "typical" respiratory symptoms and lobar pneumonia from those more likely to present with "atypical" generalized symptoms (such as fever, headache, sweating and myalgia) and bronchopneumonia.[4] ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Viral * 3 Diagnosis * 4 Epidemiology * 5 Terminology * 6 References * 7 External links ## Signs and symptoms[edit] Usually the atypical causes also involve atypical symptoms: * No response to common antibiotics such as sulfonamide[5] and beta-lactams like penicillin. * No signs and symptoms of lobar consolidation,[6][7] meaning that the infection is restricted to small areas, rather than involving a whole lobe. As the disease progresses, however, the look can tend to lobar pneumonia. * Absence of leukocytosis. * Extrapulmonary symptoms, related to the causing organism.[8] * Moderate amount of sputum, or no sputum at all (i.e. non-productive). * Lack of alveolar exudate.[9] * Despite general symptoms and problems with the upper respiratory tract (such as high fever, headache, a dry irritating cough followed later by a productive cough with radiographs showing consolidation), there are in general few physical signs. The patient looks better than the symptoms suggest.[2][5] ## Cause[edit] The most common causative organisms are (often intracellular living) bacteria:[8] Chlamydia pneumoniae Mild form of pneumonia with relatively mild symptoms. Chlamydia psittaci Causes psittacosis. Coxiella burnetii Causes Q fever. Francisella tularensis Causes tularemia. Legionella pneumophila Causes a severe form of pneumonia with a relatively high mortality rate, known as legionellosis or Legionnaires' disease. Mycoplasma pneumoniae [10] Usually occurs in younger age groups and may be associated with neurological and systemic (e.g. rashes) symptoms. Atypical pneumonia can also have a fungal, protozoan or viral cause.[11][12] In the past, most organisms were difficult to culture. However, newer techniques aid in the definitive identification of the pathogen, which may lead to more individualized treatment plans. ### Viral[edit] Known viral causes of atypical pneumonia include respiratory syncytial virus (RSV), influenza A and B, parainfluenza, adenovirus, severe acute respiratory syndrome (SARS),[13] Middle East respiratory syndrome (MERS), COVID-19 acute respiratory syndrome[14] and measles.[15] ## Diagnosis[edit] Chest radiographs (X-ray photographs) often show a pulmonary infection before physical signs of atypical pneumonia are observable at all.[5] This is occult pneumonia. In general, occult pneumonia is rather often present in patients with pneumonia and can also be caused by Streptococcus pneumoniae, as the decrease of occult pneumonia after vaccination of children with a pneumococcal vaccine suggests.[16][17] Infiltration commonly begins in the perihilar region (where the bronchus begins) and spreads in a wedge- or fan-shaped fashion toward the periphery of the lung field. The process most often involves the lower lobe, but may affect any lobe or combination of lobes.[5] ## Epidemiology[edit] Mycoplasma is found more often in younger than in older people.[18][19] Older people are more often infected by Legionella.[19] ## Terminology[edit] "Primary atypical pneumonia" is called primary because it develops independently of other diseases. It is commonly known as "walking pneumonia" because its symptoms are often mild enough that one can still be up and about.[20][21] "Atypical pneumonia" is atypical in that it is caused by atypical organisms (other than Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis).[22] These atypical organisms include special bacteria, viruses, fungi, and protozoa. In addition, this form of pneumonia is atypical in presentation with only moderate amounts of sputum, no consolidation, only small increases in white cell counts, and no alveolar exudate.[15][8] At the time that atypical pneumonia was first described, organisms like Mycoplasma, Chlamydophila, and Legionella were not yet recognized as bacteria and instead considered viruses. Hence "atypical pneumonia" was also called "non-bacterial".[23] In literature the term atypical pneumonia is current, sometimes contrasted with viral pneumonia (see below) and sometimes, though incorrectly, with bacterial pneumonia. Many of the organisms causative of atypical pneumonia are unusual types of bacteria (Mycoplasma is a type of bacteria without a cell wall and Chlamydias are intracellular bacteria). As the conditions caused by the various agents have different courses and respond to different treatments, the identification of the specific causative pathogen is important. ## References[edit] 1. ^ "Atypical Pneumonia (Walking Pneumonia)". Cleveland Clinic. 2. ^ a b Walter C, McCoy MD (1946). "Primary atypical pneumonia: A report of 420 cases with one fatality during twenty-seven month at Station Hospital, Camp Rucker, Alabama". Southern Medical Journal. 39 (9): 696–706. doi:10.1097/00007611-194609000-00005. PMID 20995425. 3. ^ Pneumonia, Atypical Bacterial at eMedicine 4. ^ Pneumonia, Typical Bacterial at eMedicine 5. ^ a b c d Commission on Acute Respiratory Diseases, Fort Bragg, North Carolina (April 1944). "Primary Atypical Pneumonia" (PDF). American Journal of Public Health and the Nations Health. 34 (4): 347–57. doi:10.2105/AJPH.34.4.347. PMC 1625001. PMID 18015969. 6. ^ Gouriet F, Drancourt M, Raoult D (October 2006). "Multiplexed serology in atypical bacterial pneumonia". Ann. N. Y. Acad. Sci. 1078 (1): 530–40. Bibcode:2006NYASA1078..530G. doi:10.1196/annals.1374.104. PMID 17114771. 7. ^ Hindiyeh M, Carroll KC (June 2000). "Laboratory diagnosis of atypical pneumonia". Semin Respir Infect. 15 (2): 101–13. doi:10.1053/srin.2000.9592. PMID 10983928. 8. ^ a b c Cunha BA (May 2006). "The atypical pneumonias: clinical diagnosis and importance". Clin. Microbiol. Infect. 12 (Suppl 3): 12–24. doi:10.1111/j.1469-0691.2006.01393.x. PMC 7128183. PMID 16669925. Archived from the original on 2013-01-05. 9. ^ Robbins and Cotran Pathologic Basis of Disease, 8th edition, Kumar et al., Philadelphia, 2010, p. 714 10. ^ Mycoplasma+Pneumoniae at the US National Library of Medicine Medical Subject Headings (MeSH) 11. ^ Diseases Database 12. ^ Tang YW (December 2003). "Molecular diagnostics of atypical pneumonia" (PDF). Acta Pharmacol. Sin. 24 (12): 1308–13. PMID 14653964. Archived from the original (PDF) on 2011-07-08. 13. ^ "Severe Acute Respiratory Syndrome (SARS) – multi-country outbreak". Archived from the original on 7 December 2008. Retrieved 2008-12-21. 14. ^ Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Gengfu; Shi, Zheng-Li (23 January 2020). "Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin". bioRxiv. doi:10.1101/2020.01.22.914952. S2CID 211003249. 15. ^ a b Diseases Database Causes of atypical pneumonia 16. ^ Murphy CG, van de Pol AC, Harper MB, Bachur RG (March 2007). "Clinical predictors of occult pneumonia in the febrile child". Acad Emerg Med. 14 (3): 243–49. doi:10.1197/j.aem.2006.08.022. PMID 17242382. 17. ^ Rutman MS, Bachur R, Harper MB (January 2009). "Radiographic pneumonia in young, highly febrile children with leukocytosis before and after universal conjugate pneumococcal vaccination". Pediatric Emergency Care. 25 (1): 1–7. doi:10.1097/PEC.0b013e318191dab2. PMID 19116501. S2CID 10894988. 18. ^ Schneeberger PM, Dorigo-Zetsma JW, van der Zee A, van Bon M, van Opstal JL (2004). "Diagnosis of atypical pathogens in patients hospitalized with community-acquired respiratory infection". Scand. J. Infect. Dis. 36 (4): 269–73. doi:10.1080/00365540410020127. PMID 15198183. 19. ^ a b "Pneumonia". National Heart, Lung and Blood Institute. 20. ^ What Is Walking Pneumonia? 21. ^ Walking pneumonia: What does it mean? 22. ^ Memish ZA, Ahmed QA, Arabi YM, Shibl AM, Niederman MS (October 2007). "Microbiology of community-acquired pneumonia in the Gulf Corporation Council states". J Chemother. 19 Suppl 1: 17–23. doi:10.1080/1120009x.2007.11782430. PMID 18073166. S2CID 37758739. 23. ^ "Primary atypical pneumonia" at Dorland's Medical Dictionary ## External links[edit] Classification D * ICD-10: J18.9 * ICD-9-CM: 483 * DiseasesDB: 1132 External resources * MedlinePlus: 000079 * v * t * e Diseases of the respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis * v * t * e Pneumonia Infectious pneumonias * Bacterial pneumonia * Viral pneumonia * Fungal pneumonia * Parasitic pneumonia * Atypical pneumonia * Community-acquired pneumonia * Healthcare-associated pneumonia * Hospital-acquired pneumonia * Ventilator-associated pneumonia * Severe acute respiratory syndrome Pneumonias caused by infectious or noninfectious agents * Aspiration pneumonia * Lipid pneumonia * Eosinophilic pneumonia * Bronchiolitis obliterans organizing pneumonia Noninfectious pneumonia * Chemical pneumonitis * Idiopathic pneumonia 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	Atypical pneumonia	c1412002	6,229	wikipedia	https://en.wikipedia.org/wiki/Atypical_pneumonia	2021-01-18T18:38:00	{"icd-9": ["486"], "wikidata": ["Q2633267"]}
For a discussion of the genetic heterogeneity of quantitative trait loci (QTL) for mean platelet volume (MPV)/platelet count (PLT), see MPVCQTL1 (612573). Mapping Gieger et al. (2011) performed metaanalyses of genomewide association studies (GWAS) for MPV and PLT. Their analyses included 18,600 (13 studies, MPV) and 48,666 (23 studies, PLT) individuals of European descent, respectively, and up to approximately 2.5 million genotyped or imputed single-nucleotide polymorphisms (SNPs). Gieger et al. (2011) identified 2 SNPs in the 7q22.3 region, rs342293 and rs342275, that are 3 nucleotides away from each other at the FLJ36031-PIK3CG locus (601232) as significantly associated with MPV, with a p value of 7.03 x 10(-57), and PLT, with a p value of 5.57 x 10(-25). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	MEAN PLATELET VOLUME/COUNT QUANTITATIVE TRAIT LOCUS 6	c3553341	6,230	omim	https://www.omim.org/entry/614646	2019-09-22T15:54:37	{"omim": ["614646"]}
A number sign (#) is used with this entry because of evidence that autoinflammation with arthritis and dyskeratosis (AIADK) is caused by heterozygous or homozygous mutation in the NLRP1 gene (606636) on chromosome 17p13. Description Autoinflammation with arthritis and dyskeratosis is characterized by recurrent fever, widespread skin dyskeratosis, arthritis, elevated biologic markers of inflammation, and mild autoimmunity with a high transitional B-cell level (summary by Grandemange et al., 2016). Clinical Features Girard et al. (2006) reported a 6-year-old boy with skin lesions that were first noted at 2 months of age and were associated with chronic diarrhea due to recurrent Giardia intestinalis infections, complicated by partial villous atrophy. Clinical examination showed moderate growth retardation and widespread multiple minute digitate hyperkeratoses covering extensive areas of the limbs, shoulders, and flanks, with brownish-purple pigmented macules with indistinct edges present in the areas of keratotic lesions. He also had symmetric tender warty keratotic lesions on both soles, and comedo-like papules and vermiculated atrophic scars on his cheeks. Perifollicular cylindrical keratotic sheaths (hair casts) were present on hair of the vertex and occipital region, although the scalp itself appeared normal. He had diffuse xerosis as well as impaired sweating, and ophthalmologic examination revealed xerophthalmia with punctate keratitis. Laboratory examination showed hypereosinophilia, elevated IgE and IgA, and reduced levels of retinol-binding protein and vitamins A and C. Histologic examination of a spiky skin lesion showed hyperkeratosis with a thick keratotic follicular plug, in addition to numerous dyskeratotic epithelial cells within the corresponding follicular epithelium. Examination of a hair cast confirmed the tubular nature of the keratin surrounding the pilar shaft. Girard et al. (2006) designated the disorder as vitamin A deficiency-associated follicular hyperkeratosis (phrynoderma). Grandemange et al. (2016) studied an affected boy and girl who were double first cousins from a consanguineous Algerian family, as well as a similarly affected Dutch girl. Both cousins presented dermatologic anomalies in the first few months of life and had recurrent episodes of unprovoked fever lasting 3 to 4 days. The 16-year-old boy, who had previously been described by Girard et al. (2006), showed sustained high levels of IgG and IgA, and exhibited uveitis without signs of corneal dyskeratosis. Arthritis developed at age 12 years and affected his wrists, knees, and ankles. His 8-year-old cousin, who presented with congenital progressive disseminated follicular hyperkeratosis, developed arthritis of her knees at age 5 years, which subsequently involved her wrists, hands, and ankles. Antinuclear antibodies were negative in the boy, and slightly positive in his cousin. The 10-year-old Dutch girl presented at age 6 months with failure to thrive, hepatosplenomegaly, and filiform hyperkeratosis. At age 19 months, she developed immune hemolytic anemia and thyroiditis, and was positive for antinuclear and antiparietal cell antibodies. By 2 years of age she was having daily high-spiking fevers and inflammation, and showed chronic candidiasis and sustained high levels of IgG. At 4 years of age, she had respiratory insufficiency due to subglottic edema, at which time massive hepatosplenomegaly was noted and she underwent splenectomy. At 5 years of age, she developed arthritis in both knees. Ophthalmologic examination due to progressive photophobia showed corneal dyskeratosis and neovascularization. Skeletal x-rays in the 2 affected girls showed medial metaphyseal lesions in both femora, and the Dutch girl also showed abnormal striations of the distal femoral metaphyses as well as dense and irregular condensations in the distal femoral and proximal tibial metaphyseal plates. Histopathology of skin lesions showed acanthosis with scattered to confluent dyskeratotic keratinocytes down to the basal layers. All 3 patients had persistently low levels of vitamin A; however, supplementation worsened the disease in the Algerian girl and was ineffective in the Dutch girl. Analysis of circulating immune cells showed abnormal B-cell distribution, with increased transitional B cells. All 3 patients exhibited elevated serum levels of the inflammasome biomarkers caspase-1 (147678) and IL18 (600953) compared to the heterozygous Algerian parents or healthy controls; the Dutch girl also showed markedly elevated levels of IL1B (147720). Mapping In a consanguineous Algerian family segregating autosomal recessive autoinflammation with arthritis and dyskeratosis, Grandemange et al. (2016) performed homozygosity mapping and identified 2 homozygous regions with parametric lod scores greater than 2: one on chromosome 8 (lod score, 2.18) and the other on chromosome 17 (lod score, 2.77). Molecular Genetics In a consanguineous Algerian family segregating autosomal recessive autoinflammation with arthritis and dyskeratosis, negative for mutation in 3 known autoinflammatory genes, Grandemange et al. (2016) performed exome sequencing and identified homozygosity for a missense mutation in the NLRP1 gene (R726W; 606636.0006). Sanger sequencing of NLRP1 in a similarly affected Dutch girl revealed heterozygosity for a de novo missense mutation (P1214R; 606636.0007); the presence of pathogenic variants in other known or candidate autoinflammatory genes was excluded by next-generation sequencing, as well as by Sanger sequencing of the AIRE (607358) and CASP10 (601762) genes. Screening of 17 additional patients with comparable clinical features did not identify any NLRP1 mutations. Grandemange et al. (2016) noted that both autosomal recessive and autosomal dominant inheritance had been described in other autoinflammatory diseases such as Mediterranean fever (see 134610), but that the underlying mechanisms were still unclear. INHERITANCE \- Autosomal dominant \- Autosomal recessive GROWTH Other \- Failure to thrive \- Growth retardation, moderate HEAD & NECK Eyes \- Photophobia \- Xerophthalmia \- Punctate keratitis \- Uveitis \- Corneal dyskeratosis \- Corneal neovascularization Neck \- Thyroiditis (patient A) RESPIRATORY Larynx \- Verrucous lesions on vocal cords Airways \- Subglottic edema (Patient A) ABDOMEN Liver \- Massive hepatomegaly (Patient A) Spleen \- Splenomegaly (requiring splenectomy, Patient A) SKELETAL Limbs \- Polyarticular arthritis (involving wrists, knees, and ankles) \- Bilateral medial metaphyseal lesions in femora \- Abnormal striations of distal femoral metaphyses \- Dense and irregular condensations in metaphyseal plates of distal femur and proximal tibia Hands \- Arthritis of the hands SKIN, NAILS, & HAIR Skin \- Xerosis \- Impaired sweating \- Widespread follicular hyperkeratosis \- Filiform hyperkeratosis \- Brownish-purple pigmented macules in areas of hyperkeratosis \- Papules with pseudocomedones \- Palmoplantar symmetric hyperkeratosis Skin Histology \- Hyperkeratosis \- Acanthosis \- Mild papillomatosis \- Prominent granular cell layer \- Dyskeratotic eosinophilic cells throughout all layers \- Keratotic follicular plugs \- Dyskeratotic epithelial cells within follicular epithelium \- Tubular keratotic sheath surrounding pilar shaft Nails \- Dyskeratotic nails Hair \- Hair casts METABOLIC FEATURES \- Recurrent episodes of fever HEMATOLOGY \- Hemolytic anemia, autoimmune (patient A) IMMUNOLOGY \- Chronic candidiasis (patient A) \- Recurrent Giardia intestinalis infections \- Elevated IgG \- Elevated IgA \- Elevated IgE \- Hypereosinophilia \- Antinuclear antibodies \- Antiparietal antibodies (patient A) \- M-protein present (intermittently, patient A) LABORATORY ABNORMALITIES \- Persistently elevated C-reactive protein (CRP) \- Hypereosinophilia \- Reduced levels of vitamin A \- Reduced levels of retinal-binding protein \- Reduced levels of vitamin C MISCELLANEOUS \- Variable features present \- Based on report of 2 double first cousins and 1 unrelated sporadic heterozygote (patient A) MOLECULAR BASIS \- Caused by mutation in the NLR family, pyrin domain-containing-1 gene (NLRP1, 606636.0006 ) ▲ 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	AUTOINFLAMMATION WITH ARTHRITIS AND DYSKERATOSIS	c4479278	6,231	omim	https://www.omim.org/entry/617388	2019-09-22T15:46:00	{"omim": ["617388"]}
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: "Mondini dysplasia" – news · newspapers · books · scholar · JSTOR (April 2018) (Learn how and when to remove this template message) Mondini dysplasia Other namesFamilial nonsyndromal Mondini dysplasia SpecialtyAudiology Mondini dysplasia, also known as Mondini malformation and Mondini defect, is an abnormality of the inner ear that is associated with sensorineural hearing loss. This deformity was first described in 1791 by Mondini after examining the inner ear of a deaf boy. The Mondini dysplasia describes a cochlea with incomplete partitioning and a reduced number of turns, an enlarged vestibular aqueduct and a dilated vestibule. A normal cochlea has two and a half turns, a cochlea with Mondini dysplasia has one and a half turns; the basal turns being normally formed with a dilated or cystic apical turn to the cochlear. The hearing loss can deteriorate over time either gradually or in a step-wise fashion, or may be profound from birth.[1] Hearing loss associated with Mondini dysplasia may first become manifest in childhood or early adult life. Some children may pass newborn hearing screen to lose hearing in infancy but others present with a hearing loss at birth. Hearing loss is often progressive and because of the associated widened vestibular aqueduct may progress in a step-wise fashion associated with minor head trauma. Vestibular function is also often affected. While the hearing loss is sensorineural a conductive element may exist probably because of the third window effect of the widened vestibular aqueduct. The Mondini dysplasia can occur in cases of Pendred Syndrome and Branchio-oto-renal syndrome and in other syndromes, but can occur in non-syndromic deafness. ## References[edit] 1. ^ Shah, SM; Prabhu, SS; Merchant, RH (2001-10-01). "Mondini defect". Journal of Postgraduate Medicine. 47 (4). ## External links[edit] Classification D External resources * eMedicine: article/2037435 * v * t * e Congenital malformations and deformations of ears Size * Macrotia * Microtia * Anotia Position * Low-set ears Other * Accessory auricle * Mondini dysplasia This article about a disease of the ear and mastoid process 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	Mondini dysplasia	c1857078	6,232	wikipedia	https://en.wikipedia.org/wiki/Mondini_dysplasia	2021-01-18T18:57:43	{"gard": ["8215"], "umls": ["C1857078", "C0395941"], "wikidata": ["Q1944248"]}
Minamata disease The hand of Tomoko Uemura, Minamata disease victim SpecialtyToxicology, Neurology, Psychiatry Minamata disease (Japanese: 水俣病, Hepburn: Minamata-byō), sometimes referred to as Chisso-Minamata disease (チッソ水俣病, Chisso-Minamata-byō), is a neurological disease caused by severe mercury poisoning. Signs and symptoms include ataxia, numbness in the hands and feet, general muscle weakness, loss of peripheral vision, and damage to hearing and speech. In extreme cases, insanity, paralysis, coma, and death follow within weeks of the onset of symptoms. A congenital form of the disease can also affect fetuses in the womb. Minamata disease was first discovered in the city of Minamata, Kumamoto Prefecture, Japan, in 1956. It was caused by the release of methylmercury in the industrial wastewater from a chemical factory owned by the Chisso Corporation, which continued from 1932 to 1968. It has also been suggested that some of the mercury sulfate in the wastewater was also metabolized to methylmercury by bacteria in the sediment.[1] This highly toxic chemical bioaccumulated and biomagnified in shellfish and fish in Minamata Bay and the Shiranui Sea, which, when eaten by the local population, resulted in mercury poisoning. While cat, dog, pig, and human deaths continued for 36 years, Chisso and the Kumamoto prefectural government did little to prevent the epidemic. The animal effects were severe enough in cats that they came to be named as having "dancing cat fever" (猫踊り病).[2] As of March 2001, 2,265 victims had been officially recognised as having Minamata disease (1,784 of whom had died)[3] and over 10,000 had received financial compensation from Chisso.[4] By 2004, Chisso had paid US$86 million in compensation, and in the same year was ordered to clean up its contamination.[5] On March 29, 2010, a settlement was reached to compensate as-yet uncertified victims.[6] A second outbreak of Minamata disease occurred in Niigata Prefecture in 1965. The original Minamata disease and Niigata Minamata disease are considered two of the Four Big Pollution Diseases of Japan. ## Contents * 1 1908–1955 * 2 1956–1959 * 2.1 Finding the cause * 2.2 Identification of mercury * 3 1959 * 3.1 Compensation of fishermen and patients, 1959 * 3.2 Wastewater treatment * 4 1959–1969 * 4.1 Continued pollution * 4.2 Congenital Minamata disease * 4.3 Outbreak of Niigata Minamata disease * 5 1969–1973 * 5.1 Official government recognition * 5.2 Struggle for a new agreement * 5.3 Uncertified patients' fight to be recognised * 6 Epidemiology * 7 Democratizing effects * 8 Society and culture * 8.1 Media * 8.2 Today * 9 See also * 10 References * 11 Further reading * 12 External links ## 1908–1955[edit] See also: Timeline of Minamata disease In 1908, the Chisso Corporation first opened a chemical factory in Minamata, Kumamoto Prefecture, located on the west coast of the southern island of Kyūshū. Initially producing fertilisers, the factory followed the nationwide expansion of Japan's chemical industry, branching out into production of acetylene, acetaldehyde, acetic acid, vinyl chloride, and octanol, among others. The Minamata factory became the most advanced in all of Japan, both before and after World War II.[7] The waste products resulting from the manufacture of these chemicals were released into Minamata Bay through the factory wastewater. These pollutants had an environmental impact. Fisheries were damaged in terms of reduced catches, and in response Chisso reached two separate compensation agreements with the fishery cooperative in 1926 and 1943.[8] The rapid expansion of the Chisso factory spurred on the local economy, and as the company prospered so did Minamata. This fact, combined with the lack of other industry, meant that Chisso had great influence in the city. At one point, over half of the tax revenue of Minamata City authority came from Chisso and its employees, and the company and its subsidiaries were responsible for creating a quarter of all jobs in Minamata.[9] The city was even dubbed Chisso's "castle town", in reference to the capital cities of feudal lords who ruled Japan during the Edo period.[10] The Chisso factory first started acetaldehyde production in 1932, producing 210 tons that year. By 1951, production had jumped to 6,000 tons per year and reached a peak of 45,245 tons in 1960.[11] Throughout, the factory's output amounted to between a quarter and a third of Japan's total acetaldehyde production. The chemical reaction used to produce the acetaldehyde used mercury sulfate as a catalyst. Starting in August 1951, the co-catalyst was changed from manganese dioxide to ferric sulfide.[12] A side reaction of this catalytic cycle led to the production of a small amount (about 5% of the outflow[13]) of an organic mercury compound, namely methylmercury.[14] This highly toxic compound was released into Minamata Bay from the change of the co-catalyst in 1951 until 1968, when this production method was discontinued.[15] ## 1956–1959[edit] On 21 April 1956, a five-year-old girl was examined at Chisso's factory hospital in Minamata. The physicians were puzzled by her symptoms: difficulty walking, difficulty speaking, and convulsions. Two days later, her younger sister also began to exhibit the same symptoms and she, too, was hospitalised. The girls' mother informed doctors that her neighbour's daughter was also experiencing similar problems. After a house-to-house investigation, eight further patients were discovered and hospitalised. On 1 May, the hospital director reported to the local public health office the discovery of an "epidemic of an unknown disease of the central nervous system", marking the official discovery of Minamata disease.[16] To investigate the epidemic, the city government and various medical practitioners formed the Strange Disease Countermeasures Committee (奇病対策委員会, Kibyō Taisaku Iinkai) at the end of May 1956. Owing to the localised nature of the disease, it was suspected to be contagious and as a precaution patients were isolated and their homes disinfected. Although contagion was later disproved, this initial response contributed to the stigmatisation and discrimination experienced by Minamata victims from the local community. During its investigations, the committee uncovered surprising anecdotal evidence of the strange behaviour of cats and other wildlife in the areas surrounding patients' homes. From around 1950 onward, cats had been seen to have convulsions, go mad, and die. Locals called it the "cat dancing disease" (猫踊り病, neko odori byō), owing to their erratic movement.[2] Crows had fallen from the sky, seaweed no longer grew on the sea bed, and fish floated dead on the surface of the sea. As the extent of the outbreak was understood, the committee invited researchers from Kumamoto University (or Kumadai) to help in the research effort.[17] The Kumamoto University Research Group was formed on 24 August 1956. Researchers from the School of Medicine began visiting Minamata regularly and admitted patients to the university hospital for detailed examinations. A more complete picture of the symptoms exhibited by patients was gradually uncovered. The disease developed without any prior warning, with patients complaining of a loss of sensation and numbness in their hands and feet. They became unable to grasp small objects or fasten buttons. They could not run or walk without stumbling, their voices changed in pitch, and many patients complained of difficulties seeing, hearing, and swallowing. In general, these symptoms deteriorated and were followed by severe convulsions, coma, and eventually death. By October 1956, forty patients had been discovered, fourteen of whom had died: an alarming case fatality rate of 35%.[18] ### Finding the cause[edit] Researchers from Kumadai also began to focus on the cause of the strange disease. They found that the victims, often members of the same family, were clustered in fishing hamlets along the shore of Minamata Bay. The staple food of victims was invariably fish and shellfish from Minamata Bay. The cats in the local area, which tended to eat scraps from the family table, had died with symptoms similar to those now discovered in humans. This led the researchers to believe that the outbreak was caused by some kind of food poisoning, with contaminated fish and shellfish being the prime suspects. On 4 November, the research group announced its initial findings: "Minamata disease is rather considered to be poisoning by a heavy metal, presumably it enters the human body mainly through fish and shellfish."[19] ### Identification of mercury[edit] Methylmercury, an organic mercury compound released in factory wastewater and the cause of Minamata disease As soon as the investigation identified a heavy metal as the causal substance, the wastewater from the Chisso factory was immediately suspected as the origin. The company's own tests revealed that its wastewater contained many heavy metals in concentrations sufficiently high to bring about serious environmental degradation, including lead, mercury, manganese, arsenic, thallium, and copper, plus the chalcogen selenium. Identifying which particular poison was responsible for the disease proved to be extremely difficult and time-consuming. During 1957 and 1958, many different theories were proposed by different researchers. At first, manganese was thought to be the causal substance due to the high concentrations found in fish and the organs of the deceased. Thallium, selenium, and a multiple contaminant theory were also proposed, but in March 1958, visiting British neurologist Douglas McAlpine suggested that Minamata symptoms resembled those of organic mercury poisoning, so the focus of the investigation centered on mercury. In February 1959, the mercury distribution in Minamata Bay was investigated. The results shocked the researchers involved. Large quantities of mercury were detected in fish, shellfish, and sludge from the bay. The highest concentrations centred around the Chisso factory wastewater canal in Hyakken Harbour and decreased going out to sea, clearly identifying the plant as the source of contamination. Pollution was so heavy at the mouth of the wastewater canal, a figure of 2 kg of mercury per ton of sediment was measured: a level that would be economically viable to mine. Indeed, Chisso did later set up a subsidiary to reclaim and sell the mercury recovered from the sludge.[20] Hair samples were taken from the victims of the disease and also from the Minamata population in general. In patients, the maximum mercury level recorded was 705 parts per million (ppm), indicating very heavy exposure and in nonsymptomatic Minamata residents, the level was 191 ppm. This compared to an average level of 4 ppm for people living outside the Minamata area.[20] On 12 November 1959, the Ministry of Health and Welfare's Minamata Food Poisoning Subcommittee published its results: > Minamata disease is a poisoning disease that affects mainly the central nervous system and is caused by the consumption of large quantities of fish and shellfish living in Minamata Bay and its surroundings, the major causative agent being some sort of organic mercury compound.[21] ## 1959[edit] The Chisso factory and its wastewater routes During the Kumadai investigation, the causal substance had been identified as a heavy metal and it was widely presumed that the Chisso factory was the source of the contamination. Chisso was coming under closer scrutiny and to deflect criticism, the wastewater output route was changed. Chisso knew of the environmental damage caused by its wastewater and was well aware that it was the prime suspect in the Minamata disease investigation. Despite this, from September 1958, instead of discharging its waste into Hyakken Harbour (the focus of investigation and source of original contamination), it discharged wastewater directly into Minamata River. The immediate effect was the death of fish at the mouth of the river, and from that point on, new Minamata disease victims began to appear in other fishing villages up and down the coast of the Shiranui Sea, as the pollution spread over an even greater area.[22] Chisso failed to co-operate with the Kumadai research team. It withheld information on its industrial processes, leaving researchers to speculate what products the factory was producing and by what methods.[23] The Chisso factory's hospital director, Hajime Hosokawa, established a laboratory in the research division of the facility to carry out his own experiments into Minamata disease in July 1959. Food to which factory wastewater had been added was fed to healthy cats. Seventy-eight days into the experiment, cat 400 exhibited symptoms of Minamata disease and pathological examinations confirmed a diagnosis of organic mercury poisoning. Chisso did not reveal these significant results to the investigators and ordered Hosokawa to stop his research.[24] In an attempt to undermine Kumadai researchers' organic mercury theory, Chisso and other parties with a vested interest that the factory remain open (including the Ministry of International Trade and Industry and the Japan Chemical Industry Association) funded research into alternative causes of the disease, other than its own waste.[25] ### Compensation of fishermen and patients, 1959[edit] This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (April 2017) (Learn how and when to remove this template message) Further information: Minamata disease compensation agreements of 1959 Polluting wastewater had damaged the fisheries around Minamata ever since the opening of the Chisso factory in 1908. The Minamata Fishing Cooperative had managed to win small payments of "sympathy money" (見舞い金, mimaikin) from the company in 1926 and again in 1943, but after the outbreak of Minamata disease, the fishing situation was becoming critical. Fishing catches had declined by 91% between 1953 and 1957. The Kumamoto prefectural government issued a partial ban on the sale of fish caught in the heavily polluted Minamata Bay – but not an all-out ban, which would have legally obliged it to compensate the fishermen. The fishing cooperative protested against Chisso and angrily forced their way into the factory on 6 August and 12 August, demanding compensation. A committee was set up by Minamata Mayor Todomu Nakamura to mediate between the two sides, but this committee was stacked heavily in the company's favour. On 29 August, the fishing cooperative agreed to the mediation committee's proposal, stating: "In order to end the anxiety of the citizens, we swallow our tears and accept". Chisso paid the cooperative ¥20 million (US$183,477) and set up a ¥15 million ($137,608) fund to promote the recovery of fishing. Protestors at the gates of the Chisso factory (W. Eugene Smith) Since the change of route of wastewater output in 1958, pollution had spread up and down the Shiranui Sea, damaging fisheries there as well. Emboldened by the success of the small Minamata cooperative, the Kumamoto Prefectural Alliance of Fishing Cooperatives also decided to seek compensation from Chisso. On 17 October, 1,500 fishermen from the alliance descended on the factory to demand negotiations. When this produced no results, the alliance members took their campaign to Tokyo, securing an official visit to Minamata by members of the Japanese Diet. During the visit on 2 November, alliance members forced their way into the factory and rioted, causing many injuries and ¥10 million ($100,000) worth of damage. The violence was covered widely in the media, bringing the nation's attention to the Minamata issue for the first time since the outbreak began. Another mediation committee was set up, and an agreement was hammered out and signed on 17 December. Some ¥25 million of "sympathy money" was paid to the alliance and a ¥65 million fishing recovery fund was established. In 1959, the victims of Minamata disease were in a much weaker position than the fishermen. The recently formed Minamata Disease Patients Families Mutual Aid Society was much more divided than the fishing cooperatives. Patients' families were the victims of discrimination and ostracism from the local community. Local people felt that the company (and their city that depended upon it) was facing economic ruin. To some patients, this ostracism by the community represented a greater fear than the disease itself. After beginning a sit-in at the Chisso factory gates in November 1959, the patients asked Kumamoto Prefecture Governor Hirosaku Teramoto to include the patients' request for compensation with the mediation that was ongoing with the prefectural fishing alliance. Chisso agreed and after a few weeks' further negotiation, another "sympathy money" agreement was signed. Patients who were certified by a Ministry of Health and Welfare committee would be compensated: adult patients received ¥100,000 ($917) per year; children ¥30,000 ($275) per year, and families of dead patients would receive a one-off ¥320,000 ($2935) payment. ### Wastewater treatment[edit] On 21 October 1959, Chisso was ordered by the Ministry of International Trade and Industry to switch back its wastewater drainage from the Minamata River to Hyakken Harbour and to speed up the installation of wastewater treatment systems at the factory. Chisso installed a Cyclator purification system on 19 December 1959, and opened it with a special ceremony. Chisso's president Kiichi Yoshioka drank a glass of water supposedly treated through the Cyclator to demonstrate that it was safe. In fact, the wastewater from the factory, which the company knew still contained mercury and led to Minamata disease when fed to cats, was not treated through the Cyclator at the time. Testimony at a later Niigata Minamata disease trial proved that Chisso knew the Cyclator to be completely ineffective: "The purification tank was installed as a social solution and did nothing to remove organic mercury."[26] The deception was successful and almost all parties involved in Minamata disease were duped into believing that the factory's wastewater had been made safe from December 1959 onward. This widespread assumption meant that doctors were not expecting new patients to appear, resulting in numerous problems in the years to follow as the pollution continued. In most people's minds, the issue of Minamata disease had been resolved. ## 1959–1969[edit] The years between the first set of "sympathy money" agreements in 1959 and the start of the first legal action to be taken against Chisso in 1969 are often called the "ten years of silence". In fact, much activity on the part of the patients and fishermen took place during this period, but nothing had a significant impact on the actions of the company or the coverage of Minamata in the Japanese media. ### Continued pollution[edit] Despite the almost universal assumption to the contrary, the wastewater treatment facilities installed in December 1959 had no effect on the level of organic mercury being released into the Shiranui Sea. The pollution and the disease it caused continued to spread. The Kumamoto and Kagoshima prefectural governments conducted a joint survey in late 1960 and early 1961 into the level of mercury in the hair of people living around the Shiranui Sea. The results confirmed that organic mercury had spread all around the inland sea and that people were still being poisoned by contaminated fish. Hundreds of people were discovered to have levels greater than 50 ppm of mercury in their hair, the level at which people are likely to experience nerve damage. The highest result recorded was that of a woman from Goshonoura island who had 920 ppm in her sample. The prefectural governments did not publish the results and did nothing in response to these surveys. The participants who had donated hair samples were not informed of their result, even when they requested it. A follow-up study ten years later discovered that many had died from "unknown causes".[27] ### Congenital Minamata disease[edit] Local doctors and medical officials had noticed for a long time an abnormally high frequency of cerebral palsy and other infantile disorders in the Minamata area. In 1961, a number of medical professionals, including Masazumi Harada (later to receive an honour from the United Nations for his body of work on Minamata disease), set about re-examining children diagnosed with cerebral palsy. The symptoms of the children closely mirrored those of adult Minamata disease patients, but many of their mothers did not exhibit symptoms. The fact that these children had been born after the initial outbreak and had never been fed contaminated fish also led their mothers to believe they were not victims. At the time the medical establishment believed the placenta would protect the foetus from toxins in the bloodstream, which is indeed the case with most chemicals. What was not known at the time was that exactly the opposite is the case with methylmercury: the placenta removes it from the mother's bloodstream and concentrates the chemical in the foetus. After several years of study and the autopsies of two children, the doctors announced that these children were suffering from an as yet unrecognised congenital form of Minamata disease. The certification committee convened on 29 November 1962 and agreed that the two dead children and the sixteen children still alive should be certified as patients, and therefore liable for "sympathy" payments from Chisso, in line with the 1959 agreement.[28] ### Outbreak of Niigata Minamata disease[edit] Further information: Niigata Minamata disease Minamata disease broke out again in 1965, this time along the banks of the Agano River in Niigata Prefecture. The polluting factory (owned by Showa Denko) employed a chemical process using a mercury catalyst very similar to that used by Chisso in Minamata. As in Minamata, from the autumn of 1964 to the spring of 1965, cats living along the banks of the Agano River had been seen to go mad and die. Before long, patients appeared with identical symptoms to patients living on the Shiranui Sea, and the outbreak was made public on 12 June 1965. Researchers from the Kumamoto University Research Group and Hajime Hosokawa (who had retired from Chisso in 1962) used their experience from Minamata and applied it to the Niigata outbreak. In September 1966, a report was issued proving Showa Denko's pollution to be the cause of this second Minamata disease outbreak. Unlike the patients in Minamata, the victims of Showa Denko's pollution lived a considerable distance from the factory and had no particular link to the company. As a result, the local community was much more supportive of patients' groups and a lawsuit was filed against Showa Denko in March 1968, only three years after discovery. The events in Niigata catalysed a change in response to the original Minamata incident. The scientific research carried out in Niigata forced a re-examination of that done in Minamata and the decision of Niigata patients to sue the polluting company allowed the same response to be considered in Minamata. Masazumi Harada has said that, "It may sound strange, but if this second Minamata disease had not broken out, the medical and social progress achieved by now in Kumamoto... would have been impossible."[29] Around this time, two other pollution-related diseases were also grabbing headlines in Japan. Victims of Yokkaichi asthma and Itai-itai disease were forming citizens' groups and filed lawsuits against the polluting companies in September 1967 and March 1968, respectively. As a group, these diseases came to be known as the four big pollution diseases of Japan.[30] Slowly but surely, the mood in Minamata and Japan as a whole was shifting. Minamata patients found the public gradually becoming more receptive and sympathetic as the decade wore on. This culminated in 1968 with the establishment in Minamata of the Citizens' Council for Minamata Disease Countermeasures, which was to become the chief citizens' support group to the Minamata patients. A founding member of the citizens' council was Michiko Ishimure, a local housewife and poet who later that year published Pure Land, Poisoned Sea: Our Minamata disease (苦海浄土―わが水俣病, Kugai Jōdo: Waga Minamatabyō), a book of poetic essays that received national acclaim. ## 1969–1973[edit] ### Official government recognition[edit] Finally on 26 September 1968 – twelve years after the discovery of the disease (and four months after Chisso had stopped production of acetaldehyde using its mercury catalyst) – the Japanese government issued an official conclusion as to the cause of Minamata disease: > Minamata disease is a disease of the central nervous system, a poisoning caused by long-term consumption, in large amounts, of fish and shellfish from Minamata Bay. The causative agent is methylmercury. Methylmercury produced in the acetaldehyde acetic acid facility of Shin Nihon Chisso's Minamata factory was discharged in factory wastewater... Minamata disease patients last appeared in 1960, and the outbreak has ended. This is presumed to be because consumption of fish and shellfish from Minamata Bay was banned in the fall of 1957, and the fact that the factory had waste-treatment facilities in place from January 1960. The conclusion contained many factual errors: eating fish and shellfish from other areas of the Shiranui Sea, not just Minamata Bay, could cause the disease; eating small amounts, as well as large amounts of contaminated fish over a long time also produced symptoms; the outbreak had not, in fact, ended in 1960 nor had mercury-removing wastewater facilities been installed in January 1960. Nevertheless, the government announcement brought a feeling of relief to a great many victims and their families. Many felt vindicated in their long struggle to force Chisso to accept responsibility for causing the disease and expressed thanks that their plight had been recognised by their social superiors. The struggle now focused on to what extent the victims should be compensated.[31] ### Struggle for a new agreement[edit] In light of the government announcement, the patients of the Mutual Aid Society decided to ask for a new compensation agreement with Chisso and submitted the demand on 6 October. Chisso replied that it was unable to judge what would be fair compensation and asked the Japanese government to set up a binding arbitration committee to decide. This proposal split the members of the patients' society, many of whom were extremely wary of entrusting their fate to a third party, as they had done in 1959 with unfortunate results. At a meeting on the 5 April 1969, the opposing views within the society could not be reconciled and the organisation split into the pro-arbitration group and the litigation group (who decided to sue the company). That summer, Chisso sent gifts to the families who opted for arbitration rather than litigation. Minamata patients and family members hold photographs of their dead during a demonstration (W. E. Smith) An arbitration committee was duly set up by the Ministry of Health and Welfare on 25 April, but it took almost a year to draw up a draft compensation plan. A newspaper leak in March 1970 revealed that the committee would ask Chisso to pay only ¥2 million ($5,600) for dead patients and ¥140,000 to ¥200,000 ($390 to $560) per year to surviving patients. The arbitration group were dismayed by the sums on offer. They petitioned the committee, together with patients and supporters of the litigation group, for a fairer deal. The arbitration committee announced their compensation plan on 25 May in a disorderly session at the Ministry of Health and Welfare in Tokyo. Thirteen protesters were arrested. Instead of accepting the agreement as they had promised, the arbitration group asked for increases. The committee was forced to revise its plan and the patients waited inside the ministry building for two days while they did so. The final agreement was signed on 27 May. Payments for deaths ranged from ¥1.7 million to ¥4 million ($4,700 to $11,100), one-time payments from ¥1 million to ¥4.2 million ($2,760 to $11,660) and annual payments between ¥170,000 and ¥380,000 ($470 to $1,100) for surviving patients. On the day of the signing, the Minamata Citizens' Council held a protest outside the Chisso factory gates. One of the Chisso trade unions held an eight-hour strike in protest at the poor treatment of the arbitration group by their own company.[32] The litigation group, representing 41 certified patients (17 already deceased) in 28 families, submitted their suit against Chisso in the Kumamoto District Court on 14 June 1969. The leader of the group, Eizō Watanabe (a former leader of the Mutual Aid Society), declared, "Today, and from this day forth, we are fighting against the power of the state." Those who decided to sue the company came under fierce pressure to drop their lawsuits. One woman was visited personally by a Chisso executive and harassed by her neighbours. She was blackballed by the community, her family's fishing boat used without permission, their fishing nets were cut, and human faeces were thrown at her in the street.[33] The litigation group and their lawyers were helped substantially by an informal national network of citizens' groups that had sprung up around the country in 1969. The Associations to Indict [Those Responsible for] Minamata Disease (水俣病を告発する会, Minamata-byō o Kokuhatsu Suru Kai) were instrumental in raising awareness and funds for the lawsuit. The Kumamoto branch, in particular, was especially helpful to the case. In September 1969, they set up a Trial Research Group, which included law professors, medical researchers (including Harada), sociologists and even Michiko Ishimure to provide useful material to the lawyers to improve their legal arguments. Their report, Corporate Responsibility for Minamata Disease: Chisso's Illegal Acts,[34] published in August 1970, formed the basis of the ultimately successful lawsuit.[32] The trial lasted almost four years. The litigation group's lawyers sought to prove Chisso's corporate negligence. Three main legal points had to be overcome to win the case. First, the lawyers had to show that methylmercury caused Minamata disease and that the company's factory was the source of pollution. The extensive research by Kumadai and the government's conclusion meant that this point was proved quite easily. Second, they needed to show that Chisso could and should have anticipated the effect of its wastewater and taken steps to prevent the tragedy (i.e., was the company negligent in its duty of care). Third, it had to disprove that the "sympathy money" agreement of 1959, which forbade the patients from claiming any further compensation, was a legally binding contract. The trial heard from patients and their families, but the most important testimony came from Chisso executives and employees. The most dramatic testimony came from Hosokawa, who spoke on 4 July 1970 from his hospital bed where he was dying of cancer. Hosokawa explained his experiments with cats, including the infamous "cat 400", which developed Minamata disease after being fed factory wastewater. He also spoke of his opposition to the 1958 change in wastewater output route to Minamata River. Hosokawa's testimony was backed up by a colleague who also told how Chisso officials had ordered them to halt their cat experiments in the autumn of 1959. Hosokawa died three months after giving his testimony. Former factory manager Eiichi Nishida admitted that the company put profits ahead of safety, resulting in dangerous working conditions and a lack of care with mercury. Former Chisso President Kiichi Yoshioka admitted that the company promoted a theory of dumped World War II explosives, though it knew it to be unfounded. The verdict handed down on 20 March 1973 represented a complete victory for the patients of the litigation group: > The defendant's factory was a leading chemical plant with the most advanced technology and ... should have assured the safety of its wastewater. The defendant could have prevented the occurrence of Minamata disease or at least have kept it at a minimum. We cannot find that the defendant took any of the precautionary measures called for in this situation whatsoever. The presumption that the defendant had been negligent from beginning to end in discharging wastewater from its acetaldehyde plant is amply supported. The defendant cannot escape liability for negligence. The "sympathy money" agreement was found to be invalid and Chisso was ordered to make one-time payments of ¥18 million ($66,000) for each deceased patient and from ¥16 million to ¥18 million ($59,000 to $66,000) for each surviving patient. The total compensation of ¥937 million ($3.4 million) was the largest sum ever awarded by a Japanese court.[35] ### Uncertified patients' fight to be recognised[edit] While the struggles of the arbitration and litigation groups against Chisso were continuing, a new group of Minamata disease sufferers emerged. To qualify for compensation under the 1959 agreement, patients had to be officially recognised by various ad hoc certification committees according to their symptoms. However, in an effort to limit the liability and financial burden on the company, these committees were sticking to a rigid interpretation of Minamata disease. They required that patients must exhibit all symptoms of Hunter-Russell syndrome – the standard diagnosis of organic mercury poisoning at the time, which originated from an industrial accident in the United Kingdom in 1940. The committee certified only patients exhibiting explicit symptoms of the British syndrome, rather than basing their diagnosis on the disease in Japan. This resulted in many applicants being rejected by the committee, leaving them confused and frustrated.[36] ## Epidemiology[edit] As of March 2001, 2,265 victims had been officially certified (1,784 of whom have died)[3] and over 10,000 people had received financial compensation from Chisso,[4] although they were not recognised as official victims. The issue of quantifying the impact of Minamata disease is complicated, as a full epidemiological study has never been conducted and patients were recognised only if they voluntarily applied to a certification council to seek financial compensation.[37][38] Many victims of Minamata disease faced discrimination and ostracism from the local community if they came out into the open about their symptoms. Some people feared the disease to be contagious, and many local people were fiercely loyal to Chisso, depending on the company for their livelihoods. In this atmosphere, sufferers were reluctant to come forward and seek certification. Despite these factors, over 17,000 people have applied to the council for certification. Also, in recognising an applicant as a Minamata disease sufferer, the certification council qualified that patient to receive financial compensation from Chisso. For that reason, the council has always been under immense pressure to reject claimants and minimise the financial burden placed on Chisso. Rather than being a council of medical recognition, the decisions of the council were always affected by the economic and political factors surrounding Minamata and the Chisso corporation. Furthermore, compensation of the victims led to continued strife in the community, including unfounded accusations that some of the people who sought compensation did not actually suffer from the disease.[39] More properly, the impact should be called a criminal 'poisoning', not a clinical 'disease'. These forms of obfuscation are commonly experienced by 'environmental victims' in many countries.[40] ## Democratizing effects[edit] According to Timothy S. George, the environmental protests that surrounded the disease appeared to aid in the democratization of Japan.[41] When the first cases were reported and subsequently suppressed, the rights of the victims were not recognised, and they were given no compensation. Instead, the afflicted were ostracised from their community due to ignorance about the disease, as people were afraid that it was contagious. The people directly impacted by the pollution of Minamata Bay were not originally allowed to participate in actions that would affect their future. Disease victims, fishing families, and company employees were excluded from the debate. Progress occurred when Minamata victims were finally allowed to come to a meeting to discuss the issue. As a result, postwar Japan took a small step toward democracy. Through the evolution of public sentiments, the victims and environmental protesters were able to acquire standing and proceed more effectively in their cause. The involvement of the press also aided the process of democratization because it caused more people to become aware of the facts of Minamata disease and the pollution that caused it. However, although the environmental protests did result in Japan becoming more democratized, it did not completely rid Japan of the system that first suppressed the fishermen and victims of Minamata disease. ## Society and culture[edit] Toshiko Akiyoshi, touched by the plight of the fishing village, wrote a jazz suite, "Minamata", that was to be the central piece of the Toshiko Akiyoshi-Lew Tabackin Big Band's 1976 album on RCA, Insights. The piece was constructed in three parts, to musically reflect the tragedy – "Peaceful Village", "Prosperity & Consequence", and "Epilogue". Akiyoshi used Japanese vocalists to sing the Japanese lyrics of a tone poem that were part of the composition. The album won many awards in jazz circles, including Downbeat's best album award, largely on the strength of this piece, which brought some further attention to the tragedy.[42] Insights (Toshiko Akiyoshi – Lew Tabackin Big Band) The song "Kepone Factory" on Dead Kennedys' In God We Trust, Inc. makes reference to the disaster in its chorus. The song "The Disease of the Dancing Cats" by the band Bush on "The Science of Things" album is in reference to the disaster. ### Media[edit] Photographic documentation of Minamata started in the early 1960s. One photographer who arrived in 1960 was Shisei Kuwabara, straight from university and photo school, who had his photographs published in Weekly Asahi as early as May 1960. The first exhibition of his photographs of Minamata was held in the Fuji Photo Salon in Tokyo in 1962, and the first of his book-length anthologies, Minamata Disease, was published in Japan in 1965. He has returned to Minamata many times since.[43] A dramatic photographic essay by W. Eugene Smith brought world attention to Minamata disease. His Japanese wife and he lived in Minamata from 1971 to 1973. The most famous and striking photo of the essay, Tomoko Uemura in Her Bath (1972), shows Ryoko Uemura, holding her severely deformed daughter, Tomoko, in a Japanese bath chamber. Tomoko was poisoned by methylmercury while still in the womb. The photo was very widely published. It was posed by Smith with the co-operation of Ryoko and Tomoko to dramatically illustrate the consequences of the disease. It has subsequently been withdrawn from circulation at the request of Tomoko's family, so does not appear in recent anthologies of Smith's works.[44] Smith and his wife were extremely dedicated to the cause of the victims of Minamata disease, closely documenting their struggle for recognition and right to compensation. Smith was himself attacked and seriously injured by Chisso employees in an incident in Goi, Ichihara city, near Tokyo on January 7, 1972, in an attempt to stop the photographer from further revealing the issue to the world.[45] The 54-year-old Smith survived the attack, but his sight in one eye deteriorated and his health never fully recovered before his death in 1978. Johnny Depp plays W. Eugene Smith in Minamata (2020) a drama based on the book written by Smith's wife. Japanese photographer Takeshi Ishikawa, who assisted Smith in Minamata, has since exhibited his own photographs documenting the disease. His photographs cover the years 1971 to the present, with Minamata victims as his subjects.[46] The prominent Japanese documentary filmmaker Noriaki Tsuchimoto made a series of films, starting with Minamata: The Victims and Their World (1971) and including The Shiranui Sea (1975), documenting the incident and siding with the victims in their struggle against Chisso and the government. ### Today[edit] Memorial at the Minamata Disease Municipal Museum Minamata disease remains an important issue in contemporary Japanese society. Lawsuits against Chisso and the prefectural and national governments are still continuing and many regard the government responses to date as inadequate.[47] The company's "historical overview" in its current website makes no mention of their role in the mass contamination of Minamata and the dreadful aftermath.[48] Their 2004 Annual Report, however, reports an equivalent of about US$50 million (5,820 million yen) in "Minamata Disease Compensation Liabilities". From 2000 to 2003, the company also reported total compensation liabilities of over US$170 million. Their 2000 accounts also show that the Japanese and Kumamoto prefectural governments waived an enormous US$560 million in related liabilities. Their FY2004 and FY2005 reports refer to Minamata disease as "mad hatter's disease", a term coined from the mercury poisoning experienced by hat-makers of the last few centuries (cf. Erethism).[49] A memorial service was held at the Minamata Disease Municipal Museum on 1 May 2006 to mark 50 years since the official discovery of the disease. Despite bad weather, the service was attended by over 600 people, including Chisso chairman Shunkichi Goto and Environment Minister Yuriko Koike.[50] On Monday, March 29, 2010, a group of 2,123 uncertified victims reached a settlement with the government of Japan, the Kumamoto Prefectural government, and Chisso Corporation to receive individual lump-sum payments of 2.1 million yen and monthly medical allowances.[6][51] Most congenital patients are now in their forties and fifties and their health is deteriorating. Their parents, who are often their only source of care, are into their seventies or eighties or already deceased. Often, these patients find themselves tied to their own homes and the care of their family, effectively isolated from the local community. Some welfare facilities for patients do exist. One notable example is Hot House (ほっとはうす, Hotto Hausu), a vocational training centre for congenital patients as well as other disabled people in the Minamata area. Hot House members are also involved in raising awareness of Minamata disease, often attending conferences and seminars as well as making regular visits to elementary schools throughout Kumamoto Prefecture.[52] ## See also[edit] * Heavy metal poisoning * Minamata Convention on Mercury * Ontario Minamata disease * Mercury in fish ## References[edit] 1. ^ Hamdy MK, Noyes OR. (1975). "Formation of Methyl Mercury by Bacteria" (PDF). Appl. Microbiol. 30 (3): 424–432. doi:10.1128/AEM.30.3.424-432.1975. PMC 187198. PMID 1180551.CS1 maint: uses authors parameter (link) and references therein. 2. ^ a b Withrow SJ, Vail DM. (2007). Withrow and MacEwen's Small Animal Clinical Oncology (4th ed.). St. Louis, MO: Elsevier. pp. 73–4. ISBN 978-0-721-60558-6.CS1 maint: uses authors parameter (link) 3. ^ a b Official government figure as of March 2001. See "Minamata Disease: The History and Measures, ch2" 4. ^ a b See "Minamata Disease Archives" Archived 2016-03-03 at the Wayback Machine, Frequently asked questions, Question 6 5. ^ Jane Hightower (2008). Diagnosis Mercury: Money, Politics and Poison, Island Press, p. 77. 6. ^ a b "Agreement reached to settle Minamata suit", Asahi Shimbun news, 31 March 2010, retrieved 1 April 2010 7. ^ Nabi, Shabnum (2014). "Methylmercury and Minamata Disease". Toxic Effects of Mercury. Springer, New Delhi. pp. 187–199. doi:10.1007/978-81-322-1922-4_25. ISBN 9788132219217. 8. ^ Harada, p15 9. ^ George, pp35-36 10. ^ George, p26 11. ^ Report of the Social Scientific Study Group on Minamata Disease, In the Hope of Avoiding Repetition of a Tragedy of Minamata Disease, National Institute for Minamata Disease, p. 13. 12. ^ Eto et al. (2010) 13. ^ Clark RB. (1997). Marine Pollution (4th ed.). New York, NY: Oxford University Press. p. 161. ISBN 978-0-198-50069-8. 14. ^ For further information on the chemistry of the reaction that lead to the production of methylmercury see "Information on Mercury" Archived 2011-07-11 at the Wayback Machine by Mercury Technology Services, retrieved around the 24 October 2006 15. ^ Gilhooly, Rob, "Mercury rising: Niigata struggles to bury its Minamata ghosts", Japan Times, 13 June 2015 16. ^ Harada, p10 17. ^ Nicol, C.W., "Minamata: a saga of suffering and hope", Japan Times, 7 October 2012, p. 10 18. ^ Harada, pp23-24 19. ^ Harada, pp26-27 20. ^ a b Harada, p50 21. ^ Harada, p52 22. ^ Harada, pp38-39 23. ^ Ui, Chapter 4 – section IV 24. ^ George, pp60-61 25. ^ See "The Stockholm Appeal" Archived 2013-01-25 at the Wayback Machine by Soshisha – The Supporting Center for Minamata Disease, retrieved 08 January 2011 26. ^ Harada, p56 27. ^ George, pp144-145 28. ^ Harada, pp68-77 29. ^ Harada, p90 30. ^ George, pp174-175 31. ^ George, pp187-190 32. ^ a b George, pp191-202 (Arbitration Group) 33. ^ George, p205 34. ^ Corporate Responsibility for Minamata Disease: Chisso's Illegal Acts (水俣病に対する企業の責任：チッソの不法行為, Minamata-byō ni Tai Suru Kigyō no Sekinin: Chisso no Fuhō Kōi) 35. ^ George, pp241-249 36. ^ Harada, pp156-157 and George, p208 37. ^ See "Mercury poisoning of thousands confirmed" by Jonathan Watts, The Guardian, 16 October 2001, retrieved 24 October 2006. 38. ^ Kawamura, Hiroki (2017). "The relation between law and technology in Japan: liability for technology-related mass damage in the cases of Minamata disease, asbestos, and the Fukushima Daiichi nuclear disaster". Contemporary Japan. 30 (1): 3–27. doi:10.1080/18692729.2018.1423459. S2CID 159882741. 39. ^ See "Ten Things to Know about Minamata Disease" Archived 2012-07-25 at the Wayback Machine by Soshisha – The Supporting Center for Minamata Disease 40. ^ Williams, C. (1998) Environmental Victims: New Risks new Injustice. London Earthscan. 41. ^ George, Timothy S. (2001). Minamata: Pollution and the Struggle for Democracy in Postwar Japan. Harvard University Asia Center. ISBN 0-674-00785-9. 42. ^ Record Review magazine vol 2 no 3 August 1978 – Scott Yanow; Downbeat (http://www.downbeat.com/default.asp?sect=stories&subsect=story_detail&sid=704); liner notes for Toshiko Akiyoshi/Lew Tabackin Big Band LP, Insights 1976 RCA VICTOR AFL1-2678 STEREO 43. ^ "Shisei Kuwabara – 'Minamata': The Starting point of the work of the photojournalist, Shisei Kuwabara", KMoPA. (In Japanese, despite the English title.) Accessed 4 January 2012. 44. ^ Read the thoughts of a photography magazine editor surrounding the controversy of the photograph's withdrawal: "Tomoko Uemura, R.I.P." by Jim Hughes, The Digital Journalist, retrieved 24 October 2006. 45. ^ Smith, pp94-95 46. ^ Hirano, Keiji, "Life with Minamata disease in photos", Japan Times, 15 November 2012, p. 3 47. ^ "Minamata's latest chapter", Japan Times editorial, 3 October 2006, retrieved 29 October 2006 (free registration required) 48. ^ Chisso Corporation. "Historical Overview". Chisso Corporation official site. Chisso. Retrieved 8 May 2013. 49. ^ FY2004 and FY2005 financial results. URL retrieved 2008-03-07. 50. ^ "Memorial service marks Minamata tragedy's 50th year", Japan Times, 2 May 2006, retrieved 29 October 2006 (free registration required) 51. ^ Hirano, Keiji, Kyodo News, "Mercury pact falls short on Minamata", Japan Times, 1 March 2012, p. 3. 52. ^ "Advanced welfare should arise from Minamata" by Takeko Kato, Asahi Shimbun, 10 May 2006, retrieved 29 October 2006 ## Further reading[edit] * "Minamata Disease: The History and Measures", The Ministry of the Environment, (2002), retrieved 17 January 2007 * "Minamata Disease Archives" by the National Institute for Minamata Disease, retrieved 29 October 2006 * Harada, Masazumi. (1972). Minamata Disease. Kumamoto Nichinichi Shinbun Centre & Information Center/Iwanami Shoten Publishers. ISBN 4-87755-171-9 C3036 * George, S. Timothy. (2001). Minamata: Pollution and the Struggle for Democracy in Postwar Japan. Harvard University Press. ISBN 0-674-00785-9 * Ui, Jun. (1992). Industrial Pollution in Japan. United Nations University Press. ISBN 92-808-0548-7. Chapter 4, section IV * Smith, W. E. and Smith, A. M. (1975). Minamata. Chatto & Windus, Ltd. (London), ISBN 0-7011-2131-9 * Eto, K., Marumoto, M. and Takeya, M. (2010) "The pathology of methylmercury poisoning (Minamata disease)", retrieved 7 December 2013 * Oiwa, Keibo. (2001). Rowing the Eternal Sea: The Story of a Minamata Fisherman. Rowman & Littlefield Publishers. ISBN 0-7425-0021-7 * Steingraber, Sandra. (2001). Having Faith: An Ecologist Journey to Motherhood. Perseus Publishing. ISBN 0-425-18999-6 * Approaches to Water Pollution Control, Minamata City, Kumamoto Prefecture * Allchin, Douglas. The Poisoning of Minamata * Saito, Hisashi. (2009). Niigata Minamata Disease: Methyl Mercury Poisoning in Niigata, Japan. Niigata Nippo. * Walker, Brett. (2010) "Toxic Archipelago: A History of Industrial Disease in Japan." University of Washington Press. ISBN 0-295-98954-8 ## External links[edit] Classification D * ICD-10: T56.1 * ICD-9-CM: 985.0 External resources * MedlinePlus: 001651 Wikimedia Commons has media related to Minamata disease. Wikiquote has quotations related to: Minamata disease * ATSDR – ToxFAQs: Mercury – Frequently asked questions about Mercury * National Institute for Minamata Disease * Minamata Disease: The History and Measures – The Ministry of the Environment's summary of Minamata disease * Soshisha – The Supporting Center for Minamata Disease and the Minamata Disease Museum * Aileen Archive – Copyright holder of W. Eugene Smith's Minamata photos * Photograph by W. Eugene Smith – Tomoko Uemura in Her Bath, 1972 * Minamata disease – Chapter from Industrial Pollution in Japan by Dr Jun Ui * Toxic Archipelago: Industrial Pollution in Japan – A talk by Brett Walker, September 16, 2010 * Minamata Timeline by Minamata City Council. * Minamata disease museum * v * t * e Minamata disease * Timeline of Minamata disease * 1959 compensation agreements * Niigata Minamata disease * Ontario Minamata disease * Minamata: The Victims and Their World * The Shiranui Sea * v * t * e Four Big Pollution Diseases of Japan * Itai-itai disease * Minamata disease * Niigata Minamata disease * Yokkaichi asthma * v * t * e Toxicology * History of poison * Toxinology Fields * Aquatic toxicology * Ecotoxicology * Occupational toxicology * Entomotoxicology * Environmental toxicology * Forensic toxicology * Medical toxicology * In vitro toxicology * Toxicogenomics Concepts * Acceptable daily intake * Acute toxicity * Bioaccumulation * Biomagnification * Fixed-dose procedure * Lethal dose * Poison * Toxic capacity * Toxicant * Toxin * Toxicity class * Venom Treatments * Activated carbon * Antidote * Cathartic * Chelation therapy * Gastric lavage * Hemodialysis * Hemoperfusion * Whole bowel irrigation Incidents * 1858 Bradford sweets poisoning * 2007 pet food recalls * Bhopal disaster * Minamata disease * Niigata Minamata disease * Poisoning of Alexander Litvinenko * Seveso disaster * Consumption of Tide Pods * Visakhapatnam gas leak * List of poisonings Related topics * Biological warfare * Carcinogen * Food safety * Hazard symbol * List of extremely hazardous substances * Mutagen * Occupational safety and health * Category * Commons * WikiProject * v * t * e Consumer food safety Adulterants, food contaminants * 3-MCPD * Aldicarb * Antibiotic use in livestock * Cyanide * Formaldehyde * HGH controversies * Lead poisoning * Melamine * Mercury in fish * Sudan I Flavorings * Monosodium glutamate (MSG) * Salt * Sugar * High-fructose corn syrup Intestinal 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contamination incidents * Devon colic * Swill milk scandal * Esing Bakery incident * 1858 Bradford sweets poisoning * 1900 English beer poisoning * Morinaga Milk arsenic poisoning incident * Minamata disease * 1971 Iraq poison grain disaster * Toxic oil syndrome * 1985 diethylene glycol wine scandal * UK mad cow disease outbreak * 1993 Jack in the Box E. coli outbreak * 1996 Odwalla E. coli outbreak * 2006 North American E. coli outbreaks * ICA meat repackaging controversy * 2008 Canada listeriosis outbreak * 2008 Chinese milk scandal * 2008 Irish pork crisis * 2008 United States salmonellosis outbreak * 2011 Germany E. coli outbreak * 2011 United States listeriosis outbreak * 2013 Bihar school meal poisoning * 2013 horse meat scandal * 2015 Mozambique beer poisoning * 2017 Brazil weak meat scandal * 2017–18 South African listeriosis outbreak * 2018 Australian rockmelon listeriosis outbreak * 2018 Australian strawberry contamination * Food safety incidents in China * Food safety incidents in Taiwan * Food safety in Australia * Foodborne illness * outbreaks * death toll * United States Regulation, standards, watchdogs * Acceptable daily intake * E number * Food labeling regulations * Food libel laws * International Food Safety Network * ISO 22000 * Nutrition facts label * Organic certification * The Non-GMO Project * Quality Assurance International * Food Standards Agency Institutions * Institute for Food Safety and Health * European Food Safety Authority * International Food Safety Network * Spanish Agency for Food Safety and Nutrition * Food Information and Control Agency (Spain) * Centre for Food Safety (Hong Kong) * Ministry of Food and Drug Safety (South Korea) Authority control * GND: 4210050-1 * NDL: 00567656 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Minamata disease	c0086626	6,233	wikipedia	https://en.wikipedia.org/wiki/Minamata_disease	2021-01-18T18:59:15	{"gard": ["3575"], "mesh": ["D020262"], "icd-9": ["985.0"], "icd-10": ["T56.1"], "orphanet": ["1917"], "wikidata": ["Q338857"]}
N-acetylglutamate synthase deficiency (NAGS) is type of metabolic disorder that affects the processing of proteins and removal of ammonia from the body. When proteins are processed by the body, ammonia is formed. Individuals with NAGS are not able to remove ammonia from the body and have symptoms due to toxic levels of ammonia that build up in the blood. NAGS and other similar disorders are a type of metabolic condition known as a urea cycle disorder. Signs and symptoms in newborns with NAGS may include a lack of energy, unwillingness to eat, seizures, unusual body movements, and poorly controlled breathing or body temperature. Complications may include coma, developmental delay, and learning disability. Some people have a less severe form of the deficiency with earliest symptoms manifesting later in life, particularly following high-protein meals, illness, or other stress. Signs and symptoms may include sudden vomiting, lack of coordination, confusion, and coma. NAGS is caused by mutations in the NAGS gene and is inherited in an autosomal recessive fashion. Treatment may include maintaining a low protein diet and using medications that provide alternative routes to remove ammonia from the body. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	N-acetylglutamate synthase deficiency	c0268543	6,234	gard	https://rarediseases.info.nih.gov/diseases/7158/n-acetylglutamate-synthase-deficiency	2021-01-18T17:58:48	{"mesh": ["C536109"], "omim": ["237310"], "umls": ["C0268543"], "orphanet": ["927"], "synonyms": ["Hyperammonemia due to N-Acetylglutamate Synthetase Deficiency", "NAGS deficiency", "NAG synthetase deficiency", "N-acetyl glutamate synthetase deficiency"]}
Melanosis coli Other namesPseudomelanosis coli, Melanosis coli identified on colonoscopy as a brownish moiré pattern on the wall of the colon. Micrograph of melanosis coli, with the characteristic mucosal lipofuscin-laden macrophages (brown). Melanosis coli, also pseudomelanosis coli, is a disorder of pigmentation of the wall of the colon, often identified at the time of colonoscopy. It is benign, and may have no significant correlation with disease. The brown pigment is lipofuscin in macrophages, not melanin. ## Contents * 1 Cause * 2 Histologic appearance * 3 Prognosis * 4 Relation to true melanoses * 5 Non-colonic pseudomelanoses * 6 References * 7 External links ## Cause[edit] Further information: Factitious diarrhea The most common cause of melanosis coli is the extended use of laxatives, and commonly anthraquinone containing laxatives such as senna, aloe vera and other plant glycosides.[1] The anthranoid laxatives pass through the gastrointestinal tract unabsorbed until they reach the large intestine, where they are changed into their active forms. The resulting active compounds cause damage to the cells in the lining of the intestine and leads to apoptosis (a form of cell death). The damaged (apoptotic) cells appear as darkly pigmented bodies that may be taken up by scavenger cells known as macrophages. When enough cells have been damaged, the characteristic pigmentation of the bowel wall develops. The condition can develop after just a few months of laxative use.[2] However, other causes are identified, including an increase in colonic epithelial apoptosis.[3] Endoscopically, the mucosa may show a brownish discoloration in a moiré pattern.[citation needed] ## Histologic appearance[edit] On biopsy, melanosis coli shows characteristic pigment-laden macrophages within the mucosa on PAS staining.[4] The histologic differential diagnosis of mucosal pigmentation is: lipofuscin (melanosis coli), hemosiderin-laden macrophages, and melanin (rare). * Micrograph showing melanosis coli, which appears as brown pigmentation in the macrophages in the lamina propria. * Micrograph of melanosis coli. H&E stain. * Micrograph of melanosis coli. H&E stain. ## Prognosis[edit] No adverse effects or consequences of melanosis coli have been identified.[4] ## Relation to true melanoses[edit] The condition is unrelated to true melanoses, such as Peutz–Jeghers syndrome and smoker's melanosis.[5] Peutz–Jeghers syndrome causes pigmentation of the skin and mucous surfaces with melanin, and polyps in the digestive tract. ## Non-colonic pseudomelanoses[edit] Pseudomelanoses of other parts of the gastrointestinal tract have also been reported, and are of unclear relevance.[6] Patients with colostomies can have melanosis involving the stoma, which is also of no significance.[7] ## References[edit] 1. ^ Müller-Lissner, SA. (Oct 1993). "Adverse effects of laxatives: fact and fiction". Pharmacology. 47 (Suppl 1): 138–45. doi:10.1159/000139853. PMID 8234421. 2. ^ http://www.medicinenet.com/melanosis_coli/page2.htm 3. ^ Byers, R.J.; Marsh, P.; Parkinson, D.; Haboubi, N.Y (October 2003). "Melanosis coli is associated with an increase in colonic epithelial apoptosis and not with laxative use". Histopathology. 30 (2): 160–164. doi:10.1046/j.1365-2559.1997.d01-574.x. PMID 9067741. 4. ^ a b Wittoesch, JH.; Jackman, RJ.; McDonald, JR. (1958). "Melanosis coli: general review and a study of 887 cases". Dis Colon Rectum. 1 (3): 172–80. doi:10.1007/bf02616828. PMID 13537819. S2CID 46183745. 5. ^ Vellappally, S.; Fiala, Z.; Smejkalová, J.; Jacob, V.; Somanathan, R. (2007). "Smoking related systemic and oral diseases". Acta Medica (Hradec Kralove). 50 (3): 161–6. doi:10.14712/18059694.2017.76. PMID 18254267. 6. ^ Ghadially, FN.; Walley, VM. (Sep 1994). "Melanoses of the gastrointestinal tract". Histopathology. 25 (3): 197–207. doi:10.1111/j.1365-2559.1994.tb01319.x. PMID 7821887. 7. ^ Fleischer, I.; Bryant, D. (May 1995). "Melanosis coli or mucosa ischemia? A case report". Ostomy Wound Manage. 41 (4): 44, 46–7. PMID 7598783. ## External links[edit] Classification D * ICD-10: K63.8 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Melanosis coli	c0221391	6,235	wikipedia	https://en.wikipedia.org/wiki/Melanosis_coli	2021-01-18T19:02:01	{"umls": ["C0221391"], "wikidata": ["Q1919035"]}
A rare defect of tropomyosin characterized by decreased fetal movements and generalized muscle stiffness at birth. Additional features include joint contractures, short stature, kyphosis, dysmorphic features, temperature dysregulation, and variably severe respiratory involvement with hypoxemia. Muscle biopsy shows mild myopathic features. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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 generalized hypercontractile muscle stiffness syndrome	None	6,236	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=476406	2021-01-23T17:05:28	{}
Pelizaeus-Merzbacher disease is a disorder that affects the brain and spinal cord. It is a type of leukodystrophy and is characterized by problems with coordination, motor skills, and learning. The age of onset and the severity of the symptoms varies greatly depending on the type of disease. It is caused by an inability to form myelin due to mutations in the PLP1 gene. It is passed through families in an X-linked recessive pattern. The condition primarily affects males. Treatment requires a multidisciplinary team approach, with members dictated by the presenting 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	Pelizaeus-Merzbacher disease	c0205711	6,237	gard	https://rarediseases.info.nih.gov/diseases/4265/pelizaeus-merzbacher-disease	2021-01-18T17:58:25	{"mesh": ["D020371"], "omim": ["312080"], "orphanet": ["702"], "synonyms": ["PMD", "Pelizaeus Merzbacher disease", "Pelizaeus Merzbacher brain sclerosis"]}
## Summary ### Clinical characteristics. Glycogen storage disease type V (GSDV, McArdle disease) is a metabolic myopathy characterized by exercise intolerance manifested by rapid fatigue, myalgia, and cramps in exercising muscles. Symptoms are usually precipitated by isometric exercise or sustained aerobic exercise. Most individuals improve their exercise tolerance by exploiting the "second-wind" phenomenon with relief of myalgia and fatigue after a few minutes of rest. Age of onset is frequently in the first decade of life but can vary; however, diagnosis is typically delayed as myalgia and fatigability are dismissed/overlooked. Fixed muscle weakness occurs in approximately 25% of affected individuals, is more likely to involve proximal muscles, and is more common in individuals of advanced age. Approximately 50% of affected individuals have recurrent episodes of myoglobinuria that can – on occasion – eventually result in acute renal failure. ### Diagnosis/testing. The diagnosis of GSDV is established in a proband with suggestive findings and by identification of biallelic PYGM (encoding glycogen phosphorylase, muscle form) pathogenic variants on molecular genetic testing or – if genetic test results are not diagnostic – by assay of muscle myophosphorylase enzyme activity. ### Management. Treatment of manifestations: Although no cure for GSDV is available, affected individuals benefit from moderate-intensity aerobic training (e.g., walking or brisk walking, bicycling) to increase cardiorespiratory fitness and muscle oxidative capacity. Pre-exercise ingestion of sports drinks containing simple carbohydrates improves exercise tolerance and may protect against exercise-induced rhabdomyolysis. Surveillance: Annual routine physical examination and review of diet. Agents/circumstances to avoid: To prevent occurrence of cramps and myoglobinuria, avoid intense isometric exercise and maximal aerobic exercise. Evaluation of relatives at risk: When the family-specific PYGM pathogenic variants are known, early detection of GSDV in relatives at risk ensures proper management to prevent muscle injury leading to rhabdomyolysis and to improve long-term outcome, particularly by development of a healthy lifestyle (i.e., regular exercise such as brisk walking) in childhood. ### Genetic counseling. GSDV is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes are asymptomatic. Once the pathogenic variants in the family are known, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. ## Diagnosis ### Suggestive Findings Glycogen storage disease type V should be suspected in individuals with the following supportive findings. Clinical findings * Childhood onset of exercise-induced muscle contractures and pain, especially during the first approximately ten minutes of exercise. Although symptoms are frequently noted in physical education classes or on the school playground, their significance is not usually recognized, and diagnosis is delayed until most affected individuals are older. * Second-wind phenomenon, i.e., improvement in exercise-induced muscle cramps and/or pain after a brief rest period when exercise intensity is reduced, or after the first (~) ten minutes of continuous exercise at the same constant, moderate intensity (see Other findings, Cycle and walking tests). * Episodes of rhabdomyolysis (which can result in myoglobinuria) triggered by persistent skeletal muscle activity despite symptoms (i.e., before getting into the second-wind phenomenon), intense exertion, anaerobic activity (e.g., sprinting to catch a bus), lifting heavy weights, isometric contraction (e.g., carrying weights), and sustained muscle contraction [Scalco et al 2015] * Unusual clinical presentations such as difficulty with mastication, dysphagia, and oral motor function appear to be more common in younger individuals. Other rare presentations are spontaneous compartment syndrome [Triplet et al 2017] or acute contracture of posterior neck muscles (e.g., during dental procedures) [Scalco et al 2016]. * Some affected individuals have minimal symptoms (i.e., only during strenuous exercise) with essentially no limitations in activities of daily living [Pinós et al 2015]. * Physical activity habits may explain variability in phenotypic manifestations of GSDV: individuals who are physically active at work or during their leisure time are less affected [Lucia et al 2012]. Other findings * A wide range of high resting serum creatine kinase [CK] activity. Mean values frequently exceed 1,000 IU/L (normal reference values: <200 IU/L). * Cycle and walking tests are physiologic exertion tests used to detect the pathognomonic heart rate response of the second-wind phenomenon observed in all individuals with GSDV. The cycle test is positive when the first ~10 minutes of cycling elicits a marked increase in heart rate (>30-40 beats/min) at a moderate, constant load (~40 watts for most adults) and frequent muscle symptoms (myalgia and contractures), followed by a decrease in both heart rate (from ~150 to ~120 beats/min) and muscle symptoms [Lucia et al 2012]. Corresponding to a heart rate of 60%-70% of the predicted maximum heart rate (i.e., 220 beats/min minus age in years) The walking test can be performed in less specialized clinical settings [Buckley et al 2014]. * Forearm non-ischemic exercise test detects low values of post-exercise plasma lactate-to-ammonia ratio in persons with GSDV, is easy to perform in clinical settings, and has high sensitivity and specificity [Hogrel et al 2015]. ### Establishing the Diagnosis The diagnosis of glycogen storage disease type V is established in a proband with suggestive findings and by identification of biallelic PYGM pathogenic variants on molecular genetic testing (see Table 1) or – if genetic test results are not diagnostic – by assay of muscle myophosphorylase enzyme activity. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing or genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of glycogen storage disease type V 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 glycogen storage disease type V 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 glycogen storage disease type V, options can include single-gene testing or a multigene panel: * Single-gene testing. Sequence analysis of PYGM 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 only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications [García-Consuegra et al 2009]. Sequencing of PYGM cDNA of peripheral blood cells has proven useful in individuals with a gene variant of uncertain pathogenicity that has apparently synonymous effects [García-Consuegra et al 2016]. * A metabolic myopathy or rhabdomyolysis multigene panel that includes PYGM and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype [Olpin et al 2015, Santalla et al 2017]. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the diagnosis of glycogen storage disease type V 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 an option [Walters et al 2018]. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Glycogen Storage Disease Type V View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method PYGMSequence analysis 399% 4 Gene-targeted deletion/duplication analysis 5Unknown 6, 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\. García-Consuegra et al [2016], Santalla et al [2017] 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. No data on detection rate of gene-targeted deletion/duplication analysis are available. 7\. A 1,094-bp deletion variant, c.1969+214_2177+369del, extends from intron 16 to intron 17 [García-Consuegra et al 2009]. A clinical utility card regarding genetic test usage for PYGM has been published [Taylor et al 2018]. Assay of myophosphorylase enzyme activity. Myophosphorylase E.C. 2.4.1.1 is the muscle isoenzyme of glycogen phosphorylase (GP). Qualitative histochemistry or quantitative biochemical analysis in a muscle biopsy or muscle homogenate is diagnostic. In persons with GSDV, residual activity of myophosphorylase is virtually undetectable. ## Clinical Characteristics ### Clinical Description Glycogen storage disease type V (GSDV) is a metabolic myopathy with onset frequently in the first decade of life. Clinical heterogeneity exists; about 10% of all affected individuals have mild manifestations (e.g., fatigue or poor stamina without contractures) and remain virtually asymptomatic during daily activities of living [Santalla et al 2017], whereas a more severe, rapidly progressive form may manifest shortly after birth. In some individuals, progressive weakness manifests in the sixth or seventh decade of life. The fixed weakness that occurs in approximately 20% of affected individuals is more likely to involve proximal muscles and is more common in individuals older than age 40 years [Santalla et al 2017]. Most affected individuals learn to adjust their daily activities and can lead relatively normal lives. The usual presentation of GSDV is exercise intolerance (including contractures, stiffness, and/or weakness of the muscles in use), myalgia, and fatigue in the first few minutes of exercise. These symptoms are usually precipitated by isometric exercise (e.g., carrying weights) or sustained vigorous "aerobic" exercise (e.g., stair climbing, jogging), and typically are relieved by rest. Any skeletal muscle can be affected. Recurrent episodes of myoglobinuria as a consequence of such exercise are observed in about 50% of affected individuals [Santalla et al 2017]. Atypical presentations have been also described, such as difficulty with mastication, dysphagia, and oral motor function (which appear to be more common in younger individuals) [Kouwenberg et al 2018], spontaneous compartment syndrome [Mull et al 2015, Triplet et al 2017], and acute contracture of the posterior neck muscles [Scalco et al 2016]. While most affected individuals remember painful symptoms from early childhood, the disorder is rarely diagnosed before adulthood (i.e., usually after age 20 years, median age 33 years) [Santalla et al 2017, Scalco et al 2017]. Some people notice in middle age a worsening of their symptoms that may be accompanied by some muscle wasting. Presentation with exertional dyspnea has been described. Most individuals learn to improve their exercise tolerance by exploiting the second-wind phenomenon, a unique feature of GSDV, which is relief of myalgia and rapid fatigue after a few minutes of rest. The metabolic events underlying the second wind are the increased supply of blood-borne glucose and free fatty acids as exercise progresses, leading to an increase in the rate of metabolism of these fuels inside working muscle fibers. The ability to develop a second wind is greatly increased in those who stay physically fit with regular aerobic exercise, such as walking. In contrast, continuing to exercise in the presence of severe pain might result in muscle damage (rhabdomyolysis) and myoglobinuria. Myoglobinuria due to rhabdomyolysis following intense exercise occurs in approximately 50% of individuals; despite the risk of acute renal failure, very few develop it. While kidney failure is almost always reversible, emergency treatment is required [Lucia et al 2012]. It is noteworthy that a history of dark urine could help avoid misdiagnosis and complications of GSDV [Scalco et al 2016, Martinez-Thompson et al 2017]. Other presentations of GSDV: * Severe paraspinal wasting and weakness [Witting et al 2014] * Incidental finding of severe obstructive hypertrophic cardiomyopathy [Moustafa et al 2013] * Acute renal failure in the absence of exertion * HyperCKemia (asymptomatic elevations of serum CK activity) up to 17,000 IU/L in the infantile myopathy and preadolescents. Pathophysiology. The two types of exercise: * Aerobic exercise includes walking, gentle swimming, jogging, and cycling. During aerobic exercise, the fuel used by skeletal muscle depends on several factors including the following: type, intensity, and duration of exercise; physical condition; and dietary regimen. Because aerobic exercise favors the utilization of blood-borne substrates, such as fatty acids, it is better tolerated by individuals with GSDV and thus beneficial as a therapeutic regimen. * "Anaerobic" exercise is intense and cannot be sustained (e.g., weight lifting or 100-meter dash). Normally, during anaerobic exercise, myophosphorylase converts glycogen to glucose, which enters the glycolytic pathway and produces ATP "anaerobically" (or with no need for oxygen). The first few minutes of any exercise have an anaerobic component. Depending on intensity and duration of the exercise, muscle uses different fuel sources such as anaerobic glycolysis, blood glucose, muscle glycogen, and aerobic glycolysis, followed by fatty acid oxidation. At rest the main energy source is blood free fatty acids. These molecules are oxidized in the mitochondrial beta-oxidation pathway to produce acetyl-CoA, which is further metabolized through the Krebs cycle and the mitochondrial respiratory chain resulting in ATP production. ### Genotype-Phenotype Correlations Several studies in European populations have not found an association between severity of clinical findings and PYGM genotype [Santalla et al 2017]. ### Prevalence The prevalence of GSDV in the Dallas-Fort Worth, Texas, area was estimated at 1:100,000. The Spanish McArdle Disease patient registry reported a minimum prevalence in this country of nearly 1:170,000 [Lucia et al 2012, Santalla et al 2017]. ## Differential Diagnosis The differential diagnosis of glycogen storage disease type V (GSDV) includes mitochondrial myopathy (mitochondrial myopathy is genetically heterogeneous [see Mitochondrial Disorders Overview]) and the disorders associated with the genes listed in Table 2. Because most of the disorders in Table 2 have different forms (i.e., hepatic and muscle), information included in the table pertains to the myopathic forms that are usually manifest in children or adults. For the purposes of differential diagnosis, clinicians should be aware that the second-wind phenomenon is virtually pathognomonic for GSDV. ### Table 2. Other Genes of Interest in the Differential Diagnosis of Glycogen Storage Disease Type V (GSDV) View in own window Gene(s) 1Differential Diagnosis DisorderMOIClinical Features of Differential Diagnosis Disorder Overlapping w/GSDVDistinguishing from GSDV ACADVLVLCAD deficiencyAR * Exercise intolerance * Intermittent rhabdomyolysis * Precipitants: prolonged exercise, fasting, cold, fever * Normal basal CK CAV3Isolated hyperCKemia (OMIM 123320) 2ADPersistent hyperCKemia (4- to 17-fold higher than normal) * No clinical findings of muscle disease * Normal lactate exercise testing CPT2Carnitine palmitoyl transferase II deficiencyAR * Myoglobinuria * Cramps, premature fatigue * Precipitants: after prolonged exercise, fasting, fever * Basal CK (inter-episodic) normal HADHA HADHBMitochondrial trifunctional protein deficiency (OMIM 609015)AREpisodic myoglobinuriaMild sensorimotor axonal peripheral neuropathy LDHAGSDXI 3 (OMIM 612933)ARExertional myoglobinuria * ↑ lactate & pyruvate on exercise testing * Uterine muscle may be stiff during pregnancy. PFKMGSDVII 4 (OMIM 232800)AR * Exercise intolerance cramps & myglobinuria * No ↑ of lactate on exercise test * Compensated hemolysis * Hyperuricemia PGAM2GSDX 5 (OMIM 261670)AR * Myoglobinuria, intolerance for strenuous exercise * Basal serum CK ↑ PGK1Phosphoglycerate kinase 1 deficiency (OMIM 300653)XL * Muscle cramps w/exercise * Rhabdomyolysis * Hemolytic anemia * CNS involvement PHKA1 PHKB PHKG2Phosphorylase kinase deficiency, muscle formsXL AR * Exercise intolerance * Myalgia, cramps * Myoglobinuria * Progressive muscle weakness AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; GSD = glycogen storage disease; MOI = mode of inheritance; VLCAD = very long-chain acyl-CoA dehydrogenase; XL = X-linked 1\. Genes are in alphabetic order. 2\. Also referred to as "creatine phosphokinase, elevated serum" 3\. Lactate dehydrogenase deficiency 4\. Phosphofructokinase deficiency 5\. Phosphoglycerate mutase deficiency ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type V (GSDV), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Physical examination with emphasis on muscle strength/weakness * Basal serum CK activity * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Currently, simple healthy lifestyle interventions (i.e., following a diet rich in complex carbohydrates and regular exercise practice), the most effective means of preventing and managing exercise intolerance in GSDV, require a proactive attitude of clinicians, exercise professionals, and patient advocates [Nogales-Gadea et al 2016]. The benefits of a professionally supervised exercise program are safety and ease of implementation. Patients with GSDV generally adapt well to regular exercise; training should be designed to ensure gradual progression of exercise intensity, especially in the more severely affected patients. For children, it is important to provide parents, caregivers, and educators (especially physical education teachers) with appropriate information to ensure their best possible management. Patients who commit to a supervised, gradual exercise program are able to improve their fitness levels almost as effectively as healthy individuals. Indeed, affected individuals may become virtually asymptomatic during activities of daily living. It should also be noted that physical activity in general has been associated with improvements in peak oxygen uptake (VO2peak, or "cardiorespiratory fitness" [CRF]), an important health indicator. For more details on exercise recommendations and pre-exercise nutrition schedules see Nogales-Gadea et al [2016]. A systematic review of physical training for GSDV published in the Cochrane Database found no randomized or quasi-randomized controlled trials of aerobic training in people with GSDV; however, three studies using small numbers of participants provided some evidence that aerobic training improves CRF without adverse events and called for larger controlled trials of aerobic training in patients with GSDV [Quinlivan et al 2011]. Historically, patients with GSDV have been advised to avoid resistance (strength) exercises and other forms of physical activity involving high mechanical loads such as prolonged isometric contraction. However, a recent study of seven adults (5 female) showed improved muscle strength and mass (clinically as well as objectively using dual-energy x-ray absorptiometry) following a four-month-long resistance training program (i.e., weight lifting with qualified instruction and supervision and a two-month detraining period [Santalla et al 2014]. Further evidence on the safety of this type of exercise was reported in two other patients [Pietrusz et al 2018]. #### Pharmacologic and Nutritional Treatments A revised and updated systematic review in the Cochrane Database of nutritional and pharmacologic trials for GSDV [Quinlivan et al 2014 (updated from 2008)] indicate that high-dose oral ribose, fat-rich diet, glucagon, verapamil, vitamin B6, high-protein diet, branched-chain amino acid supplementation, dantrolene sodium, high-dose creatine, intravenous gentamicin, ketogenic diet, and intralipid infusion treatments showed no benefit. Treatments that showed some benefit included oral sucrose, carbohydrate-rich diet, ramipril, and low-dose creatine. The study concluded that: (1) consuming a sugary drink before planned strenuous exercise can improve performance but is not practical for day-to-day living; (2) a diet rich in complex carbohydrates may be superior to a diet rich in protein; however, because of the small number of participants, evidence was insufficiently strong to indicate a significant clinical benefit; (3) ramipril 2.5 mg orally daily showed some subjective improvement in participants with the DD-ACE polymorphism, which is thought to have a modulating effect on the condition; however, there was no improvement in objective measures of exercise performance; and (4) low-dose creatine supplementation demonstrated a statistically significant (albeit modest) benefit in the tolerance to ischemic exercise in a small number of individuals [Quinlivan et al 2014]. Details of interventions with pre-exercise nutrition and physical exercise recommendations are set forth in Nogales-Gadea et al [2016]. Because of the rarity of GSDV, multicenter collaboration and standardized assessment protocols are needed for future treatment trials. ### Prevention of Primary Manifestations See Treatment of Manifestations and Agents/Circumstances to Avoid. ### Surveillance Appropriate surveillance includes the following: * Annual routine physical examination * Annual review of diet ### Agents/Circumstances to Avoid Exercises that should be avoided in patients with GSDV [Lucia et al 2008, Quinlivan et al 2011, Lucia et al 2012] are the following: * Static muscle contractions (e.g., handgrip exercises) * Static muscle contractions or heavy loads on low muscle mass (e.g., weight lifting), unless performed under programmed supervision of clinicians and exercise/fitness specialists [Santalla et al 2014, Nogales-Gadea et al 2016] * Dynamic exercises at a high-intensity level (e.g., competitive ball games) * Exercises with a high involvement of eccentric (lengthening) muscle contractions (e.g., jumps) * Very intense dynamic aerobic exercise (e.g., running, strenuous swimming, or cycling) except in very fit individuals who are also well trained for the specific activity General anesthetics. Risk of acute muscle damage is reported with certain general anesthetics (usually muscle relaxants and inhaled anesthetics), although in practice, problems appear to be rare. Nonetheless, measures for preventing muscle ischemia and rhabdomyolysis should be taken in individuals with GSDV [Bollig 2013]. ### Evaluation of Relatives at Risk It is appropriate to clarify the clinical/genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual as early diagnosis of GSDV may improve long-term outcome by heightening awareness of the need to avoid repetitive episodes of muscle damage that may lead to rhabdomyolysis and fixed weakness. * Molecular genetic testing can be used for evaluation of relatives at risk if the PYGM pathogenic variants in the family are known. * If the family-specific PYGM pathogenic variants are not known, a reliable and accurate diagnosis of GSDV could be reached following the criteria described in Diagnosis. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management GSDV does not appear to adversely affect pregnancy or childbirth [Lucia et al 2012, Stopp et al 2018]. ### Therapies Under Investigation Preclinical studies (animal models) have shown that sodium valproate, a histone deacetylase inhibitor, (1) increases GP expression in muscle fibers from McArdle sheep [Howell et al 2015] and (2) induces the expression of the brain isoenzyme, GP-BB, with a decrease of glycogen accumulation in primary skeletal muscle cultures derived from a McArdle knock-in mouse [de Luna et al 2015]. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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	Glycogen Storage Disease Type V	c0017924	6,238	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1344/	2021-01-18T21:23:05	{"mesh": ["D006012"], "synonyms": ["Glycogenosis Type V", "GSDV", "McArdle Disease", "Muscle Glycogen Phosphorylase Deficiency", "Myophosphorylase Deficiency", "PYGM Deficiency"]}
Abortion in Papua New Guinea is only legal if the abortion will save the mother's life.[1] In Papua New Guinea, if an abortion is performed on a woman for any other reason, the violator is subject to fourteen years in prison.[1] A woman who performs a self-induced abortion may be imprisoned for seven years.[1] Papua New Guinea law allows courts to take local customs and traditions into consideration in cases of abortion, so some medical practitioners in regions where local traditions allow abortion in cases of rape or incest may not face charges.[1] ## References[edit] 1. ^ a b c d Abortion Policies: Oman to Zimbabwe. United Nations Publications. 2001. ISBN 9789211513653. Retrieved 23 November 2014. * v * t * e Abortion in Oceania Sovereign states * Australia * Federated States of Micronesia * Fiji * Kiribati * Marshall Islands * Nauru * New Zealand * Palau * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu Associated states of New Zealand * Cook Islands * Niue Dependencies and other territories * American Samoa * Christmas Island * Cocos (Keeling) Islands * Easter Island * French Polynesia * Guam * Hawaii * New Caledonia * Norfolk Island * Northern Mariana Islands * Pitcairn Islands * Tokelau * Wallis and Futuna * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category This abortion-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	Abortion in Papua New Guinea	None	6,239	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Papua_New_Guinea	2021-01-18T18:50:46	{"wikidata": ["Q19568860"]}
A rare neurologic disease characterized by impairment of higher visual processing skills and other posterior cortical functions without any evidence of ocular abnormalities, relatively intact memory and language in the early stages, and atrophy of posterior brain regions. ## Epidemiology Posterior Cortical Atrophy (PCA) prevalence is unknown, largely due to the lack of awareness of the syndrome, delayed diagnosis and the variable terminology referring to it (now partially addressed through international consensus criteria). ## Clinical description Early PCA symptoms include visuoperceptual and visuospatial dysfunction, apraxia and alexia. Features of Bálint syndrome (simultanagnosia, optic ataxia and oculomotor apraxia) and Gerstmann syndrome (acalculia, agraphia, finger agnosia and left-right disorientation) are commonly described. The disorder typical onset is between 50-65 years of age. Earliest reported symptoms include difficulties with complex visual behaviors (e.g. driving, reading, and telling the time from an analogue watch). Reading problems include getting lost on the page (visual disorientation), overlapping or miscombined letters (visual crowding) or better reading of small than large print. Odd visual manifestations like abnormally prolonged color after-images and perception of movement of static stimuli are also reported. People with PCA tend to have relatively well preserved memory, insight, and judgment early in the disease course, though language (word finding problems, phonological errors) often emerge early. It should also be noted that PCA is a relatively heterogenous syndrome with some experiencing a very focal visual syndrome, whilst others show a more mixed cognitive picture with prominent visual but also evident episodic memory deficits from early in the disease course. Individuals with PCA often experience anxiety and depression from early on. Extrapyramidal signs, myoclonus, and grasp reflex have also been reported in PCA patients. An international consensus classification frameworkdistinguishes two syndromic description levels. Classification 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. ## Etiology A third level of the international classification framework provides disease-level descriptions of the underlying causes of the PCA syndrome, based on available pathophysiological biomarker evidence. This distinguishes between Alzheimer's disease as the most common underlying pathology (PCA-AD), and other causes including Lewy Body disease (PCA-LBD), corticobasal degeneration (PCA-CBD) and prion disease (PCA-prion). ## Diagnostic methods PCA is an under-recognized disorder resulting often in a significant delay in diagnosis. Diagnosis of this clinico-radiological syndrome is based on neurological assessment, specific visual and cognitive testing, and (optional supportive) brain imaging and routine blood tests. MRI characteristically shows bilateral atrophy in the occipital, parietal and posterior temporal lobes, often asymmetric being more pronounced in the right hemisphere. Single photon emission computed tomography (SPECT) or PET show hypometabolism of the posterior cerebral areas as well as in the frontal eye fields in more advanced stages. Conclusive diagnosis of the underlying disease is confirmed on brain autopsy, though CSF and amyloid imaging may help to refine the clinical diagnosis. ## Differential diagnosis Differential diagnosis includes the most commonly associated neuropathology Alzheimer disease, but may also include Lewy body disease, cortico-basal degeneration, and prion diseases such as Creutzfeldt-Jakob disease. ## Management and treatment There is currently no cure for any of the neurodegenerative conditions that most commonly underly the PCA syndrome. Medications like acetylcholinesterase inhibitors, used in the treatment of Alzheimer's disease, are available and might bring relief for some symptoms. Management of PCA is based on visual aids, rehabilitation programs that include psychoeducation, compensatory strategies, and cognitive exercises to cope with visual disabilities. Antidepressant treatments may benefit individuals with PCA who have relatively preserve insight into their decline and often deal with depression, irritability, frustration and a loss of self-confidence. People with PCA and their caregivers are likely to have different needs to people with more typical presentations of Alzheimer's disease, and may benefit from specialized support groups. ## Prognosis Prognosis is poor as PCA is progressive disorder. Life expectancy after PCA diagnosis is thought to be similar (8-12 years) to individuals affected with Alzheimer's disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Posterior cortical atrophy	c4275079	6,240	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=54247	2021-01-23T19:01:17	{"icd-10": ["G31.1"], "synonyms": ["Benson syndrome", "Biparietal Alzheimer disease", "PCA"]}
A rare genetic developmental defect during embryogenesis characterized by the association of the classic features of Joubert syndrome (congenital midbrain-hindbrain malformations causing hypotonia, abnormal breathing and eye movements, ataxia and cognitive impairment) together with the skeletal anomalies of Jeune asphyxiating thoracic dystrophy (short ribs, long and narrow thorax causing respiratory failure, short-limbs, short stature, and polydactyly). Additional variable manifestations include cystic kidneys, liver fibrosis, and retinal dystrophy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 with Jeune asphyxiating thoracic dystrophy	c3810212	6,241	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=397715	2021-01-23T18:34:12	{"omim": ["615636", "616546"], "icd-10": ["Q04.3"], "synonyms": ["JBTS with JATD", "Joubert syndrome with JATD"]}
A rare, genetic, primary immunodeficiency disease characterized by increased susceptibility to recurrent and/or severe bacterial and viral infections (in particular, sinopulmonary bacterial and herpesvirus infections), chronic benign lymphoproliferation (manifesting as lympadenopathy, hepatosplenomegaly and focal nodular lymphoid hyperplasia), and/or autoimmune disease (including immune cytopenias, juvenile arthritis, glomerulonephritis and sclerosing cholangitis). Immunophenotypically, variable degrees of agammaglobulinemia with increased IgM levels, increased circulating transitional B cells, decreased naïve CD4 and CD8 T-cells with increased CD8 effector/memory T cells 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	Activated PI3K-delta syndrome	c3714976	6,242	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=397596	2021-01-23T18:43:08	{"gard": ["11983"], "mesh": ["C585640"], "omim": ["615513", "616005"], "umls": ["C3714976"], "icd-10": ["D81.8"], "synonyms": ["APDS", "Senescent T-cells-lymphadenopathy-immunodeficiency syndrome due to p110delta-activating mutation"]}
Wysocki and MacKiewicz (1965) described father and son with abnormal beta (2A)-globulin and a defect in coagulation and immunologic responses. A circulating anticoagulant directed against factor VIII and various manifestations interpreted as autoimmune were described. In 3 other family members, beta (2A)-globulin was increased and in 2 was associated with a clotting defect. Another relative had the clotting defect without the protein abnormality. Except for the father and son, these persons were all asymptomatic. Inheritance \- Autosomal dominant Immunology \- Abnormal immunologic response \- Autoimmune manifestations Lab \- Abnormal beta (2A)-globulin \- Circulating anticoagulant directed against factor VIII Heme \- Coagulation defect ▲ 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	GLOBULIN ANOMALY INVOLVING BETA (2A)-GLOBULIN	c1842009	6,243	omim	https://www.omim.org/entry/137900	2019-09-22T16:40:41	{"mesh": ["C564229"], "omim": ["137900"]}
A number sign (#) is used with this entry because of evidence that specific granule deficiency-1 (SGD1) is caused by homozygous mutation in the CEBPE gene (600749) on chromosome 14q11. ### Genetic Heterogeneity of Specific Granule Deficiency See also SGD2 (617475), caused by mutation in the SMARCD2 gene (601736) on chromosome 17q23. Clinical Features In mammals, neutrophils contain 2 principal types of granules. The first type, azurophil granules, appear early in neutrophil development and contain lysosomal enzymes, lysozyme (LYZ; 153450), and myeloperoxidase (MPO; 606989). The second type, specific granules, are formed later, lack MPO and hydrolases, but contain lactoferrin (LF; 150210) and the remainder of the cell's complement of lysozyme. Specific granules are detected at the electron microscopic level by cytochemical demonstration of their lack of MPO and at the light microscopic level by positive immunochemical staining for lactoferrin with the use of specific antisera. Breton-Gorius et al. (1980) found total lack of specific granules (and lactoferrin) in a 6-year-old boy with recurrent infections. Neutrophils also exhibited abnormal nuclear segmentation, nuclear clefts, abnormally weak cytochemical reaction for alkaline phosphatase, and an increased number of mitochondria and ribosomes. Degranulation of azurophil granules occurred normally following phagocytosis. Neutrophil count was normal. The parents were first cousins; a sister had died at the age of 1 year of an infection. Reports of possibly identical cases were found. Whether the defect was in the synthesis of lactoferrin itself or represented failure of specific granule production was not clear. Boxer et al. (1982) restudied a patient reported by Strauss et al. (1974). Ganz et al. (1988) found that both patients with SGD whom they studied had almost complete absence of defensins, which in normal cells constitute more than 30% of the protein of azurophil granules. The polymorphonuclear leukocytes from these patients contained normal or mildly decreased amounts of cathepsin and elastase, these being components of polymorphonuclear leukocytes with microbicidal/cytotoxic activity that are found to be absent in patients with Chediak-Higashi syndrome (214500). Lomax et al. (1989) studied mRNA transcription and protein synthesis of 2 neutrophil granule proteins, lactoferrin and myeloperoxidase, in SGD. Whereas nucleated marrow cells produced normal amounts of myeloperoxidase, there was no detectable synthesis of lactoferrin. Transcripts of the expected size for lactoferrin were detectable in the nucleated marrow cells of 2 SGD patients, but were markedly diminished in abundance when compared with the RNA of normal cells. Because lactoferrin is secreted by the glandular epithelia of several tissues, Lomax et al. (1989) also assessed lactoferrin in the nasal secretions of 1 SGD patient. Nasal secretory lactoferrin was of the same molecular weight as neutrophil lactoferrin and was secreted in normal amounts. From these data, Lomax et al. (1989) concluded that lactoferrin deficiency in SGD neutrophils is tissue specific and is secondary to an abnormality of RNA production. Gallin (1990) suggested that since there is abnormal packaging of all neutrophil specific granule contents in neutrophil lactoferrin deficiency, a defective granule packaging gene may be involved. Gombart et al. (2001) stated that only 5 cases of SGD had been reported worldwide. Neutrophils of individuals with SGD display atypical bilobed nuclei, lack expression of all secondary and tertiary granule proteins, and possess defects in chemotaxis, disaggregation, receptor upregulation, and bactericidal activity, resulting in frequent and severe bacterial infections. Since SGD individuals express normal levels of lactoferrin and transcobalamin in their saliva but not in either their plasma or neutrophils, the molecular basis for SGD was hypothesized to involve a mutation in a myeloid-specific transcription factor. The CEBPE gene (600749) encodes such a transcription factor, which is expressed primarily during granulocytic differentiation. Targeted disruption of the Cebpe gene in mice leads to defects in terminal differentiation of neutrophils with phenotypic and functional defects closely paralleling those of SGD. Molecular Genetics In a patient with specific granule deficiency, Lekstrom-Himes et al. (1999) identified a homozygous frameshift mutation (600749.0001) in the CEBPE gene. His unaffected parents, first cousins once removed, were heterozygous for the mutation. In a patient with specific granule deficiency, Gombart et al. (2001) identified a homozygous frameshift mutation (600749.0002) in the CEBPE gene. The parents were heterozygous for the mutation. Misc \- Recurrent infections Lab \- Absent neutrophil specific granules \- Absent neutrophil lactoferrin \- Abnormal neutrophil nuclear segmentation \- Neutrophil nuclear clefts \- Low neutrophil alkaline phosphatase \- Increased neutrophil mitochondria and ribosomes \- Normal degranulation of azurophil granules after phagocytosis \- Normal neutrophil count Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	SPECIFIC GRANULE DEFICIENCY 1	c0398593	6,244	omim	https://www.omim.org/entry/245480	2019-09-22T16:26:01	{"mesh": ["C562873"], "omim": ["245480", "617475"], "orphanet": ["169142"], "synonyms": ["LACTOFERRIN-DEFICIENT NEUTROPHILS", "Neutrophil-specific granule deficiency", "Alternative titles", "NEUTROPHIL LACTOFERRIN DEFICIENCY"]}
A number sign (#) is used with this entry because of evidence that opsismodysplasia is caused by homozygous or compound heterozygous mutation in the INPPL1 gene (600829) on chromosome 11q13. Description Opsismodysplasia is a rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death in utero or secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges (summary by Below et al., 2013 and Fradet and Fitzgerald, 2017). Clinical Features Opsismodysplasia was suggested by Maroteaux et al. (1982) as the designation for a skeletal dysplasia that shows late bone maturation; the Greek root for the first part of the word means 'delayed maturation.' The disorder was observed at birth; predominantly rhizomelic micromelia, facial dysmorphia, prominent brow, large fontanels, depressed nasal bridge, small anteverted nose with long philtrum, and short feet and hands with sausage-like fingers were features. Death from pulmonary infection was frequent. Growth of the limbs and vertebrae was slow. One patient, aged 3 years and 9 months, showed no femoral, tibial, or carpal nuclei. Maroteaux et al. (1982) studied 4 cases. They referred to a fifth possible case reported by Zonana et al. (1977). One set of parents had ages 44 and 38; consanguinity in other cases suggested autosomal recessive inheritance. Consistent with the designation, the characteristic radiographic signs include very retarded bone maturation, as well as marked shortness of the bones of the hands and feet with concave metaphyses and thin, lamellar vertebral bodies. In studies of the growth cartilage in 1 case, Maroteaux et al. (1984) found a wide hypertrophic area containing thick connective tissue septa, irregular provisional calcification, and vascular invasion. Type I collagen was detected in the hypertrophic area by immunohistochemical and microchemical tests. Beemer and Kozlowski (1994) described the disorder in a 2-year-old boy with first-cousin parents. At 16 months, there were no carpal or tarsal ossification centers and the bones of the hands and feet showed severe abnormalities. There was also absence of ossification in the distal femur and proximal tibia. Santos and Saraiva (1995) described a typical case in a Portuguese male infant born to consanguineous parents. Macrostomia was the only finding in this patient that had not previously been reported in this disorder. Cormier-Daire et al. (2003) described 12 cases in 9 families, all of which had major delay in epiphyseal ossification, platyspondyly, metaphyseal cupping, and very short metacarpals and phalanges. Six cases were diagnosed by prenatal ultrasound and the pregnancies were terminated; of the 6 other cases, one died at 3 months of age of respiratory illness, but the other 5 were still alive and were aged 28 months to 15 years, demonstrating that patients with this disease can survive well beyond the neonatal period. Initial radiographic findings were characteristic of the disease; x-ray follow-up of the survivors showed persistence of an extremely delayed epiphyseal ossification with dysplastic carpal ossification, marked shortness of the metacarpals, and metaphyseal irregularities in the knee. Histopathologic examination of fetal bones and cartilage showed wide and numerous epiphyseal vascular canals; chondrocyte density in the resting cartilage was increased, many cells were arranged in clusters, and some of them were ballooned. At the growth plate level, the proliferative zone was very disorganized, with a nearly absent columnar organization. The mineralized matrix trabeculae were thick and irregular. These anomalies were observed in all cases but varied markedly in severity among cases, paralleling the variability of the x-ray manifestations. Lee et al. (2015) provided details of a 33-week-gestation hydropic stillborn (ISDR R02-170) with a clinical diagnosis of Schneckenbecken dysplasia (269250) who was previously reported by Hiraoka et al. (2007). The patient had midfacial hypoplasia, handlebar clavicles, short ribs, hypoplastic vertebrae with rounded anterior ends, short long bones with widened metaphyseal ends, and a snail-like projection in the ileum. Histomorphology of the cartilage growth plate showed poor hypertrophic column formation with fibrous septae between the columns, areas of hypercellularity with decreased extracellular matrix and hypervascularity, chondrocytes with central round nuclei, as well as thickened primary trabeculae and a fibrous band entering the growth plate from the growth collar. Feist et al. (2016) reported 2 fetuses of phenotypically normal parents with a lethal skeletal dysplasia consistent with severe opsismodysplasia. Findings included short limbs with flared metaphyses, bowed radii, femora, and tibiae, irregular ossification of hands and feet, and marked platyspondyly. One of the fetuses also had progressive ventriculomegaly and developed hydrops. Fradet and Fitzgerald (2017) found that the outcomes in 31 reported patients with opsismodysplasia caused by mutation in the INPPL1 gene varied widely from fetal deaths and deaths in the newborn period to one individual who was 24 years old at the time of evaluation. Inheritance Maroteaux et al. (1984) favored autosomal recessive transmission because 2 affected sibs with first-cousin parents were observed by Zonana et al. (1977). Tyler et al. (1999) described a family with 2 marriages of first cousins with a total of 5 children with opsismodysplasia. The diagnosis was based on clinical, radiologic, and immunohistochemical findings. Testing with type I collagen antibodies showed abnormally high levels in the hypertrophic area of growth cartilage. This family substantiated the hypothesis of autosomal recessive inheritance. Molecular Genetics In a consanguineous family in which 2 sibs had opsismodysplasia, Below et al. (2013) performed linkage analysis and whole-genome sequencing and identified a missense mutation in the candidate gene INPPL1 (600829.0001) that was homozygous in both affected sibs and heterozygous in the parents. Sanger sequencing of INPPL1 in an unrelated family with opsismodysplasia revealed that the affected child was homozygous for a nonsense mutation (600829.0002). Screening the INPPL1 gene in 10 more unrelated opsismodysplasia families identified homozygous or compound heterozygous mutations in 7 (see, e.g., 600829.0003 and 600829.0004). In each of 5 families for which parental DNA was available, heterozygosity was confirmed in the unaffected parents. Overall, INPPL1 mutations were found in 7 (58%) of 12 families studied. Below et al. (2013) noted that the clinical characteristics of individuals with INPPL1-related opsismodysplasia were indistinguishable from those without INPPL1 mutations and included individuals with severe renal phosphate wasting and those in whom no such abnormality was reported. In the probands from 3 unrelated families with opsismodysplasia in whom mutation in the SBDS (607444), SLC35D1 (610804), and TRIP11 (604505) genes had been excluded, Huber et al. (2013) performed exome capture-sequencing and identified a single gene, INPPL1, in which homozygous or compound heterozygous mutations were present in all 3 (see, e.g., 600829.0005-600829.0008). Screening of INPPL1 in 7 additional opsismodysplasia families revealed 7 additional mutations for a total of 12 distinct INPPL1 mutations in the 10 families. All 16 patients clearly fulfilled the diagnostic criteria for opsismodysplasia, but were variable in severity: 7 pregnancies were terminated based on prenatal findings including hygroma, short long bones, short extremities, and narrow thorax; 4 children died in infancy (see, e.g., 600829.0009); and the 5 remaining patients ranged in age from 3 to 19 years and had normal cognitive development, severe short stature, lower limb deformity, and severe scoliosis, with atlantoaxial instability in 1 patient. In a 33-week-gestation hydropic stillborn (ISDR R01-170) with a clinical diagnosis of Schneckenbecken dysplasia (SHNKND; 269250) in whom Hiraoka et al. (2007) had excluded mutation in the SLC35D1 gene (610804), Lee et al. (2015) identified homozygosity for a splice site mutation in the INPPL1 gene (600829.0004). The authors suggested that this represented a second locus for SHNKND; however, Fradet and Fitzgerald (2017) concluded that additional families with SHNKND would be needed to confirm a role for INPPL1 in that disorder. In 2 fetuses of phenotypically normal parents with severe opsismodysplasia, Feist et al. (2016) identified compound heterozygous mutations in the INPPL1 gene. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Fradet and Fitzgerald (2017) reviewed the variants in the INPPL1 gene identified in patients with opsismodysplasia. The 25 mutations found in 20 families were spread throughout the gene and included 3 nonsense, 1 in-frame, 7 missense, 9 frameshift, and 5 splice site mutations. The majority of the mutations (17/25) were expected to lead to premature stop codons, resulting in a null allele. Six of the 7 missense mutations were located in the catalytic domain and presumably inactivated the phosphatase function of the SHIP2 protein. All patients had mutations in homozygous or compound heterozygous state and heterozygous parents were unaffected, suggesting that SHIP2 needs to be disabled for complete penetrance of the phenotype. No clear genotype-phenotype correlation was noted. The oldest surviving patient reported in the literature was 24 years old and was compound heterozygous for a frameshift and a missense mutation (Gln251His) located outside the catalytic domain, leading the authors to speculate that a small amount of enzyme activity might be enough to ameliorate the severity of the phenotype. INHERITANCE \- Autosomal recessive GROWTH Height \- Dwarfism, identifiable at birth HEAD & NECK Head \- Large fontanelles \- Macrocephaly Face \- Frontal bossing \- Long philtrum Eyes \- Hypertelorism Nose \- Short nose \- Flattened nasal bridge \- Anteverted nostrils Neck \- Short neck \- Nuchal edema RESPIRATORY \- Susceptibility to respiratory infections CHEST External Features \- Narrow thorax \- Bell-shaped thorax Ribs Sternum Clavicles & Scapulae \- Anterior and posterior rib flaring \- Rib cupping ABDOMEN External Features \- Prominent abdomen GENITOURINARY Kidneys \- Renal phosphate wasting (in some patients) SKELETAL Skull \- Severe platyspondyly \- Hypoplastic vertebral bodies Spine \- Severe scoliosis Pelvis \- Square iliac bones \- Horizontal acetabular roof \- Medial and lateral spurs \- Hypoplastic ischia \- Hypoplastic pubis Limbs \- Rhizomelic shortening \- Very short long bones \- Metaphyseal cupping \- Marked delay in epiphyseal appearance Hands \- Short hands \- Very short tubular bones \- Metaphyseal cupping Feet \- short feet \- Very short tubular bones \- Metaphyseal cupping NEUROLOGIC Central Nervous System \- Hypotonia METABOLIC FEATURES \- Hypophosphatemia (in some patients) PRENATAL MANIFESTATIONS Amniotic Fluid \- Polyhydramnios MISCELLANEOUS \- May result in death in neonatal period or early childhood MOLECULAR BASIS \- Caused by mutation in the inositol polyphosphate phosphatase-like 1 gene (INPPL1, 600829.0001 ) ▲ 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	OPSISMODYSPLASIA	c0432219	6,245	omim	https://www.omim.org/entry/258480	2019-09-22T16:24:07	{"mesh": ["C537122"], "omim": ["258480"], "orphanet": ["2746"]}
Pulmonary arterial hypertension (PAH) is a group of diseases characterized by elevated pulmonary arterial resistance leading to right heart failure. PAH is progressive and potentially fatal. PAH may be idiopathic and/ or familial, or induced by drug or toxin (drug-or toxin-induced PAH, see these terms) or associated with other diseases like congenital heart disease, connective tissue disease, HIV, schistosomiasis, portal hypertension (PAH associated with other disease, see this term). ## Epidemiology Prevalence of PAH, in all of its forms, is estimated around 5/1,000,000. ## Clinical description Most forms of PAH develop in adults, and in rare cases in children; women are twice as likely as men to be affected. Initial symptoms include dyspnea, syncope, chest pain, palpitations and pedal edema. Precordial signs include loud and palpable second heart sound, pulmonary ejection click and murmurs of pulmonary and tricuspid regurgitation. 70% of patients present with severe heart failure. More rarely, abdominal distension, clubbing of digits and Raynaud phenomenon (predominantly in females) are observed. Hemoptysis has also been reported. ## Etiology PAH is caused by vascular remodeling of pulmonary arteries leading to widespread obliteration of the smallest arteries; sufficient occlusion of these vessels increases the resistance to pulmonary blood flow and a compensating increased pressure in the right ventricle. Mutations in BMPR2 gene (2q33) and also in ACVRL1(12q13), Endoglin(9q34), CAV1 (7q31), KCNK3(2p23),Smad9 (13q12) and TBX4 (17q21)have been described in heritable PAH. Mutations in PAH predisposing genes were identified in patients with idiopathic and/or familial form of PAH and in PAH associated with intake of drugs or toxins. Patients carrying a mutation in PAH predisposing gene, and those displaying a familial form of the disease (with or without mutations identified), are grouped under the term heritable PAH (see this term). ## Diagnostic methods Chest X-ray reveals an enlarged pulmonary artery and lung hyper perfusion and ECG shows right ventricular strain and hypertrophy. Echocardiography allows an estimate of pulmonary artery systolic pressure and detects cardiac disease. Right-heart catheterization is essential to establish the diagnosis:. PAH is diagnosed when resting mean pulmonary artery pressure is >25mmHg and a normal Pulmonary capillary wedge pressure. ## Differential diagnosis Rarer forms of pulmonary hypertension include pulmonary veno-occlusive disease /pulmonary capillary hemangiotosis (PVOD /PCH, see these terms).Differential diagnoses include asthma, chronic obstructive pulmonary disease, hypoplastic left heart syndrome, chronic thromboembolic pulmonary hypertension and complete atrio-ventricular canal - left heart obstruction (see these terms). ## Antenatal diagnosis Pregnancy is considered to be associated with a high rate of mortality (30-50%) in PAH patients. Prenatal genetic testing could be considered in cases of heritable PAH (see this term). ## Genetic counseling Genetic counseling and testing have to be proposed to patients with idiopathic or heritable form of PAH (transmitted as an autosomal dominant disease with an incomplete penetrance) and to patients displaying drug-or toxin-induced PAH. ## Management and treatment Management includes general measures (aggressive management of respiratory tract infections, annual influenza vaccination, family planning) and medical therapy (oxygen, anticoagulants, diuretics, digoxin. Calcium channel blockers are indicated only in patients with acute vasodilator response to Nitric oxide during right heart catheterization. Endothelin receptor agonists (ambrisentan,), prostanoids (epoprostenol) and phosphodiestrease inhibitors (sildenafill) have been used. Lung transplantation is the last option for resistant patients. ## Prognosis Prognosis varies between different forms, but is generally poor; the mean survival rate after diagnosis is <3 years. However, early therapeutic intervention may lead to better survival. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Pulmonary arterial hypertension	c0152171	6,246	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=182090	2021-01-23T18:10:41	{"gard": ["7501"], "mesh": ["C536282"], "umls": ["C0152171", "C1701938", "C2973725"], "synonyms": ["PAH"]}
A number sign (#) is used with this entry because of evidence that multiple endocrine neoplasia type IIB (MEN2B) is caused by heterozygous mutation in the RET gene (164761) on chromosome 10q11. Most patients (95%) carry a specific M918T mutation (164761.0013) in exon 16 of the RET gene. Description Multiple endocrine neoplasia type IIB (MEN2B) is an autosomal dominant hamartoneoplastic syndrome characterized by aggressive medullary thyroid carcinoma (MTC), pheochromocytoma, mucosal neuromas, and thickened corneal nerves. Most affected individuals have characteristic physical features, including full lips, thickened eyelids, high-arched palate, and marfanoid habitus. Other more variable features include skeletal anomalies and gastrointestinal problems (review by Morrison and Nevin, 1996). For a discussion of genetic heterogeneity of multiple endocrine neoplasia (MEN), see MEN1 (131100). Clinical Features Williams and Pollock (1966) described 2 unrelated patients with multiple true neuromas, pheochromocytoma and thyroid carcinoma. The thyroid cancer was of the medullary type (MTC) as in MEN2A. Although the association of pheochromocytoma with neurofibromatosis is well known, the nervous tumor is a true neuroma, i.e., consists mainly of nerve cells, in this condition. The patients sometimes have cafe-au-lait spots. The neuromas occur as pedunculated nodules on the eyelid margins, lips and tongue. The lips are diffusely hypertrophied. The father of one of Williams and Pollock's cases had very thick lips and eyelid and tongue lesions as did his daughters. He had a medullary thyroid cancer and died at age 38 after an abdominal operation, having had symptoms suggestive of pheochromocytoma. Schimke et al. (1968) also reported cases. Cunliffe et al. (1968) demonstrated calcitonin-secretion in a medullary carcinoma of the thyroid. The patient was a 19-year-old girl with acne, features of Marfan syndrome, neuromas of tongue and eyelid, prominent lips, nodular goiter, pigmentation of hands, feet and circumoral area, proximal myopathy, loose motions, and flushing attacks. The features suggesting Marfan syndrome were high arched palate, pectus excavatum, bilateral pes cavus, high patella and scoliosis. Marfanoid habitus and pes cavus are striking features in most. Megacolon with plexus hyperplasia is a feature (Carney and Hayles, 1977). Colonic diverticula also occur. Mucosal neuromas involve the lips, anterior tongue, conjunctiva and nasal and laryngeal mucosa. Medullated nerve fibers traverse the cornea. Bartlett et al. (1968) described affected persons in 6 generations. Prophylactic thyroidectomy should be performed when the phenotype is recognized (Wolfe et al., 1973). In addition to histaminase, DOPA decarboxylase is high in medullary carcinoma of the thyroid (Atkins et al., 1973). The latter enzyme is found in pheochromocytomas also. Carney et al. (1976) and Dyck et al. (1979) described a kindred with 7 affected persons in 3 generations. In contrast to MEN2A, no parathyroid disease was found in any of them. The authors proposed the designation 'multiple endocrine neoplasia, type 2b.' Carney et al. (1980) confirmed the lack of clinically important involvement of the parathyroids in this disorder. Kullberg and Nieuwenhuijzen Kruseman (1987) described a patient who was known to have had liver metastases of medullary carcinoma of the thyroid for at least 22 years. Other features illustrating an indolent course of the disorder were displayed by affected members of this family. Derangement of esophageal motility with an achalasia-type clinical picture may be a leading problem (Baylin, 1989). Fryns and Chrzanowska (1988) gave a review. Mutation in a gene controlling a paracrine or an autocrine growth factor seemed a possibility in this disorder. Morrison and Nevin (1996) presented a review of this syndrome. They used the term Wagenmann-Froboese syndrome, because Wagenmann (1922) and Froboese (1923) initially described this disorder. Thyroid carcinoma and multiple mucosal neuromata occur in virtually all affected persons. Neoplasias of enteric ganglia were found in more than 40% of patients; pheochromocytoma in 50%; and marfanoid habitus in 75%. The absence of mucosal neuromata in persons with MEN2A is the main criterion for differential diagnosis. Enlarged nerves of the gastrointestinal tract (ganglioneuromatosis), often with megacolon, is a feature of MEN2B; corneal nerve thickening (medullated corneal nerve fibers) is a comparable feature, as are mucosal neuromas. Kane et al. (1995) described an unusual kindred in which medullary thyroid carcinoma was associated with corneal nerve thickening without other aspects of the multiple endocrine neoplasia syndromes. The grandfather and 1 daughter, both of whom had corneal nerve thickening, had medullary thyroid carcinoma, and a daughter of that daughter had both corneal nerve thickening and C-cell hyperplasia. Three adults in the middle generation had corneal nerve thickening only. DNA sequence analysis revealed no mutations in exon 10 or 11, or in exon 16 of the RET gene, regions where mutations had been described for MEN2A and MEN2B, respectively. ### Clinical Variability Dennehy et al. (1995) reported a 2-generation family in which a mother and her 2 children had prominent corneal nerves and lesions of the tongue resembling neuromas, but had no evidence of endocrine abnormalities. Targeted screening excluded the RET M918T mutation (164761.0013). Gordon et al. (1998) reported 4 unrelated patients with a pure mucosal neuroma syndrome that presented as a partial MEN2B phenotype, but without medullary thyroid carcinoma, other endocrine tumors, or germline or somatic RET mutations. Three patients presented in the teenage years and one at age 5 years with multiple unilateral neuromas affecting the facial mucosa, including the mouth, tongue, eyes, nose, and lips. One patient had neuromas affecting multiple branches of the trigeminal nerve. Two patients had medullated corneal nerve fibers, but no Lisch nodules. Extensive endocrine workup in all 4 patients showed no abnormalities. Prophylactic thyroidectomy was performed in 1 patient, but histology showed no evidence of C-cell hyperplasia or tumor nodules. None of the patients or tumor tissues carried the RET M918T mutation (164761.0013), and 3 patients studied did not have mutations in other selected RET exons. Gordon et al. (1998) concluded that pure mucosal neuroma syndrome does not appear to be a forme fruste of MEN2B at the genetic level. Gomez et al. (1998) reported a mother and daughter with multiple mucosal neuromas and visible corneal nerves. Neither had a marfanoid habitus, and endocrine workup was normal, and the RET M918T mutation was not found. The authors concluded that familial multiple mucosal neuromas is a distinct entity. Spyer et al. (2006) reported a 13-year-old girl who presented with photophobia and was noted to have prominent corneal nerve fibers. She also had many features of MEN2B, including thick lips, multiple bilateral mucosal neuromas, a marfanoid habitus, and high-arched palate. Extensive endocrine workup revealed no abnormalities, but prophylactic thyroidectomy was performed. Histologic examination of the thyroid showed no evidence of medullary thyroid carcinoma or C-cell hyperplasia. Direct sequencing of exons 1-20 of the RET gene showed no mutations. She remained well over 18 years of follow-up. Spyer et al. (2006) concluded that patients with features of the mucosal neuroma syndrome do not need to have a thyroidectomy, but should be followed for possible endocrine abnormalities. Babovic-Vuksanovic et al. (2012) reported 4 unrelated females with a similar constellation of physical features, including marfanoid habitus, coarse facial features, and multiple painful subcutaneous neurofibromas and nodules of the peripheral nerves occurring all over the body. All presented in the teenage or young adult years (range, 13-24 years) with clinical sequelae of the tumors. Two had orbital soft tissue swelling and proptosis/ptosis due to tumors of the corneal or trigeminal nerves, resulting in unilateral loss of vision in 1 patient. The other 2 patients presented with hemiparesis, and 1 also had lumbosacral pain due to multiple spinal nerve tumors. Histology showed neurofibromas with abundant mucin. All had a history of or later developed multiple painful subcutaneous nodules that were shown to be neurofibromas with abundant mucin. Tumors occurred in the head and neck region, spinal cord, trunk, and limbs. Other more variable features included pectus excavatum, scoliosis, and keloid scars. None had Lisch nodules, axillary or inguinal freckling, or cafe au lait spots. Two patients had evidence of a neuronal migration defect in the brain, with schizencephaly, but only 1 patient had seizures and learning disabilities. One patient had a severe axonal and demyelinating polyneuropathy. None had a family history of a similar disorder, and mutations in multiple candidate genes, including NF1 (613113), NF2 (607379), SMARCB1 (601607), RET, and PTEN (601728), were excluded in 2 patients. Babovic-Vuksanovic et al. (2012) noted the phenotypic similarities to MEN2B and to mucosal neuroma syndrome, but concluded that the unusual findings of a developmental brain anomaly and nonmucosal nerve neurofibromas in their patients may represent a new condition. Mapping Jackson et al. (1988) found evidence suggesting that MEN3 (MEN2B) maps to chromosome 10, probably in the same region as MEN2A (171400). It is possible that MEN2A and MEN2B are allelic disorders; if indeed such is the case, there would be every justification for calling them MEN2A and MEN2B rather than MEN2 and MEN3. Norum (1989) presented compelling evidence that MEN3 is allelic to MEN2: both mapped to chromosome 10 near the centromere and are on the same side of the RBP3 gene (180290). Lairmore et al. (1991) presented evidence that the MEN2B locus maps in the pericentric region of chromosome 10. They found no evidence for linkage genetic heterogeneity among families with medullary thyroid carcinoma, MEN2B, or MEN2A. By genetic linkage analysis, Gardner et al. (1993) demonstrated that the MEN2B locus is flanked by D10S141 and RBP3, proximally and distally, respectively; both markers are located in 10q11.2. Molecular Genetics In 9 unrelated MEN2B patients, Hofstra et al. (1994) identified a substitution of a threonine for a methionine in the tyrosine kinase domain of the RET protein (M918T; 164761.0013). The M918T mutation in the tyrosine kinase domain is the only RET mutation identified in cases of MEN2B (Bongarzone et al., 1998). Carlson et al. (1994) estimated that 50% of cases of MEN2B arise de novo. A single identical point mutation in the catalytic core of the tyrosine kinase domain of RET has been found to be associated with both inherited and de novo MEN2B. Carlson et al. (1994) analyzed 25 cases of de novo MEN2B in order to determine the parental origin of the mutated RET allele. In all cases, the new mutation was of paternal origin. They observed a distortion of sex ratio in both de novo MEN2B patients and the affected offspring of MEN2B-transmitting males. Specifically, as pointed out by Sapienza (1994), the report by Carlson et al. (1994) and that of another group includes 45 females and 24 males with de novo MEN2B. These results suggested a differential susceptibility of RET mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development. Clinical Management Prophylactic total thyroidectomy before the age of 4 years was proposed for children with this disorder (Morrison et al., 1991; Utiger, 1994). Because the optimal age of thyroidectomy is poorly established and the course of medullary thyroid carcinoma in MEN2B is ill-defined, Leboulleux et al. (2002) reviewed 18 patients in a single-center retrospective study: 9 men and 9 women with a mean age of 13 years at diagnosis. The diagnosis of MTC was based on the presence of a thyroid nodule or involved neck lymph nodes and on dysmorphic features of MEN2B in 60% and 40% of the cases, respectively. The classic M918T mutation in exon 16 of the RET gene was found in all 16 patients in whom it was investigated. At diagnosis, 2 patients had stage I MTC, 15 had stage III, and 1 had stage IV disease. Five- and 10-year overall survival rates were 85% and 75%, respectively. Leboulleux et al. (2002) concluded that the study confirmed the need for early treatment of MTC in patients with the MEN2B syndrome, preferably within the first 6 months of life. The phenotype of MTC occurring in the MEN2B syndrome was, however, not more aggressive than sporadic MTC or MTC occurring in other familial syndromes. INHERITANCE \- Autosomal dominant GROWTH Height \- Marfanoid body habitus Other \- Failure to thrive in infancy HEAD & NECK Face \- Coarse-appearing facies Eyes \- Pedunculated nodules on eyelid margins \- Eyelid and corneal neuromas \- Medullated corneal nerve fibers \- Thickened, anteverted eyelid \- Large, prominent eyebrow Mouth \- Neuromas of lips and tongue \- Thick lips \- High arched palate Neck \- Nodular goiter CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum ABDOMEN Gastrointestinal \- Megacolon \- Colonic diverticulosis \- Constipation \- Diarrhea \- Ganglioneuroma SKELETAL Spine \- Scoliosis \- Kyphosis \- Lordosis Limbs \- Joint laxity \- Slipped capital femoral epiphyses Feet \- Pes cavus SKIN, NAILS, & HAIR Skin \- Flushing attacks MUSCLE, SOFT TISSUES \- Myopathy NEUROLOGIC Central Nervous System \- Hypotonia \- Developmental delay ENDOCRINE FEATURES \- Parathyroid hyperplasia NEOPLASIA \- Ganglioneuroma \- Pheochromocytoma \- Medullary thyroid carcinoma \- Parathyroid disease rare LABORATORY ABNORMALITIES \- Pentagastrin stimulation test \- Elevated calcitonin \- Increased urinary epinephrine MISCELLANEOUS \- Medullary thyroid cancer is aggressive and can occur in childhood \- Fifty percent of cases are sporadic MOLECULAR BASIS \- Caused by mutation in the RET protooncogene (RET, 164761.0013 ) ▲ 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	MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB	c0025268	6,247	omim	https://www.omim.org/entry/162300	2019-09-22T16:37:33	{"doid": ["10016"], "mesh": ["D018813"], "omim": ["162300"], "icd-9": ["258.03"], "icd-10": ["E31.23"], "orphanet": ["653", "247709"], "synonyms": ["Alternative titles", "MEN IIB", "NEUROMATA, MUCOSAL, WITH ENDOCRINE TUMORS", "WAGENMANN-FROBOESE SYNDROME", "MULTIPLE ENDOCRINE NEOPLASIA, TYPE III, FORMERLY"], "genereviews": ["NBK1257"]}
X-linked creatine deficiency primarily affects development of the brain and nervous system. Symptoms can begin at any age, but usually begin in early childhood. These symptoms can include mild to severe intellectual disability, delayed speech development, behavioral problems, and seizures. The intellectual disability may get worse over time. X-linked creatine deficiency is caused by a SLC6A8 gene that is not working correctly. It is inherited in an X-linked pattern. Diagnosis is based on screening tests, clinical exam, and genetic testing. Treatment is focused on managing the 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	X-linked creatine deficiency	c1845862	6,248	gard	https://rarediseases.info.nih.gov/diseases/1608/x-linked-creatine-deficiency	2021-01-18T17:57:04	{"mesh": ["C535598"], "omim": ["300352"], "umls": ["C1845862"], "orphanet": ["52503"], "synonyms": ["Mental retardation , X-linked with seizures, short stature and midface hypoplasia", "Mental retardation , X-linked, with creatine transport deficiency", "X-linked creatine transporter deficiency", "X-linked creatine deficiency syndrome", "Creatine deficiency, X-linked"]}
A rare inborn error of metabolism characterized by abnormally high urinary excretion of glutaric acid due to peroxisomal glutaryl-CoA oxidase deficiency. There is no association with a specific clinical phenotype. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Glutaric acidemia type 3	c0342873	6,249	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=35706	2021-01-23T18:35:57	{"gard": ["12469"], "mesh": ["C562818"], "omim": ["231690"], "umls": ["C0342873"], "icd-10": ["E72.3"], "synonyms": ["Glutaric aciduria type 3", "Glutaryl-CoA oxidase deficiency"]}
A number sign (#) is used with this entry because Partington syndrome (PRTS) can be caused by a 24-bp duplication, resulting in a polyalanine (polyA) repeat expansion, in the aristaless-related homeobox gene (ARX; 300382). Description Partington syndrome is an X-linked developmental disorder characterized by mental retardation and variable movement disturbances. Partington syndrome is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from hydranencephaly and lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1; 308350) to nonsyndromic mental retardation (300419). Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008). Clinical Features Partington et al. (1988) described a family (MRXS1) in which 10 males widely distributed in the pedigree and connected through females showed a syndrome of mild to moderate mental retardation and episodic dystonic movements of the hands. Some had dysarthria. X-linked recessive inheritance was supported by several facts: all affected individuals were male, and there was no male-to-male transmission; 1 woman had affected sons by different husbands and another had an obligate carrier daughter by 1 husband and an affected son by another; and the number of affected males (without the probands), unaffected males, and females in the offspring of obligate heterozygotes was satisfactorily close to the expected ratio of 1:1:2. Claes et al. (1996) reported a family (MRX36) in which 4 males (3 brothers and a nephew) were affected with a nonspecific form of mental retardation with normal physical and neurologic findings. Two females showed an intelligence level in the low to normal range, possibly as a result of heterozygous carrier status, and a 20-month-old girl showed delayed psychomotor development. Frints et al. (2002) reexamined the 3 brothers originally reported by Claes et al. (1996). Mild facial dysmorphism was noted in 2, with mild hypertelorism, short palpebral fissures, and large mouth. Neurologic examination showed mild dystonic movements of the hands and feet in 2, and perioral dystonic movements in the third. One patient showed mild cogwheel rigidity and another showed a Parkinson-like tremor on the left side. One patient had no expressive language capabilities and the other 2 had language development of 2.5 to 3 years. Frints et al. (2002) noted that ARX gene mutations have also been described in Partington syndrome and suggested that the family reported by Claes et al. (1996) had mild clinical features of PRTS. Frints et al. (2002) described 2 Belgian brothers with Partington syndrome. The brothers had a delayed and aberrant grasp reflex which resulted in feeding difficulties in early childhood. Dystonic hand movements became more evident during childhood. They had dysarthria with difficulties initiating speech and stuttering. The elder brother walked at 18 months of age, whereas the younger brother could sit at 1 year and walked at 19.5 months. Both brothers had mild to moderate mental retardation. Their behavior was generally friendly, quiet, and social, although the elder brother developed depressive mood and anger outbursts in his late 20s. EEG, EMG, and head MRI studies were normal in both. Szczaluba et al. (2006) reported 18 individuals from 5 families with an X-linked mental retardation syndrome due to a hemizygous 24-bp duplication in the ARX gene. The phenotype was variable but most consistent with Partington syndrome. All patients had intellectual impairment. Twelve presented with focal hand dystonia, and 6 had EEG abnormalities with seizures. Other variable features included dysarthria (4 patients) and lower limb spasticity/foot dystonia (4 patients). One family showed enlargement of the testes, and 1 patient had a subarachnoid cyst. Affected individuals tended to have long triangular facies. Mapping By linkage analysis of an affected family, Partington et al. (1988) mapped the gene responsible for PRTS to the distal part of chromosome Xp (maximum lod score of 2.11 at theta = 0.00 at marker DXS41). Claes et al. (1996) performed linkage analysis on the MRX36 family. A maximum lod score of 1.97 was obtained at markers DXS989, DXS1218, DMD49, and DMD45 when the infant girl was excluded from the analysis, but rose to 3.31 at DXS1218, defining a candidate region of less than 5 cM (Xp22.1-p21.1), when she was not included. Frints et al. (2002) determined that 2 affected Belgian brothers shared a haplotype in the PRTS region at Xp22.1. Molecular Genetics In the original Australian family reported by Partington et al. (1988) and in the unrelated Belgian family reported by Frints et al. (2002), Stromme et al. (2002) found an expanded alanine repeat in the ARX gene. The polyA expansion was due to the 24-bp duplication (300382.0002). The mutation occurred against different haplotypes in the 2 families. In one of the brothers reported by Claes et al. (1996), Bienvenu et al. (2002) identified the 24-bp in-frame duplication in the ARX gene. Frints et al. (2002) noted that the mutation had not been found in the affected infant girl or her mother, indicating that the mental retardation in the girl was caused by another factor. Partington et al. (2004) reported 3 new families with X-linked mental retardation due to the 24-bp duplication in the ARX gene. They reviewed the clinical findings in the 46 XLMR patients from 9 families that had been reported with this mutation and noted that mental retardation ranged from mild to severe. Infantile spasms (West syndrome; 308350) occurred in 12.5% and less severe forms of seizures in 37.5%. Characteristic dystonic movements of the hands were seen in 63% and dysarthria in 54%. Partington et al. (2004) suggested that focal dystonia in association with mental retardation may be diagnostic of this mutation. INHERITANCE \- X-linked recessive HEAD & NECK Face \- Long, triangular face SKELETAL \- Joint contractures NEUROLOGIC Central Nervous System \- Mental retardation \- Focal dystonia, usually of the hands \- Dysarthria \- Speech delay \- Seizures \- EEG abnormalities \- Lower limb spasticity \- Lower limb dystonia MOLECULAR BASIS \- Caused by mutation in the X-linked aristaless-related homeobox gene (ARX, 300382.0002 ). ▲ 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	PARTINGTON X-LINKED MENTAL RETARDATION SYNDROME	c0796250	6,250	omim	https://www.omim.org/entry/309510	2019-09-22T16:17:51	{"doid": ["14744"], "mesh": ["C536300"], "omim": ["309510"], "orphanet": ["94083"], "synonyms": ["PARTINGTON SYNDROME", "Partington-Mulley syndrome", "Alternative titles", "MENTAL RETARDATION, X-LINKED 36", "X-linked intellectual disability-dystonia-dysarthria syndrome", "MENTAL RETARDATION, X-LINKED, WITH DYSTONIC MOVEMENTS, ATAXIA, AND SEIZURES", "MENTAL RETARDATION, X-LINKED, SYNDROMIC 1"]}
A number sign (#) is used with this entry because of evidence that bone marrow failure syndrome-2 (BMFS2) is caused by homozygous mutation in the ERCC6L2 gene (615667) on chromosome 9q22. Description Bone marrow failure syndrome-2 is an autosomal recessive disorder characterized by trilineage bone marrow failure, learning disabilities, and microcephaly. Cutaneous features and increased chromosome breakage are not features (Tummala et al., 2014). For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675). Clinical Features Tummala et al. (2014) reported 2 unrelated patients, each born of consanguineous parents, with a bone marrow failure syndrome. The patients presented at ages 12 and 19 years, respectively. Each had trilineage bone marrow failure with hypocellular bone marrow. Bone marrow of 1 patient showed dysplasia. Both patients also had microcephaly and learning difficulties. One had abnormal facies and ear anomalies, and the other had hypotonia in infancy. Neither had mucocutaneous features or chromosomal breakage. One patient had shortened telomeres. Zhang et al. (2016) reported an adolescent male, born of consanguineous parents, who presented with mild bone marrow failure and microcephaly without the typical Fanconi anemia (see 227650) phenotype. The patient's cells showed increased sensitivity to ionizing radiation and to phleomycin, suggesting a defect in DNA double-strand break (DSB) repair. Inheritance The transmission pattern of BMFS2 in the family reported by Tummala et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics By exome sequencing of 2 unrelated patients with bone marrow failure syndrome, Tummala et al. (2014) identified 2 different homozygous truncating mutations in the ERCC6L2 gene (R655X, 615667.0001 and c.1236_1239del, 615667.0002). Fluorescence labeling of patient cells showed that the mutant truncated proteins were mislocalized to the endoplasmic reticulum, autophagic vacuoles, and lysosomes, suggesting that normal localization was impaired by aggregation of the mutant protein and retention for degradation. Tummala et al. (2014) noted that a DNA-damage response mediated by ERCC6L2 is required during cell proliferation and tissue maintenance, and suggested that the mutations resulted in an increase in reactive oxygen species and the accumulation of DNA damage in cells, which underlie the disease manifestations observed in the affected individuals. By linkage analysis and whole-exome sequencing in an adolescent male with bone marrow failure syndrome, Zhang et al. (2016) identified homozygosity for the previously reported R655X mutation in the ERCC6L2 gene. The mutation affected both the ERCC6L2 short isoform and the ERCC6L2 long isoform, HEBO. Transduction of wildtype HEBO complemented the DNA DSB repair defect in the patient's fibroblasts, whereas transduction of wildtype ERCC6L2 short isoform had no effect. Zhang et al. (2016) concluded that truncation of HEBO due to the R655X mutation caused the DNA DSB repair defect in the patient's cells. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly Face \- Abnormal facies Ears \- Ear abnormalities NEUROLOGIC Central Nervous System \- Learning difficulties \- Neonatal hypotonia HEMATOLOGY \- Bone marrow failure \- Decreased hemoglobin \- Thrombocytopenia \- Hypocellular bone marrow IMMUNOLOGY \- Leukopenia LABORATORY ABNORMALITIES \- Shortened telomeres (in 1 of 2 patients) MISCELLANEOUS \- Onset in childhood \- Two unrelated patients have been reported (last curated March 2014) MOLECULAR BASIS \- Caused by mutation in the ERCC6-like 2 gene (ERCC6L2, 615667.0001 ) ▲ 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	BONE MARROW FAILURE SYNDROME 2	c3810350	6,251	omim	https://www.omim.org/entry/615715	2019-09-22T15:51:14	{"mesh": ["C536572"], "omim": ["615715"], "orphanet": ["401764"], "synonyms": ["Trilineage bone marrow failure-developmental delay syndrome"]}
In a kindred in which multiple members had somewhat short stature, round facies, and brachydactyly type E (113300), Czeizel and Goblyos (1989) described also the appearance of the secundum type of atrial septal defect (ASD II). The shortening of the metacarpals was most pronounced in the 4th metacarpal, but not limited to that bone. Cardiac \- Atrial septal defect (ASD II) Limbs \- Brachydactyly \- Short metacarpals, esp. 4th \- Variable short metatarsals Growth \- Short stature Facies \- Round facies Inheritance \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	BRACHYDACTYLY, TYPE E, WITH ATRIAL SEPTAL DEFECT, TYPE II	c1862101	6,252	omim	https://www.omim.org/entry/113301	2019-09-22T16:44:09	{"mesh": ["C566193"], "omim": ["113301"]}
A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by vertebral segmentation defects associated with cardiac (patent ductus arteriosus, atrial septal defect, hypoplastic left heart) and renal (hypoplastic kidneys, chronic kidney disease) anomalies. Additional reported features include limb defects, short stature, global developmental delay, intellectual disability, and sensorineural hearing loss, among others. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 vertebral-cardiac-renal anomalies syndrome	c4540004	6,253	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=521438	2021-01-23T17:02:42	{"omim": ["617660", "617661", "618845"], "synonyms": ["Congenital NAD deficiency disorder"]}
For other uses, see Ramsay Hunt syndrome. Ramsay Hunt syndrome (RHS) type 2 Other namesHerpes zoster oticus SpecialtyInfectious disease Ramsay Hunt syndrome type 2, also known as herpes zoster oticus, is a disorder that is caused by the reactivation of varicella zoster virus in the geniculate ganglion, a nerve cell bundle of the facial nerve.[1] Ramsay Hunt syndrome type 2 typically presents with inability to move many facial muscles, pain in the ear, taste loss on the front of the tongue, dry eyes and mouth, and a vesicular rash. ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 3.1 Clinical diagnosis * 3.2 Diagnostic procedures * 4 Prevention * 5 Treatment * 6 History * 7 References * 8 External links ## Signs and symptoms[edit] Symptoms include acute facial nerve paralysis, pain in the ear, taste loss in the front two-thirds of the tongue, dry mouth and eyes, and an erythematous vesicular rash[2] in the ear canal, the tongue, and/or hard palate.[citation needed] Since the vestibulocochlear nerve is in proximity to the geniculate ganglion, it may also be affected, and patients may also suffer from tinnitus, hearing loss, and vertigo. Involvement of the trigeminal nerve can cause numbness of the face.[citation needed] ## Pathophysiology[edit] Ramsay Hunt syndrome type 2 refers to shingles of the geniculate ganglion. After initial infection, varicella zoster virus lies dormant in nerve cells in the body, where it is kept in check by the immune system. Given the opportunity, for example during an illness that suppresses the immune system, the virus travels to the end of the nerve cell, where it causes the symptoms described above.[2] The affected ganglion is responsible for the movements of facial muscles, the touch sensation of a part of ear and ear canal, the taste function of the frontal two-thirds of the tongue, and the moisturization of the eyes and the mouth. The syndrome specifically refers to the combination of this entity with weakness of the muscles activated by the facial nerve. In isolation, the latter is called Bell's palsy.[3] However, as with shingles, the lack of lesions does not definitely exclude the existence of a herpes infection. Even before the eruption of vesicles, varicella zoster virus can be detected from the skin of the ear.[4] ## Diagnosis[edit] Ramsay Hunt Syndrome Type 2 can be diagnosed based on clinical features, however, in ambiguous cases PCR or direct immunofluorescent assay of vesicular fluid can help with the diagnosis. Laboratory studies such as WBC count, ESR and electrolytes should be obtained to distinguish infectious versus inflammatory etiologies.[citation needed] ### Clinical diagnosis[edit] On physical exam look for vesicular exanthema on the external auditory canal, concha and or pinna. Dry eyes with possible lower cornea epithelium damage due to incomplete closure of eyelids.[citation needed] ### Diagnostic procedures[edit] Ramsay Hunt Syndrome type 2 can usually be diagnosed based on clinical features. However, for suspected cases with unclear presentation, varicella zoster virus can be isolated from vesicle fluid. Tear culture PCR can have positive varicella zoster virus. However 25-35% of patients with Bell's palsy can have false positive varicellar zoster virus detected in tears. If central nervous system complications such as meningitis, ventriculitis or meningoencephalitis are suspected, prompt lumbar puncture with spinal fluid analysis and imaging (CT head) are recommended.[citation needed] ## Prevention[edit] See also: Varicella vaccine Shingles is prevented by immunizing against the causal virus, varicella zoster, for example through Shingrix, a stronger version of chickenpox vaccine.[citation needed] ## Treatment[edit] Treatment with prednisone and the antiviral drug acyclovir 800 mg 5 times a day is controversial, with some studies showing complete recovery in patients if started within the first three days of facial paralysis.[5] Chances of recovery appear to decrease when treatment is delayed. Delay of treatment may result in permanent facial nerve paralysis. However, some studies demonstrate that even when steroids are started promptly, only 22% of all patient achieve full recovery of facial paralysis.[6] Treatment apparently has no effect on the recovery of hearing loss.[7] Diazepam is sometimes used to treat the vertigo.[8] ## History[edit] The syndrome is named for James Ramsay Hunt, the eminent neurologist who first described it.[9][10] ## References[edit] 1. ^ Ramsay Hunt, J.R. (1907). "On herpetic inflammations of the geniculate ganglion: a new syndrome and its complications". Journal of Nervous and Mental Disease. 34 (2): 73–96. doi:10.1097/00005053-190702000-00001. 2. ^ a b Sweeney, C.J.; Gilden, D.H. (August 2001). "Ramsay Hunt syndrome". Journal of Neurology, Neurosurgery, and Psychiatry. 71 (2): 149–54. doi:10.1136/jnnp.71.2.149. PMC 1737523. PMID 11459884. 3. ^ Kim, In Sup; Shin, Seung-Ho; Kim, Jinn; Lee, Won-Sang; Lee, Ho-Ki (2007). "Correlation between MRI and Operative Findings in Bell's Palsy and Ramsay Hunt Syndrome". Yonsei Medical Journal. 48 (6): 963–968. doi:10.3349/ymj.2007.48.6.963. PMC 2628199. PMID 18159587. 4. ^ Murakami, S.; Honda, N.; Mizobuchi, M.; Nakashiro, Y.; Hato, N.; Gyo, K. (1998). "Rapid diagnosis of varicella zoster virus infection in acute facial palsy". Neurology. 51 (4): 1202–1205. doi:10.1212/wnl.51.4.1202. PMID 9781562. 5. ^ Murakami, Shingo; Hato, Naohito; Horiuchi, Joji; Honda, Nobumitsu; Gyo, Kiyofumi; Yanagihara, Naoaki (1 March 1997). "Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: Significance of early diagnosis and treatment". Annals of Neurology. 41 (3): 353–357. doi:10.1002/ana.410410310. PMID 9066356. 6. ^ Finsterer, Josef (2008). "Management of peripheral facial nerve palsy". European Archives of Oto-Rhino-Laryngology. 265 (7): 743–752. doi:10.1007/s00405-008-0646-4. PMC 2440925. PMID 18368417. 7. ^ Kim, Y.H.; Chang, M.Y.; Jung, H.H.; Park, Y.S.; Lee, S.H.; Lee, J.H.; Oh, S.H.; Chang, S.O.; Koo, J.W. (2010). "Prognosis of Ramsay Hunt syndrome presenting as cranial polyneuropathy". Laryngoscope. 120 (11): 2270–2276. doi:10.1002/lary.21108. PMID 20824789. 8. ^ NINDS Herpes Zoster Oticus Information Page at NINDS 9. ^ synd/2246 at Who Named It? 10. ^ "The Ramsay Hunt syndrome". Proceedings of the Royal Society of Medicine. 47 (5): 371–384. May 1954. PMC 1918846. PMID 13167057. ## External links[edit] Classification D * ICD-10: B02.2 (ILDS B02.270), G53.0 * ICD-9-CM: 053.11 * MeSH: D016697 * DiseasesDB: 11176 External resources * MedlinePlus: 001647 * eMedicine: neuro/420 * Patient UK: Ramsay Hunt syndrome type 2 * NINDS Herpes Zoster Oticus Information Page National Institute of Neurological Disorders and Stroke * Vaccine at Centers for Disease Control and Prevention * v * t * e Infectious diseases – viral systemic diseases Oncovirus DNA virus HBV Hepatocellular carcinoma HPV Cervical cancer Anal cancer Penile cancer Vulvar cancer Vaginal cancer Oropharyngeal cancer KSHV Kaposi's sarcoma EBV Nasopharyngeal carcinoma Burkitt's lymphoma Hodgkin lymphoma Follicular dendritic cell sarcoma Extranodal NK/T-cell lymphoma, nasal type MCPyV Merkel-cell carcinoma RNA virus HCV Hepatocellular carcinoma Splenic marginal zone lymphoma HTLV-I Adult T-cell leukemia/lymphoma Immune disorders * HIV * AIDS Central nervous system Encephalitis/ meningitis DNA virus Human polyomavirus 2 Progressive multifocal leukoencephalopathy RNA virus MeV Subacute sclerosing panencephalitis LCV Lymphocytic choriomeningitis Arbovirus encephalitis Orthomyxoviridae (probable) Encephalitis lethargica RV Rabies Chandipura vesiculovirus Herpesviral meningitis Ramsay Hunt syndrome type 2 Myelitis * Poliovirus * Poliomyelitis * Post-polio syndrome * HTLV-I * Tropical spastic paraparesis Eye * Cytomegalovirus * Cytomegalovirus retinitis * HSV * Herpes of the eye Cardiovascular * CBV * Pericarditis * Myocarditis Respiratory system/ acute viral nasopharyngitis/ viral pneumonia DNA virus * Epstein–Barr virus * EBV infection/Infectious mononucleosis * Cytomegalovirus RNA virus * IV: Human coronavirus 229E/NL63/HKU1/OC43 * Common cold * MERS coronavirus * Middle East respiratory syndrome * SARS coronavirus * Severe acute respiratory syndrome * SARS coronavirus 2 * Coronavirus disease 2019 * V, Orthomyxoviridae: Influenza virus A/B/C/D * Influenza/Avian influenza * V, Paramyxoviridae: Human parainfluenza viruses * Parainfluenza * Human orthopneumovirus * hMPV Human digestive system Pharynx/Esophagus * MuV * Mumps * Cytomegalovirus * Cytomegalovirus esophagitis Gastroenteritis/ diarrhea DNA virus Adenovirus Adenovirus infection RNA virus Rotavirus Norovirus Astrovirus Coronavirus Hepatitis DNA virus HBV (B) RNA virus CBV HAV (A) HCV (C) HDV (D) HEV (E) HGV (G) Pancreatitis * CBV Urogenital * BK virus * MuV * Mumps * v * t * e Varicella zoster Varicella zoster virus * Varicellovirus Diseases * Chickenpox * Herpes zoster * Postherpetic neuralgia * Ramsay Hunt syndrome type II * Disseminated herpes zoster * Progressive outer retinal necrosis * Ophthalmic zoster Treatment * Aciclovir * Vidarabine * VZV immune globulin Prevention * Varicella vaccine * Zoster vaccine * Pox party Other * Michiaki Takahashi [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Ramsay Hunt syndrome type 2	c0017409	6,254	wikipedia	https://en.wikipedia.org/wiki/Ramsay_Hunt_syndrome_type_2	2021-01-18T18:54:19	{"gard": ["7525"], "mesh": ["D016697"], "umls": ["C0017409"], "orphanet": ["3020"], "wikidata": ["Q1648128"]}
A rare genodermatosis characterised by the presence of hyperpigmented and hypopigmented macules, principally located on the extremities and limbs. ## Clinical description The first manifestations of the disease generally appear during early childhood. ## Etiology A mutation has been identified in the double-stranded RNA-specific adenosine deaminase (ADAR) gene. ## Genetic counseling Transmission is autosomal dominant. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Dyschromatosis symmetrica hereditaria	c0406775	6,255	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=41	2021-01-23T18:42:58	{"gard": ["334"], "mesh": ["C535729"], "omim": ["127400"], "umls": ["C0406775"], "icd-10": ["L81.8"], "synonyms": ["Acropigmentation of Dohi"]}
## Clinical Features Divry and Van Bogaert (1946) described brothers who presented with epilepsy, pseudobulbar syndrome, extrapyramidal signs, dementia, hemianopsia, and 'marbled skin' resulting from a telangiectatic network. Brain examination showed corticomeningeal angiomatosis and myelination of the white substance of the centrum ovale. Martin et al. (1973) studied 2 sibs, a male and a female, who demonstrated this condition. Both presented similar symptoms of epileptic seizures during the second decade, visual field defects, migraines with focal paresthesias, mental disturbances and progressive dementia. Surgery to relieve these symptoms was unsuccessful. Necropsy revealed diffuse capillarovenous noncalcifying leptomeningeal angiomatoses in the depths of the sulci, becoming more prominent toward the occipital lobes. All the abnormally proliferated vessels showed fibrotic changes. The brain showed diffuse anoxic cortical encephalopathy with areas of atrophy and secondary degeneration of the white matter. These changes became most severe in the parietal-occipital-temporal areas. The brainstem showed signs of fibrillary gliosis of some nuclei and tracts, particularly the vestibular and reticular nuclei, trigeminal spinal tracts, and pyramidal tracts. These patients had no other physical abnormalities or marbling of the skin. Bussone et al. (1984) reported a 30-year-old man who developed generalized seizures at age 18 years. Over the following several years, he had progressive mental deterioration and developed dysarthria and writing difficulties. He also had hypertension and a deficit of the right lower facial nerve. Brain imaging showed dilatation of the ventricles and diffuse hypodensity of the white matter. Skin findings included a cutaneous venous pattern and cutis marmorata. The disorder was progressive, with the patient developing truncal ataxia, mood instability, and poor cooperation. Angiography showed tapering of the distal branches of the carotid arteries and cerebellar vessels, as well as changes in the meningeal branches. Skin biopsy of external abdominal vessels only showed mild defects of the zonulae occludens between endothelial cells. There was no evidence of calcification. INHERITANCE \- Autosomal recessive \- Isolated cases HEAD & NECK Eyes \- Visual field defects \- Hemianopsia CARDIOVASCULAR Vascular \- Hypertension (reported in 1 patient) \- Leptomeningeal angiomatosis \- Distal tapering of the carotid, cerebellar, and meningeal arteries \- Prominent venous pattern SKIN, NAILS, & HAIR Skin \- Prominent venous pattern \- Cutis marmorata \- Marbled skin due to telangiectasia NEUROLOGIC Central Nervous System \- Dementia, progressive \- Seizures \- Dysarthria \- Pseudobulbar symptoms \- Migraine \- Ataxia \- Broad-based gait \- Leptomeningeal angiomatosis \- Distal tapering of the carotid, cerebellar, and meningeal arteries \- Brain atrophy \- Ventricular dilatation \- Hypodensity of the white matter Behavioral Psychiatric Manifestations \- Emotional lability MISCELLANEOUS \- Onset in second decade \- Death about 20 years after symptom onset ▲ 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	ANGIOMATOSIS, DIFFUSE CORTICOMENINGEAL, OF DIVRY AND VAN BOGAERT	c1859783	6,256	omim	https://www.omim.org/entry/206570	2019-09-22T16:30:58	{"mesh": ["C536367"], "omim": ["206570"], "synonyms": ["Alternative titles", "DIVRY-VAN BOGAERT SYNDROME"]}
Antecubital pterygium is characterized by and antecubital webbing, posterior subluxation (dislocation) of radial head, maldevelopment of radioulnar joint, and limited elbow extension with unimpeded elbow flexion. Most reported cases come from the island of Mauritius or nearby islands. It is inherited in an autosomal dominant fashion. This condition is sometimes found as a symptom of nail-patella 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	Antecubital pterygium	c1867439	6,257	gard	https://rarediseases.info.nih.gov/diseases/4570/antecubital-pterygium	2021-01-18T18:02:05	{"mesh": ["C566738"], "omim": ["178200"], "umls": ["C1867439"], "orphanet": ["2987"], "synonyms": ["Pterygium antecubital"]}
Human disease Scurvy Other namesMoeller's disease, Cheadle's disease, scorbutus,[1] Barlow's disease, hypoascorbemia,[1] vitamin C deficiency Scorbutic gums, a symptom of scurvy. The triangle-shaped area between the teeth show redness of the gums. SpecialtyEndocrinology SymptomsWeakness, feeling tired, changes to hair, sore arms and legs, gum disease, easy bleeding[1][2] CausesLack of vitamin C[1] Risk factorsMental disorders, unusual eating habits, alcoholism, intestinal malabsorption, dialysis[2] Diagnostic methodBased on symptoms[2] TreatmentVitamin C supplements,[1] Citrus fruits FrequencyRare[2] Scurvy is a disease resulting from a lack of vitamin C (ascorbic acid).[1] Early symptoms of deficiency include weakness, feeling tired and sore arms and legs.[1][2] Without treatment, decreased red blood cells, gum disease, changes to hair, and bleeding from the skin may occur.[1][3] As scurvy worsens there can be poor wound healing, personality changes, and finally death from infection or bleeding.[2] It takes at least a month of little to no vitamin C in the diet before symptoms occur.[1][2] In modern times, scurvy occurs most commonly in people with mental disorders, unusual eating habits, alcoholism, and older people who live alone.[2] Other risk factors include intestinal malabsorption and dialysis.[2] While many animals produce their own vitamin C, humans and a few others do not.[2] Vitamin C is required to make the building blocks for collagen.[2] Diagnosis is typically based on physical signs, X-rays, and improvement after treatment.[2] Treatment is with vitamin C supplements taken by mouth.[1] Improvement often begins in a few days with complete recovery in a few weeks.[2] Sources of vitamin C in the diet include citrus fruit and a number of vegetables (such as red peppers, broccoli, and tomatoes).[2] Cooking often decreases vitamin C in foods.[2] Scurvy is rare compared to other nutritional deficiencies.[2] It occurs more often in the developing world in association with malnutrition.[2] Rates among refugees are reported at 5 to 45 percent.[4] Scurvy was described as early as the time of ancient Egypt.[2] It was a limiting factor in long-distance sea travel, often killing large numbers of people.[5] During the Age of Sail, it was assumed that 50 percent of the sailors would die of scurvy on a given trip.[6] A Scottish surgeon in the Royal Navy, James Lind, is generally credited with proving that scurvy can be successfully treated with citrus fruit in 1753.[7] Nevertheless, it wouldn't be until 1795 before health reformers such as Gilbert Blane persuaded the Royal Navy to routinely give lemon juice to its sailors.[6][7] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Pathogenesis * 4 Diagnosis * 4.1 Differential diagnosis * 5 Prevention * 6 Treatment * 7 History * 7.1 Early modern era * 7.2 18th century * 7.3 19th century * 7.4 20th century * 7.5 21st century * 7.6 Human trials * 8 Evolution * 9 Name * 10 References * 11 Further reading * 12 External links ## Signs and symptoms[edit] Early symptoms are malaise and lethargy. After one to three months, patients develop shortness of breath and bone pain. Myalgias may occur because of reduced carnitine production. Other symptoms include skin changes with roughness, easy bruising and petechiae, gum disease, loosening of teeth, poor wound healing, and emotional changes (which may appear before any physical changes). Dry mouth and dry eyes similar to Sjögren's syndrome may occur. In the late stages, jaundice, generalised edema, oliguria, neuropathy, fever, convulsions, and eventual death are frequently seen.[8] * A child presenting a "scorbutic tongue" due to vitamin C deficiency. * A child with scurvy in flexion posture. * Photo of the chest cage with pectus excavatum and scorbutic rosaries. ## Cause[edit] Scurvy, including subclinical scurvy, is caused by a deficiency of dietary vitamin C since humans are unable to metabolically synthesize vitamin C. Provided the diet contains sufficient vitamin C, the lack of working L-gulonolactone oxidase (GULO) enzyme has no significance, and in modern Western societies, scurvy is rarely present in adults, although infants and elderly people are affected.[9] Virtually all commercially available baby formulas contain added vitamin C, preventing infantile scurvy. Human breast milk contains sufficient vitamin C, if the mother has an adequate intake. Commercial milk is pasteurized, a heating process that destroys the natural vitamin C content of the milk.[6] Scurvy is one of the accompanying diseases of malnutrition (other such micronutrient deficiencies are beriberi and pellagra) and thus is still widespread in areas of the world depending on external food aid.[10] Although rare, there are also documented cases of scurvy due to poor dietary choices by people living in industrialized nations.[11][12][13][14][15] ## Pathogenesis[edit] X-ray of the knee joint (arrow indicates scurvy line). Vitamins are essential to the production and use of enzymes that are involved in ongoing processes throughout the human body.[6] Ascorbic acid is needed for a variety of biosynthetic pathways, by accelerating hydroxylation and amidation reactions. In the synthesis of collagen, ascorbic acid is required as a cofactor for prolyl hydroxylase and lysyl hydroxylase. These two enzymes are responsible for the hydroxylation of the proline and lysine amino acids in collagen. Hydroxyproline and hydroxylysine are important for stabilizing collagen by cross-linking the propeptides in collagen. Collagen is a primary structural protein in the human body, necessary for healthy blood vessels, muscle, skin, bone, cartilage, and other connective tissues. Defective connective tissue leads to fragile capillaries, resulting in abnormal bleeding, bruising, and internal hemorrhaging. Collagen is an important part of bone, so bone formation is also affected. Teeth loosen, bones break more easily, and once-healed breaks may recur.[6] Defective collagen fibrillogenesis impairs wound healing. Untreated scurvy is invariably fatal.[16] ## Diagnosis[edit] Diagnosis is typically based on physical signs, X-rays, and improvement after treatment.[2] ### Differential diagnosis[edit] Various childhood onset disorders can mimic the clinical and X-ray picture of scurvy such as: * Rickets * Osteochondrodysplasias especially osteogenesis imperfecta * Blount's disease * Osteomyelitis ## Prevention[edit] Foods and their Vitamin C content per 100 grams Item Vitamin C contents (mg) Camu Camu 2000.00 Amla 610.00 Urtica 333.00 Guava 228.30 Blackcurrant 181.00 Kiwifruit 161.30 Chili pepper 144.00 Parsley 133.00 Green kiwifruit 92.70 Broccoli 89.20 Brussels sprout 85.00 Bell pepper 80.40 Papaya 62.00 Strawberry 58.80 Orange 53.20 Lemon 53.00 Cabbage 36.60 Spinach 28.00 Turnip 27.40 Potato 19.70 Scurvy can be prevented by a diet that includes vitamin C-rich foods such as amla, bell peppers (sweet peppers), blackcurrants, broccoli, chili peppers, guava, kiwifruit, and parsley. Other sources rich in vitamin C are fruits such as lemons, limes, oranges, papaya, and strawberries. It is also found in vegetables, such as brussels sprouts, cabbage, potatoes, and spinach. Some fruits and vegetables not high in vitamin C may be pickled in lemon juice, which is high in vitamin C. Though redundant in the presence of a balanced diet,[17] various nutritional supplements are available, which provide ascorbic acid well in excess of that required to prevent scurvy.[citation needed] Some animal products, including liver, muktuk (whale skin), oysters, and parts of the central nervous system, including the adrenal medulla, brain, and spinal cord, contain large amounts of vitamin C, and can even be used to treat scurvy. Fresh meat from animals which make their own vitamin C (which most animals do) contains enough vitamin C to prevent scurvy, and even partly treat it. In some cases (notably French soldiers eating fresh horse meat), it was discovered that meat alone, even partly cooked meat, could alleviate scurvy. Scott's 1902 Antarctic expedition used lightly fried seal meat and liver, whereby complete recovery from incipient scurvy was reported to have taken less than two weeks.[18] ## Treatment[edit] Scurvy will improve with doses of vitamin C as low as 10 mg per day though doses of around 100 mg per day are typically recommended.[19] Most people make a full recovery within 2 weeks.[20] ## History[edit] Symptoms of scurvy have been recorded in Ancient Egypt as early as 1550 BCE.[21] In Ancient Greece, the physician Hippocrates (460-370 BCE) described symptoms of scurvy, specifically a "swelling and obstruction of the spleen."[22][23] In 406 CE, the Chinese monk Faxian wrote that ginger was carried on Chinese ships to prevent scurvy.[24] The knowledge that consuming foods containing vitamin C is a cure for scurvy has been repeatedly forgotten and rediscovered into the early 20th century.[25] ### Early modern era[edit] In the 13th century, the Crusaders frequently suffered from scurvy. In the 1497 expedition of Vasco da Gama, the curative effects of citrus fruit were already known[25][26] and confirmed by Pedro Álvares Cabral and his crew in 1507.[27] The Portuguese planted fruit trees and vegetables in Saint Helena, a stopping point for homebound voyages from Asia, and left their sick, who had scurvy and other ailments, to be taken home by the next ship if they recovered.[28] In 1500, one of the pilots of Cabral's fleet bound for India noted that in Malindi, its king offered the expedition fresh supplies such as lambs, chickens, and ducks, along with lemons and oranges, due to which "some of our ill were cured of scurvy".[29][30] Unfortunately, these travel accounts did not stop further maritime tragedies caused by scurvy, first because of the lack of communication between travelers and those responsible for their health, and because fruits and vegetables could not be kept for long on ships.[31] In 1536, the French explorer Jacques Cartier, exploring the St. Lawrence River, used the local natives' knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree (eastern white cedar) to make a tea that was later shown to contain 50 mg of vitamin C per 100 grams.[32][33] Such treatments were not available aboard ship, where the disease was most common. In February 1601, Captain James Lancaster, while sailing to Sumatra, landed on the northern coast to specifically obtain lemons and oranges for his crew to stop scurvy.[34] Captain Lancaster conducted an experiment using four ships under his command. One ship's crew received routine doses of lemon juice while the other three ships did not receive any such treatment. As a result, members of the non-treated ships started to contract scurvy, with many dying as a result.[35] During the Age of Exploration (between 1500 and 1800), it has been estimated that scurvy killed at least two million sailors.[36] Jonathan Lamb wrote: "In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;...all mainly to scurvy."[37] In 1579, the Spanish friar and physician Agustin Farfán published a book in which he recommended oranges and lemons for scurvy, a remedy that was already known in the Spanish Navy.[38] In 1593, Admiral Sir Richard Hawkins advocated drinking orange and lemon juice as a means of preventing scurvy.[39] In 1614, John Woodall, Surgeon General of the East India Company, published The Surgion's Mate as a handbook for apprentice surgeons aboard the company's ships. He repeated the experience of mariners that the cure for scurvy was fresh food or, if not available, oranges, lemons, limes, and tamarinds.[40] He was, however, unable to explain the reason why, and his assertion had no impact on the prevailing opinion of the influential physicians of the age, that scurvy was a digestive complaint. Apart from ocean travel, even in Europe, until the late Middle Ages, scurvy was common in late winter, when few green vegetables, fruits and root vegetables were available. This gradually improved with the introduction from the Americas of potatoes; by 1800, scurvy was virtually unheard of in Scotland, where it had previously been endemic.[41]:11 ### 18th century[edit] James Lind, a pioneer in the field of scurvy prevention A 1707 handwritten book by Mrs. Ebot Mitchell, discovered in a house in Hasfield, Gloucestershire, contains a "Recp.t for the Scurvy" that consisted of extracts from various plants mixed with a plentiful supply of orange juice, white wine or beer.[42] In 1734, the Leiden-based physician Johann Bachstrom published a book on scurvy in which he stated, "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens; which is alone the primary cause of the disease", and urged the use of fresh fruit and vegetables as a cure.[43][44][45] It was not until 1747 that James Lind formally demonstrated that scurvy could be treated by supplementing the diet with citrus fruit, in one of the first controlled clinical experiments reported in the history of medicine.[46][47] As a naval surgeon on HMS Salisbury, Lind had compared several suggested scurvy cures: hard cider, vitriol, vinegar, seawater, oranges, lemons, and a mixture of balsam of Peru, garlic, myrrh, mustard seed and radish root. In A Treatise on the Scurvy (1753)[2][46] Lind explained the details of his clinical trial and concluded "the results of all my experiments was, that oranges and lemons were the most effectual remedies for this distemper at sea.”[6][46] However, the experiment and its results occupied only a few paragraphs in a work that was long and complex and had little impact. Lind himself never actively promoted lemon juice as a single 'cure'. He shared medical opinion at the time that scurvy had multiple causes – notably hard work, bad water, and the consumption of salt meat in a damp atmosphere which inhibited healthful perspiration and normal excretion – and therefore required multiple solutions.[6][48] Lind was also sidetracked by the possibilities of producing a concentrated 'rob' of lemon juice by boiling it. This process destroyed the vitamin C and was therefore unsuccessful.[6] During the 18th century, disease killed more British sailors than wartime enemy action. It was mainly by scurvy that George Anson, in his celebrated voyage of 1740–1744, lost nearly two-thirds of his crew (1,300 out of 2,000) within the first 10 months of the voyage.[6][49] The Royal Navy enlisted 184,899 sailors during the Seven Years' War; 133,708 of these were "missing" or died from disease, and scurvy was the leading cause.[50] Although throughout this period sailors and naval surgeons were increasingly convinced that citrus fruits could cure scurvy, the classically trained physicians who determined medical policy dismissed this evidence as mere anecdotes, as it did not conform to their theories of disease. Literature championing the cause of citrus juice, therefore, had no practical impact. Medical theory was based on the assumption that scurvy was a disease of internal putrefaction brought on by faulty digestion caused by the hardships of life at sea and the naval diet. Although this basic idea was given different emphases by successive theorists, the remedies they advocated (and which the navy accepted) amounted to little more than the consumption of 'fizzy drinks' to activate the digestive system, the most extreme of which was the regular consumption of 'elixir of vitriol' – sulphuric acid taken with spirits and barley water, and laced with spices. In 1764, a new variant appeared. Advocated by Dr David MacBride and Sir John Pringle, Surgeon General of the Army and later President of the Royal Society, this idea was that scurvy was the result of a lack of 'fixed air' in the tissues which could be prevented by drinking infusions of malt and wort whose fermentation within the body would stimulate digestion and restore the missing gases.[51] These ideas received wide and influential backing, when James Cook set off to circumnavigate the world (1768–1771) in HM Bark Endeavour, malt and wort were top of the list of the remedies he was ordered to investigate. The others were beer, Sauerkraut and Lind's 'rob'. The list did not include lemons.[52] Cook did not lose a single man to scurvy, and his report came down in favour of malt and wort, although it is now clear that the reason for the health of his crews on this and other voyages was Cook's regime of shipboard cleanliness, enforced by strict discipline, as well as frequent replenishment of fresh food and greenstuffs.[53] Another beneficial rule implemented by Cook was his prohibition of the consumption of salt fat skimmed from the ship's copper boiling pans, then a common practice elsewhere in the Navy. In contact with air, the copper formed compounds that prevented the absorption of vitamins by the intestines.[54] The first major long distance expedition that experienced virtually no scurvy was that of the Spanish naval officer Alessandro Malaspina, 1789–1794. Malaspina's medical officer, Pedro González, was convinced that fresh oranges and lemons were essential for preventing scurvy. Only one outbreak occurred, during a 56-day trip across the open sea. Five sailors came down with symptoms, one seriously. After three days at Guam all five were healthy again. Spain's large empire and many ports of call made it easier to acquire fresh fruit.[55] Although towards the end of the century MacBride's theories were being challenged, the medical authorities in Britain remained committed to the notion that scurvy was a disease of internal 'putrefaction' and the Sick and Hurt Board, run by administrators, felt obliged to follow its advice. Within the Royal Navy, however, opinion – strengthened by first-hand experience of the use of lemon juice at the siege of Gibraltar and during Admiral Rodney's expedition to the Caribbean – had become increasingly convinced of its efficacy. This was reinforced by the writings of experts like Gilbert Blane[56] and Thomas Trotter[57] and by the reports of up-and-coming naval commanders. With the coming of war in 1793, the need to eliminate scurvy acquired a new urgency. But the first initiative came not from the medical establishment but from the admirals. Ordered to lead an expedition against Mauritius, Rear Admiral Gardner was uninterested in the wort, malt and elixir of vitriol which were still being issued to ships of the Royal Navy, and demanded that he be supplied with lemons, to counteract scurvy on the voyage. Members of the Sick and Hurt Board, recently augmented by two practical naval surgeons, supported the request, and the Admiralty ordered that it be done. There was, however, a last minute change of plan. The expedition against Mauritius was cancelled. On 2 May 1794, only HMS Suffolk and two sloops under Commodore Peter Rainier sailed for the east with an outward bound convoy, but the warships were fully supplied with lemon juice and the sugar with which it had to be mixed. Then in March 1795, came astonishing news. Suffolk had arrived in India after a four-month voyage without a trace of scurvy and with a crew that was healthier than when it set out. The effect was immediate. Fleet commanders clamoured also to be supplied with lemon juice, and by June the Admiralty acknowledged the groundswell of demand in the navy had agreed to a proposal from the Sick and Hurt Board that lemon juice and sugar should in future be issued as a daily ration to the crews of all warships.[58] It took a few years before the method of distribution to all ships in the fleet had been perfected and the supply of the huge quantities of lemon juice required to be secured, but by 1800, the system was in place and functioning. This led to a remarkable health improvement among the sailors and consequently played a critical role in gaining the advantage in naval battles against enemies who had yet to introduce the measures. ### 19th century[edit] Page from the journal of Henry Walsh Mahon showing the effects of scurvy, from his time aboard HM Convict Ship Barrosa (1841/2) The surgeon-in-chief of Napoleon's army at the Siege of Alexandria (1801), Baron Dominique-Jean Larrey, wrote in his memoirs that the consumption of horse meat helped the French to curb an epidemic of scurvy. The meat was cooked but was freshly obtained from young horses bought from Arabs, and was nevertheless effective. This helped to start the 19th-century tradition of horse meat consumption in France.[59] Lauchlin Rose patented a method used to preserve citrus juice without alcohol in 1867, creating a concentrated drink known as Rose's lime juice. The Merchant Shipping Act of 1867 required all ships of the Royal Navy and Merchant Navy to provide a daily lime ration of one pound to sailors to prevent scurvy.[60] The product became nearly ubiquitous, hence the term "limey", first for British sailors, then for English immigrants within the former British colonies (particularly America, New Zealand and South Africa), and finally, in old American slang, all British people.[61] The plant Cochlearia officinalis, also known as "common scurvygrass", acquired its common name from the observation that it cured scurvy, and it was taken on board ships in dried bundles or distilled extracts. Its very bitter taste was usually disguised with herbs and spices; however, this did not prevent scurvygrass drinks and sandwiches from becoming a popular fad in the UK until the middle of the nineteenth century, when citrus fruits became more readily available.[62] West Indian limes began to supplement lemons, when Spain's alliance with France against Britain in the Napoleonic Wars made the supply of Mediterranean lemons problematic, and because they were more easily obtained from Britain's Caribbean colonies[25] and were believed to be more effective because they were more acidic. It was the acid, not the (then-unknown) Vitamin C that was believed to cure scurvy. In fact, the West Indian limes were significantly lower in Vitamin C than the previous lemons and further were not served fresh but rather as lime juice, which had been exposed to light and air, and piped through copper tubing, all of which significantly reduced the Vitamin C. Indeed, a 1918 animal experiment using representative samples of the Navy and Merchant Marine's lime juice showed that it had virtually no antiscorbutic power at all.[25] The belief that scurvy was fundamentally a nutritional deficiency, best treated by consumption of fresh food, particularly fresh citrus or fresh meat, was not universal in the 19th and early 20th centuries, and thus sailors and explorers continued to suffer from scurvy into the 20th century. For example, the Belgian Antarctic Expedition of 1897–1899 became seriously affected by scurvy when its leader, Adrien de Gerlache, initially discouraged his men from eating penguin and seal meat. In the Royal Navy's Arctic expeditions in the 19th century it was widely believed that scurvy was prevented by good hygiene on board ship, regular exercise, and maintaining the morale of the crew, rather than by a diet of fresh food. Navy expeditions continued to be plagued by scurvy even while fresh (not jerked or tinned) meat was well known as a practical antiscorbutic among civilian whalers and explorers in the Arctic. Even cooking fresh meat did not entirely destroy its antiscorbutic properties, especially as many cooking methods failed to bring all the meat to high temperature. The confusion is attributed to a number of factors:[25] * while fresh citrus (particularly lemons) cured scurvy, lime juice that had been exposed to light, air and copper tubing did not – thus undermining the theory that citrus cured scurvy; * fresh meat (especially organ meat and raw meat, consumed in arctic exploration) also cured scurvy, undermining the theory that fresh vegetable matter was essential to preventing and curing scurvy; * increased marine speed via steam shipping, and improved nutrition on land, reduced the incidence of scurvy – and thus the ineffectiveness of copper-piped lime juice compared to fresh lemons was not immediately revealed. In the resulting confusion, a new hypothesis was proposed, following the new germ theory of disease – that scurvy was caused by ptomaine, a waste product of bacteria, particularly in tainted tinned meat. Infantile scurvy emerged in the late 19th century because children were being fed pasteurized cow's milk, particularly in the urban upper class. While pasteurization killed bacteria, it also destroyed vitamin C. This was eventually resolved by supplementing with onion juice or cooked potatoes. Native Americans helped save some newcomers from scurvy by directing them to eat wild onions.[63] ### 20th century[edit] By the early 20th century, when Robert Falcon Scott made his first expedition to the Antarctic (1901–1904), the prevailing theory was that scurvy was caused by "ptomaine poisoning", particularly in tinned meat.[64] However, Scott discovered that a diet of fresh meat from Antarctic seals cured scurvy before any fatalities occurred.[65] In 1907, an animal model which would eventually help to isolate and identify the "antiscorbutic factor" was discovered. Axel Holst and Theodor Frølich, two Norwegian physicians studying shipboard beriberi contracted by ship's crews in the Norwegian Fishing Fleet, wanted a small test mammal to substitute for the pigeons then used in beriberi research. They fed guinea pigs their test diet of grains and flour, which had earlier produced beriberi in their pigeons, and were surprised when classic scurvy resulted instead. This was a serendipitous choice of animal. Until that time, scurvy had not been observed in any organism apart from humans and had been considered an exclusively human disease. Certain birds, mammals, and fish are susceptible to scurvy, but pigeons are unaffected, since they can synthesize ascorbic acid internally. Holst and Frølich found they could cure scurvy in guinea pigs with the addition of various fresh foods and extracts. This discovery of an animal experimental model for scurvy, which was made even before the essential idea of "vitamins" in foods had been put forward, has been called the single most important piece of vitamin C research.[66] In 1915, New Zealand troops in the Gallipoli Campaign had a lack of vitamin C in their diet which caused many of the soldiers to contract scurvy. It is thought that scurvy is one of many reasons that the Allied attack on Gallipoli failed.[67] Vilhjalmur Stefansson, an arctic explorer who had lived among the Inuit, proved that the all-meat diet they consumed did not lead to vitamin deficiencies. He participated in a study in New York's Bellevue Hospital in February 1928, where he and a companion ate only meat for a year while under close medical observation, yet remained in good health.[68] In 1927, Hungarian biochemist Szent-Györgyi isolated a compound he called "hexuronic acid".[69] Szent-Györgyi suspected hexuronic acid, which he had isolated from adrenal glands, to be the antiscorbutic agent, but he could not prove it without an animal-deficiency model. In 1932, the connection between hexuronic acid and scurvy was finally proven by American researcher Charles Glen King of the University of Pittsburgh.[70] King's laboratory was given some hexuronic acid by Szent-Györgyi and soon established that it was the sought-after anti-scorbutic agent. Because of this, hexuronic acid was subsequently renamed ascorbic acid. ### 21st century[edit] Rates of scurvy in most of the world are low.[71] Those most commonly affected are malnourished people in the developing world and the homeless.[72] There have been outbreaks of the condition in refugee camps.[73] Case reports in the developing world of those with poorly healing wounds have occurred.[74] ### Human trials[edit] Notable human dietary studies of experimentally induced scurvy were conducted on conscientious objectors during World War II in Britain and on Iowa state prisoner volunteers in the late 1960s.[75][76] These studies both found that all obvious symptoms of scurvy previously induced by an experimental scorbutic diet with extremely low vitamin C content could be completely reversed by additional vitamin C supplementation of only 10 mg per day. In these experiments, no clinical difference was noted between men given 70 mg vitamin C per day (which produced blood levels of vitamin C of about 0.55 mg/dl, about 1⁄3 of tissue saturation levels), and those given 10 mg per day (which produced lower blood levels). Men in the prison study developed the first signs of scurvy about 4 weeks after starting the vitamin C-free diet, whereas in the British study, six to eight months were required, possibly because the subjects were pre-loaded with a 70 mg/day supplement for six weeks before the scorbutic diet was fed.[75] Men in both studies, on a diet devoid or nearly devoid of vitamin C, had blood levels of vitamin C too low to be accurately measured when they developed signs of scurvy, and in the Iowa study, at this time were estimated (by labeled vitamin C dilution) to have a body pool of less than 300 mg, with daily turnover of only 2.5 mg/day.[76] ## Evolution[edit] The vast majority of animals and plants are able to synthesize vitamin C, through a sequence of enzyme-driven steps, which convert monosaccharides to vitamin C. However, some mammals have lost the ability to synthesize vitamin C, notably simians and tarsiers. These make up one of two major primate suborders, haplorrhini, and this group includes humans.[77] The strepsirrhini (non-tarsier prosimians) can make their own vitamin C, and these include lemurs, lorises, pottos, and galagos. Ascorbic acid is also not synthesized by at least two species of caviidae, the capybara[78] and the guinea pig. There are known species of birds and fish that do not synthesize their own vitamin C. All species that do not synthesize ascorbate require it in the diet. Deficiency causes scurvy in humans, and somewhat similar symptoms in other animals.[79][80][81] Animals that can contract scurvy all lack the L-gulonolactone oxidase (GULO) enzyme, which is required in the last step of vitamin C synthesis. The genomes of these species contain GULO as pseudogenes, which serve as insight into the evolutionary past of the species.[82][83][84] ## Name[edit] In babies, scurvy is sometimes referred to as Barlow's disease, named after Thomas Barlow,[85] a British physician who described it in 1883.[86] However, Barlow's disease may also refer to mitral valve prolapse (Barlow's syndrome), first described by John Brereton Barlow in 1966.[87] ## References[edit] 1. ^ a b c d e f g h i j "Scurvy". GARD. 1 September 2016. Archived from the original on 26 January 2017. Retrieved 26 September 2016. 2. ^ a b c d e f g h i j k l m n o p q r s t Agarwal, A; Shaharyar, A; Kumar, A; Bhat, MS; Mishra, M (June 2015). "Scurvy in pediatric age group - A disease often forgotten?". Journal of Clinical Orthopaedics and Trauma. 6 (2): 101–7. doi:10.1016/j.jcot.2014.12.003. PMC 4411344. PMID 25983516. 3. ^ "Vitamin C". Office of Dietary Supplements. 11 February 2016. Archived from the original on 30 July 2017. Retrieved 18 July 2017. 4. ^ Renzaho, Andre M. N. (2016). Globalisation, Migration and Health: Challenges and Opportunities. World Scientific. p. 94. ISBN 978-1-78326-889-4. Archived from the original on 8 September 2017. 5. ^ Toler, Pamela D. (2012). Mankind: The Story of All of Us. Running Press. p. 296. ISBN 978-0762447176. Archived from the original on 8 September 2017. 6. ^ a b c d e f g h i Price, Catherine (2017). "The Age of Scurvy". Distillations. Vol. 3 no. 2. pp. 12–23. Retrieved April 17, 2018. 7. ^ a b Hemilä, Harri (29 May 2012). "A Brief History of Vitamin C and its Deficiency, Scurvy". Archived from the original on 9 July 2014. Retrieved 25 May 2014. 8. ^ Lynne Goebel, MD. "Scurvy Clinical Presentation". Medscape Reference. Archived from the original on 23 June 2011. 9. ^ Hampl JS, Taylor CA, Johnston CS (2004). "Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey, 1988 to 1994". American Journal of Public Health. 94 (5): 870–5. doi:10.2105/AJPH.94.5.870. PMC 1448351. PMID 15117714. 10. ^ WHO (4 June 2001). "Area of work: nutrition. Progress report 2000" (PDF). Archived from the original (PDF) on 16 December 2006. Cite journal requires `\|journal=` (help) 11. ^ Davies IJ, Temperley JM (1967). "A case of scurvy in a student". Postgraduate Medical Journal. 43 (502): 549–50. doi:10.1136/pgmj.43.502.539. PMC 2466190. PMID 6074157. 12. ^ Sthoeger ZM, Sthoeger D (1991). "[Scurvy from self-imposed diet]". Harefuah (in Hebrew). 120 (6): 332–3. PMID 1879769. 13. ^ Ellis CN, Vanderveen EE, Rasmussen JE (1984). "Scurvy. A case caused by peculiar dietary habits". Archives of Dermatology. 120 (9): 1212–4. doi:10.1001/archderm.120.9.1212. PMID 6476860. 14. ^ McKenna KE, Dawson JF (1993). "Scurvy occurring in a teenager". Clinical and Experimental Dermatology. 18 (1): 75–7. doi:10.1111/j.1365-2230.1993.tb00976.x. PMID 8440062. S2CID 42245389. 15. ^ Feibel, Carrie (15 August 2016). "The Return of Scurvy? Houston Neurologist Diagnoses Hundreds of Patients with Vitamin Deficiencies". Houston Public Media. University of Houston. Archived from the original on 16 August 2016. Retrieved 2016-08-17. 16. ^ "Forgotten Knowledge: The Science of Scurvy". Archived from the original on 10 May 2016. Retrieved 29 April 2016. 17. ^ Rivers, JM (1987). "Safety of high-level vitamin C ingestion". Annals of the New York Academy of Sciences. 498 (1 Third Confere): 445–54. Bibcode:1987NYASA.498..445R. doi:10.1111/j.1749-6632.1987.tb23780.x. PMID 3304071. S2CID 1410094. 18. ^ Scott, R.F. (1905). The Voyage of the Discovery. London. pp. 541–545. [26 September 1902] [The expedition members] Heald, Mr. Ferrar, and Cross have very badly swollen legs, whilst Heald's are discoloured as well. The remainder of the party seem fairly well, but not above suspicion; Walker's ankles are slightly swollen. [15 October 1902] [After a fresh seal meat diet at base camp] within a fortnight of the outbreak there is scarcely a sign of it remaining [...] Heald's is the only case that hung at all [...] and now he is able to get about once more. Cross's recovery was so rapid that he was able to join the seal-killing party last week. 19. ^ Manual of Nutritional Therapeutics. Lippincott Williams & Wilkins. 2008. p. 161. ISBN 9780781768412. 20. ^ "Scurvy". nhs.uk. 21. ^ Bradley S, Buckler MD, Anjali Parish MD (2018-08-27). "Scurvy". EMedicine. Archived from the original on 12 February 2010. 22. ^ Hippocrates described symptoms of scurvy in book 2 of his Prorrheticorum and in his Liber de internis affectionibus. (Cited by James Lind, A Treatise on the Scurvy, 3rd ed. (London, England: G. Pearch and W. Woodfall, 1772), page 285 Archived 1 January 2016 at the Wayback Machine) Symptoms of scurvy were also described by: (i) Pliny, in Naturalis historiae, book 3, chapter 49; and (ii) Strabo, in Geographicorum, book 16. (Cited by John Ashhurst, ed., The International Encyclopedia of Surgery, vol. 1 (New York, New York: William Wood and Co., 1881), page 278 Archived 5 May 2016 at the Wayback Machine) 23. ^ Stone I (1966). "On the genetic etiology of scurvy". Acta Geneticae Medicae et Gemellologiae (Roma). 15 (4): 345–50. doi:10.1017/s1120962300014931. PMID 5971711. Archived from the original on 10 February 2008. 24. ^ Pickersgill, Barbara (2005). Prance, Ghillean; Nesbitt, Mark (eds.). The Cultural History of Plants. Routledge. pp. 163–164. ISBN 0415927463. 25. ^ a b c d e (Cegłowski 2010) 26. ^ As they sailed farther up the east coast of Africa, they met local traders, who traded them fresh oranges. 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[...] There were 'wild groves' of oranges, lemons and other fruits that ripened all the year round, large pomegranates and figs. 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Timeline of Britain. Canary Press. 40. ^ Bown, Stephen R (2003). Scurvy: How a Surgeon, a Mariner and a Gentleman Solved the Greatest Medical Mystery of the Age of Sail. New York: Viking. ISBN 978-0-312-31391-3. 41. ^ https://www.unhcr.org/4cbef0599.pdf 42. ^ "Cure for Scurvy discovered by a woman". The Daily Telegraph. 5 March 2009. Archived from the original on 25 January 2016. 43. ^ Bartholomew, Michael (2002). "James Lind and scurvy: A revaluation". Journal for Maritime Research. 4 (1): n/a. doi:10.1080/21533369.2002.9668317. PMID 20355298. S2CID 42109340. 44. ^ Johann Friedrich Bachstrom, Observationes circa scorbutum [Observations on scurvy] (Leiden ("Lugdunum Batavorum"), Netherlands: Conrad Wishof, 1734) p. 16. From page 16: Archived 1 January 2016 at the Wayback Machine " … sed ex nostra causa optime explicatur, quae est absentia, carentia & abstinentia a vegetabilibus recentibus, … " ( … but [this misfortune] is explained very well by our [supposed] cause, which is the absence of, lack of, and abstinence from fresh vegetables, … ) 45. ^ "The Blood of Nelson" by Glenn Barnett — Military History — Oct 2006. 46. ^ a b c James Lind (1772). A Treatise on the Scurvy: In Three Parts, Containing an Inquiry Into the Nature, Causes, an Cure, of that Disease, Together with a Critical and Chronological View of what Has Been Published on the Subject. S. Crowder (and six others). p. 149. (Also archived second edition (1757)) 47. ^ Baron, Jeremy Hugh (2009). "Sailors' scurvy before and after James Lind - a reassessment". Nutrition Reviews. 67 (6): 315–332. doi:10.1111/j.1753-4887.2009.00205.x. PMID 19519673. 48. ^ Bartholomew, M (Jan 2002). "James Lind and Scurvy: a Revaluation". 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"[no] party wintering in the Antarctic Regions will have great difficulty in providing themselves with fresh food; and, as we have proved, where such conditions exist there need be no fear of the dreaded word 'scurvy'." 66. ^ Norum KR, Grav HJ (June 2002). "[Axel Holst and Theodor Frølich--pioneers in the combat of scurvy]". Journal of the Norwegian Medical Association. 122 (17): 1686–7. PMID 12555613. 67. ^ Wilson Nick, Ngheim Nhung, Summers Jennifer, Carter Mary-Ann, Harper Glyn, Wilson Nicholas (2013). "A nutritional analysis of New Zealand Military food rations at Gallipoli in 1915: likely contribution to scurvy and other nutrient deficiency disorders". New Zealand Medical Journal. 126 (1373): 12–29. PMID 23797073.CS1 maint: multiple names: authors list (link) 68. ^ McClellan Walter S., Du Bois Eugene F. (1930). "Prolonged meat diet experiment" (PDF). J Biol Chem. 87: 651–668. Archived (PDF) from the original on 1 January 2016. 69. ^ Carpenter, Kenneth J. (22 June 2004). 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"Guinea pigs possess a highly mutated gene for L-gulono-gamma-lactone oxidase, the key enzyme for L-ascorbic acid biosynthesis missing in this species". The Journal of Biological Chemistry. 267 (30): 21967–72. PMID 1400507. 84. ^ Ohta Y, Nishikimi M (October 1999). "Random nucleotide substitutions in primate nonfunctional gene for L-gulono-gamma-lactone oxidase, the missing enzyme in L-ascorbic acid biosynthesis". Biochimica et Biophysica Acta. 1472 (1–2): 408–11. doi:10.1016/S0304-4165(99)00123-3. PMID 10572964. 85. ^ Evans PR (December 1983). "Infantile scurvy: the centenary of Barlow's disease". British Medical Journal (Clinical Research Ed.). 287 (6408): 1862–3. doi:10.1136/bmj.287.6408.1862. PMC 1550031. PMID 6423046. 86. ^ Carpenter, Kenneth J. (1988). The History of Scurvy and Vitamin C. Cambridge University Press. p. 172. ISBN 978-0-521-34773-0. 87. ^ Barlow JB, Bosman CK (February 1966). "Aneurysmal protrusion of the posterior leaflet of the mitral valve. An auscultatory-electrocardiographic syndrome". American Heart Journal. 71 (2): 166–78. doi:10.1016/0002-8703(66)90179-7. PMID 4159172. ## Further reading[edit] * Bown, Stephen R. Scurvy: How a Surgeon, a Mariner, and a Gentleman Solved the Greatest Medical Mystery of the Age of Sail. * Carpenter, K.J. (1986). The History of Scurvy and Vitamin C. Cambridge. * Cegłowski, Maciej (7 March 2010). "Scott and Scurvy". IdleWords.com. * Vale, B. & Edwards, G. (2011). Physician to the Fleet: The Life and Times of Thomas Trotter 1760-1832. Boydell.CS1 maint: uses authors parameter (link) ## External links[edit] Wikimedia Commons has media related to Scurvy. Look up scurvy in Wiktionary, the free dictionary. * "Scurvy (Scorbutus)". The Encyclopaedia Britannica; A Dictionary of Arts, Sciences, Literature and General Information. XXIV (SAINTE-CLAIRE DEVILLE to SHUTTLE) (11th ed.). Cambridge, England and New York: At the University Press. 1911. p. 517. Retrieved 22 October 2018 – via Internet Archive. Classification D * ICD-10: E54 * ICD-9-CM: 267 * OMIM: 240400 * MeSH: D012614 * DiseasesDB: 13930 External resources * MedlinePlus: 000355 * eMedicine: med/2086 derm/521 ped/2073 radio/628 * v * t * e Malnutrition Protein-energy malnutrition * Kwashiorkor * Marasmus * Catabolysis Vitamin deficiency B vitamins * B1 * Beriberi * Wernicke–Korsakoff syndrome * Wernicke's encephalopathy * Korsakoff's syndrome * B2 * Riboflavin deficiency * B3 * Pellagra * B6 * Pyridoxine deficiency * B7 * Biotin deficiency * B9 * Folate deficiency * B12 * Vitamin B12 deficiency Other * A: Vitamin A deficiency * Bitot's spots * C: Scurvy * D: Vitamin D deficiency * Rickets * Osteomalacia * Harrison's groove * E: Vitamin E deficiency * K: Vitamin K deficiency Mineral deficiency * Sodium * Potassium * Magnesium * Calcium * Iron * Zinc * Manganese * Copper * Iodine * Chromium * Molybdenum * Selenium * Keshan disease Growth * Delayed milestone * Failure to thrive * Short stature * Idiopathic General * Anorexia * Weight loss * Cachexia * Underweight Authority control * BNE: XX529929 * BNF: cb123371089 (data) * GND: 4232112-8 * LCCN: sh85119180 * NDL: 00564577 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Scurvy	c1855867	6,258	wikipedia	https://en.wikipedia.org/wiki/Scurvy	2021-01-18T18:56:12	{"gard": ["10406"], "mesh": ["D012614", "C565486"], "umls": ["C1415369", "C1855867"], "icd-9": ["267"], "wikidata": ["Q163865"]}
Xp22.3 microdeletion syndrome is a microdeletion syndrome resulting from a partial deletion of the chromosome X. Phenotype is highly variable (depending on length of deletion), but is mainly characterized by X linked ichthyosis, mild-moderate intellectual deficit, Kallmann syndrome, short stature, chondrodysplasia punctata and ocular albinism. Epilepsy, attention deficit-hyperactivity disorder, autism and difficulties with social communication can be associated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Xp22.3 microdeletion syndrome	c4512072	6,259	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1643	2021-01-23T18:47:55	{"icd-10": ["Q99.8"], "synonyms": ["Del(X)(p23)"]}
Mismatch repair cancer syndrome Other namesBrain tumor-polyposis syndrome, Glioma-polyposis syndrome This condition is inherited in an autosomal recessive manner SpecialtyOncology Mismatch repair cancer syndrome (MMRCS) is a cancer syndrome associated with biallelic DNA mismatch repair mutations.[1] It is also known as Turcot syndrome (after Jacques Turcot, who described the condition in 1959) and by several other names.[1] In MMRCS, neoplasia typically occurs in both the gut and the central nervous system (CNS).[1] In the large intestine, multiple colonic polyps develop; in the CNS, brain tumors. ## Contents * 1 Genetics * 2 Diagnosis * 3 Treatment * 4 History * 5 See also * 6 References * 7 External links ## Genetics[edit] Under the name constitutional mismatch repair-deficiency, (CMMR-D), it has been mapped to MLH1, MSH2, MSH6 or PMS2.[2] Monoallelic mutations of these genes are observed in the condition known as Lynch syndrome or hereditary nonpolyposis colorectal cancer, while biallelic mutations are observed in CMMR-D.[3] People expressing the HNPCC (which itself is considered autosomal dominant) trait are considered carriers of CMMR-D, thus CMMR-D is classified as autosomal recessive.[citation needed] The term "childhood cancer syndrome" has also been proposed.[4][5] Café-au-lait macules have been observed.[6] ## Diagnosis[edit] Childhood to early adult onset HNPCC \+ malignant gliomas. The polyps developed tend to be larger, fewer, and progress to malignancy earlier than those seen in familial adenomatous polyposis,[1] a clinically similar condition with different underlying mutations. Diagnostic testing consists of a blood sample being collected, and a genetic specialist compares two copies of a patient's gene to normal MMR genes. If there are differences in the genes, the specialists are able to further test and decide if the patient has the deficiency. [7] ## Treatment[edit] This section is empty. You can help by adding to it. (July 2017) ## History[edit] OMIM currently includes "Turcot syndrome" under Mismatch repair cancer syndrome. Turcot syndrome is the association between familial polyposis of the colon and brain tumors[8] like medulloblastoma, malignant glioma. It was first reported by Canadian surgeon Jacques Turcot (1914-1977 ) et al. in 1959 and hence carries the first author's name.[9] ## See also[edit] * Gardner syndrome ## References[edit] 1. ^ a b c d Online Mendelian Inheritance in Man (OMIM): 276300 2. ^ Kratz CP, Holter S, Etzler J, Lauten M, Pollett A, Niemeyer CM, Gallinger S, Wimmer K (June 2009). "Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome" (PDF). Journal of Medical Genetics. 46 (6): 418–20. doi:10.1136/jmg.2008.064212. PMID 19293170. S2CID 42347878. 3. ^ Wimmer K, Etzler J (September 2008). "Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?". Human Genetics. 124 (2): 105–22. doi:10.1007/s00439-008-0542-4. PMID 18709565. S2CID 32654505. 4. ^ Krüger S, Kinzel M, Walldorf C, Gottschling S, Bier A, Tinschert S, von Stackelberg A, Henn W, Görgens H, Boue S, Kölble K, Büttner R, Schackert HK (January 2008). "Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1". European Journal of Human Genetics. 16 (1): 62–72. doi:10.1038/sj.ejhg.5201923. PMID 17851451. 5. ^ Tan TY, Orme LM, Lynch E, Croxford MA, Dow C, Dewan PA, Lipton L (March 2008). "Biallelic PMS2 mutations and a distinctive childhood cancer syndrome". Journal of Pediatric Hematology/Oncology. 30 (3): 254–7. doi:10.1097/MPH.0b013e318161aa20. PMID 18376293. 6. ^ Jackson CC, Holter S, Pollett A, Clendenning M, Chou S, Senter L, Ramphal R, Gallinger S, Boycott K (June 2008). "Café-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2". Pediatric Blood & Cancer. 50 (6): 1268–70. doi:10.1002/pbc.21514. PMID 18273873. 7. ^ "Constitutional Mismatch Repair Deficiency Syndrome". www.stjude.org. Retrieved 2020-03-10. 8. ^ "Turcot syndrome" at Dorland's Medical Dictionary 9. ^ Turcot J, Despres JP, St Pierre F (1959). "Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases". Diseases of the Colon and Rectum. 2: 465–8. doi:10.1007/bf02616938. PMID 13839882. S2CID 27477524. ## External links[edit] * Turcot syndrome; CNS tumors with Familial polyposis of the colon at NIH's Office of Rare Diseases Classification D * OMIM: 276300 * MeSH: C536928 * DiseasesDB: 29793 External resources * eMedicine: ped/828 * Orphanet: 252202 * v * t * e Digestive system neoplasia GI tract Upper Esophagus * Squamous cell carcinoma * Adenocarcinoma Stomach * Gastric carcinoma * Signet ring cell carcinoma * Gastric lymphoma * MALT lymphoma * Linitis plastica Lower Small intestine * Duodenal cancer * Adenocarcinoma Appendix * Carcinoid * Pseudomyxoma peritonei Colon/rectum * Colorectal polyp: adenoma, hyperplastic, juvenile, sessile serrated adenoma, traditional serrated adenoma, Peutz–Jeghers Cronkhite–Canada * Polyposis syndromes: Juvenile * MUTYH-associated * Familial adenomatous/Gardner's * Polymerase proofreading-associated * Serrated polyposis * Neoplasm: Adenocarcinoma * Familial adenomatous polyposis * Hereditary nonpolyposis colorectal cancer Anus * Squamous cell carcinoma Upper and/or lower * Gastrointestinal stromal tumor * Krukenberg tumor (metastatic) Accessory Liver * malignant: Hepatocellular carcinoma * Fibrolamellar * Hepatoblastoma * benign: Hepatocellular adenoma * Cavernous hemangioma * hyperplasia: Focal nodular hyperplasia * Nodular regenerative hyperplasia Biliary tract * bile duct: Cholangiocarcinoma * Klatskin tumor * gallbladder: Gallbladder cancer Pancreas * exocrine pancreas: Adenocarcinoma * Pancreatic ductal carcinoma * cystic neoplasms: Serous microcystic adenoma * Intraductal papillary mucinous neoplasm * Mucinous cystic neoplasm * Solid pseudopapillary neoplasm * Pancreatoblastoma Peritoneum * Primary peritoneal carcinoma * Peritoneal mesothelioma * Desmoplastic small round cell tumor * v * t * e Metabolic disease: DNA replication and DNA repair-deficiency disorder DNA replication * Separation/initiation: RNASEH2A * Aicardi–Goutières syndrome 4 * Termination/telomerase: DKC1 * Dyskeratosis congenita DNA repair Nucleotide excision repair * Cockayne syndrome/DeSanctis–Cacchione syndrome * Thymine dimer * Xeroderma pigmentosum * IBIDS syndrome MSI/DNA mismatch repair * Hereditary nonpolyposis colorectal cancer * Muir–Torre syndrome * Mismatch repair cancer syndrome MRN complex * Ataxia telangiectasia * Nijmegen breakage syndrome Other * RecQ helicase * Bloom syndrome * Werner syndrome * Rothmund–Thomson syndrome/Rapadilino syndrome * Fanconi anemia * Li-Fraumeni syndrome * Severe combined immunodeficiency [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Mismatch repair cancer syndrome	c0265325	6,260	wikipedia	https://en.wikipedia.org/wiki/Mismatch_repair_cancer_syndrome	2021-01-18T19:01:12	{"gard": ["420"], "mesh": ["C536928"], "umls": ["C0265325"], "orphanet": ["99817", "252202"], "wikidata": ["Q736633"]}
MYH9-related disease (MYH9-RD) is an inherited giant platelet disorder with a complex phenotype characterized by congenital thrombocytopenia and possible subsequent manifestations of sensorineural hearing loss, presenile cataracts, elevation of liver enzymes, and/or progressive nephropathy often leading to end-stage renal disease (ESRD). Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly and Sebastian syndrome, previously described as distinct disorders, represent some of the different clinical presentations of MYH9-RD. ## Epidemiology Prevalence in Italy is estimated at 1/400,000-1/300,000. More than 300 MYH9-RD pedigrees have been reported worldwide. ## Clinical description Thrombocytopenia is present at birth and can be associated with spontaneous bleeding (usually mild or moderate). Bleeding symptoms include easy bruising, epistaxis, gum bleeding, and/or menorrhagia. Life-threatening hemorrhage is rare. Patients have an increased risk of hemorrhages after surgery, biopsy, or deliveries. Hearing loss is seen in almost all cases with the age of onset ranging from the 1st to 6th decade and the severity of hearing loss varying greatly (from mild defects to profound deafness). Proteinuric nephropathy occurs in about 30% of patients and in 75% is diagnosed before the age of 35. The majority of patients with kidney damage progress to ESRD within a few years. Patients that develop kidney involvement later in life often have a slower progression towards ESRD. Cataracts occur in about 20% of patients, are often bilateral and usually appear in early adulthood, but congenital cases have been reported. ## Etiology MYH9-RD is due to mutations in the MYH9 gene (22q13.1), encoding the heavy chain of the isoform A of the non-muscle myosin of class II (myosin-9). Myosin-9 is expressed in most cell types and tissues, including blood cells, cochlea, kidney, and hepatocytes. Neutrophil inclusions originate from co-precipitation of mutant myosin-9 with wild-type proteins within the cytoplasm. ## Diagnostic methods Diagnosis is suspected on hematological findings and possible association with extra-hematological manifestations. Diagnosis is confirmed by immunofluorescence assay on peripheral blood slides revealing typical myosin-9 neutrophil inclusions. Kidney damage is revealed by proteinuria with or without renal failure. Audiometric and ophthalmologic examinations identify a hearing defect and/or cataract, respectively. About 50% of patients have chronic or intermittent elevation of liver enzymes. Molecular genetic testing can identify the causative MYH9 mutation, which can predict the clinical evolution. ## Differential diagnosis Differential diagnoses include Bernard-Soulier syndrome, Alport syndrome and immune thrombocytopenia purpura (see these terms). ## Antenatal diagnosis Prenatal diagnosis is possible in families where a disease causing mutation has been identified. ## Genetic counseling MYH9-RD is inherited in an autosomal dominant manner with sporadic de novo mutations also being observed. Genetic counseling is possible. ## Management and treatment In cases of severe hemorrhages or before major hemostatic stresses (pregnancy, surgery), platelet transfusions (when possible from HLA-matched donors) are recommended. Eltrombopag has been successful in increasing platelet counts and abolishing the tendency to bleed. Desmopressin can shorten bleeding time in some patients; a test dose should be given to observe responsiveness. Surgery treats cataracts. A cochlear implant was beneficial in one patient with severe deafness. Angiotensin receptor blockers and/or angiotensin-converting enzyme inhibitors may reduce proteinuria in those with renal involvement. ESRD requires treatment with dialysis or kidney transplantation. Regular blood counts, annual urine analysis as well as audiometric and ophthalmologic evaluations are recommended. Medications that interfere with platelet function should be avoided. ## Prognosis Overall life-expectancy is not affected. Quality of life can be seriously affected in patients who develop kidney involvement and deafness, as well as in rare cases with severe spontaneous bleeding. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	MYH9-related disease	c1854520	6,261	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=182050	2021-01-23T16:59:59	{"gard": ["180"], "mesh": ["C535507"], "omim": ["155100", "600208"], "umls": ["C1854520"], "icd-10": ["D69.4"], "synonyms": ["MYH9-RD", "MYH9-related disorder", "MYH9-related syndrome", "MYH9-related syndromic thrombocytopenia"]}
Human spinal cord disorder Central cord syndrome Central cord syndrome is the top diagram SpecialtyNeurology Neurosurgery Central cord syndrome (CCS) is the most common form of cervical spinal cord injury. It is characterized by loss of motion and sensation in arms and hands. It usually results from trauma which causes damage to the neck, leading to major injury to the central corticospinal tract of the spinal cord.[1] The syndrome is more common in people over the age of 50 because osteoarthritis in the neck region causes weakening of the vertebrae. CCS most frequently occurs among older persons with cervical spondylosis,[2] however, it also may occur in younger individuals.[3] CCS is the most common incomplete spinal cord injury syndrome. It accounts for approximately 9% of traumatic SCIs.[4] After an incomplete injury, the brain still has the capacity to send and receive some signals below the site of injury. Sending and receiving of signals to and from parts of the body is reduced, not entirely blocked. CCS gives a greater motor loss in the upper limbs than in the lower limbs, with variable sensory loss. It was first described by Schneider in 1954.[5] It is generally associated with favorable prognosis for some degree of neurological and functional recovery. However, factors such as age, preexisting conditions, and extent of injury will affect the recovery process. ## Contents * 1 Presentation * 2 Causes * 3 Management * 3.1 Nonsurgical * 3.2 Surgical * 4 See also * 5 References * 6 External links ## Presentation[edit] CCS is characterized by disproportionately greater motor impairment in upper compared to lower extremities, and variable degree of sensory loss below the level of injury in combination with bladder dysfunction and urinary retention.[6] This syndrome differs from that of a complete lesion, which is characterized by total loss of all sensation and movement below the level of the injury.[citation needed] ## Causes[edit] In older patients, CCS most often occurs after acute hyperextension injury in an individual with long-standing cervical spondylosis. A slow, chronic cause in this age group is when the cord gets caught and squeezed between a posterior intervertebral disc herniation against the anterior cord and/or with posterior pressure on the cord from hypertrophy of the ligamentum flavum (Lhermitte's sign may be the experience that causes the patient to seek medical diagnosis). However, CCS is not exclusive to older patients as younger individuals can also sustain an injury leading to CCS. Typically, younger patients are more likely to get CCS as a result of a high-force trauma or a bony instability in the cervical spine.[6][7] Historically, spinal cord damage was believed to originate from concussion or contusion of the cord with stasis of axoplasmic flow, causing edematous injury rather than destructive hematomyelia. More recently, autopsy studies have demonstrated that CCS may be caused by bleeding into the central part of the cord, portending less favorable prognosis. Studies also have shown from postmortem evaluation that CCS probably is associated with selective axonal disruption in the lateral columns at the level of the injury to the spinal cord with relative preservation of the grey matter.[6] ## Management[edit] ### Nonsurgical[edit] In many cases, individuals with CCS can experience a reduction in their neurological symptoms with conservative management. The first steps of these intervention strategies include admission to an intensive care unit (ICU) after initial injury. After entering the ICU, early immobilization of the cervical spine with a neck collar would be placed on the patient to limit the potential of further injury.[7] Cervical spine restriction is maintained for approximately six weeks until the individual experiences a reduction in pain and neurological symptoms.[7] Inpatient rehabilitation is initiated in the hospital setting, followed by outpatient physical therapy and occupational therapy to assist with recovery.[citation needed] An individual with a spinal cord injury may have many goals for outpatient occupational and physiotherapy. Their level of independence, self-care, and mobility are dependent on their degree of neurological impairment. Rehabilitation organization and outcomes are also based on these impairments.[8] The physiatrist, along with the rehabilitation team, work with the patient to develop specific, measurable, action-oriented, realistic, and time-centered goals.[citation needed] With respect to physical therapy interventions, it has been determined that repetitive task-specific sensory input can improve motor output in patients with central cord syndrome. These activities enable the spinal cord to incorporate both supraspinal and afferent sensory information to help recover motor output.[9] This occurrence is known as "activity dependent plasticity". Activity dependent plasticity is stimulated through such activities as: locomotor training, muscle strengthening, voluntary cycling, and functional electrical stimulation (FES) cycling[10] ### Surgical[edit] Surgical intervention is usually given to those individuals who have increased instability of their cervical spine, which cannot be resolved by conservative management alone. Further indications for surgery include a neurological decline in spinal cord function in stable patients as well as those who require cervical spinal decompression.[11] ## See also[edit] * Spinal cord injury * Anterior cord syndrome * Posterior cord syndrome * Brown-Séquard syndrome ## References[edit] 1. ^ Quencer RM, Bunge RP, Egnor M, Green BA, Puckett W, Naidich TP, Post MJ, Norenberg M (1992). "Acute traumatic central cord syndrome: MRI-pathological correlations". Neuroradiology. 34 (2): 85–94. doi:10.1007/BF00588148. PMID 1603319. 2. ^ "Disease course". Myelopathy.org. Archived from the original on 2018-06-26. Retrieved 2018-06-26. 3. ^ Rich V, McCaslin E (2006). "Central Cord Syndrome in a High School Wrestler: A Case Report". J Athl Train. 41 (3): 341–4. PMC 1569555. PMID 17043705.[permanent dead link] 4. ^ McKinley W, Santos K, Meade M, Brooke K (2007). "Incidence and Outcomes of Spinal Cord Injury Clinical Syndromes". J Spinal Cord Med. 30 (3): 215–24. doi:10.1080/10790268.2007.11753929. PMC 2031952. PMID 17684887. 5. ^ Schneider RC, Cherry G, Pantek H (1954). "The syndrome of acute central cervical spinal cord injury; with special reference to the mechanisms involved in hyperextension injuries of cervical spine". J. Neurosurg. 11 (6): 546–77. doi:10.3171/jns.1954.11.6.0546. PMID 13222164. 6. ^ a b c Harrop, James S; Ashwini Sharan; Jonathon Ratliff (2006). "Central cord injury: pathophysiology, management, and outcomes". The Spine Journal. 6 (6 Suppl. 1): 198S–206S. doi:10.1016/j.spinee.2006.04.006. PMID 17097539. 7. ^ a b c Nowak, Douglas D.; Joseph K. Lee; Daniel E. Gelb; Kornelis A. Poelstra; Steven C. Ludwig (December 2009). "Central Cord Syndrome". Journal of the American Academy of Orthopaedic Surgeons. 17 (12): 756–765. doi:10.5435/00124635-200912000-00004. PMID 19948700. 8. ^ Behrman, Andrea, L.; Harkema, Susan J. (2007). "Physical Rehabilitation as an Agent for Recovery After Spinal Cord Injury". Physical Medicine and Rehabilitation Clinics of North America. 18 (2): 183–202. doi:10.1016/j.pmr.2007.02.002. PMID 17543768. 9. ^ Behram, A.L.; Harkema, S.J. (2007). "Physical Rehabilitation as an Agent for Recovery After Spinal Cord Injury". Physical Medicine and Rehabilitation Clinics of North America. 18 (2): 183–202. doi:10.1016/j.pmr.2007.02.002. PMID 17543768. 10. ^ Yadla, S.; Klimo, J.; Harrop, J.S. (2010). "Traumatic Central Cord Syndrome: Etiology, Management, and Outcomes". Topics in Spinal Cord Injury Rehabilitation. 15 (3): 73–84. doi:10.1310/sci1503-73. 11. ^ Yadla, Sanjay; Paul Klimo; James S. Harrop (2010). "Traumatic Central Cord Syndrome: Etiology, Management, and Outcomes". Topics in Spinal Cord Injury Rehabilitation. 15 (3): 73–84. doi:10.1310/sci1503-73. Archived from the original on 2012-07-16. ## External links[edit] * NINDS Central Cord Syndrome Information Page Classification D * ICD-10: S14.1, S24.1, S34.1, T09.3 * ICD-9-CM: C1-4 952.03, C5-7 952.08, T1-6 952.13, T7-12 952.18, Lumbar 952.2, Sacral 952.3 * MeSH: D020210 * DiseasesDB: 33409 * SNOMED CT: 282787000 External resources * eMedicine: pmr/22 * v * t * e Focal lesions of the spinal cord General * Myelopathy * Myelitis * Spinal cord compression By location * Brown-Séquard syndrome * Posterior cord syndrome * Anterior cord syndrome * Central cord syndrome * Cauda equina syndrome Other * Polio * Demyelinating disease * Transverse myelitis * Tropical spastic paraparesis * Epidural abscess * Syringomyelia * Syringobulbia * Morvan's syndrome * Sensory ataxia * Tabes dorsalis * Abadie's sign * Subacute combined degeneration of spinal cord * Vascular myelopathy * Anterior spinal artery syndrome * Foix–Alajouanine 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	Central cord syndrome	c0560651	6,262	wikipedia	https://en.wikipedia.org/wiki/Central_cord_syndrome	2021-01-18T18:54:49	{"mesh": ["D020210"], "icd-9": ["952.2", "952.13", "952.18", "952.03", "952.08", "952.3"], "wikidata": ["Q3288189"]}
"Fear of everything" redirects here. For the 2011 British film, see A Fantastic Fear of Everything. Vague and persistent dread of some unknown evil A woman diagnosed with panphobia, from Alexander Morison's 1843 book The Physiognomy of Mental Diseases Panphobia, omniphobia, pantophobia, or panophobia is a vague and persistent dread of some unknown evil.[1] Panphobia is not registered as a type of phobia in medical references. ## Contents * 1 History * 2 Diagnosis * 3 See also * 4 References ## History The term panphobia was first coined by Théodule-Armand Ribot in his 1911 work The Psychology of the Emotions.[2] He defined it as "a state in which a patient fears everything or nothing, where anxiety, instead of being riveted on one object, floats as in a dream, and only becomes fixed for an instant at a time, passing from one object to another, as circumstances may determine." The term comes from the Greek πᾶν - pan, neuter of "πᾶς" - pas, "all"[3] and φόβος - phobos, "fear".[4] The Greek root word pan (ex. pan-ic) describes "the unpleasant state inflicted by the intervention of the god Pan."[2] Pan is characterized as a human–animal hybrid who "appeared as the agent of panic fear (that collective, animal-like disorder that seizes military camps at rest, especially at night) and of a form of individual possession (panolepsy)."[5] According to Herodotus, it was Pan who was able to lead the Athenians to victory in the Battle of Marathon, forcing the Persians to flee.[2] It has been argued that pantophobia may actually be considered the more accurate name to describe the non-specificity associated with a fear of all.[2] ## Diagnosis There is no specific phobia in the DSM-5 which provides criteria for an all-encompassing fear of everything, though the defining symptom for generalized anxiety disorder in this manual is "excessive anxiety and worry (apprehensive expectation) about a number of events or activities." Another very relatable state of mind is paranoia, in which one fears that unknown threats could, and most likely will, come from anyone, with distrust potentially leading to a loss of touch with reality. Delusional disorder is a more severe form of this type of disorder. Relevant academic literature may point to panphobia as merely a piece of such more complex states of mental disorder. Pseudoneurotic schizophrenia may be diagnosable in patients who, in addition to panphobia, also exhibit symptoms of pananxiety, panambivalence, and to a lesser extent, chaotic sexuality.[6] These persons differ from generalized anxiety sufferers in that they have "free-floating anxiety that rarely subsides" and are clinically diagnosable as having borderline personality disorder in the DSM-IV-TR. No significant changes related to this personality disorder were made in transitioning to the DSM-5, suggesting the diagnostic criteria are still appropriate.[7] ## See also * A Fantastic Fear of Everything (2011 British film) * Borderline personality disorder * Generalized anxiety disorder * List of phobias * Paranoia * Pseudoneurotic schizophrenia ## References 1. ^ Dorland, W. (2007). Dorland's medical dictionary for health consumers. Saunders, an imprint of Elsevier. 2. ^ a b c d Papakostas, Yiannis G.; Eftychiadis, Aristotelis; Papakostas, George I.; Christodoulou, George N. (2003). "A Historical Inquiry into the Appropriateness of the Term 'Panic Disorder'". History of Psychiatry. 14 (2): 195–204. doi:10.1177/0957154X030142004. PMID 14518489. S2CID 1041461. 3. ^ πᾶς, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus 4. ^ φόβος, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus 5. ^ Jones, Lindsay. "Encyclopedia of Religion". Gale, Cengage Learning. Retrieved 8 April 2014. 6. ^ Sadock, Benjamin James Sadock; Virginia Alcott (2007). Kaplan & Sadock's synopsis of psychiatry: behavioral sciences/clinical psychiatry (10th ed.). Philadelphia: Wolter Kluwer/Lippincott Williams & Wilkins. p. 479. ISBN 978-0781773270. 7. ^ "Highlights of Changes from DSM-IV-TR to DSM-5" (PDF). American Psychiatric Association. Retrieved 9 April 2014. Look up panphobia in Wiktionary, the free dictionary. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Panphobia	None	6,263	wikipedia	https://en.wikipedia.org/wiki/Panphobia	2021-01-18T19:02:00	{"wikidata": ["Q3497893"]}
A rare unclassified acute myeloid leukemia characterized by a proliferation of immature cells exclusively of the erythroid lineage without a significant myeloblastic component. Microscopically, the cells may be undifferentiated or proerythroblastic in appearance. Patients may present with pancytopenia with fatigue, infections, and mucocutaneous bleedings, as well as weight loss, fever, and night sweats. Prognosis is poor. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 erythroid leukemia	c0023440	6,264	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=318	2021-01-23T18:38:00	{"gard": ["9620"], "mesh": ["D004915"], "omim": ["133180"], "umls": ["C0023440"], "icd-10": ["C94.0"], "synonyms": ["AML M6", "Acute myeloid leukemia M6", "Erythroleukemia"]}
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: "Myocardial bridge" – news · newspapers · books · scholar · JSTOR (December 2020) Myocardial bridge Angiogram showing myocardial bridging resulting in arterial compression. A myocardial bridge (MB) is a congenital heart defect in which one of the coronary arteries tunnels through the heart muscle itself (myocardium). In normal patients, the coronary arteries rest on top of the heart muscle and feed blood down into smaller vessels (ex. septal arteries) which then take blood into the heart muscle itself (i.e. populate throughout the myocardium). However, if a band of muscle forms around one of the coronary arteries during the fetal stage of development, then a myocardial bridge is formed - a "bridge" of heart muscle over the artery. Each time the heart squeezes to pump blood, the band of muscle exerts pressure and constricts the artery, reducing blood flow to the heart. This defect is present from birth. It is important to note that even a very thin ex. < 1 mm and/or short ex. 20 mm MB can cause significant symptoms. MBs can range from a few mm in length to 10 cm or more. ## Contents * 1 Prevalence * 2 Symptoms * 2.1 Complications * 3 Diagnosis * 4 Treatment * 5 Common misconceptions * 6 Patient success stories * 7 See also * 8 References ## Prevalence[edit] The true prevalence of MBs is still largely unknown, as studies have made vastly different assessments. As a 2017 Stanford paper by Rogers, et al.[1] points out: > Estimations of the prevalence of MBs vary... at least in part as a result of several key variables, including the means of identification (eg, computed tomography (CT), intravascular ultrasound (IVUS), or autopsy), which vessels are examined, and which definition of a bridge is applied (eg, only a “deep” bridge vs both “superficial” and “deep” bridges). Perhaps the most fundamental variable is whether an MB is even considered. Unlike hypertrophic cardiomyopathy, which will usually be obvious to the pathologist, MBs can be easily obscured by epicardial and pericardial fat. As such, autopsy series have estimated the prevalence between 5% and 86%. The largest autopsy report, which included 1056 subjects, found a prevalence of 26%, 88% of which involved the LAD. One population-based study with CT estimated a prevalence of 22.5%. As a result of these studies and others, an estimated prevalence of approximately 25% is generally accepted. ## Symptoms[edit] While many people have very tiny myocardial bridges that cause no symptoms, others have longer and/or deeper bridges causing significant symptoms, including children. For example, some patients cannot run or exercise at all, others can exercise despite symptoms such as shortness of breath or feelings of tightness in the chest, and still others find improvement of symptoms during exercise. Many competitive athletes have had severe myocardial bridges and unroofing surgery.[2] The symptoms of myocardial bridges differ slightly from patient to patient depending on the length, depth, and location of the bridge. Common symptoms include:[1][3] * Dizziness * Shortness of breath * Fatigue * Chest pain/angina * Palpitations/arrhythmia i.e. irregular heart rhythm * Squeezing/tightness/pressure/pain in chest, shoulder, jaw, armpit, neck, and/or down the arm * Inability to exercise, walk, do chores, have to sit/lie down * Feeling like chest is “going to explode” * Feeling of something “clamping down” in the chest * Fainting/passing out and/or feeling like one is about to faint ### Complications[edit] Myocardial bridges can cause numerous complications - which are often as misunderstood in the medical community as the condition itself. These include: * angina pectoris (chest pain radiating from the heart) * endothelial dysfunction, which causes vasospasms \- both sometimes very severe * arrhythmia (irregular heartbeats) * tachycardia (abnormally high heart rate) * plaque forming just before (proximal to) the myocardial bridge Note that studies have shown that plaque does not form inside myocardial bridges, yet there is virtually always plaque just before the myocardial bridge in adults. Some common triggers of myocardial bridge symptoms are: * exertion/exercise * anything that raises the heart rate, even positive events * low-oxygen environments ex. hot humid weather, high altitude * sitting/lying/doing nothing for long periods Notably, high heart rate or tachycardia greatly increases ischemia (low oxygen to the heart) caused by myocardial bridges. Studies such as Ripa et al., 2007[4] have shown that this is because the compressed artery reopens only very slowly each heartbeat and thus stays in a state of semi-compression for most or all of the diastolic period. Thus as the heart rate increases, the time the artery has to reopen (diastolic period) decreases dramatically - to the point that with very high heart rates, the artery never fully reopens and blood flow is constantly reduced. ## Diagnosis[edit] There are three key tests currently used to diagnose myocardial bridges by Stanford University: CT scan, cardiac catheterization, and stress ultrasound. 1. CT scan \- on which the myocardial bridge often appears as a compressed or squashed area of the artery in which, notably, the fatty areas surrounding the artery (shown in black on CT scans) disappear, since the artery is tunneling through muscle not fat in this area. CTs often allow an assessment of an approximate length and depth of the myocardial bridge, but compression cannot be assessed accurately from a CT scan.[5] 2. IVUS cardiac catheterization including dFFR measured during dobutamine challenge - from which readings of dFFR and percentage compression as well as measurements of the approximate length and depth (shown as the halo or echolucent band) of the MB are taken. It is critical to note that in order to be meaningful in diagnosing a myocardial bridge, it is critical to measure dFFR i.e. the diastolic period, not mean FFR. This is because, contrary to a common misconception, myocardial bridges cause compression of the artery during diastole as well as systole, as explained above. This has been shown in multiple studies.[6][7] It is also critical that the dobutamine challenge be used, elevating the heart rate, because dFFR decreases significantly at high heart rates as shown by Yoshino et al., 2014.[8] 3. Stress echocardiogram (i.e. before and after running on a treadmill) - used to identify evidence of ischemia i.e. a lack of oxygen delivered to the ventricle due to the MB. This test does not visualize the MB itself but rather its effects on the ventricle. Multiple studies have shown that ischemia from MBs is indicated by the appearance "septal buckling" in the stress echocardiogram, as the septum gives out under stress.,[9][10] which a 2013 paper by Lin et al. describes as "a transient focal buckling in the end-systolic to early-diastolic motion of the septum with apical sparing which correlates prospectively with the presence of LAD MB."[9] As much of the science of testing for MBs is relatively new, patients frequently go undiagnosed. Stanford's center for myocardial bridges has offered second opinion services from a distance for some ten years, including to numerous international patients.[citation needed] Notably, EKG is not a reliable or conclusive diagnostic tool for diagnosing MBs. Some symptomatic MB patients show normal EKG results and others abnormal. Many doctors have suggested that there is a need for more awareness of MBs among doctors and better testing, including testing of young people as the disease is congenital. According to a 2007 study by Ripa et al.: "Clinical suspicion of a myocardial bridge would be warranted in all cases of typical or atypical chest pain in subjects who have a low probability of atherosclerosis because they are free from the traditional cardiovascular risk factors, particularly in the young."[4] In a 2017 article in Stanford Medical Center's official blog Scope, Dr. Ingela Schnittger stated: "Many of these patients have these heartbreaking stories to tell. They can’t hold a job, they can’t travel, they can’t take care of their families. Most cardiologists are completely at a loss. They know myocardial bridges exist, but they have been taught they are benign and never cause problems... When these patients go to the ER, and they go there a lot, all the cardiology tests come back normal. They’re told, 'Here’s a little Valium. I think you’re anxious.' They get belittled, not taken seriously, and they get really depressed."[11] ## Treatment[edit] Myotomy, commonly known as unroofing surgery, is the first-line surgical treatment for myocardial bridges.[1][12] It is the only treatment that actually removes the myocardial bridge itself, releasing the artery from compression. Unroofing surgery today is done via open heart (sternum), thoracotomy (through the ribs), and also using robot-assisted surgery (through tiny keyholes in the chest). Full open heart surgery is usually reserved for very large myocardial bridges and/or specific situations which make thoracotomy difficult. By far, Stanford University has done more unroofing surgeries than any other hospital in the world, with over 200 unroofings completed since starting a decade ago. In 2019, University of Chicago surgeon Dr. Husam Balkhy emerged as a provider of robotic-assisted unroofing surgery, with some patients being possible candidates for this route.[13] If done properly, unroofing removes the entire band of muscle affecting the artery, restoring more blood flow. Stanford University Medical Center's 2016 study by Pargaonkar et al.[14] showed that unroofing surgery “significantly improves anginal symptoms” and improves “all five dimensions of the SAQ” i.e. Seattle Angina Questionnaire. Some residual symptoms caused by complications from a lifetime of living with a myocardial bridge may continue after unroofing surgery such as endothelial dysfunction, vasospasm, plaque, narrowed artery. However, these often improve slowly over a year or more once the myocardial bridge is gone.[citation needed] A few cases have occurred in various hospitals in which patients have not been completely unroofed, leaving segments of the MB, resulting in lingering symptoms. A critical point is that the endothelial dysfunction and vasospasms caused by myocardial bridges cannot start to heal until unroofing surgery is done, because the MB continues to squeeze on the artery, damaging the artery lining. Bypass surgery is not the first line treatment for myocardial bridges for two main reasons:[1] 1. Competitive flow problem - blood can flow the wrong way i.e. continue to flow down the original artery instead of the new artery that has been grafted on. 2. Jailed septal arteries still jailed - a jailed artery is a septal artery (a branch off the coronary artery) which lies inside the myocardial bridge and is thus also compressed with each heartbeat. Septal arteries are critical as they carry blood into the heart septum. Bypass surgery alone does not remedy jailed septal arteries, which still do not get blood flow. Notably, many myocardial bridge patients have had bypass surgery only to later need unroofing surgery after the bypass proved unsuccessful.[1] However, papers by Ekeke et al., 2015 [15] and others have shown bypass surgery is helpful as an addition to supplement unroofing surgery, but only when there is significant plaque just before (proximal to) the myocardial bridge or anatomic anomalies increase the risk of recurrence of such plaque. A 2013 Russian study by Bockeria et al.[16] concludes that this competitive flow problem is much more likely to occur if the LIMA artery is used for the graft rather than the SVG, so the SVG is recommended. Stents are never indicated as a treatment for myocardial bridges because trials have shown they are prone to breaking when the artery is squeezed each heartbeat.[1] Unroofing surgery has been performed in the United States, Belgium, Spain, Italy, England, China, Russia, United Arab Emirates among other countries. Hospitals which have performed unroofing surgery include: * Stanford University Medical Center - surgeon Dr. Jack Boyd; team leader Dr. Ingela Schnittger * University of Chicago Medical Center - surgeon Dr. Husam Balkhy * Mayo Clinic, Rochester, Minnesota * Cleveland Clinic * Cleveland Clinic Abu Dhabi \- surgeon Dr. Johannes Bonatti (currently in Austria) * Texas Heart Institute * Kaiser Permanente, Santa Clara, CA - Dr. David Scoville * Baylor Scott and White Hospital, Texas - surgeon Dr. Jeffrey Wu * Spectrum Health Butterworth Hospital, Michigan – Dr. Marzia Leacche * Hospital de las Cruces, Barakaldo, Basque Country, Spain - Dr. Crespo and Dr. Aramendi * Istanbul University Hospital - Dr. Ihsan Bakir In many other countries, including a number of highly developed countries such as the UK, Australia, New Zealand, Ireland, Sweden, and Singapore, unroofing surgery for myocardial bridges remains unavailable, and in some the condition remains unrecognized as a medical problem. ## Common misconceptions[edit] According to Stanford University Medical Center, MBs are often misunderstood by doctors, who may have been taught that the condition is always benign.[1] As a result, patients are often denied treatment. But a great deal of science has emerged in the past decade to clarify the condition. In particular, Stanford has published over 15 articles on MBs since 2014. One commonly recurring reason for denial of treatment is the idea that myocardial bridges do not significantly affect blood flow. But this myth has been debunked by Stanford and also Daoud and Wafa 2012 who say: > Normally, only 15% of coronary blood flow occurs during systole and because myocardial bridging is a systolic event on angiography, its clinical significance and relevance have been questioned. [However] angiographic and intravascular ultrasonographic studies demonstrated that vessel compression during systole is followed by the delay in the increase in luminal diameter during diastole, thus affecting the predominant phase of coronary perfusion, especially during episodes of tachycardia. These data suggest that angina, acute coronary syndromes, and arrhythmias in patients with myocardial bridging may be explained by the reduced ischemic threshold.”[17] In other words, while the myocardial bridge itself only compresses the artery while the heart squeezes (systolic period), which is only 15% of the time in the heartbeat cycle, in fact the artery stays compressed long after the heart relaxes. This is because arteries are sturdy and pliable, so after being compressed they are very slow to reopen, remaining in some level of semi-compression for most if not all of the diastolic period i.e. the other 85% of the heartbeat cycle (hence the critical need for dFFR testing in diagnosing myocardial bridges). Thus the coronary artery is fully open to allow normal blood flow for only a small percentage of each heartbeat cycle. This problem is further exacerbated by tachycardia (high heart rate), which can bring the duration of normal blood flow to zero, as explained below. Dr. Ingela Schnittger, head of the Myocardial Bridge Research Center at Stanford, has appeared on BBC Radio to explain this. ## Patient success stories[edit] ‘I have my life back’: Kathy Hoseth battled inexplicable chest pains much of her life—until she finally found the cardiothoracic surgeon who could remedy her condition. by Zinta Aistars Spectrum Health Beat, September 2019 https://healthbeat.spectrumhealth.org/sharp-lifelong-chest-pain-myocardial-bridge-surgery-women-cardiac-disparities/?hootPostID=43ea49e6229634fc9c07a04f4d036b59 Treating an Overlooked Condition by Samantha Beal Stanford Children's Health, February 22, 2017 https://healthier.stanfordchildrens.org/en/treating-an-overlooked-heart-condition/ Abu Dhabi surgeons complete Middle East's first robotic surgery for rare heart condition Cleveland Clinic Abu Dhabi, December 13, 2017 https://www.clevelandclinicabudhabi.ae/en/media-center/news/pages/abu-dhabi-surgeons-complete-middle-easts-first-robotic-surgery-for-rare-heart-condition.aspx Why Does Kyle Watson Keep Running? If He Stops, He'll Die. Runner's World September 2018 https://www.runnersworld.com/runners-stories/a22739738/kyle-watson-runs-to-live/ Understanding a Woman's Heart Means Knowing What to Look For Stanford Medicine, February 27, 2012 https://med.stanford.edu/news/all-news/2012/02/understanding-a-womans-heart-means-knowing-what-to-look-for.html ## See also[edit] * Cardiac CT * Angiography ## References[edit] 1. ^ a b c d e f g Rogers, Ian S.; Tremmel, Jennifer A.; Schnittger, Ingela (September 2017). "Myocardial bridges: Overview of diagnosis and management". Congenital Heart Disease. 12 (5): 619–623. doi:10.1111/chd.12499. PMID 28675696. 2. ^ "Why Does Kyle Watson Keep Running? If He Stops, He'll Die". Runner's World. 5 September 2018. 3. ^ Myocardial Bridging: Symptoms. Stanford Health Care. https://stanfordhealthcare.org/medical-conditions/blood-heart-circulation/myocardial-bridging/symptoms.html 4. ^ a b Ripa, Chiara; Cristina Melatini, Maria; Olivieri, Fabiola; Antonicelli, Roberto (27 April 2011). "Myocardial bridging: A 'forgotten' cause of acute coronary syndrome - a case report". International Journal of Angiology. 16 (3): 115–118. doi:10.1055/s-0031-1278262. PMC 2733018. PMID 22477305. 5. ^ Myocardial Bridges on Coronary Computed Tomography Angiography-- Correlation with Intravascular Ultrasound and Fractional Flow Reserve. Forsdahl, Rogers, Schnittger et al. 2017. Circ J. doi:10.1253/circj. CJ-17-0284. 6. ^ Tremmel, Jennifer A.; Schnittger, Ingela (18 November 2014). "Myocardial Bridging". Journal of the American College of Cardiology. 64 (20): 2178–2179. doi:10.1016/j.jacc.2014.07.993. PMID 25457408. 7. ^ Escaned, Javier; Cortés, Jorge; Flores, Alex; Goicolea, Javier; Alfonso, Fernando; Hernández, Rosana; Fernández-Ortiz, Antonio; Sabaté, Manel; Bañuelos, Camino; Macaya, Carlos (July 2003). "Importance of diastolic fractional flow reserve and dobutamine challenge in physiologic assessment of myocardial bridging". Journal of the American College of Cardiology. 42 (2): 226–233. doi:10.1016/s0735-1097(03)00588-6. PMID 12875756. 8. ^ Fractional flow reserve with dobutamine challenge and coronary microvascular endothelial dysfunction in symptomatic myocardial bridging. Yoshino et al, 2014. Circulation Journal. 9. ^ a b A Novel Stress Echocardiography Pattern for Myocardial Bridge With Invasive Structural and Hemodynamic Correlation. Lin, Tremmel, Yamada, et al. (J Am Heart Assoc. 2013;2:e000097 doi: 10.1161/JAHA.113.000097) 10. ^ Stress echocardiography pattern: a promising noninvasive test for detection of myocardial bridging with haemodynamic relevance. Mariachiara Siciliano;Federico Migliore;Piergiuseppe Piovesana, 2016. Journal of Cardiovascular Medicine 11. ^ Stanford researcher’s sleuthing uncovers mystery of heart anomaly. Tracie White. Scope blog of Stanford University Medical Center. October 17, 2016. https://scopeblog.stanford.edu/2016/10/17/stanford-researchers-sleuthing-uncovers-mystery-of-heart-anomaly/ 12. ^ Boyd, Jack H.; Pargaonkar, Vedant S.; Scoville, David H.; Rogers, Ian S.; Kimura, Takumi; Tanaka, Shigemitsu; Yamada, Ryotaro; Fischbein, Michael P.; Tremmel, Jennifer A.; Mitchell, Robert Scott; Schnittger, Ingela (May 2017). "Surgical Unroofing of Hemodynamically Significant Left Anterior Descending Myocardial Bridges". The Annals of Thoracic Surgery. 103 (5): 1443–1450. doi:10.1016/j.athoracsur.2016.08.035. PMID 27745841. 13. ^ Robotic totally endoscopic off-pump unroofing of left anterior descending coronary artery myocardial bridge: A report of two cases. Mirzai, Patel, Balkhy. June 18, 2019. Journal of Cardiac Surgery. doi=10.1111/jocs.14094 14. ^ Pargaonkar et al. Effect of Surgical Unroofing of a Myocardial Bridge on Exercise Induced QT interval Dispersion and Anginal Symptoms in Patients with Angina in the Absence of Obstructive Coronary Artery Disease. Journal of the American College of Cardiology 15. ^ Myocardial bridging over the left anterior descending: Myotomy, bypass, or both? Ekeke et al. 2015. Journal of Thoracic Cardiovascular Surgery. 16. ^ Bockeria, Leo A.; Sukhanov, Sergey G.; Orekhova, Ekaterina N.; Shatakhyan, Mesrop P.; Korotayev, Dmitry A.; Sternik, Leonid (May 2013). "Results of Coronary Artery Bypass Grafting in Myocardial Bridging of Left Anterior Descending Artery". Journal of Cardiac Surgery. 28 (3): 218–221. doi:10.1111/jocs.12101. PMID 23574298. 17. ^ Daoud, Eid M.; Wafa, Ahmed A. (June 2013). "Does isolated myocardial bridge really interfere with coronary blood flow?". The Egyptian Heart Journal. 65 (2): 65–70. doi:10.1016/j.ehj.2012.05.003. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Myocardial bridge	c0948355	6,265	wikipedia	https://en.wikipedia.org/wiki/Myocardial_bridge	2021-01-18T18:44:08	{"mesh": ["D054084"], "umls": ["C0948355", "C1827939"], "wikidata": ["Q6947900"]}
A number sign (#) is used with this entry because of evidence that immunodeficiency-40 (IMD40) is caused by homozygous or compound heterozygous mutation in the DOCK2 gene (603122) on chromosome 5q35. Description Immunodeficiency-40 is an autosomal recessive primary form of combined immunodeficiency mainly affecting T-cell number and function, with other more variable defects in B-cell and NK-cell function. Patients have onset of severe invasive bacterial and viral infections in early childhood and may die without bone marrow transplantation (summary by Dobbs et al., 2015). Clinical Features Dobbs et al. (2015) reported 5 unrelated patients with a primary combined immunodeficiency disorder presenting in infancy. Three patients were born of consanguineous parents of Lebanese or Turkish origin. All patients developed invasive bacterial and viral infections associated with T-cell lymphopenia and reduced in vitro T-cell proliferation. Two patients also had B-cell lymphopenia, and most had poor antibody responses despite normal levels of IgG and IgA. Two patients had impaired NK cell degranulation despite normal NK cell numbers. Two patients died, whereas the remaining 3 underwent successful bone marrow transplantation. Inheritance The transmission pattern of IMD40 in the families reported by Dobbs et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In 5 unrelated children with IMD40, Dobbs et al. (2015) identified 7 different biallelic mutations in the DOCK2 gene (see, e.g., 603122.0001-603122.0005). The mutations were found by whole-exome sequencing, sometimes combined with linkage analysis, and segregated with the disorder in the families. Four of the mutations led to premature termination of the protein, and 3 were missense mutations affecting conserved residues, consistent with a loss of function. T cells derived from 2 patients showed decreased or absent DOCK2 protein expression and decreased or absent GTP-bound RAC1 (602048) after activation with an anti-CD3 monoclonal antibody. Patient lymphocytes also showed defective chemotactic responses associated with decreased amounts of polymerized filamentous actin. Pathogenesis By detailed immunologic studies on cells derived from IMD40 patients, Dobbs et al. (2015) found T-cell lymphopenia, impaired T-cell proliferative responses in vitro, impaired antibody production, and defective NK cell degranulation. In addition, patient plasmacytoid dendritic cells showed defective production of both alpha- (IFNA1; 147660) and gamma-interferon (IFNG; 147570) after stimulation, which may have contributed to viral susceptibility. Patient fibroblasts showed decreased levels of DOCK2, and in vitro studies showed that fibroblasts had enhanced levels of viral replication and decreased viability in response to viral infection compared to controls. These defects could be normalized by treatment with interferon or after expression of wildtype DOCK2. The findings in fibroblasts suggested that DOCK2 mutations also impair cell-intrinsic, nonhematopoietic immunity, which may explain the invasiveness of the viral infections observed in these patients. INHERITANCE \- Autosomal recessive IMMUNOLOGY \- Immunodeficiency \- Invasive bacterial, viral, and mycobacterial infections \- T-cell lymphopenia \- Defective T-cell proliferative responses \- B-cell lymphopenia (in some patients) \- Impaired antibody production (in some patients) \- Impaired NK cell degranulation (in some patients) \- Impaired interferon production MISCELLANEOUS \- Onset at birth \- Death in childhood occurs without bone marrow transplantation MOLECULAR BASIS \- Caused by mutation in the dedicator of cytokinesis 2 gene (DOCK2, 603122.0001 ) ▲ 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	IMMUNODEFICIENCY 40	c4225328	6,266	omim	https://www.omim.org/entry/616433	2019-09-22T15:48:55	{"omim": ["616433"], "orphanet": ["447737"], "synonyms": []}
The term pustular psoriasis is used for a heterogeneous group of diseases that share pustular skin characteristics.[1] Pustular Psoriasis Severe pustular psoriasis. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 Classification * 3 Management * 4 References * 5 External links ## Signs and symptoms[edit] Characteristics may vary according to the subtype of pustular psoriasis. For example, it can be localized, commonly to the hands and feet (localized pustular psoriasis), or generalized with widespread patches appearing randomly on any part of the body (generalized pustular psoriasis).[2][3] However, all forms of pustular psoriasis share in common the presence of red and tender blotchy skin covered with pustules.[1] Pustular psoriasis can be localized, commonly to the hands and feet (palmoplantar pustulosis), or generalized with widespread patches occurring randomly on any part of the body. Acrodermatitis continua is a form of localized psoriasis limited to the fingers and toes that may spread to the hands and feet.[4] Pustulosis palmaris et plantaris is another form of localized pustular psoriasis similar to acrodermatitis continua with pustules erupting from red, tender, scaly skin found on the palms of the hands and the soles of the feet.[1] Generalized pustular psoriasis (GPP) is also known as (von Zumbusch) acute generalized pustular psoriasis in acute cases, and as impetigo herpetiformis during pregnancy.[3][5] GPP is a rare and severe form of psoriasis that may require hospitalization. This form of psoriasis is characterized by an acute onset of numerous pustules on top of tender red skin. This skin eruption is often accompanied by a fever, muscle aches, nausea, and an elevated white blood cell count.[1] Annular pustular psoriasis (APP), a rare form of GPP, is the most common type seen during childhood.[6] APP tends to occur in women more frequently than in men, and is usually less severe than other forms of generalized pustular psoriasis such as impetigo herpetiformis.[6] This form of psoriasis is characterized by ring-shaped plaques with pustules around the edges and yellow crusting.[6] APP most often affects the torso, neck, arms, and legs.[6] ## Diagnosis[edit] ### Classification[edit] Pustular psoriasis is classified into two major forms: localized and generalized pustular psoriasis.[1] Within these two categories there are several variants: Classification of Localized and Generalized Pustular Psoriasis Localized pustular psoriasis * Palmoplantar pustulosis (acute and chronic) * Acrodermatitis continua (of Hallopeau) Generalized pustular psoriasis * (von Zumbusch) acute generalized pustular psoriasis * Acute generalized pustular psoriasis of pregnancy (impetigo herpetiformis) * Infantile and juvenile * Subacute circinate and annular ## Management[edit] injection of methotrexate This section is empty. You can help by adding to it. (May 2018) ## References[edit] 1. ^ a b c d e Raychaudhuri, Smriti K.; Maverakis, Emanual; Raychaudhuri, Siba P. (2014-04-01). "Diagnosis and classification of psoriasis". Autoimmunity Reviews. 13 (4–5): 490–495. doi:10.1016/j.autrev.2014.01.008. ISSN 1873-0183. PMID 24434359. 2. ^ Kawada, Akira; Tezuka, Tadashi; Nakamizo, Yoshio; Kimura, Hideto; Nakagawa, Hidemi; Ohkido, Muneo; Ozawa, Akira; Ohkawara, Akira; Kobayashi, Hitoshi (2003). "A survey of psoriasis patients in Japan from 1982 to 2001". Journal of Dermatological Science. 31 (1): 59–64. doi:10.1016/s0923-1811(02)00142-1. PMID 12615365. 3. ^ a b Baker, Harvey; Ryan, Terence J. (1968-12-01). "Generalized Pustular Psoriasis". British Journal of Dermatology. 80 (12): 771–793. doi:10.1111/j.1365-2133.1968.tb11947.x. ISSN 1365-2133. PMID 4236712. 4. ^ Rosenberg, Benjamin E.; Strober, Bruce E. (2004-11-30). "Acrodermatitis continua". Dermatology Online Journal. 10 (3): 9. ISSN 1087-2108. PMID 15748579. 5. ^ Oumeish, Oumeish Youssef; Parish, Jennifer L. (2006). "Impetigo herpetiformis". Clinics in Dermatology. 24 (2): 101–104. doi:10.1016/j.clindermatol.2005.10.009. PMID 16487882. 6. ^ a b c d Naik HB, Cowen EW (July 2013). "Autoinflammatory pustular neutrophilic diseases". Dermatol Clin. 31 (3): 405–25. doi:10.1016/j.det.2013.04.001. PMC 3703099. PMID 23827244. ## External links[edit] Classification D * ICD-10: L40.1 * ICD-9-CM: 696.1 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	Pustular psoriasis	c0152081	6,267	wikipedia	https://en.wikipedia.org/wiki/Pustular_psoriasis	2021-01-18T18:52:14	{"gard": ["12813"], "umls": ["C0152081"], "wikidata": ["Q30314007"]}
Hyperkalemic periodic paralysis is a condition that causes episodes of extreme muscle weakness or paralysis, usually beginning in infancy or early childhood. Most often, these episodes involve a temporary inability to move muscles in the arms and legs. Episodes tend to increase in frequency until mid-adulthood, after which they occur less frequently in many people with the condition. Factors that can trigger attacks include rest after exercise, potassium-rich foods such as bananas and potatoes, stress, fatigue, alcohol, pregnancy, exposure to hot or cold temperatures, certain medications, and periods without food (fasting). Muscle strength usually returns to normal between attacks, although many affected people continue to experience mild stiffness (myotonia), particularly in muscles of the face and hands. Most people with hyperkalemic periodic paralysis have increased levels of potassium in their blood (hyperkalemia) during attacks. Hyperkalemia results when the weak or paralyzed muscles release potassium ions into the bloodstream. In other cases, attacks are associated with normal blood potassium levels (normokalemia). Ingesting potassium can trigger attacks in affected individuals, even if blood potassium levels do not go up. ## Frequency Hyperkalemic periodic paralysis affects an estimated 1 in 200,000 people. ## Causes Mutations in the SCN4A gene can cause hyperkalemic periodic paralysis. The SCN4A gene provides instructions for making a protein that plays an essential role in muscles used for movement (skeletal muscles). For the body to move normally, these muscles must tense (contract) and relax in a coordinated way. One of the changes that helps trigger muscle contractions is the flow of positively charged atoms (ions), including sodium, into muscle cells. The SCN4A protein forms channels that control the flow of sodium ions into these cells. Mutations in the SCN4A gene alter the usual structure and function of sodium channels. The altered channels stay open too long or do not stay closed long enough, allowing more sodium ions to flow into muscle cells. This increase in sodium ions triggers the release of potassium from muscle cells, which causes more sodium channels to open and stimulates the flow of even more sodium ions into these cells. These changes in ion transport reduce the ability of skeletal muscles to contract, leading to episodes of muscle weakness or paralysis. In 30 to 40 percent of cases, the cause of hyperkalemic periodic paralysis is unknown. Changes in other genes, which have not been identified, likely cause the disorder in these cases. ### Learn more about the gene associated with Hyperkalemic periodic paralysis * SCN4A ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Hyperkalemic periodic paralysis	c0238357	6,268	medlineplus	https://medlineplus.gov/genetics/condition/hyperkalemic-periodic-paralysis/	2021-01-27T08:25:45	{"gard": ["195"], "mesh": ["D020513"], "omim": ["170500"], "synonyms": []}
HSD10 disease, neonatal type is the most severe form of HSD10 disease, a rare neurometabolic disorder. It is characterized by severe metabolic/lactic acidosis in the neonatal period, little psychomotor development, seizures and severe progressive hypertrophic cardiomyopathy. Hepatic involvement and coagulopathy are rare. The disease is fatal within the first months of life. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	HSD10 disease, neonatal type	c3266731	6,269	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=391457	2021-01-23T19:09:43	{"mesh": ["C564560"], "omim": ["300438"], "icd-10": ["E72.8"], "synonyms": ["2-methyl-3-hydroxybutyric aciduria, neonatal type", "2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, neonatal type", "HSD10 deficiency, neonatal type", "MHBD deficiency, neonatal type"]}
Pyomyositis is rare bacterial infection of the skeletal muscle (the muscles used for movement). Signs and symptoms may include pain and tenderness of the affected muscle, fever, and abscess formation. If left untreated, the abscess may extend into the bone and joint or blood poisoning may occur. Approximately 90% of cases are caused by the bacterium, Staphylococcus aureus. Risk factors for the condition include strenuous activity, muscle trauma, skin infections, infected insect bites, illicit drug injections, connective tissue disorders, and diabetes. Treatment generally includes surgical drainage of the abscess and antibiotics. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Pyomyositis	c1704275	6,270	gard	https://rarediseases.info.nih.gov/diseases/4614/pyomyositis	2021-01-18T17:58:01	{"mesh": ["D052880"], "umls": ["C1704275"], "orphanet": ["764"], "synonyms": []}
Leri pleonosteosis SpecialtyRheumatology Leri's pleonosteosis is a rare rheumatic condition. It was first described by the French physician Leri in 1921.[1] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 References ## Presentation[edit] The clinical features of this condition include[citation needed] * Flattened facial features * Flexion contractures of the interphalangeal joints of hand and foot. * Limited motion of multiple joints * Short broad metacarpals, metatarsals and phalanges Thickening of the skin may occur in a fashion similar to that occurs in scleroderma. The thumbs may be angled in a lateral direction (valgus deformity). The knees may be angled backwards (genu recurvatum). Abnormalities of the upper spinal cord may also occur.[citation needed] ## Genetics[edit] It is inherited in an autosomal dominant fashion.[citation needed]The pathogenesis of this condition appears to be due to over expression of two genes - GDF6 and SDC2.[2] These genes are located on the long arm of chromosome 8(8q22.1). ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (September 2017) ## References[edit] 1. ^ Leri A (1921) Une maladie congenitale et hereditaire de l'ossification: la pleonosteose familiale. Bull Mem Soc Med Hop Paris 45: 1228-1230 2. ^ Banka S, Cain SA, Carim S, Daly SB, Urquhart JE, Erdem G, Harris J, Bottomley M, Donnai D, Kerr B, Kingston H, Superti-Furga A, Unger S, Ennis H, Worthington J, Herrick AL, Merry CL, Yue WW, Kielty CM, Newman WG (2014) Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis. Ann Rheum Dis doi: 10.1136/annrheumdis-2013-204309 This article about a disease of musculoskeletal and connective tissue 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	Leri pleonosteosis	c1835450	6,271	wikipedia	https://en.wikipedia.org/wiki/Leri_pleonosteosis	2021-01-18T19:05:10	{"gard": ["88"], "mesh": ["C537118"], "umls": ["C1835450", "C0265311"], "orphanet": ["2900"], "wikidata": ["Q17115004"]}
## Summary ### Clinical characteristics. C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface) that is rarely inherited in a simple mendelian fashion. C3G affects individuals of all ages, with a median age at diagnosis of 23 years. Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3. Spontaneous remission of C3G is uncommon, and about half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis, occasionally developing the late comorbidity of impaired visual acuity. ### Diagnosis/testing. The definitive diagnosis of C3G requires a renal biopsy with specialized immunofluorescence and electron microscopy studies both for diagnosis and to distinguish between the two major subtypes of C3G: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE). ### Management. Treatment of manifestations: Nonspecific therapies used to treat numerous chronic glomerular diseases, including angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, and lipid-lowering agents (in particular hydroxymethylglutaryl coenzyme A reductase inhibitors). Complement inhibition with a terminal pathway blocker may alter disease course in some individuals. When ESRD develops, treatment options are limited to dialysis or transplantation. C3G recurs in nearly all grafts and is the predominant cause of graft failure in 50%-90% of transplant recipients. Prevention of primary manifestations: Plasma replacement therapy in individuals with pathogenic variants in CFH may be effective in controlling complement activation and slowing progression of ESRD. Surveillance: Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum, complete biannual assessment of the complement pathway, periodic eye examinations to evaluate the fundus. Evaluation of relatives at risk: If the family history is positive for renal disease, evaluation of apparently asymptomatic at-risk relatives can include molecular genetic testing (if the pathogenic variants in the family are known), urinalysis, and comprehensive analysis of the complement system. ### Genetic counseling. C3G is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. Multiple affected persons within a single nuclear family are reported only occasionally, with both dominant and recessive inheritance being described. ## Diagnosis C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface); it is rarely inherited in a simple mendelian fashion. ### Suggestive Findings C3G should be suspected in individuals of all ages who present with one of the following: * Hematuria * Proteinuria * Hematuria and proteinuria * Acute nephritic syndrome * Nephrotic syndrome * Persistent hypocomplementemia (low serum levels of complement component C3) ### Establishing the Diagnosis The diagnosis of C3G is established in a proband with typical findings on renal biopsy. Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes listed in Table 1. Note: Identification of a pathogenic variant may help to direct treatment of the individual. Renal biopsy. The definitive diagnosis of C3G requires a renal biopsy with specialized studies (see Figure 1) both for diagnosis and to distinguish between C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). #### Figure 1. Disease-specific characteristic IF, EM, and LM biopsy images in C3 glomerulopathy (C3G) A. Immunofluoresence (IF) shows bright staining for C3, which must be at least two orders of magnitude greater than any other immune reactant. Note the diffuse glomerular (more...) * Immunofluorescence (IF). The diagnosis of C3G can only be made with IF studies of a renal biopsy. * The predominant staining of C3 is key in delivering a C3G diagnosis. * IF should be predominantly positive for C3 with C3 intensity at least two orders of magnitude greater than any other immune reactant (i.e., IgA, IgG, IgM, and C1q) (Figure 1A). * Electron microscopy (EM) is used to distinguish between C3GN and DDD, a clinically relevant distinction (Figure 1). EM should demonstrate dense transformation of the glomerulus. * In C3GN there are light, hump-like and clustered deposits, which are found in the mesangium or in the subendothelial and/or subepithelial spaces. * In DDD, the deposits are darker, denser, segmental, discontinuous, ribbon-like, or diffuse and are most frequently located in the lamina densa of the glomerular basement membrane (GBM) (Figure 1B-C). * Light microscopy (LM) is necessary to quantitate changes associated with chronic kidney disease and risk for progression of ESRD. LM most commonly demonstrates mild mesangial cell hypercellularity (45% of cases), although membranoproliferative (25%), crescentic (18%), and acute proliferative and exudative (12%) patterns are also seen (Figure 1D). Note: Timing of the biopsy is important. If the presentation suggests post-infectious glomerulonephritis (PIGN; see Figure 2), waiting for three months is typically recommended. During that interval, the hypocomplementemia, hematuria, and proteinuria that are characteristic of both PIGN and C3G should resolve in cases of PIGN [Walker et al 2007, Nester & Smith 2016, Goodship et al 2017]. #### Figure 2. Schematic representation of disease types Post-infectious glomerulonephritis (PIGN), C3 glomerulopathy (C3G), and other disease types fall under the classification "glomerular diseases with dominant C3" immunofluorescence (IF) staining, with the term (more...) Molecular genetic testing approaches can include a multigene panel, more comprehensive genomic testing, and serial single-gene testing: * A multigene panel that includes C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, DGKE, 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. Note: Analysis of CFH-related genes is complicated by the high degree of sequence identity between CFH and the downstream CFH-related genes (CFHR1-CFHR5). This similarity results in susceptibility to nonallelic homologous recombination (NAHR) events, large-scale deletions or duplications (copy number variants), and generation of hybrid CFH genes. Molecular assays must be specifically designed to detect the spectrum of changes that can occur in this region. * More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. * Serial single-gene testing. Sequence analysis can be performed on a gene-by-gene basis, although this approach is generally not recommended because there are no phenotypic clues to inform the order of genes to be tested and because rare/novel variants can be present in multiple genes [Bu et al 2016]. If single-gene testing is performed, gene-targeted deletion/duplication testing over the CFHR1-CFHR5 region should also be completed in all cases. ### Table 1. Molecular Genetic Testing Used in C3G View in own window Gene 1, 2Proportion of C3G Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Sequence analysis 4Gene-targeted deletion/duplication analysis 5 C3~11% 6~100%Unknown CD460%~2% 7100%Unknown CFB<1% 8100%Unknown CFH~12% 9~98%~2% CFHR1 duplication 102 individualsNA100% 11 CFHR1/CFHR5 hybrid allele 103 individualsNA100% 12 CFHR3/CFHR1 hybrid allele 105 individualsNA100% 13 CFHR5See footnote 14See footnote 15Unknown (general population); 100% (Cyprus) 14 CFHR5/CFHR2 hybrid allele 102 individualsNA100% 16 CFI~5% 17100%Unknown DGKΕ13 individuals 18~100%Unknown 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. See Molecular Genetics for information on allelic variants detected in this gene. 4\. 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. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Martínez-Barricarte et al [2010], Abrera-Abeleda et al [2011], Imamura et al [2015], Bu et al [2016], Iatropoulos et al [2016] 7\. Servais et al [2012], Nester & Smith [2013a] 8\. Imamura et al [2015] 9\. Ault et al [1997], Dragon-Durey et al [2004], Licht et al [2006], Servais et al [2012], Sethi et al [2012b], Zhang et al [2012], Johnson et al [2014], Bu et al [2016], Iatropoulos et al [2016] 10\. CFHR hybrid alleles are the gene fusion products of nonallelic homologous recombination between the highly homologous CFHR genes [Gale et al 2010, Malik et al 2012, Tortajada et al 2013, Chen et al 2014, Medjeral-Thomas et al 2014, Xiao et al 2016, Togarsimalemath et al 2017] (for details of exon arrangements see Figure 3). 11\. Tortajada et al [2013] 12\. Togarsimalemath et al [2017] 13\. Malik et al [2012] 14\. Four individuals of non-Cypriot origin; however, hundreds of affected individuals with a duplication of exons 2 and 3, presumably due to a founder effect, have been identified in Cyprus [Gale et al 2010, Athanasiou et al 2011, Deltas et al 2013]. 15\. Three patients of non-Cypriot origin have been reported with variants detectable by sequencing [Sethi et al 2012a, Vernon et al 2012, Besbas et al 2014]. 16\. Chen et al [2014], Medjeral-Thomas et al [2014], Xiao et al [2016] 17\. Servais et al [2012], Nester & Smith [2016] 18\. Ozaltin et al [2013], Westland et al [2014], Azukaitis et al [2017] See Figure 3. #### Figure 3. Complement factor H-related hybrid proteins and C3G Adapted from Togarsimalemath et al [2017] and references therein ## Clinical Characteristics ### Clinical Description Age of onset. C3 glomerulopathy (C3G) affects individuals of all ages. Lu et al [2012] report a 1:1 female:male distribution and a median age at diagnosis of 23 years. In comparing the two major subtypes, the median age at time of diagnosis in C3 glomerulonephritis (C3GN) is higher than in dense deposit disease (DDD). In childhood, DDD is more frequently diagnosed than C3GN [Nester & Smith 2016, Riedl et al 2017]. Renal disease. Individuals with C3G typically present with one of the following findings: * Hematuria * Proteinuria * Hematuria and proteinuria * Acute nephritic syndrome * Nephrotic syndrome Hypocomplementemia. Individuals with C3G have low levels of complement component C3. Complement dysregulation can be mediated by autoantibodies (see Pathophysiology). Autoantibodies that may be detected in individuals with C3G: * Serum C3 nephritic factor (C3NeFs). C3NeFs are present in up to ~50% of individuals with C3GN and ~80% of individuals with DDD [Salvadori & Bertoni 2016]. * Factor H autoantibodies (FHAAs). Blanc et al [2015] reported the prevalence of FHAAs in C3G individuals to be 11%. * Factor B autoantibodies (FBAAs). FBAAs have been linked to C3G; their role in disease remains unclear [Pickering et al 2013]. Course and progression * Spontaneous remission of C3G is uncommon [Habib et al 1975, Cameron et al 1983, Marks & Rees 2000, Thomas et al 2014]. While the disease can remain stable for years despite persistent proteinuria, in some individuals rapid fluctuations in proteinuria occur, with episodes of acute renal deterioration in the absence of obvious triggering events. Efforts to move individuals to remission have not been successful [Daina et al 2012, McCaughan et al 2012]. Current data suggest that C3G remains a chronic disease subject to acute exacerbations, with constant activation of the complement alternative pathway (AP) [Goodship et al 2017]. * About half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis [Lu et al 2007, Servais et al 2012, Nester & Smith 2016, Goodship et al 2017], occasionally developing the late comorbidity of impaired visual acuity [Recalde et al 2016]. * Progression to ESRD can be rapid [Smith et al 2007, Nester & Smith 2013b, Servais et al 2013]. * Age and sex of an individual are not significant predictors of disease course. * Native kidney survival is comparable in C3GN and DDD [Servais et al 2013, Nester & Smith 2016]. Acquired partial lipodystrophy (APL). APL may develop as a direct aftermath of complement activation in 5%-17% of persons with C3G [Barbour et al 2013b, Goodship et al 2017]. The association between APL and C3G is related to the effects of AP dysregulation on both kidneys and adipose tissue [Goodship et al 2017]. The deposition of activated complement components in adipose tissue destroys adipocytes in areas where factor D (fD, also known as adipsin) is high; loss of subcutaneous fat in the upper half of the body typically precedes the onset of kidney disease by several years. Eye findings. Individuals with C3G develop drusen as a result of complement activation, often in early adulthood [Barbour et al 2013b, Thomas et al 2014, Goodship et al 2017]. The whitish-yellow deposits, which lie within Bruch's membrane beneath the retinal pigment epithelium of the retina, are similar in composition and structure to the deposits observed in the kidney [D'Souza et al 2009, Lu et al 2012, Barbour et al 2013b]. The retinal distribution of drusen is variable [Thomas et al 2014, Goodship et al 2017] and initially has little impact on visual acuity or visual fields. However, vision loss can occur later in life [Cebeci et al 2016]. Recent investigations convey the importance of the complications that result from drusen [Cebeci et al 2016, Dalvin et al 2016, Savige et al 2016]. Tests of retinal function such as dark adaptation, electroretinography, and electrooculography can gradually become abnormal, and vision can deteriorate as subretinal neovascular membranes, macular detachment, and central serous retinopathy develop [Cebeci et al 2016, Dalvin et al 2016, Savige et al 2016]. The long-term risk for visual problems in individuals with C3G is approximately 10%. No correlation exists between disease severity in the kidney and in the eye. #### Pathophysiology See Figure 4. Fluid-phase dysregulation of the alternate pathway (AP) of the complement cascade is the triggering pathophysiologic event in C3G, and dysregulation of the C3 convertase alone is necessary and sufficient to result in C3G [Martínez-Barricarte et al 2010, Paixão-Cavalcante et al 2012, Zhang et al 2012]. #### Figure 4. Complement alternative pathway (AP) Left. Three phases of complement activity are illustrated: During disease progression, activation of downstream complement proteins in the solid phase, in particular cleavage of C5 to C5a and C5b, can contribute to tissue injury in the micro-environment of the renal glomerulus [Appel et al 2005, Smith et al 2007]. Current consensus considers that in C3G, uncontrolled regulation of the AP may be due to both genetic and/or acquired drivers of disease [Servais et al 2012, Nester & Smith 2016, Goodship et al 2017]. Acquired drivers of disease include autoantibodies such as C3 nephritic factors (C3NeFs), C4 nephritic factors (C4NeFs), C5 nephritic factors (C5NeFs), factor H autoantibodies (FHAA), and factor B autoantibodies (FBAA). C3NeFs and C5NeFs are most commonly detected and are autoantibodies that recognize neoantigenic epitopes on C3bBb, the C3 convertase of the AP, and on C3bBbC3b, the C5 convertase of the terminal pathway, respectively (see Figure 4) [Paixão-Cavalcante et al 2012, Zhang et al 2012, Nester & Smith 2013a, Nicolas et al 2014]. C3 convertases cleave C3 into C3b and C3a, while C5 convertases cleave C5 into C5a and C5b. In the presence of C3NeFs and C5NeFs, the half-lives of C3 convertase and C5 convertase are increased. Persistent cleavage of C3 drives down serum concentrations of C3 and increases serum concentrations of its cleavage products, C3c and C3d, while persistent cleavage of C5 increases serum concentrations of soluble C5b-9. C4NeFs are found in fewer than 5% of individuals with C3GN and stabilize the C3 convertase of the classic and lectin pathways (C4b2a) [Zhang et al 2017]. Nephritic factors may persist in serum throughout the disease course [Schwertz et al 2001, Paixão-Cavalcante et al 2012, Zhang et al 2012]. Serum concentrations of C3NeFs can vary over time [Appel et al 2005, Paixão-Cavalcante et al 2012, Zhang et al 2012, Servais et al 2013, Rabasco et al 2015]. Their presence is nearly always associated with evidence of complement activation such as decrease in serum concentration of C3 and increase in serum concentration of C3 cleavage products (e.g., C3c and C3d), but the relationship between nephritic factors, C3, and prognosis is not clear [Paixão-Cavalcante et al 2012, Zhang et al 2012, Rabasco et al 2015]. The observed differences may be reconciled by several observations relevant to C3NeFs, which have been most thoroughly studied. First, not all C3NeFs recognize the same epitope on C3bBb; second, the methods for their detection vary; third, many studies do not report titers; and fourth, there is good evidence that the triggering epitopes can change over time [Ohi et al 1992, Spitzer & Stitzel 1996, Paixão-Cavalcante et al 2012, Zhang et al 2012]. The consequence of AP dysregulation in C3G is kidney damage. As the degree of chronic damage increases, renal outcome ultimately becomes independent of the degree of complement dysregulation. With sufficient chronic damage, even if complement normalcy is restored, the likelihood of improving or stabilizing renal function becomes remote and ESRD ensues. Factor H autoantibodies (FHAA) have been reported in individuals with C3G; epitope mapping shows that these autoantibodies bind the N-terminus of fH [Zhang et al 2012, Blanc et al 2015, Goodship et al 2017]. Factor B autoantibodies (FBAA) have been linked to C3G; however, their role in disease remains unclear [Pickering et al 2013]. FBAAs were identified in a person with DDD without serum C3NeFs. FBAAs bind to and stabilize C3 convertase, targeting both fB and C3b, enhancing the consumption of C3. C5 convertase formation from C3 convertase is prevented, thus interfering with activation of the terminal complement cascade [Strobel et al 2010]. Additional studies have identified FBAAs targeting fB and C3b in two individuals with DDD; C3 convertase activity was increased although no C3NeFs were identified [Chen et al 2011]. As a general rule, C3Nefs, FHAAs, and FBAAs extend the half-life and stabilize C3 convertase, which leads to persistent AP activation in the fluid phase [Noris & Remuzzi 2015]. ### Genotype-Phenotype Correlations To date, the most striking genotype-phenotype correlation has been with CFHR fusion genes and the C3GN phenotype (as opposed to the DDD phenotype) (see Figure 3). ### Nomenclature C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Prior to adopting the C3G classification [Pickering et al 2013], dense deposit disease (DDD) was also described as membranoproliferative glomerulonephritis type 2 (MPGN2). C3 glomerulonephritis (C3GN) was recognized as atypical MPGN1 (Burkholder variant of MPGN1) and atypical MPGN3 (Strife and Anders variant of MPGN3) [D'Agati & Bomback 2012, Sethi et al 2016]. ### Prevalence The rarity of C3G makes it difficult to estimate prevalence, although from epidemiologic studies, its prevalence in the USA is estimated at 2-3 per 1,000,000 [Smith et al 2007]. ## Differential Diagnosis ### Table 3. Disorders to Consider in the Differential Diagnosis of C3G View in own window DisorderGene(s)MOIClinical Features of This Disorder Overlapping w/C3GDistinguishing from C3G Post-infectious glomerulonephritis 1NAAcquiredHematuria, proteinuria, nephritic syndrome, edema, ↓ serum C3, C3 glomerular deposition, subepithelial hump-like depositsPost-infection (throat or skin) often due to Group A hemolytic streptococcus bacterium; ↓ levels of C3 resolve w/in 3 mos; glomerular codeposition of C3 & IgG Immune-complex MPGN 2NAAcquiredHematuria, proteinuria, C3 deposits, subendothelial & subepithelial deposits, progressive diseaseImmune complex-mediated, often low complement C4 levels; codeposition of C3 & IgG/IgM/C1q/C4 on IF Juvenile acute non-proliferative glomerulonephritis 3NAAcquiredMesangial cell proliferation, subepithelial deposits on EMC3 levels typically remaining in lower limits of normal Familial lecithin-cholesterol acyltransferase deficiency 4LCATARESRD, glomerular pattern of IF similar to dense deposit diseaseAbnormal lipoprotein (lipoprotein X); corneal opacities; normochromic anemia; capillary endothelial damage; cross-striated & vacuole structures Partial lipodystrophy 5Several genesAD/ARLoss of subcutaneous fat in upper half of the bodyNo renal disease; no dysregulation of complement alternative pathway Age-related macular degeneration 6Many genesADDrusenAbsence of renal disease Malattia Leventinese & Doyne honeycomb retinal dystrophy 7EFEMP1ADDrusenAbsence of renal disease AD = autosomal dominant; AR = autosomal recessive; EM = electron microscopy; IF = immunofluorescence; MOI = mode of inheritance; MPGN = membranoproliferative glomerulonephritis 1\. Sotsiou [2001], Kambham [2012], Sethi et al [2013], Khalighi et al [2016] 2\. Sethi & Fervenza [2011], Noris & Remuzzi [2015], Nester & Smith [2016] 3\. West et al [2000], Fujita et al [2007] 4\. Sessa et al [2001], Ossoli et al [2015] 5\. Eisinger et al [1972], Mathieson & Peters [1997], Licht & Mengel [2008], Licht & Fremeaux-Bacchi [2009], Gale & Owen-Casey [2014] 6\. Hageman et al [2005] , Licht & Mengel [2008], Licht & Fremeaux-Bacchi [2009], Gale & Owen-Casey [2014] 7\. Stone et al [1999], Mullins et al [2001], Sohn et al [2015], Hulleman [2016], Vaclavik & Munier [2016] ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with C3G, the following evaluations are recommended if they have not already been completed: * Evaluate the complement system by measuring serum/plasma concentrations of C3, C3c, C3d, C4, C5, fB, Ba, Bb, fH, fI, properdin, and s(C5b-9). * Quantitate the degree of complement function by measuring CH50 and APH50. * Measure autoantibodies including C3NeFs, C4NeFs, C5NeFs, FHAA, and FBAA. * Establish the extent of renal disease by measuring serum creatinine concentration, and monitor creatinine clearance, proteinuria, and hematuria. * Quantitate the degree of chronic renal damage by renal biopsy. * Obtain a baseline ophthalmologic examination. * Consult with a clinical geneticist and/or genetic counselor. ### Treatment of Manifestations Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G. Nonspecific therapies are most commonly used. Nonspecific therapies have been shown to be effective in numerous chronic glomerular diseases. The judicious use of these agents along with optimal blood pressure control is of benefit in individuals with C3G. * Angiotensin-converting enzyme inhibitors and angiotensin II type-1 receptor blockers decrease proteinuria in many glomerular diseases and slow the progression to renal failure [Licht et al 2006, Lu et al 2012, Nester & Smith 2016, Riedl et al 2017]. A retrospective study found that the combination of angiotensin blockers and immunosuppressants (steroids) is more effective than each therapy alone in preventing the development of renal failure [Nasr et al 2009, Nester & Smith 2013b, Thomas et al 2014, Cook 2017]. * Lipid-lowering agents, and in particular hydroxymethylglutaryl coenzyme A reductase inhibitors, may delay progression of renal disease as well as correct endothelial cell dysfunction and alter long-term atherosclerotic risks in the presence of hyperlipidemia [Nester & Smith 2013b, Thomas et al 2014]. These agents are not widely used in children. * Complement inhibition with a terminal pathway blocker may alter disease course. Eculizumab is a recombinant humanized monoclonal antibody that targets C5. It blocks cleavage of C5 by C5 convertase, thereby having two effects: (1) an anti-inflammatory effect caused by preventing the release of C5a, a potent anaphylatoxin; and (2) an anticomplement effect caused by preventing formation of the terminal complement complex (see Figure 4). Reports of its use in individuals with C3G have demonstrated limited success [ClinicalTrials.gov NCT00838513, Bomback et al 2012]. * Individuals with C3G treated with eculizumab have not produced a uniform response [Noris & Remuzzi 2015]. * Early administration of eculizumab prior to sclerotic tissue formation provides better results, reduces proteinuria, and improves kidney health [Vivarelli & Emma 2014]; however, success of this therapeutic is limited in C3G because proximal complement control is not restored (see Figure 4). Renal allografts. When end-stage renal disease (ESRD) develops, treatment options are limited to dialysis or transplantation. When an individual with C3G elects to undergo a renal transplant, it is important to recognize that C3G recurs in nearly all grafts and is the predominant cause of graft failure in 50%-90% of transplant recipients [Appel et al 2005, Angelo et al 2011, Lu et al 2012, Servais et al 2012, Zand et al 2014, Salvadori & Bertoni 2016, Goodship et al 2017]. Data suggesting that any therapeutic interventions reverse this course are limited, although isolated reports have described the use of plasmapheresis, which appears to be of equivocal benefit [Fremeaux-Bacchi et al 1994, Kurtz & Schlueter 2002]. A thorough complement and genetic evaluation of the transplant recipient is recommended pre-transplantation as results may inform post-transplant care. In addition, a genetic assessment is recommended for relatives being considered as kidney donors. ### Prevention of Primary Manifestations Most treatments for C3G are ineffective; however, plasma replacement therapy in individuals with pathogenic variants in CFH has been reported by some authors to be effective in controlling complement activation and slowing progression of ESRD [Licht et al 2006]. Other authors report that the benefit of plasma exchange is inconsistent in reducing progression to ESRD [Kurtz & Schlueter 2002, McCaughan et al 2012, Servais et al 2013, Thomas et al 2014]. ### Surveillance The following are appropriate: * Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum Note: Frequency of follow up and testing required is determined by the degree of renal dysfunction. * Complete biannual assessment of the complement pathway * Periodic eye examinations to evaluate the fundus ### Evaluation of Relatives at Risk There are very few familial cases of C3G. However, if the family history is positive for renal disease, it is appropriate to evaluate apparently asymptomatic sibs of a proband and at-risk relatives to identify those who would benefit from periodic observation and continued follow up for management of renal disease. Evaluations can include: * Molecular genetic testing if the pathogenic variants in the family are known. Penetrance rates, however, are not known. * Urinalysis * Comprehensive analysis of the complement system if the pathogenic variants in the family are not known. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Chronic kidney disease does not preclude pregnancy, but any pregnancy in a woman with C3G should be followed by a nephrologist and obstetrician with expertise in caring for pregnant women with chronic kidney disease [Nava et al 2017, Piccoli et al 2018]. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Numerous anti-complement therapies are entering clinical trials for individuals with C3G. These trials are registered under ClinicalTrials.gov. 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	C3 Glomerulopathy	c4087273	6,272	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1425/	2021-01-18T21:38:54	{"synonyms": ["C3G", "Glomerulonephritis with Dominant C3"]}
Garrod's pads (also known as violinist's pads[1]) are a cutaneous condition characterized by calluses on the dorsal aspect of the interphalangeal joints,[2] i.e. the back side of the finger joints. They are often seen in violin, viola, and cello players, along with fiddler's neck and other dermatologic conditions peculiar to string musicians.[2] Although Garrod's pads are conventionally described as appearing on the proximal interphalangeal joint, distal interphalangeal joint involvement has also been described.[2] Garrod's pads are named after Archibald Garrod who first documented them in 1904 in association with Dupuytren's contracture.[3] H.A. Bird described them as an incidental finding in a professional violinist and proposed that they arise in such cases due to repeated extreme tension of the extensor tendons over the interphalangeal joints.[4] Bird noted that violin players use the left hand for a markedly different task than the right hand, with the extensor tendons in the left hand subjected to considerable tension, and that Garrod's pads only arise on the left hand in such cases. This unilateral finding differentiates the occupational hazard of Garrod's pads from more significant disorders. Among violinists and violists, Garrod's pads apparently arise as a protective mechanism for the skin and subcutaneous tissues above the tendons; Bird notes that they do not protect against external trauma unlike most calluses.[4] Patients with Dupuytren's contracture are four times more likely to have coexisting Garrod's pads.[5][6] ## See also[edit] * Knuckle pads * Harpist's finger * Fiddler's neck * Cellist's chest * Cello scrotum * Paget-Schroetter syndrome * List of cutaneous conditions * List of eponymously named medical signs ## 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. ^ a b c Rimmer, S.; Spielvogel, R. L. (1990). "Dermatologic problems of musicians". Journal of the American Academy of Dermatology. 22 (4): 657–663. doi:10.1016/0190-9622(90)70093-W. PMID 2138638. 3. ^ Garrod, A. E. (1904). "Concerning Pads upon the Finger Joints and their Clinical Relationships". British Medical Journal. 2 (2270): 8. doi:10.1136/bmj.2.2270.8. PMC 2354178. PMID 20761632. 4. ^ a b Bird, H. A. (1987). "Development of Garrod's pads in the fingers of a professional violinist". Annals of the Rheumatic Diseases. 46 (2): 169–170. doi:10.1136/ard.46.2.169. PMC 1002087. PMID 3827341. 5. ^ Cutis. Technical Publishing Company. 1994. p. 160. Retrieved 13 November 2017. 6. ^ Young, Christopher J.; Gladman, Marc A. (2013). Examination Surgery: A Guide to Passing the Fellowship Examination in General Surgery. Elsevier Health Sciences. p. 213. ISBN 9780729541480. Retrieved 13 November 2017. 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	Garrod's pad	c0264000	6,273	wikipedia	https://en.wikipedia.org/wiki/Garrod%27s_pad	2021-01-18T19:01:20	{"umls": ["C0264000"], "wikidata": ["Q5524074"]}
## Summary ### Clinical characteristics. HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes: * Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present; * Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and * Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present. Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women. ### Diagnosis/testing. The diagnosis of HFE hemochromatosis in a proband is established by identification of biallelic HFE pathogenic variants on molecular genetic testing. ### Management. Treatment of manifestations: * Clinical HFE hemochromatosis: induction treatment by phlebotomy to achieve serum ferritin concentration ≤50 ng/mL. * Biochemical HFE hemochromatosis: start phlebotomy when serum ferritin concentration is >300 ng/mL. * Non-expressing p.Cys282Tyr homozygotes: phlebotomy is not indicated, because these individuals do not have iron overload. Prevention of secondary complications: Vaccination against hepatitis A and B. Surveillance: * Clinical HFE hemochromatosis: Once the serum ferritin concentration is ≤50 ng/mL, monitor serum ferritin concentration every three to four months. Maintain serum ferritin <300 ng/mL (men) and <200 ng/mL (women) thereafter; perform standard screening for primary liver cancer in individuals who have cirrhosis. * Biochemical HFE hemochromatosis and non-expressing p.Cys282Tyr homozygotes: Begin annual measurement of serum ferritin concentration when serum ferritin concentration exceeds 300 ng/mL (men) and 200 ng/mL (women). Agents/circumstances to avoid: Medicinal iron, mineral supplements, excess vitamin C, and uncooked seafood; alcohol consumption in those with hepatic involvement; and daily ingestion of more than 500 mg of supplemental ascorbic acid / vitamin C. Evaluation of relatives at risk: Offer molecular genetic testing to the adult sibs of a proband homozygous for p.Cys282Tyr to allow early diagnosis and surveillance. ### Genetic counseling. HFE hemochromatosis is inherited in an autosomal recessive manner. Risk to sibs: When both parents of a person with hemochromatosis are heterozygous for an HFE p.Cys282Tyr variant, the risk to sibs of inheriting two HFE p.Cys282Tyr variants is 25%. Because the HFE p.Cys282Tyr heterozygote prevalence in persons of European origin is high (11%, or 1/9), some parents of HFE p.Cys282Tyr homozygotes have two abnormal HFE alleles. If one parent is heterozygous and the other parent homozygous for two abnormal HFE alleles, the risk to each sib of inheriting two HFE pathogenic alleles is 50%. Risk to offspring: Offspring of an individual with HFE hemochromatosis inherit one HFE p.Cys282Tyr variant from the parent with HFE hemochromatosis. Because the chance that the other parent is a heterozygote for HFE p.Cys282Tyr is 1/9, the risk that the offspring will inherit two HFE p.Cys282Tyr variants is approximately 5%. Prenatal testing: Although prenatal testing for a pregnancy at increased risk is possible once the HFE pathogenic variants have been identified in an affected family member, prenatal testing is not usually performed because HFE hemochromatosis is an adult-onset, treatable disorder with low clinical penetrance. ## Diagnosis The European Association for the Study of the Liver (EASL) published clinical practice guidelines including diagnosis of HFE hemochromatosis [European Association for the Study of the Liver 2010]. The American Association for the Study of Liver Disease (AASLD) has published practice guidelines for diagnosis of hemochromatosis [Bacon et al 2011] (full text). Experts at the 2017 Hemochromatosis International meeting published an objective and practical set of recommendations for treatment of persons with hemochromatosis and p.Cys282Tyr homozygosity based on published scientific studies and guidelines in a form suitable for patients and other persons without medical training [Adams et al 2018]. ### Suggestive Findings HFE hemochromatosis should be suspected in individuals with a combination of the following clinical signs of advanced iron overload, biochemical evidence of hemochromatosis, and/or family history of HFE hemochromatosis. Clinical signs of advanced iron overload * Diabetes mellitus * Progressive increase in skin pigmentation * Hepatomegaly * Hepatic cirrhosis * Arthropathy (especially involving the metacarpophalangeal joints) * Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma) * Cardiomyopathy * Hypogonadism (usually hypogonadotropic) Biochemical evidence of hemochromatosis * Elevated serum transferrin-iron saturation (TS) is an early and reliable indicator of risk for iron overload in HFE hemochromatosis; TS is not age-related in adults and is not significantly associated with the presence or absence of clinical findings or increased serum ferritin levels. Approximately 80% of individuals with HFE hemochromatosis have had a fasting serum TS of at least 60% (men) or at least 50% (women) on two or more occasions in the absence of other known causes of elevated TS. * Elevated serum ferritin concentration. Serum ferritin generally increases progressively over time in individuals with untreated clinical HFE hemochromatosis. An elevated serum ferritin concentration alone is not specific for iron overload because serum ferritin is an acute-phase reactant and elevated serum ferritin levels may be caused by non-iron liver disorders or inflammatory or neoplastic disorders (especially when the serum TS is normal). Commonly accepted normal serum ferritin values from the HEIRS Study are <300 ng/mL in men and <200 ng/mL in women [Adams et al 2005]. * No "typical" range for serum ferritin values for persons with HFE hemochromatosis has been defined. Values range from subnormal to several thousands. An algorithm for screening for HFE hemochromatosis has been developed (see Figure 1). #### Figure 1. Algorithm for screening for HFE hemochromatosis using LFTs (liver function tests) and TS (transferrin saturation) Originally published in Eijkelkamp et al [2000]; reused with permission ### Establishing the Diagnosis The diagnosis of HFE hemochromatosis is established in a proband with the identification of biallelic pathogenic variants in HFE, typically p.Cys282Tyr, by molecular genetic testing (see Table 1). Molecular testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, 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 HFE hemochromatosis 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 HFE hemochromatosis 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 HFE hemochromatosis, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. Single-gene testing * Targeted analysis for HFE p.Cys282Tyr and p.His63Asp can be performed first. Note: Other pathogenic variants common in some populations have been described: * Northern Italian: p.Glu168Ter and p.Trp169Ter [Piperno et al 2000] * French: p.Ser65Cys [Bacon et al 2011] * Vietnamese: c.1006+1G>A [Barton et al 2015] * Perform sequence analysis of HFE, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Note: HFE whole-gene deletion has been found to be the most common pathogenic variant in the Sardinian population [Le Gac et al 2010]. A multigene panel that includes HFE and other genes of interest (see Differential Diagnosis) may be used to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the diagnosis of HFE hemochromatosis 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 most commonly used; genome sequencing is also possible. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in HFE Hemochromatosis View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method HFETargeted analysis~99% 3 Sequence analysis 4~99% 5 Gene-targeted deletion/duplication analysis 6Rare 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\. Individuals of European ancestry; approximately 60%-90% of individuals of European ancestry with HFE hemochromatosis are homozygous for variant p.Cys282Tyr, 1% are homozygous for p.His63Asp, and 3%-8% are compound heterozygous for p.Cys282Tyr / p.His63Asp [Feder et al 1996, Morrison et al 2003, Barton et al 2015]. 4\. 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. 5\. Population-specific pathogenic variants have been described, including p.Glu168Ter and p.Trp169Ter, found with allele frequencies of 25% and 8.4% (respectively) in individuals with hemochromatosis in two northern regions of Italy [Piperno et al 2000]. The prevalence of HFE p.Ser65Cys is greatest in French populations. The HFE splice site variant c.1006+1G>A occurs in Vietnamese with and without phenotypic evidence of iron overload [Barton et al 2015]. HFE gene deletion is the most common pathogenic HFE allele in the Sardinian population [Le Gac et al 2010]. 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\. ALU-mediated HFE gene deletion is the most common cause of hemochromatosis in the Sardinian population [Le Gac et al 2010]. ## Clinical Characteristics ### Clinical Description HFE hemochromatosis comprises three phenotypes: * Clinical HFE hemochromatosis (individuals with end-organ damage [e.g., cirrhosis, diabetes, cardiac failure, skin hyperpigmentation] secondary to iron storage) * Biochemical HFE hemochromatosis (individuals with elevated transferrin saturation [TS], not otherwise explained) with evidence of iron overload (elevated serum ferritin concentration) * Non-expressing p.Cys282Tyr homozygotes (p.Cys282Tyr homozygotes without clinical or biochemical evidence of iron overload [i.e., normal serum ferritin concentration]) Some individuals with HFE hemochromatosis may be identified because they have signs and symptoms related to iron overload (i.e., clinical HFE hemochromatosis). Other individuals are diagnosed with HFE hemochromatosis before symptoms develop, either through detection of abnormal iron-related studies (i.e., biochemical HFE hemochromatosis) or by molecular genetic testing used in their evaluation as family members at risk for HFE hemochromatosis (expressing or non-expressing p.Cys282Tyr homozygotes). The difference between clinical and biochemical HFE hemochromatosis must be understood in the interpretation of population studies evaluating morbidity related to HFE hemochromatosis. Several large-scale screening studies in the general population have demonstrated that most individuals homozygous for p.Cys282Tyr do not have clinical HFE hemochromatosis. A significant proportion of individuals with homozygosity for p.Cys282Tyr (especially men) have biochemical HFE hemochromatosis. Factors influencing disease manifestation * Gender. Among p.Cys282Tyr homozygotes, a higher proportion of men than women (28% vs 1%) have manifestations of hemochromatosis [Allen et al 2008]. * Detection through screening. When identified through iron studies or screening of at-risk family members, 75%-90% of individuals with HFE hemochromatosis are asymptomatic. * Normal serum ferritin concentration at diagnosis is usually associated with lack of symptom development [Yamashita & Adams 2003]. * Clinical disease is more common among p.Cys282Tyr homozygous sibs of clinically affected p.Cys282Tyr homozygotes than among p.Cys282Tyr homozygotes identified outside of family studies. #### Clinical HFE Hemochromatosis Individuals with clinical HFE hemochromatosis have inappropriately high absorption of iron from a normal diet by the mucosa of the small intestine, resulting in excessive parenchymal storage of iron, which may result in damage to target organs and, potentially, organ failure. Age of onset. Symptoms related to iron overload usually appear between age 40 and 60 years in men and after menopause in women. Occasionally, HFE hemochromatosis manifests at an earlier age, but hepatic fibrosis or cirrhosis is rare before age 40 years. Early signs. Often the first signs of clinical HFE hemochromatosis are arthropathy (joint stiffness and pain) involving the metacarpophalangeal joints, progressive increase in skin pigmentation resulting from deposits of melanin and iron, diabetes mellitus resulting from pancreatic iron deposits, and cardiomyopathy resulting from cardiac parenchymal iron stores. Hepatomegaly may or may not be present early in HFE hemochromatosis. Some asymptomatic individuals have hepatomegaly on physical examination. Some men, typically those with severe iron overload, have erectile dysfunction, hypotestosteronemia, loss of muscle mass, and osteoporosis due to hypogonadotropic hypogonadism. In women, hypogonadism leads to diminished libido, amenorrhea, and infertility in some individuals. Abdominal pain, weakness, lethargy, and weight loss are common nonspecific findings [Edwards & Barton 2018]. The HEIRS Study found an odds ratio of 3.3 for liver disease among men homozygous for p.Cys282Tyr [Adams et al 2005]. With progressive iron overload, cirrhosis may develop and be complicated by portal hypertension, primary liver cancer, and end-stage liver disease [Kowdley et al 2005]. Alcohol consumption worsens the symptoms in HFE hemochromatosis [Scotet et al 2003]. Approximately 50% of individuals with cirrhosis or liver failure also have diabetes mellitus and approximately 15% have congestive heart failure or cardiac arrhythmias. Cirrhosis is more common among p.Cys282Tyr homozygotes who consume more than 60 g of alcohol per day [Fletcher et al 2002]. Age, diabetes, alcohol consumption, and severity of iron overload increase the risk of cirrhosis, after adjusting for other factors [Barton et al 2018]. Life expectancy. Individuals diagnosed and treated prior to the development of cirrhosis have normal life expectancy. Those diagnosed after the development of cirrhosis have a decreased life expectancy even with iron depletion therapy [Adams et al 2005], primarily due to the development of hepatocellular cancer. Prognosis. Individuals with cirrhosis who are treated have a better outcome than those who are not treated. Treatment of patients with cirrhosis to achieve iron depletion does not eliminate the 10%-30% risk of primary liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma). Failure to deplete iron stores after 18 months of treatment is a poor prognostic sign that reflects iron overload severity in most individuals and insufficient phlebotomy therapy in other individuals. With iron depletion, dysfunction of some organs (liver and heart) can improve. Endocrine abnormalities and arthropathy improve in 20% of treated individuals. Death in individuals with clinical HFE hemochromatosis is often caused by liver failure, primary liver cancer, extrahepatic cancers, congestive heart failure, or arrhythmia. #### Biochemical HFE Hemochromatosis It is controversial whether individuals who have biochemical HFE hemochromatosis in the absence of clinical HFE hemochromatosis are at increased risk of developing complications of iron overload and are therefore candidates for phlebotomy treatment (see Management). Ferritin levels at diagnosis. Bardou-Jacquet and colleagues concluded that HFE p.Cys282Tyr homozygotes with a serum ferritin at diagnosis between the upper limit of normal and 1,000 μg/L have lower mortality than the general population due to phlebotomy therapy [Bardou-Jacquet et al 2015a, Bardou-Jacquet et al 2015b, Bardou-Jacquet et al 2015c]. Conversely, an Australian consortium concluded that the benefits of phlebotomy for p.Cys282Tyr homozygotes with mildly elevated serum ferritin remain unproven without a randomized study with long-term follow-up [Delatycki et al 2015]. Prospective follow-up study of a few HFE Cys282Tyr homozygotes found that iron overload is not progressive in all individuals. Although serum ferritin concentration may rise in these individuals over time, end-organ damage is uncommon and is more frequently observed in men than women [Allen et al 2008, Gurrin et al 2008]. Modifying factors. It has been assumed for many years that additional modifying factors or pathogenic variants in non-HFE genes are required for expression of hemochromatosis in some p.Cys282Tyr homozygotes. An international consortium identified a modifying variant p.Asp519Gly in GNPAT in p.Cys282Tyr homozygotes, which occurs with greater frequency in men and women with severe iron overload in the absence of heavy alcohol consumption than in those without severe iron overload [McLaren et al 2015, Barton et al 2017]. GNPAT p.Asp519Gly was not an independent risk factor for cirrhosis in men and women with p.Cys282Tyr homozygosity who underwent liver biopsy [Barton et al 2018]. #### Non-Expressing p.Cys282Tyr Homozygotes Non-expressing homozygotes are unlikely to develop end-organ damage. Women represent a higher proportion of non-expressing homozygotes than men [Allen et al 2010, Gan et al 2011]. Three longitudinal population-based screening studies showed that 38%-50% of p.Cys282Tyr homozygotes develop iron overload (i.e., elevated serum ferritin concentration) and 10%-33% eventually develop hemochromatosis-related symptoms [Whitlock et al 2006] (i.e., nonspecific symptoms such as fatigue and arthralgia) or end-organ damage (e.g., cirrhosis, diabetes mellitus, and/or cardiomyopathy). The majority of HFE p.Cys282Tyr homozygotes who develop end-organ damage and corresponding manifestations are men [Allen et al 2010, European Association for the Study of the Liver 2010, Gan et al 2011]. #### Heterozygotes Some individuals who are heterozygous for either HFE p.Cys282Tyr or p.His63Asp have elevated serum TS and serum ferritin concentrations, but they do not develop complications of iron overload [Bulaj et al 1996, Allen et al 2008]. Although a threshold TS of 45% may be more sensitive than higher values for detecting HFE hemochromatosis, TS of 45% may also identify heterozygotes who are not at risk of developing other clinical abnormalities [McLaren et al 1998]. In a large study of Danish men, Pedersen & Milman [2009] showed that: * Among p.Cys282Tyr heterozygotes, 9% had elevated serum TS (≥50%), 9% had elevated ferritin (≥300 ng/mL), and 1.2% had elevation of both serum TS and ferritin. * Among p.His63Asp heterozygotes, 8% had elevated serum TS, 12% had elevated ferritin, and 2% had elevation of both TS and ferritin. ### Genotype-Phenotype Correlations Homozygotes for p.Cys282Tyr are at greater risk of developing iron overload than p.Cys282Tyr/p.His63Asp compound heterozygotes. ### Penetrance Penetrance of HFE hemochromatosis refers to the percentage of adults (men and women separately) homozygous or compound heterozygous for HFE pathogenic variants who exhibit either clinical or biochemical hemochromatosis: * p.Cys282Tyr homozygotes. Penetrance for biochemically defined iron overload among p.Cys282Tyr homozygotes is relatively high, but not 100%. In contrast, penetrance of clinically defined iron overload is low. Penetrance of clinical endpoints of iron overload have not been determined for individuals homozygous for p.Cys282Tyr. Penetrance was as low as 2% in the large study by Beutler et al [2002]. Currently, no test can predict whether an individual homozygous for p.Cys282Tyr will develop clinical HFE hemochromatosis. * p.Cys282Tyr/p.His63Asp compound heterozygotes. The penetrance of this genotype is low: 0.5%-2.0% of such individuals develop clinical evidence of iron overload [Gurrin et al 2009]. * Many p.Cys282Tyr/p.His63Asp compound heterozygotes who develop clinical evidence of iron overload have a concomitant factor (e.g., fatty liver, viral hepatitis) that may increase iron absorption, enhance liver injury, or increase TS and serum ferritin levels due to hepatocellular injury. * Male p.Cys282Tyr/p.His63Asp compound heterozygotes in the HEIRS Study were more likely to report a history of liver disease (odds ratio 1.7, p=0.05) [Adams et al 2005]. * p.His63Asp homozygotes. The penetrance of this genotype is lower than the penetrance of the p.Cys282Tyr/p.His63Asp genotype. Although biochemically defined abnormalities may be present, clinical manifestations characteristic of iron overload are rare [Gochee et al 2002]. ### Nomenclature HFE hemochromatosis has been variably described in the past as hereditary hemochromatosis, primary hemochromatosis, genetic hemochromatosis, and bronze diabetes with cirrhosis. After the description of other types of iron overload associated with pathogenic variants in non-HFE iron-related genes, HFE hemochromatosis was described as either HFE hemochromatosis or type 1 hemochromatosis. It is preferred to specify hemochromatosis according to gene or genotype. Using the term "hereditary" for hemochromatosis of known pathogenic genotype is redundant. ### Prevalence Among most populations of northern European ancestry, the prevalence of individuals homozygous for HFE p.Cys282Tyr is 2:1,000 to 5:1,000 [Barton et al 2015]. In non-Hispanic whites in North America, the prevalence of p.Cys282Tyr homozygotes is 1:200 to 1:400 [Adams et al 2005]. Among African Americans, p.Cys282Tyr homozygotes are rare (1:6,781). The prevalence of heterozygotes is 1:775. Among Asians, p.Cys282Tyr homozygotes are very rare (1:25,000). The prevalence of heterozygotes is 1:1,000. Among Hispanics, the prevalence of p.Cys282Tyr homozygotes and heterozygotes is 0.027% and 3.0%, respectively. Heterozygosity for p.His63Asp is common in most populations (northern Europeans: 25%; Hispanics: 18%; African Americans: 6%; Asians: 8.5%). Approximately one third of northern European whites are heterozygous for either p.Cys282Tyr or p.His63Asp. ## Differential Diagnosis HFE hemochromatosis differs from rarer primary iron overload disorders and secondary iron overload disorders. Primary iron overload disorders (summarized in Table 2) are characterized by increased absorption of iron from a normal diet in subjects without severe anemia. Juvenile hereditary hemochromatosis and TFR2-related hereditary hemochromatosis result from hepcidin deficiency and thus the clinical manifestations of these disorders are similar to but more severe than those of hemochromatosis associated with HFE p.Cys282Tyr homozygosity. ### Table 2. Primary Iron Overload Disorders in the Differential Diagnosis of HFE Hemochromatosis View in own window DisorderGene(s)MOIClinical Features of Differential Diagnosis Disorder Overlapping w/HFE HemochromatosisDistinguishing from HFE Hemochromatosis Juvenile hereditary hemochromatosisHJV HAMPAR * Iron accumulation in parenchymal cells * Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common * Earlier onset * More severe clinical manifestations * Hepatocellular cancer not reported (possibly due to short life span) TFR2-related hereditary hemochromatosisTFR2AR * Iron accumulation in parenchymal cells * Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common * Earlier onset * Progression similar to HJV, earlier than HFE & juvenile hemochromatosis Ferroportin-associated iron overload (OMIM 606069)SLC40A1ADIn gain-of-function (hepcidin resistance) subtype: * ↑ TS & serum ferritin * Iron deposition in hepatocytes In loss-of-function (classic) subtype: * Anemia * ↑ serum ferritin * Normal or ↓ TS * RE iron deposition * Low tolerance to phlebotomy therapy * Late onset Many persons w/classic subtype have little or no liver injury. AceruloplasminemiaCPARProgressive iron deposition in liver & pancreas causes cirrhosis & diabetes. * Heavy iron deposition in brain accounts for neurologic dysfunction in adults. * Iron deposition in retina is distinctive. * Mild iron-deficiency anemia by early adulthood; TS low * Rare; may be more common among Japanese BMP6-related iron overload (OMIM 112266)BMP6AD * Adults affected * ↑ TS & serum ferritin * Arthralgias in some individuals * Probands usually age >50 yrs * Iron overload typically mild * Iron deposition in both hepatocytes & Kupffer cells * Serum hepcidin levels normal or slightly ↑ African iron overload (OMIM 601195)?? * Iron accumulation in Kupffer cells & hepatocytes * Cirrhosis common * Affects persons of native sub-Saharan African descent * Associated w/excessive intake of dietary iron in traditional beer brewed in non-galvanized steel drums * Associated w/tuberculosis, hepatocellular carcinoma, & esophageal carcinoma ? = unknown; AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; RE = reticuloendothelial cells; TS = transferrin saturation ### Secondary Iron Overload Disorders Liver diseases include alcoholic liver disease, acute viral hepatitis, or chronic viral hepatitis C (uncommon), neoplasms, porphyria cutanea tarda, and inflammatory disorders such as rheumatoid arthritis. A very common liver condition, nonalcoholic fatty liver disease (NAFLD) (OMIM 613282), frequently causes elevated serum ferritin levels and is sometimes associated with increased hepatic iron deposition. Iron overload can result from ingested iron in foods, cooking ware, and medicines, in addition to parenteral iron from iron injections or transfusions for chronic anemia (e.g., beta-thalassemia, sickle cell disease, hereditary sideroblastic anemia, pyruvate kinase deficiency, hereditary spherocytosis, myelodysplastic syndrome with refractory anemia). Iron absorption is increased in some subtypes of heritable anemia, especially severe beta-thalassemia and hereditary sideroblastic anemia. Neonatal hemochromatosis is a severe liver disease that develops in utero and is associated with extrahepatic siderosis. Gestational alloimmune liver disease is the cause of fetal liver injury resulting in nearly all cases [Feldman & Whitington 2013]. Maternal alloimmunity accounts for the occurrence of neonatal hemochromatosis in two or more offspring of the same mother. Antenatal therapy with high-dose intravenous IgG initiated at either 18 or 14 gestational weeks prevents poor outcome of pregnancies at risk for neonatal hemochromatosis [Whitington et al 2018]. There is little evidence that neonatal hemochromatosis is a heritable disorder attributed to an as-yet-unidentified gene. Some investigators have suggested that pathogenic variants in DGUOK lead to phenotypes that resemble that of neonatal hemochromatosis (see Deoxyguanosine Kinase Deficiency). See Hemochromatosis: OMIM Phenotypic Series, to view genes associated with this phenotype in OMIM. ## Management The European Association for the Study of the Liver (EASL) published clinical practice guidelines on the management of hemochromatosis [European Association for the Study of the Liver 2010]. The American Association for the Study of Liver Disease (AASLD) published practice guidelines for diagnosis and management of hemochromatosis [Bacon et al 2011] (full text). Experts at the 2017 Hemochromatosis International meeting published an objective and practical set of recommendations on treatment of persons with hemochromatosis and p.Cys282Tyr homozygosity based on published scientific studies and guidelines in a form suitable for patients and other persons without medical training [Adams et al 2018]. ### Evaluations Following Initial Diagnosis To establish the extent of iron overload and optimal management of persons diagnosed with HFE hemochromatosis, the evaluations summarized in this section (if not performed as part of the evaluation at diagnosis) are recommended: * Serum ferritin concentration to establish iron overload status and prognosis (see Figure 2) * For p.Cys282Tyr homozygotes: * Liver biopsy remains the "gold standard" for establishing or excluding cirrhosis. * Liver biopsy to evaluate for advanced hepatic fibrosis is recommended for individuals with serum ferritin >1,000 ng/mL or elevated serum AST and ALT levels [Morrison et al 2003, Bacon et al 2011]. * Liver biopsy is not recommended for those with serum ferritin concentration <1,000 ng/mL and normal serum ALT and AST levels because their risk for advanced hepatic fibrosis is low [Bacon et al 2011, Barton et al 2018]. * MRI to estimate parenchymal iron content by utilizing the paramagnetic properties of iron: * A specialized MRI technique with excellent sensitivity for estimation of hepatic iron concentration has been approved by the FDA for clinical use [St Pierre et al 2005]. This method of quantitative MRI (R2) accurately measures liver iron concentration (LIC) within a sufficiently wide concentration range. Compared with liver biopsy, R2-LIC is noninvasive and significantly reduces biopsy sampling error [Fischer & Harmatz 2009]. In addition, T2-weighted MRI measurement of liver iron is now widely available [Brittenham et al 2003, Cheong et al 2005, Ptaszek et al 2005]. Cardiac iron concentration can be monitored using similar techniques and may be of prognostic value [Fischer & Harmatz 2009, Ramazzotti et al 2009]. #### Figure 2. Use of serum ferritin concentration to direct management #### Clinical HFE Hemochromatosis Therapeutic phlebotomy is indicated in the presence of symptoms of iron overload or evidence of end-organ damage (e.g., cirrhosis, cardiac failure, skin hyperpigmentation, diabetes, or hypogonadotropic hypogonadism): * Periodic phlebotomy is a simple, inexpensive, safe, and effective treatment. * Each unit of blood (500 mL) with a hematocrit of 40% removes 200 mg of iron. * Each mL of packed red blood cells contains 1 mg of iron. * The usual therapy is weekly phlebotomy (i.e., removal of a unit of blood) until the serum ferritin concentration is ≤50 ng/mL. Twice-weekly phlebotomy is useful to accelerate iron depletion in some patients. Some persons, especially women, tolerate phlebotomy therapy less frequently (every 10-14 days) or at lower volume per phlebotomy. * Phlebotomy is performed at intervals until the hematocrit is 75% of the baseline hematocrit. * The serum ferritin concentration is the most reliable and inexpensive way to monitor therapeutic phlebotomy. If the serum ferritin concentration is ≥50 ng/mL despite a significant reduction in hematocrit, the frequency at which phlebotomy is performed needs to be increased. After the serum ferritin concentration is ≤100 ng/mL, serum ferritin concentration should be quantified after each additional one or two treatments [Barton et al 1998]. On average, men require removal of twice as many units of blood to achieve iron depletion as women. * Maintenance phlebotomy to prevent reaccumulation of excess iron is indicated for men whose serum ferritin levels exceed 300 ng/mL and for women whose serum ferritin levels exceed 200 ng/mL [Adams & Barton 2010]. Whether lowering TS should be a target of phlebotomy therapy is debatable. Elevated TS in HFE hemochromatosis is caused by increased iron export from macrophages due to hepcidin deficiency and is not a marker of iron overload. Attempting to achieve and maintain low TS in p.Cys282Tyr homozygotes may result in iron deficiency and associated manifestations [Barton & Bottomley 2000]. * Individuals with HFE hemochromatosis rarely need iron chelation therapy. Iron chelation therapy is not recommended unless an individual has an elevated serum ferritin concentration and concomitant anemia, inadequate venous access, or another circumstance that makes therapeutic phlebotomy impossible. Therapeutic phlebotomy significantly decreases hepatic fibrosis in many persons with HFE p.Cys282Tyr homozygosity, including more than one third of those with cirrhosis. A combination of simple biochemical tests performed before phlebotomy therapy can predict those in whom fibrosis or cirrhosis is reversible [Falize et al 2006]. Orthotopic liver transplantation is the treatment for end-stage liver disease due to decompensated cirrhosis. The post-transplant survival among individuals with HFE hemochromatosis is poor [Crawford et al 2004, Kowdley et al 2005]. In a study of 18 p.Cys282Tyr homozygotes, post-transplant survival was similar to that of individuals with other causes of end-stage liver disease [Bardou-Jacquet et al 2014]. #### Biochemical HFE Hemochromatosis Both the EASL and AASLD guidelines recommend therapeutic phlebotomy for persons with biochemical HFE hemochromatosis (i.e., those who have increased body iron stores in the absence of clinical evidence of iron overload). See European Association for the Study of the Liver [2010] and Bacon et al [2011] (full text). The exact serum ferritin concentration at which therapeutic phlebotomy should be initiated is not clear. The European Association for the Study of the Liver suggests performing phlebotomy when the serum ferritin concentration exceeds 500 ng/mL. In a study of Australian p.Cys282Tyr homozygotes, there was evidence of subjective and objective improvement by reducing serum ferritin levels to <300 ng/mL [Ong et al 2017]. #### Non-Expressing p.Cys282Tyr Homozygotes These individuals do not have iron overload and thus do not need phlebotomy. ### Prevention of Secondary Complications Vaccination against hepatitis A and B is advised [Tavill 2001]. ### Surveillance #### Primary Liver Cancer Individuals who have hemochromatosis and cirrhosis may develop primary liver cancer such as hepatocellular carcinoma, cholangiocarcinoma, or a combination of these histologic types. The American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) published guidelines on surveillance for primary liver cancer among patients who have both cirrhosis and hemochromatosis. The AASLD advised surveillance using hepatic ultrasonography every six months [Bruix et al 2005, Bacon et al 2011, Bruix et al 2011]. The EASL advised both hepatic ultrasonography and measurement of serum alphafetoprotein every six months [European Association for the Study of the Liver 2010]. Authors of a recent study discussed the similarities, differences, and overall quality of hemochromatosis practice guidelines, not confined to surveillance. The conclusions were that the guidelines differed in many ways and that the overall quality of the AASLD, EASL, and Dutch practice guidelines was not high [Swinkels et al 2007, Vanclooster et al 2015]. An AASLD publication [Bruix et al 2011] stated that their surveillance algorithm [Bruix et al 2005] for hepatocellular carcinoma had been validated. #### Clinical HFE Hemochromatosis Once the serum ferritin concentration is <50 ng/mL, monitor serum ferritin every three to four months. It is reasonable to perform follow-up T2-weighted MRI for assessment of cardiac iron among persons with a history of cardiac involvement or known cardiac iron deposition. Cirrhosis is a crucial stage in the natural history of hemochromatosis; thus, the diagnosis of cirrhosis is important because management and clinical outcomes change. Individuals with cirrhosis should be evaluated regularly and screened for primary liver cancer. The AASLD practice guidelines recommend imaging every six months with ultrasonography [Bruix et al 2011]. This may be accompanied with measurement of alpha fetoprotein. Noninvasive methods that use results derived from values of serum markers such as HepaScore® and FibroMeter™ can also be used to assess the stage of liver fibrosis [Martínez et al 2011]. Although the "gold standard" for the diagnosis of cirrhosis is biopsy, FibroScan® has good sensitivity and specificity for cirrhosis [Tsochatzis et al 2011]. FibroScan transient elastography (TE) quantifies fibrosis with ultrasound in a noninvasive manner [Tsochatzis et al 2011]. The results from a meta-analysis suggested a cutoff value for diagnosis of cirrhosis of 13.01 kPa [Friedrich-Rust et al 2008]. Individuals with normal TE values on FibroScan would not need a biopsy. Individuals with intermediate or high TE values should have biopsies to confirm cirrhosis. These results should be interpreted in conjunction with clinical and biochemical parameters. The AASLD guidelines recommend that individuals with cirrhosis undergo surveillance for primary liver cancer whether they have achieved iron depletion or not [Bacon et al 2011] (full text). #### Biochemical HFE Hemochromatosis Begin annual measurement of serum ferritin concentration when values exceed normal levels [European Association for the Study of the Liver 2010]. #### Non-Expressing p.Cys282Tyr Homozygotes Begin annual measurement of serum ferritin concentration when values exceed normal levels [European Association for the Study of the Liver 2010]. ### Agents/Circumstances to Avoid Medicinal iron, mineral supplements, excess vitamin C, uncooked seafood, alcohol consumption in individuals with cirrhosis or other liver disease, and daily ingestion of more than 500 mg of supplemental ascorbic acid / vitamin C should be avoided. ### Evaluation of Relatives at Risk It is appropriate to clarify the status of adult sibs and offspring of individuals homozygous for p.Cys282Tyr in order to identify those who would benefit from prompt initiation of treatment and preventive measures. The following strategy is appropriate: 1. Offer molecular genetic testing to the adult sibs (≥18 years) of an individual homozygous for p.Cys282Tyr. 2. Measure TS and serum ferritin level of sibs who are homozygous for p.Cys282Tyr. 3. Begin phlebotomy therapy if serum ferritin concentration is elevated and if the proband has clinical HFE hemochromatosis. Sibs of probands with clinical HFE hemochromatosis have a higher prevalence of clinical HFE hemochromatosis than asymptomatic individuals with HFE hemochromatosis detected through screening programs [Bulaj et al 2000]. Targeted testing for p.Cys282Tyr is cost effective in most individuals because it has excellent negative predictive value. Genotype-based testing has a low positive predictive value because many p.Cys282Tyr homozygotes and compound heterozygotes do not develop iron overload [El-Serag et al 2000, Beutler et al 2002]. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management No guidelines exist. It is common practice to withhold phlebotomy during pregnancy. ### Therapies Under Investigation The oral iron chelator deferasirox (Exjade®) has been evaluated in a Phase I/II study of individuals with hemochromatosis. Results of this trial suggest that deferasirox is effective at reducing iron burdens within an acceptable safety profile [Phatak et al 2010]. The intravenous iron chelator deferoxamine has been studied in 24 persons with hemochromatosis [Saddi et al 1978]. Severe cardiac siderosis in a patient with juvenile hemochromatosis was treated with success using a combination of deferoxamine and deferiprone [Fabio et al 2007]. To date, the US Food and Drug Administration has not approved deferasirox, deferoxamine, or deferiprone for treatment of hemochromatosis. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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	HFE Hemochromatosis	None	6,274	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1440/	2021-01-18T21:22:21	{"synonyms": ["Hemochromatosis Type 1", "HFE-Associated Hemochromatosis", "HFE-HH"]}
Camptocormia, camptocormism or "bent spine syndrome," (BSS) is an extreme forward flexion of the thoracolumbar spine, which often worsens during standing or walking, but completely resolves when laying down. The term itself is derived from the Greek "kamptos" (to bend) and "kormos" (trunk) BSS was initially considered, especially in wartime, as a result of a psychogenic disorder. It is now recognized that in it may also be related to a number of musculo-skeletal or neurological disorders. It seems that myopathy is the primary cause of camptocormia based on electromyography, magnetic resonance imaging/computed tomography (CT/MRI scans) of paraspinal muscles, and muscle biopsy. The majority of BSS of muscular origin is related to a primary idiopathic (with unknwon cause) axial myopathy of late onset, maybe a delayed-onset paraspinal myopathy, appearing in elderly patients. Causes of secondary BSS are numerous. The main causes are muscular disorders like inflammatory myopathies, muscular dystrophies of late onset, myotonic myopathies, endocrine and metabolic myopathies, and neurological disorders, principally Parkinson’s disease. Diagnosis of axial myopathy is based upon CT/MRI scans demonstrating a lot of fatty infiltration of paravertebral muscles. General activity, walking with a cane, physiotherapy, and exercises should be encouraged. Treatment of secondary forms of BSS is dependent upon the cause. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Camptocormism	c0264162	6,275	gard	https://rarediseases.info.nih.gov/diseases/1063/camptocormism	2021-01-18T18:01:39	{"mesh": ["C537968"], "umls": ["C0264162"], "orphanet": ["1320"], "synonyms": ["Camptocormia", "Bent spine", "Bent Spine Syndrome", "Idiopathic camptocormia", "Idiopathic camptocormism", "Idiopathic progressive lumbar kyphosis"]}
Intracranial berry aneurysm-3 (ANIB3) has been mapped to chromosome 1p36. Description Rupture of an intracranial aneurysm, an outpouching or sac-like widening of a cerebral artery, leads to a subarachnoid hemorrhage, a sudden-onset disease that can lead to severe disability and death. Several risk factors such as smoking, hypertension, and excessive alcohol intake are associated with subarachnoid hemorrhage (summary by Krischek and Inoue, 2006). For a discussion of genetic heterogeneity of intracranial berry aneurysm, see ANIB1 (105800). Clinical Features Fox and Ko (1980) reported a sibship of 13, of which 6 had proven intracranial aneurysm, 5 had normal findings on cerebral arteriography, and 2 refused arteriography. The parents and other relatives were not known to be affected. The authors reasoned that 'it is hard to escape the strong possibility of a dominant inheritance' in this family. Although this may well be true, observation of several cases in a single sibship is not supportive of their conclusion. One of the sibs who refused elective angiography (Fox and Ko, 1980) was the subject of a report by Fox (1982): the 57-year-old woman suffered subarachnoid hemorrhage, was found to have 2 aneurysms by arteriography, and died suddenly 3 days before the scheduled surgery to clip them. Thus, 7 of 12 sibs had aneurysm; the status of the thirteenth sib was unknown. Roos et al. (2004) reported a large consanguineous Dutch family in which 7 of 20 sibs had an intracranial aneurysm. Three had a subarachnoid hemorrhage (SAH) at ages 37, 42, and 45 years, respectively; 1 died with suspected SAH at age 36 years, and 3 were found to have asymptomatic cerebral aneurysms on imaging studies. Ruigrok et al. (2008) reported follow-up of the family reported by Roos et al. (2004). Two additional sibs had developed aneurysms since the original report, and 1 previously thought to be affected based on brain imaging was found not to be affected. Mapping Nahed et al. (2005) performed linkage studies in a family reported by Fox and Ko (1980). At the time of the original report, there were 6 members with proven intracranial aneurysm, all in generation II. Nahed et al. (2005) extended the pedigree and with further characterization found 10 documented subjects with IAs, 1 with distinctive multiple intracranial vessel occlusions and extensive collateral vessel formation of unknown etiology, and 1 subject with abdominal aortic aneurysm at a young age (age 32 years). At the time of this follow-up, there were affected members in 3 generations and by inference in an earlier generation, represented by a presumably carrier female who had affected children by 2 different husbands. Genomewide analysis of linkage was performed using a 2-stage approach: an analysis of approximately 10,000 single-nucleotide polymorphisms (SNPs) in the 6 living affected subjects, followed by the genotyping of simple tandem repeats across resulting candidate intervals so demonstrated in all 23 members of the kindred. Analysis showed significant linkage to a single locus, with a lod score of 4.2 at 1p36.13-p34.3 under a dominant model with high penetrance. Although genomewide linkage analysis by Roos et al. (2004) found linkage to a region on chromosome 2p13, this was later found to be erroneous. Repeat linkage analysis of this large Dutch family by Ruigrok et al. (2008) found linkage to an 18.05-cM interval on chromosome 1p36.21-p36.13 between markers D1S2826 and D1S234 (maximum nonparametric lod score of 3.18 at markers D1S199, D1S552, and D1S2702). Six of the 7 patients shared a 6-marker diplotype with 1 chromosome inherited from the father and 1 from the mother, consistent with autosomal recessive inheritance. However, linkage analysis of this family also showed linkage to chromosome Xp22.32-p22.2 (ANIB5; 300870) under a model of X-linked dominant inheritance. Ruigrok et al. (2008) noted that aneurysms in this family may have a multigenic origin. INHERITANCE \- Autosomal dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	ANEURYSM, INTRACRANIAL BERRY, 3	c1862932	6,276	omim	https://www.omim.org/entry/609122	2019-09-22T16:06:37	{"doid": ["0060228"], "mesh": ["C566284"], "omim": ["105800", "609122"], "orphanet": ["231160"], "synonyms": ["Familial berry aneurysm", "Familial intracranial saccular aneurysm"]}
Multiple epiphyseal dysplasia type 4 is a multiple epiphyseal dysplasia with a late-childhood onset, characterized by joint pain involving hips, knees, wrists, and fingers with occasional limitation of joint movements, deformity of hands, feet, and knees (club foot, clinodactyly, brachydactyly), scoliosis and slightly reduced adult height. Radiographs display flat epiphyses with early arthritis of the hip, and double-layered patella. Multiple epiphyseal dysplasia type 4 follows an autosomal recessive mode of transmission. The disease is allelic to diastrophic dwarfism, atelosteogenesis type 2 and achondrogenesis type 1B with whom it forms a clinical continuum. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 epiphyseal dysplasia type 4	c1847593	6,277	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93307	2021-01-23T18:57:25	{"gard": ["9793"], "mesh": ["C535504"], "omim": ["226900"], "umls": ["C1847593"], "icd-10": ["Q77.3"], "synonyms": ["Autosomal recessive multiple epiphyseal dysplasia", "EDM4", "MED4", "Polyepiphyseal dysplasia type 4", "rMED"]}
Keratomalacia SpecialtyEndocrinology, ophthalmology Keratomalacia is an eye disorder that results from vitamin A deficiency. Vitamin A is required to maintain specialized epithelia (such as in the cornea and conjunctiva). The precise mechanism is still not known, but vitamin A is necessary for the maintenance of the specialized epithelial surfaces of the body. A lack of vitamin A leads to atrophic changes in the normal mucosal surface, with loss of goblet cells, and replacement of the normal epithelium by an inappropriate keratinized stratified squamous epithelium. In addition, the substantia propria of the cornea breaks down and liquefies, resulting in keratomalacia.[1] The resulting cornea becomes totally opaque, which is one of the most common reasons for blindness around the world, particularly in developing countries. ## See also[edit] * Acute promyelocytic leukemia * Keratoconjunctivitis sicca * Xerophthalmia ## References[edit] 1. ^ Schwartz, Robert. "Dermatologic manifestations of Vitamin A deficiency". Medscape. Retrieved 13 June 2013. ## External links[edit] Classification D * ICD-10: E50.4 * ICD-9-CM: 264.4, 371.45 * MeSH: C536156 C536156, C536156 External resources * Patient UK: Keratomalacia * patient.co.uk This article about the eye is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Keratomalacia	c0152455	6,278	wikipedia	https://en.wikipedia.org/wiki/Keratomalacia	2021-01-18T18:57:58	{"gard": ["6825"], "mesh": ["C536156"], "umls": ["C0152455"], "wikidata": ["Q379418"]}
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: "Binasal hemianopsia" – news · newspapers · books · scholar · JSTOR (June 2019) Binasal hemianopsia Other namesBinasal hemianopia Paris as seen with binasal hemianopsia SpecialtyOphthalmology Binasal hemianopsia is the medical description of a type of partial blindness where vision is missing in the inner half of both the right and left visual field. It is associated with certain lesions of the eye and of the central nervous system, such as congenital hydrocephalus. ## Contents * 1 Causes * 2 Management * 3 Etymology * 4 See also * 5 References * 6 External links ## Causes[edit] Paris as seen with full visual fields In binasal hemianopsia, vision is missing in the inner (nasal or medial) half of both the right and left visual fields. Information from the nasal visual field falls on the temporal (lateral) retina. Those lateral retinal nerve fibers do not cross in the optic chiasm. Calcification of the internal carotid arteries can impinge the uncrossed, lateral retinal fibers, leading to loss of vision in the nasal field. Clinical testing of visual fields (by confrontation) can produce a false positive result, particularly in inferior nasal quadrants. ## Management[edit] This section is empty. You can help by adding to it. (April 2018) ## Etymology[edit] The absence of vision in half of a visual field is described as hemianopsia. The absence of visual perception in one quarter of a visual field is described as quadrantanopsia. The visual field of each eye can be divided in two vertically, with the outer half being described as temporal or lateral, and the inner half being described as nasal. "Binasal hemianopsia" can be broken down as follows: * bi-: involves both left and right visual fields * nasal: involves the nasal visual field * hemi-: involves one-half of each visual field * anopsia: blindness ## See also[edit] * Bitemporal hemianopsia * Homonymous hemianopsia ## References[edit] ## External links[edit] Classification D * ICD-10: H53.4 * ICD-9-CM: 368.47 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake 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	Binasal hemianopsia	c0271208	6,279	wikipedia	https://en.wikipedia.org/wiki/Binasal_hemianopsia	2021-01-18T19:07:58	{"mesh": ["D006423"], "icd-9": ["368.47"], "icd-10": ["H53.4"], "wikidata": ["Q4086828"]}
Onychorrhexis Other namesBrittle nails SpecialtyDermatology Onychorrhexis (from the Greek words ὄνυχο- ónycho-, "nail" and ῥῆξις rhexis, "bursting"), is a brittleness with breakage of finger or toenails that may result from hypothyroidism, anemia, anorexia nervosa or bulimia, or after oral retinoid therapy.[1]:786 Onychorrhexis affects up to 20% of the population.[1]:786[2] ## See also[edit] * Nail anatomy * List of cutaneous conditions ## References[edit] 1. ^ a b James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. ## External links[edit] Classification D * ICD-10: L60.3 (ILDS L60.350) * DiseasesDB: 33353 * v * t * e Disorders of skin appendages Nail * thickness: Onychogryphosis * Onychauxis * color: Beau's lines * Yellow nail syndrome * Leukonychia * Azure lunula * shape: Koilonychia * Nail clubbing * behavior: Onychotillomania * Onychophagia * other: Ingrown nail * Anonychia * ungrouped: Paronychia * Acute * Chronic * Chevron nail * Congenital onychodysplasia of the index fingers * Green nails * Half and half nails * Hangnail * Hapalonychia * Hook nail * Ingrown nail * Lichen planus of the nails * Longitudinal erythronychia * Malalignment of the nail plate * Median nail dystrophy * Mees' lines * Melanonychia * Muehrcke's lines * Nail–patella syndrome * Onychoatrophy * Onycholysis * Onychomadesis * Onychomatricoma * Onychomycosis * Onychophosis * Onychoptosis defluvium * Onychorrhexis * Onychoschizia * Platonychia * Pincer nails * Plummer's nail * Psoriatic nails * Pterygium inversum unguis * Pterygium unguis * Purpura of the nail bed * Racquet nail * Red lunulae * Shell nail syndrome * Splinter hemorrhage * Spotted lunulae * Staining of the nail plate * Stippled nails * Subungual hematoma * Terry's nails * Twenty-nail dystrophy Hair Hair loss/ Baldness * noncicatricial alopecia: Alopecia * areata * totalis * universalis * Ophiasis * Androgenic alopecia (male-pattern baldness) * Hypotrichosis * Telogen effluvium * Traction alopecia * Lichen planopilaris * Trichorrhexis nodosa * Alopecia neoplastica * Anagen effluvium * Alopecia mucinosa * cicatricial alopecia: Pseudopelade of Brocq * Central centrifugal cicatricial alopecia * Pressure alopecia * Traumatic alopecia * Tumor alopecia * Hot comb alopecia * Perifolliculitis capitis abscedens et suffodiens * Graham-Little syndrome * Folliculitis decalvans * ungrouped: Triangular alopecia * Frontal fibrosing alopecia * Marie Unna hereditary hypotrichosis Hypertrichosis * Hirsutism * Acquired * localised * generalised * patterned * Congenital * generalised * localised * X-linked * Prepubertal Acneiform eruption Acne * Acne vulgaris * Acne conglobata * Acne miliaris necrotica * Tropical acne * Infantile acne/Neonatal acne * Excoriated acne * Acne fulminans * Acne medicamentosa (e.g., steroid acne) * Halogen acne * Iododerma * Bromoderma * Chloracne * Oil acne * Tar acne * Acne cosmetica * Occupational acne * Acne aestivalis * Acne keloidalis nuchae * Acne mechanica * Acne with facial edema * Pomade acne * Acne necrotica * Blackhead * Lupus miliaris disseminatus faciei Rosacea * Perioral dermatitis * Granulomatous perioral dermatitis * Phymatous rosacea * Rhinophyma * Blepharophyma * Gnathophyma * Metophyma * Otophyma * Papulopustular rosacea * Lupoid rosacea * Erythrotelangiectatic rosacea * Glandular rosacea * Gram-negative rosacea * Steroid rosacea * Ocular rosacea * Persistent edema of rosacea * Rosacea conglobata * variants * Periorificial dermatitis * Pyoderma faciale Ungrouped * Granulomatous facial dermatitis * Idiopathic facial aseptic granuloma * Periorbital dermatitis * SAPHO syndrome Follicular cysts * "Sebaceous cyst" * Epidermoid cyst * Trichilemmal cyst * Steatocystoma * simplex * multiplex * Milia Inflammation * Folliculitis * Folliculitis nares perforans * Tufted folliculitis * Pseudofolliculitis barbae * Hidradenitis * Hidradenitis suppurativa * Recurrent palmoplantar hidradenitis * Neutrophilic eccrine hidradenitis Ungrouped * Acrokeratosis paraneoplastica of Bazex * Acroosteolysis * Bubble hair deformity * Disseminate and recurrent infundibulofolliculitis * Erosive pustular dermatitis of the scalp * Erythromelanosis follicularis faciei et colli * Hair casts * Hair follicle nevus * Intermittent hair–follicle dystrophy * Keratosis pilaris atropicans * Kinking hair * Koenen's tumor * Lichen planopilaris * Lichen spinulosus * Loose anagen syndrome * Menkes kinky hair syndrome * Monilethrix * Parakeratosis pustulosa * Pili (Pili annulati * Pili bifurcati * Pili multigemini * Pili pseudoannulati * Pili torti) * Pityriasis amiantacea * Plica neuropathica * Poliosis * Rubinstein–Taybi syndrome * Setleis syndrome * Traumatic anserine folliculosis * Trichomegaly * Trichomycosis axillaris * Trichorrhexis (Trichorrhexis invaginata * Trichorrhexis nodosa) * Trichostasis spinulosa * Uncombable hair syndrome * Wooly hair nevus Sweat glands Eccrine * Miliaria * Colloid milium * Miliaria crystalline * Miliaria profunda * Miliaria pustulosa * Miliaria rubra * Occlusion miliaria * Postmiliarial hypohidrosis * Granulosis rubra nasi * Ross’ syndrome * Anhidrosis * Hyperhidrosis * Generalized * Gustatory * Palmoplantar Apocrine * Body odor * Chromhidrosis * Fox–Fordyce disease Sebaceous * Sebaceous hyperplasia This condition of the skin appendages 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	Onychorrhexis	c0263530	6,280	wikipedia	https://en.wikipedia.org/wiki/Onychorrhexis	2021-01-18T18:30:30	{"icd-10": ["L60.3"], "wikidata": ["Q7095163"]}
Hereditary diffuse gastric cancer is a rare epithelial tumor of the stomach, characterized by the development of diffuse (signet ring cell) gastric cancer at a young age, associated with germline heterozygous mutations of CDH1, MAP3K6 and CTNNA1 genes. In early stages it presents with non-specific and vague symptoms, in advanced stages it may cause nausea and vomiting, dysphagia, loss of appetite, abdominal mass or weight loss. Women have an increased risk of lobular breast cancer as well. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Hereditary diffuse gastric cancer	c1708349	6,281	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=26106	2021-01-23T18:55:37	{"gard": ["10900"], "mesh": ["D013274"], "omim": ["137215"], "umls": ["C1708349"], "icd-10": ["C16.9"], "synonyms": ["FDGC", "Familial diffuse cancer of stomach", "Familial diffuse gastric cancer", "HDGC", "Hereditary diffuse cancer of stomach", "Hereditary diffuse gastric adenocarcinoma"]}
A rare, acquired retinal disorder characterized by unilateral, acute onset, rapidly progressive visual field loss. Sometimes patients have photopsia and complain of floaters. Typical ophthalmoscopic finding is a unilateral, yellowish-white annular intraretinal line, splitting the retinal field to affected outer retina with thinning, and normal retina. Gradual spontaneous visual recovery has been 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	Acute annular outer retinopathy	None	6,282	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=284460	2021-01-23T19:00:25	{"synonyms": ["AAOR"]}
## Clinical Features Lehrke (1974) described a nonspecific form of X-linked mental retardation in a large kindred designated family 1. The pedigree was updated by Howard-Peebles and Roberts (1984). Affected males had lower verbal IQs than performance IQs. Several of the affected males had performance IQs above 80; however, because of the lower (12.3 points on average) verbal IQs, they were considered retarded. Mapping Gregg et al. (1996) mapped the gene for this form of X-linked mental retardation, designated MRX23, to Xq23-q24 by linkage studies in the large kindred (family 1) of Lehrke (1974). Multipoint linkage analysis gave a maximum lod score of 6.7 between markers DXS1220 and DXS424. Obligate carrier females were considered unaffected; however, IQs were not determined for these individuals. Mapping to the same region of Xq are other families of nonspecific X-linked mental retardation, designated MRX27 (Gedeon et al., 1996), MRX35 (300957), and MRX80 (Verot et al., 2003). INHERITANCE \- X-linked NEUROLOGIC Central Nervous System \- Mental retardation ▲ 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	MENTAL RETARDATION, X-LINKED 23	c2931498	6,283	omim	https://www.omim.org/entry/300046	2019-09-22T16:20:57	{"doid": ["0050776"], "mesh": ["C567906"], "omim": ["300046"], "orphanet": ["777"]}
A number sign (#) is used with this entry because of evidence that autosomal dominant axonal Charcot-Marie-Tooth disease type 2DD (CMT2DD) is caused by heterozygous mutation in the ATP1A1 gene (182310) on chromosome 1p13. Description Charcot-Marie-Tooth disease type 2DD is an autosomal dominant peripheral sensorimotor neuropathy mainly affecting the lower limbs. Affected individuals have gait impairment due to distal muscle weakness and atrophy. Some patients may also have involvement of the distal upper limbs, resulting in atrophy of the intrinsic hand muscles. The age at onset and severity of the disorder is highly variable, even within families, and those with earlier onset in late childhood or the teenage years tend to have a more severe disease course. Patients remain ambulatory even late in the disease, although some may require orthotic devices (summary by Lassuthova et al., 2018). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210). Clinical Features Lassuthova et al. (2018) reported 7 unrelated families from 4 different continents with axonal CMT. The age at symptoms onset was highly variable, ranging from 8 to 50 years, although most patients had onset in the teens or twenties. The patients had distal muscle weakness and atrophy mainly affecting the lower limbs and resulting in steppage gait and foot drop, with some also having involvement of the distal upper limbs resulting in atrophy of the intrinsic hand muscles. Proximal muscle strength was normal in virtually all patients. Most had decreased vibratory sensation and decreased or absent reflexes in the lower limbs, with occasional upper limb involvement. Nerve conduction studies, when performed, showed reduced compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes with preserved nerve conduction velocities (NCVs), diagnostic of an axonal sensorimotor neuropathy. Many patients had pes cavus. Sural nerve biopsy from an affected 33-year-old male showed a loss of large myelinated fibers, groups of regenerating axons, and some thinly myelinated large axons, also consistent with an axonal neuropathy. Expression of the disorder was highly variable, even within families. Earlier onset tended to be associated with a more severe phenotype. However, several individuals who carried mutations had normal neurologic examinations into the fifth decade, but had clear abnormalities in their NCVs. Inheritance The transmission pattern of CMT2DD in the families reported by Lassuthova et al. (2018) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of 7 unrelated families with CMT2DD, Lassuthova et al. (2018) identified 7 different heterozygous missense mutations in the ATP1A1 gene (see, e.g., 182310.0001-182310.0005). Five of the mutations occurred in a hotspot within the helical linker region (residues 592 to 608) that couples the N and P domains involved in ATP hydrolysis and phosphorylation. These mutations were predicted to cause decoupling of ATP hydrolysis and phosphorylation, which is essential for ion selectivity and driving the 2 major alternating conformations of the pump. In vitro electrophysiologic functional expression studies in Xenopus oocytes showed that 2 of the mutations (P600A, 182310.0002 and D811A, 182310.0005) resulted in significantly fewer Na(+)-dependent currents compared to wildtype. Additional functional studies using a ouabain survival assay in U2OS cells with ouabain-insensitive ATP1A1 mutants showed that several of the CMT2DD-associated mutations caused a significant decrease in cell survival, supporting a detrimental functional effect of the mutations. Lassuthova et al. (2018) suggested that ATP1A1 mutations cause a reduction in Na+/K(+)-ATPase activity, thus reducing the Na+ gradient across the axonal membrane and potentially causing increased intracellular axonal Ca(2+) levels, which would be toxic to the cell and cause axonal degeneration. The findings indicated a loss-of-function effect and indicated haploinsufficiency. The patients were ascertained from multiple large international data cohorts. INHERITANCE \- Autosomal dominant SKELETAL Hands \- Atrophy of the intrinsic hand muscles Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Distal muscle weakness due to peripheral neuropathy \- Distal muscle atrophy due to peripheral neuropathy \- Muscle cramps NEUROLOGIC Peripheral Nervous System \- Sensorimotor peripheral neuropathy \- Steppage gait \- Foot drop \- Decreased vibratory sensation, distal \- Hyporeflexia \- Areflexia \- Reduced compound muscle action potential (CMAP) amplitudes \- Reduced sensory nerve actions potential (SNAP) amplitudes \- Normal nerve conduction velocities (NCV) \- Loss of large myelinated fibers seen on sural nerve biopsy \- Regenerating axons \- Thin myelin MISCELLANEOUS \- Lower limbs more affected than upper limbs \- Some patients have upper limb involvement \- Variable age at onset (range late childhood to fifties) \- Most patients have onset in teens or twenties \- Slowly progressive \- Most patients remain ambulatory \- Some patients may have a subclinical course with minimal neurologic findings MOLECULAR BASIS \- Caused by mutation in the ATPase, Na+/K+ transporting, alpha-1 polypeptide gene (ATP1A1, 182310.0001 ) ▲ 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	CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2DD	None	6,284	omim	https://www.omim.org/entry/618036	2019-09-22T15:43:52	{"omim": ["618036"], "orphanet": ["521414"], "synonyms": ["ATP1A1-related CMT2", "ATP1A1-related autosomal dominant Charcot-Marie-Tooth disease type 2", "Alternative titles", "CMT2DD", "CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2DD"]}
A number sign (#) is used with this entry because of evidence that Fanconi anemia of complementation group R (FANCR) is caused by heterozygous mutation in the RAD51 gene (179617) on chromosome 15q15. One such patient has been reported. For a discussion of genetic heterogeneity of Fanconi anemia, see FANCA (227650). Clinical Features Ameziane et al. (2015) reported a 23-year-old man with an atypical form of Fanconi anemia. He presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, thumb and radial abnormalities, imperforate anus, and an improperly formed testicle. He did not have bone marrow failure or malignancies. Laboratory studies of patient cells showed hypersensitivity to crosslinking agents, resulting in increased chromosomal breakage and accumulation of cells in the late S-G2 phase of the cell cycle. Patient cells showed normal monoubiquitination of FANCD2 (613984), suggesting a defect downstream of the core FA complex. Additional cellular studies indicated a defect in DNA repair. Molecular Genetics In a patient with FANCR, Ameziane et al. (2015) identified a de novo heterozygous missense mutation in the RAD51 gene (A293T; 179617.0005). The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. In vitro functional expression assays showed that the mutant protein reduced the formation of D-loop intermediates, which measures homology-dependent joint molecule formation during DNA repair by homologous recombination. Biochemical studies showed that the mutation impairs the binding of RAD51 to single- and double-stranded DNA and attenuates the DNA-stimulated ATPase activity of RAD51. The mutant protein was unable to form proper and functional nucleoprotein filaments, and acted in a dominant-negative manner when coexpressed with the wildtype protein. INHERITANCE \- Autosomal dominant GROWTH Other \- Growth retardation HEAD & NECK Head \- Microcephaly ABDOMEN Gastrointestinal \- Imperforate anus GENITOURINARY External Genitalia (Male) \- Abnormal testicle SKELETAL Limbs \- Radial anomalies Hands \- Thumb anomalies NEUROLOGIC Central Nervous System \- Hydrocephalus \- Intellectual disability \- Learning disabilities HEMATOLOGY \- No bone marrow failure \- No anemia LABORATORY ABNORMALITIES \- Chromosome instability \- Increased chromosomal breakage and in response to DNA crosslinking agents \- Defective DNA repair MISCELLANEOUS \- Onset in early childhood \- One patient has been reported (last curated December 2016) MOLECULAR BASIS \- Caused by mutation in the RAD51, S. Cerevisiae, homolog of gene (RAD51, 179617.0005 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	FANCONI ANEMIA, COMPLEMENTATION GROUP R	c0015625	6,285	omim	https://www.omim.org/entry/617244	2019-09-22T15:46:22	{"doid": ["0111090"], "mesh": ["D005199"], "omim": ["617244"], "orphanet": ["84"], "genereviews": ["NBK1401"]}
"Nigua" and "Chigger flea" redirect here. For the tree, see Cornutia obovata. For Hectopsylla pulex, see Hectopsylla. Tungiasis Other namesNigua,[1] Pio and Bicho de pie,[1] or Pique[1] or Sand flea disease[2] Chigoe flea SpecialtyInfectious disease Tungiasis is an inflammatory skin disease caused by infection with the female ectoparasitic Tunga penetrans (also known as chigoe flea, jigger, nigua or sand flea; NOTE: not chigger), found in the tropical parts of Africa, the Caribbean, Central and South America, and India. Tunga penetrans is the smallest known flea, measuring 1 mm across. It is also known in Latin America as the nigua and bicho de pie (Spanish) or bicho de pé (Portuguese), literally "foot bug".[3][4] Tunga penetrans is a member of the genus Tunga, which comprises 13 species.[5][6] Tungiasis causes skin inflammation, severe pain, itching, and a lesion at the site of infection that is characterized by a black dot at the center of a swollen red lesion, surrounded by what looks like a white halo. Desquamation of the skin is always seen, especially after the flea expands during hypertrophy. As of 2009, tungiasis is present worldwide in 88 countries with varying degrees of incidence.[7] This disease is of special public health concern in highly endemic areas such as Nigeria, Trinidad and Tobago, and Brazil, where its prevalence, especially in poor communities, has been known to approach 50%.[8] The chigoe flea is properly classified as a member of the order Siphonaptera as it is a flea. Although commonly referred to as chiggers, true chiggers are mites, which are minute arachnids.[9] Mites penetrate the skin and feed on skin cells that are broken down by an enzyme they secrete from their mouthparts, but they do not lay eggs in the host as T. penetrans does. Moreover, in mites, the adult and the larval forms both feed on other animals. This is not the case with T. penetrans, as only the adults feed on mammals and it is only the female that stays attached to the host. Tunga penetrans is also known by the following names: chigoe flea, sand flea, nigua, chigger flea, jigger flea, bicho de pé, pico, sikka, kuti, and piqui, among many others.[10] ## Contents * 1 Signs and symptom * 1.1 Incubation * 2 Cause * 2.1 Reservoirs and transmission * 2.2 Lifecycle * 2.3 Fortaleza classification * 2.4 Morphology * 2.5 Reproduction * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 History * 8 References * 9 External links ## Signs and symptom[edit] Skin infection with Tunga penetrans in a human The symptoms of this disease include: * Severe pruritus * Pain * Inflammation and swelling * Lesions and ulcerations, with black dots in the center Left untreated, secondary infections, such as bacteremia, tetanus, necrosis and gangrene, can occur. In all cases, tungiasis by itself only caused morbidity, though secondary infection may lead to mortality. The life cycle section presents the Fortaleza stages from the flea's developmental perspective. The discussion is specific to symptoms of human infection. The clinical presentation in humans follows the Fortaleza Classification as the stage of infection will determine the symptoms present. The following discussion will give an overview of the symptoms beginning in stage 2 because patients are not likely to present themselves at the early stages of infection, mostly because the flea's burrowing is usually not felt. This may be due to a keratolytic enzyme secreted during stage 1.[4] The patient with a single flea may present as early as stage 2 when, though the erythema is barely perceptible, a boring pain and the curious sensation of pleasant itching occur. This inflammatory reaction is the initial immunological response to the infestation. Heavily infested patients may not notice a stage 2 infection due to the other fleas’ causing irritation as well. Feces may be seen, but this is more common in the 3rd stage.[11] Around the third day after penetration, erythema and skin tenderness are felt, accompanied by pruritus (severe itching) and a black furuncular nodule surrounded by a white halo of stretched skin caused by the expansion of the flea. Fecal coils may protrude from the center of the nodule where the flea's anus is facing upward. They should be washed off quickly as the feces may remain in the skin unless removed. During this 3a substage, pain can be severe, especially at night or, if the nodule is on the foot, while walking. Eggs will also begin to be released and a watery secretion can be observed. The radical metamorphosis during the 3rd to 6th day after penetration, or neosomy, precedes the formation of a small caldera-like rim rampart as a result of the increased thickness of the flea's chitin exoskeleton. During the caldera formation, the nodule shrinks a bit and it looks as if it is beginning to dry out; this takes 2 weeks and comprises substage 3b.[11] At the third week after penetration and substage 4a, the eggs’ release will have stopped and the lesion will become smaller and more wrinkled. As the flea is near death, fecal and water secretion will stop altogether. Pain, tenderness, and skin inflammation will still be present. Around the 25th day after penetration, the lesion looks like a black crust and the flea's carcass is removed by host repair mechanisms and the skin begins to heal. With the flea gone, inflammation may still persist for a while.[11] Although patients would not present within the 5th stage of tungiasis as the flea would be dead and no longer in the body, this stage is characterized by the reorganization of the skin (1–4 weeks) and a circular residue of 5–10 mm in diameter around the site in penetration. An intraepithelial abscess, which developed due to the presence of the flea, will drain and later heal. Although these disease residues would persist for a few months, tungiasis is no longer present.[11] In severe cases, ulcers are common, as well as complete tissue and nail deformation. A patient may be unable to walk due to severe pain if too many of the lesions are present in the feet. Suppuration (pus formation), tissue death, auto-amputation of digits (via ainhum), and chronic lymphedema may also be seen.[4] If the patient is not vaccinated, tetanus is often a complication due to secondary infection. Necrosis and gangrene are other common complications of severe infestation and superinfection. Staphylococcus aureus and Wolbachia endobacteria can be transmitted by the chigoe flea, as well as nearly 150 other different pathogens. For these reasons, the chigoe flea should be removed as soon as possible.[10][12][13] ### Incubation[edit] Because of the relatively rapid onset of tungiasis, the incubation period tends to be short. Although some reddening around the site of penetration occurs, the first symptoms are perceived in stage 2 as itching and severe pain, usually a day after penetration. ## Cause[edit] Tungiasis is strictly caused by chigoe fleas (the term transmission does not apply because Tunga penetrans is itself responsible for the disease.) The preponderance of tungiasis lesions on the toes may be because chigoe flea is a poor jumper, attaining only a high of 20 cm.[14] But the reality is more complex; for example, the jumping ability cannot explain why hands are the second-most affected body part. Lesions on the hands are better explained by playing in the sand and noting that hands are often used to remove sand from other parts of the body. The occurrence of tungiasis lesions on the toes, between them, and on the soles can be easily explained because most of the victims are poor, walk barefoot, and live in places where the sand (home to chigoe fleas) constitutes the floor. Rate of incidence therefore is greatly increased in poor communities and populations because of the lack of adequate housing.[11] This occurs in significantly higher proportions during the peak of the dry season in local communities.[15] ### Reservoirs and transmission[edit] T. penetrans has been documented to use various warm-blooded animals as reservoir hosts, including humans, pigs, dogs, cats, rats, sheep, cattle, donkeys, monkeys, birds, and elephants.[3] These hosts directly propagate the disease by being the origin of the next generation of fleas. Once the female flea expels 100–200 eggs, the cycle of transmission begins again. ### Lifecycle[edit] T. penetrans eggs, on average, are 604 μm long, The larva will hatch from the egg within one to six days, assuming the environmental conditions (e.g., moisture, humidity, etc.) are favorable.[3] After hatching, the flea will progress through two instar phases. This is unique in that most fleas go through three, instead. Over the course of that development, the flea will first decrease in size from its just-hatched size of 1,500 μm to 1,150 μm (first instar) before growing to 2,900 μm (second instar). About 6 to 8 days after hatching, the larva pupates and builds a cocoon around itself. Because it lives mostly on and below the surface of the sand, sand is used to stabilize the cocoon and help to promote its development. An environmental disturbance such as rain or a lack of sand have been shown to decrease incidence, most likely due to decreasing the environmental factors (i.e., sand) on which the flea depends for overall growth.[15] Barring any disturbances to the cocoon, an adult flea will emerge from the puparium after 9–15 days.[3] In the adult phase, the flea will occasionally feed on unsuspecting animals. Only once the female burrows into the skin can reproduction occur, as the male and female show no interest in each other in the wild.[3] The male flea dies after copulation. The female flea continues in vivo ectodevelopment, described in stages by the Fortaleza classification of tungiasis. ### Fortaleza classification[edit] In a seminal paper on the biology and pathology of Tunga penetrans, Eisele et al. (2003) provided and detailed the five stages of tungiasis, thereby detailing the in vivo development of the female chigoe flea for the first time.[11] In dividing the natural history of the disease, the Fortaleza Classification formally describes the last part of the female flea's life cycle where it burrows into its host's skin, expels eggs, and dies. Due to the nature of the discussion, overlap with other sections, particularly the one on symptoms, is unavoidable. Stage 1 is characterized by the penetration of the skin by the female chigoe flea. Running along the body, the female uses its posterior legs to push its body upward by an angle of 45–90 degrees. Penetration then starts, beginning with the proboscis going through the epidermis.[11] By stage 2 (day 1–2), penetration is complete and the flea has burrowed most of its body into the skin. Only the anus, the copulatory organs, and four rear air holes in fleas called stigmata remain on the outside of the epidermis. The anus will excrete feces that is thought to attract male fleas for mating, described in a later section. The hypertrophic zone between tergites 2 and 3 in the abdominal region begins to expand a day or two after penetration and takes the appearance of a life belt. During this time, the flea begins to feed on the host's blood.[11] Stage 3 is divided into two substages, the first of which being 2–3 days after penetration is complete. In 3a, maximum hypertrophy is achieved and the flea's midsection swells to the size of a pea. Due to the expanding flea, the outer layer of the skin is stretched thin, resulting in the appearance of a white halo around the black dot (rear end of the flea) at the center of the lesion. In 3b, the chitin exoskeleton of tergites 2 and 3 increase in thickness and gives the structure the look of a mini caldera. Egg release is common in substage 3b, as are fecal coils. The eggs tend to stick to the skin.[11] At about the 3rd week after penetration, stage 4 begins, which is also divided into two substages. In 4a, the flea loses its signs of vitality and appears near death. As a result, the lesion shrinks in size, turns brown, and appears wrinkled. The death of the flea marks the beginning of substage 4b (around day 25 post-penetration) as the body begins to eliminate the parasite through skin repair mechanisms (e.g. shedding and subsequent skin repair). At this phase, the lesion is seen as brown or black.[11] By the 5th stage of tungiasis, the carcass of the T. penetrans flea has been expelled and there are circular skin residues of the infection that remain. There are only lingering symptoms at this time, described in the next section.[11] ### Morphology[edit] In a study of 1000 freshly ejected T. penetrans eggs, it was found that females are generally smaller than males for all criteria. In some cases, though, females had a bigger epipharynx and maxillar palpus. Due to its burrowing activity, the chigoe flea has developed a well-developed lacinia and epipharynx that is used to penetrate the skin. Overall, the fleas’ head is relatively flattened, which again aids in burrowing through the epidermal and dermal layers.[3] Investigators have also found that adult T. penetrans have different morphologies with respect to the shape of their head. Some have a rounded head, others have head shapes that resemble ski ramps more than anything else; still, others demonstrate head shapes that are very linear with a slight bulge at the nose. These morphologies were seen to be host-specific, as only fleas of some head-types were found in specific hosts. This, along with genetic differences among the T. penetrans fleas that infect different host animals, may suggest that there are several species of closely related species have been grouped taxonomically under one binomial nomenclature.[3] Though the chigoe flea resembles most others in morphology, the flea has a hypertrophic region between tergites 2 and 3. As stated in Eisele et al. (2003), tergites 2 and 3, as well as the abdominal sternites, stretch considerably and are bent apart. Chitinous clasps that are built for the abdominal enlargement surround these regions and hold onto the hypertrophic zone, giving them the appearance of a three-leafed clover. (See image 7 of the life cycle diagram.) Surprisingly, the rest of the flea, including the head and the thorax, do not change in shape.,[3][11] With the rapid expansion of the flea, the morphology of the flea is now vastly different. It has gone from the smallest flea in the world to a bulging mass that measures 5–10mm in diameter. This results in a volume that is 2000 to 3000 times what it used to be.[11] ### Reproduction[edit] Females have a depression or groove at their abdominal end whereas the males have their protrusive copulatory organs in that same region. These morphological differences reflect the way the male and female copulate. In the first step toward copulation, the female penetrates an organism in an ungravid state. It is only there that the male will find her and copulate. Copulation of adults has not been observed in the wild. With the female reproductive organs pointing outward, the male will place his reproductive organs "in direction to the upright abdominal end of the female" to copulate.[3] Having copulated for only a few seconds to 2 minutes, the male will then begin to search for another female. After copulation is complete, the male will die, although sometimes he will take a blood meal before doing so. Eggs will be expelled whether or not they have been fertilized.[16] The chigoe flea eggs’ average length is 604 μm and the just hatched larvae, in their first instar, have an average length of 1,500 μm. At the second and last instar (T. penetrans is unique among the fleas in that it only has two, instead of three, instars.) the larvae decrease in size to 1,150 μm after growing to at least 2,900 μm. The development from instar 1 to instar 2 lasts less than one day.[3] On the whole, Tunga penetrans does not do very well in terms of its Darwinian fitness. In a laboratory setting in which different mediums were provided for larval growth, the rate of survival from egg to adult in the best medium was 1.05%. Only 15% of the eggs were found to develop into larvae, and of those, only 14% formed a cocoon. Moreover, only half of the pupae reached the adult phase, resulting in gender disequilibrium.[3] Although these results reflect a laboratory setting, the general lack of success for T. penetrans’s reproductive (opportunistic) R-strategy is surprising given the number of fleas that a single person can attract. The low survival rate suggests that a concentrated public health effort directed at any point in the flea’s life cycle is likely to deal a crippling blow to the overall population of the flea in the area. ## Diagnosis[edit] There are no diagnostic tests for tungiasis. This is most likely because the parasite is ectoparasitic with visible symptoms. Identification of the parasite through removal, and a patient’s traveling history, should suffice for diagnosis, though the latter is clearly more useful than the former. Localization of the lesion may be a useful diagnostic method for the clinician. A biopsy may be done, though again, it is not required for diagnosis.[8] ## Prevention[edit] Due to the high number of hosts, eradication of tungiasis is not feasible, at least not easily so. Public health and prevention strategies should then be done with elimination as the target. Better household hygiene, including having a cemented rather than a sand floor, and washing it often, would lower the rates of tungiasis significantly. Though vaccines would be useful, due to the ectoparasitic nature of chigoe flea, they are neither a feasible nor an effective tool against tungiasis. Nevertheless, due to the high incidence of secondary infection, those at risk of tungiasis should get vaccinated against tetanus. A better approach is to use repellents that specifically target the chigoe flea. One very successful repellent is called Zanzarin, a derivative of coconut oil, jojoba oil, and aloe vera. In a recent study involving two cohorts, the infestation rates dropped 92% on average for the first one and 90% for the other. Likewise, the intensity of the cohorts dropped by 86% and 87% respectively. The non-toxic nature of Zanzarin, combined with its "remarkable regression of the clinical pathology" make this a tenable public health tool against tungiasis.[17] The use of pesticide, like DDT, has also led to elimination of the Tunga penetrans, but this control/prevention strategy should be utilized very carefully, if at all, because of the possible side effects such pesticides can have on the greater biosphere. In the 1950s, there was a worldwide effort to eradicate malaria. As part of that effort, Mexico launched the Campaña Nacional para la Erradicación de Paludismo, or the National Campaign for the Eradication of Malaria. By spraying DDT in homes, the Anopheles a genus of mosquitoes known to carry the deadly Plasmodium falciparum was mostly eliminated. As a consequence of this national campaign, other arthropods were either eliminated or significantly reduced in number, including the reduviid bug responsible for Chagas disease (American Trypanosomiasis) and T. penetrans.[18] Controlled, in-home spraying of DDT is effective as it gives the home immunity against arthropods while not contaminating the local water supplies and doing as much ecological damage as was once the case when DDT was first introduced.[19] While other species gradually gained resistance to DDT and other insecticides that were used, T. penetrans did not; as a result, the incidence of tungiasis in Mexico is very low when compared to the rest of Latin America, especially Brazil, where rates in poor areas have been known to be as high or higher than 50%.[20] There was a 40-year period with no tungiasis cases in Mexico. It was not until August 1989 that three Mexican patients presented with the disease. Though there were other cases of tungiasis reported thereafter, all were acquired in Africa.[21] ## Treatment[edit] Removed parasite As the disease is self-limiting, at least when exposure to the parasite is limited, management is mostly confined to treatment. Due to the secondary infection that can cause serious medical issues, the recommended course of action upon diagnosis is a surgical extraction of the fleas followed by the application of a topical antibiotic. Care should be taken to avoid tearing the flea during the extraction procedures as severe inflammation will result. The same will occur if part of the flea is left behind. Sterile equipment should always be used, as contaminated instruments could act as mechanical vectors for pathogens to enter the body.[8] There is no drug that has proven to be effective against embedded fleas. Oral niridazole was once considered a therapeutic drug, but well-designed studies are lacking and, given the severe adverse effects, this is one drug that is likely to cause more harm than good. However, it has some anecdotal evidence of lysing the fleas altogether.[4] Oral ivermectin is considered by some in endemic areas to be a panacea against the fleas but studies using high doses have failed to validate this hypothesis. Other drugs such as topical ivermectin and metrifonate have been somewhat successful, but not enough to be significant. [2,5] For superinfections, trimethoprim, sulfamethoxazole, metronidazole, amoxicillin, (with/without clavulanate) have been used successfully, though these treat only secondary infections.[22] Successful topical treatments also include cryotherapy and electrodesiccation of the lesion. If formaldehyde, chloroform, or DDT are used topically, care should be taken when dealing with the resulting morbidity. The T. penetrans flea can also be suffocated using occlusive petrolatum, while Vaseline will kill the organism as well, most likely due to suffocation as the stigmata would be covered.[4] The gum of the mammee apple (Mammea americana), a fruit that also goes by the name Saint Domingo apricot, has also been used to kill the chigoe flea, though this has not been reported in the main T. penetrans literature.[23] Even without treatment, the burrowed fleas will die within five weeks and are naturally sloughed off as the skin sheds. ## Epidemiology[edit] For the most part, the chigoe flea lives 2–5 cm below the sand, an observation which helps explains its overall distribution. The temperature is generally too hot for the larvae to develop on the surface of the sand and the deeper sand does not have enough oxygen. This preferred ecological niche offers a way to decrease transmission among humans by investing in concrete grounds as opposed to the sand that is usually used in shacks and some favelas. Indeed, Nany et al. (2007) report that "In shacks with concreted ground being cleaned every day with water, Tunga [penetrans] larvae were hardly found."[3] In a longitudinal study conducted from March 2001 to January 2002, incidence of tungiasis was found to vary significantly with the local seasons of an endemic community in Brazil. In particular, the study found that "occurrence of tungiasis varies throughout the year and seems to follow local precipitation patterns. Maximum and minimum prevalence rates differed by more than a factor of three." The authors suggest that the correlation is due to the high humidity in the soil impairing larval development during the rainy season, as well as the more obvious reason that rain may simply wash away all stages of T. penetrans due its small size of 1mm.[15] Acting as both biological vectors and definitive hosts, humans have spread Tunga penetrans from its isolated existence in the West Indies to all of Latin America and most of Africa via sea travel. Since the chigoe flea technically has no reservoir species and the female will cause tungiasis to any mammalian organism it can penetrate, this means the flea will have a relatively large number of hosts and victims. Epidemiologically, this is important as tungiasis often causes secondary infections.[3][4][7] ## History[edit] Tungiasis had been endemic in pre-Columbian Andean society for centuries before discovery of T. penetrans as native to the West Indies.[24] The first case of tungiasis was described in 1526 by Gonzalo Fernández de Oviedo y Valdés, where he discussed the skin infection and its symptoms on crew members from Columbus's Santa Maria after they were shipwrecked on Haiti.[25] Through ship routes and further expeditions, the chigoe flea was spread to the rest of the world, particularly to the rest of Latin America and Africa. The spread to greater Africa occurred throughout the 17th and 19th centuries, specifically in 1872 when the infected crewmen of the ship Thomas Mitchell introduced it into Angola by illegal dumping of sand ballast, having sailed from Brazil.[22][26] ## References[edit] 1. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Feldmeier, Hermann; Heukelbach, Jorg; Ugbomoiko, Uade Samuel; Sentongo, Elizabeth; Mbabazi, Pamela; von Samson-Himmelstjerna, Georg; Krantz, Ingela (2014-10-30). "Tungiasis—A Neglected Disease with Many Challenges for Global Public Health". PLoS Neglected Tropical Diseases. 8 (10): e3133. doi:10.1371/journal.pntd.0003133. ISSN 1935-2727. PMC 4214674. PMID 25356978. 3. ^ a b c d e f g h i j k l m Nagy, N.; Abari, E.; D’Haese, J.; Calheiros, C.; Heukelbach, J.; Mencke, N.; Feldmeier, H.; Mehlhorn, H. (2007). "Investigations on the life cycle and morphology of Tunga penetrans in Brazil". Parasitology Research. 101 (Suppl 2): S233–42. doi:10.1007/s00436-007-0683-8. PMID 17823833. 4. ^ a b c d e f Tungiasis at eMedicine 5. ^ Beaucournu, J.-C.; Degeilh, B.; Mergey, T.; Muñoz-Leal, S.; González-Acuña, D. (2012). "Le genre Tunga Jarocki, 1838 (Siphonaptera: Tungidae). 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Acta Tropica. 99 (2–3): 126–36. doi:10.1016/j.actatropica.2006.05.013. PMID 17010927. 18. ^ Ibáñez-Bernal, Sergio. " Reportaje Sobre La Pulga Chigoe." E-mail to Fausto Bustos. 14 Feb. 2009.[verification needed] 19. ^ Allison, Anthony. Lecture on Malaria and the Sickle-Cell Connection. Human Biology 153. Stanford University. 6 Feb. 2009.[verification needed] 20. ^ Heukelbach, Jorg (2005). "Tungiasis". Revista do Instituto de Medicina Tropical de São Paulo. 47 (6): 307–13. doi:10.1590/S0036-46652005000600001. PMID 16553319. 21. ^ Ibanez-Bernal, S.; Velasco-Castrejon, O. (1996). "New Records of Human Tungiasis in Mexico (Siphonaptera: Tungidae)". Journal of Medical Entomology. 33 (6): 988–9. doi:10.1093/jmedent/33.6.988. PMID 8961652. 22. ^ a b Joseph J.; Bazile J.; Mutter J.; Shin S.; Ruddle A.; Ivers L.; Lyon E.; Farmer P. (2006). "Tungiasis in rural Haiti: a community-based response". Transactions of the Royal Society of Tropical Medicine and Hygiene. 100 (10): 970–974. doi:10.1016/j.trstmh.2005.11.006. PMID 16516941. 23. ^ "Mamey apple". Encyclopædia Britannica. August 7, 2014. 24. ^ Maco, V; Tantaleán, M; Gotuzzo, E (May 2011). "Evidence of tungiasis in pre-Hispanic America". Emerging Infectious Diseases. 17 (5): 855–62. doi:10.3201/eid1705.100542. PMC 3321756. PMID 21529395. 25. ^ Darmstadt GL, Francis JS (May 2000). "Tungiasis in a young child adopted from South America". Pediatr. Infect. Dis. J. 19 (5): 485–7. doi:10.1097/00006454-200005000-00024. PMID 10819355. 26. ^ Hoeppli R (1963). "Early references to the occurrence of Tunga penetrans in tropical Africa". Acta Trop. 20: 143–153. ## External links[edit] Classification D * ICD-10: B88.1 * ICD-9-CM: 134.1 * MeSH: D058285 * DiseasesDB: 29589 * Muehlstaedt, Michael (2008). "Periungual Tungiasis". New England Journal of Medicine. 359 (24): e30. doi:10.1056/NEJMicm074290. PMID 19073971. * v * t * e Arthropods and ectoparasite-borne diseases and infestations Insecta Louse * Body louse (pediculosis corporis) / Head louse (head lice infestation) * Crab louse (phthiriasis) Hemiptera * Bed bug (cimicosis) Fly * Dermatobia hominis / Cordylobia anthropophaga / Cochliomyia hominivorax (myiasis) * Mosquito (mosquito-borne disease) Flea * Tunga penetrans (tungiasis) Crustacea Pentastomida * Linguatula serrata (linguatulosis) * Porocephalus crotali / Armillifer armillatus (porocephaliasis) * For ticks and mites, see Template:Tick and mite-borne diseases and infestations [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Tungiasis	c0277356	6,286	wikipedia	https://en.wikipedia.org/wiki/Tungiasis	2021-01-18T19:10:26	{"gard": ["393"], "mesh": ["D058285"], "umls": ["C0277356"], "icd-9": ["134.1"], "icd-10": ["B88.1"], "orphanet": ["879"], "wikidata": ["Q2028074"]}
Prostatitis Other namesProstatosis Micrograph showing an inflamed prostate gland, the histologic correlate of prostatitis. A normal non-inflamed prostatic gland is seen on the left of the image. H&E stain. SpecialtyUrology Prostatitis is inflammation of the prostate gland. Prostatitis is classified into acute, chronic, asymptomatic inflammatory prostatitis, and chronic pelvic pain syndrome. In the United States, prostatitis is diagnosed in 8% of all urologist visits and 1% of all primary care physician visits for genitourinary symptoms.[1] ## Contents * 1 Classification * 2 See also * 3 References * 4 External links ## Classification[edit] The term prostatitis refers to inflammation of the tissue of the prostate gland. It may occur as an appropriate physiological response to an infection, or it may occur in the absence of infection.[2] In 1999, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) devised a new classification system.[3][4] For more specifics about each type of prostatitis, including information on symptoms, treatment, and prognosis, follow the links to the relevant full articles. Category Current name Old name Pain Bacteria WBCs Description I Acute prostatitis Acute bacterial prostatitis Yes Yes Yes Bacterial infection of the prostate gland that requires urgent medical treatment. II Chronic bacterial prostatitis Chronic bacterial prostatitis ± Yes Yes A relatively rare condition that usually presents as intermittent urinary tract infections. IIIa Inflammatory CP/CPPS Nonbacterial prostatitis Yes No Yes Accounts for 90–95% of prostatitis diagnoses,[5] formerly known as chronic nonbacterial prostatitis. IIIb Noninflammatory CP/CPPS Prostatodynia Yes No No IV Asymptomatic inflammatory prostatitis (none) No No Yes No history of genitourinary pain complaints, but leukocytosis is noted, usually during evaluation for other conditions. Between 6 and 19% of men have pus cells in their semen but no symptoms.[6] In 1968, Meares and Stamey determined a classification technique based upon the culturing of bacteria.[7] This classification is no longer used. The conditions are distinguished by the different presentation of pain, white blood cells (WBCs) in the urine, duration of symptoms and bacteria cultured from the urine. To help express prostatic secretions that may contain WBCs and bacteria, prostate massage is sometimes used.[8] ## See also[edit] * Interstitial cystitis — a related disease * Granulomatous prostatitis * IgG4-related prostatitis * Male accessory gland infection (MAGI) ## References[edit] 1. ^ Collins MM, Stafford RS, O'Leary MP, Barry MJ (1998). "How common is prostatitis? A national survey of physician visits". J. Urol. 159 (4): 1224–8. doi:10.1016/S0022-5347(01)63564-X. PMID 9507840. 2. ^ Kirby, Roger; Carson, Culley C. (January–February 2015). "Editor's Comment on Diagnosis and treatment of chronic prostatitis/chronic pelvic pain syndrome". Trends in Urology and Men's Health. 6 (1): 17. doi:10.1002/tre.434. 3. ^ Krieger JN, Nyberg L, Nickel JC (July 1999). "NIH consensus definition and classification of prostatitis". JAMA. 282 (3): 236–7. doi:10.1001/jama.282.3.236. PMID 10422990. 4. ^ J. Curtis Nickel (1999). Textbook of prostatitis. Taylor & Francis. pp. 27–. ISBN 978-1-901865-04-2. Retrieved 18 April 2010. 5. ^ Habermacher GM, Chason JT, Schaeffer AJ (2006). "Prostatitis/chronic pelvic pain syndrome". Annu. Rev. Med. 57: 195–206. doi:10.1146/annurev.med.57.011205.135654. PMID 16409145. 6. ^ Korrovits P, Ausmees K, Mändar R, Punab M (June 2008). "Prevalence of asymptomatic inflammatory (National Institutes of Health Category IV) prostatitis in young men according to semen analysis". Urology. 71 (6): 1010–5. doi:10.1016/j.urology.2007.12.082. PMID 18455767. 7. ^ Meares EM, Stamey TA (March 1968). "Bacteriologic localization patterns in bacterial prostatitis and urethritis". Invest Urol. 5 (5): 492–518. PMID 4870505. 8. ^ "Prostatitis: Benign Prostate Disease: Merck Manual Professional". Retrieved 2011-07-11. ## External links[edit] Classification D * ICD-10: N41 * ICD-9-CM: 601 * MeSH: D011472 * DiseasesDB: 10801 External resources * MedlinePlus: 000524 * eMedicine: emerg/488 * Patient UK: Prostatitis * Prostatitis Self Assessment Calculator * v * t * e Male diseases of the pelvis and genitals Internal Testicular * Orchitis * Hydrocele testis * Testicular cancer * Testicular torsion * Male infertility * Aspermia * Asthenozoospermia * Azoospermia * Hyperspermia * Hypospermia * Oligospermia * Necrospermia * Teratospermia Epididymis * Epididymitis * Spermatocele * Hematocele Prostate * Prostatitis * Acute prostatitis * Chronic bacterial prostatitis * Chronic prostatitis/chronic pelvic pain syndrome * Asymptomatic inflammatory prostatitis * Benign prostatic hyperplasia * Prostate cancer Seminal vesicle * Seminal vesiculitis External Penis * Balanoposthitis / Balanitis * Balanitis plasmacellularis * Pseudoepitheliomatous keratotic and micaceous balanitis * Phimosis * Paraphimosis * Priapism * Sexual dysfunction * Erectile dysfunction * Peyronie's disease * Penile cancer * Penile fracture * Balanitis xerotica obliterans Other * Hematospermia * Retrograde ejaculation * Postorgasmic illness 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	Prostatitis	c0033581	6,287	wikipedia	https://en.wikipedia.org/wiki/Prostatitis	2021-01-18T19:06:03	{"mesh": ["D011472"], "umls": ["C0033581"], "wikidata": ["Q372752"]}
Proopiomelanocortin (POMC) deficiency causes severe obesity that begins at an early age. In addition to obesity, people with this condition have low levels of a hormone known as adrenocorticotropic hormone (ACTH) and tend to have red hair and pale skin. Affected infants are usually a normal weight at birth, but they are constantly hungry, which leads to excessive feeding (hyperphagia). The babies continuously gain weight and are severely obese by age 1. Affected individuals experience excessive hunger and remain obese for life. It is unclear if these individuals are prone to weight-related conditions like cardiovascular disease or type 2 diabetes. Low levels of ACTH lead to a condition called adrenal insufficiency, which occurs when the pair of small glands on top of the kidneys (the adrenal glands) do not produce enough hormones. Adrenal insufficiency often results in periods of severely low blood sugar (hypoglycemia) in people with POMC deficiency, which can cause seizures, elevated levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia), and a reduced ability to produce and release a digestive fluid called bile (cholestasis). Without early treatment, adrenal insufficiency can be fatal. Pale skin that easily burns when exposed to the sun and red hair are common in POMC deficiency, although not everyone with the condition has these characteristics. ## Frequency POMC deficiency is a rare condition; approximately 50 cases have been reported in the medical literature. ## Causes POMC deficiency is caused by mutations in the POMC gene, which provides instructions for making the proopiomelanocortin protein. This protein is cut (cleaved) into smaller pieces called peptides that have different functions in the body. One of these peptides, ACTH, stimulates the release of another hormone called cortisol from the adrenal glands. Cortisol is involved in the maintenance of blood sugar levels. Another peptide, alpha-melanocyte stimulating hormone (α-MSH), plays a role in the production of the pigment that gives skin and hair their color. The α-MSH peptide and another peptide called beta-melanocyte stimulating hormone (β-MSH) act in the brain to help maintain the balance between energy from food taken into the body and energy spent by the body. The correct balance is important to control eating and weight. POMC gene mutations that cause POMC deficiency result in production of an abnormally short version of the POMC protein or no protein at all. As a result, there is a shortage of the peptides made from POMC, including ACTH, α-MSH, and β-MSH. Without ACTH, there is a reduction in cortisol production, leading to adrenal insufficiency. Decreased α-MSH in the skin reduces pigment production, resulting in the red hair and pale skin often seen in people with POMC deficiency. Loss of α-MSH and β-MSH in the brain dysregulates the body's energy balance, leading to overeating and severe obesity. POMC deficiency is a rare cause of obesity; POMC gene mutations are not frequently associated with more common, complex forms of obesity. Researchers are studying other factors that are likely involved in these forms. ### Learn more about the gene associated with Proopiomelanocortin deficiency * POMC ## Inheritance Pattern POMC deficiency 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 this condition each carry one copy of the mutated gene. They typically do not have POMC deficiency, but they may have an increased risk of obesity. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Proopiomelanocortin deficiency	c1857854	6,288	medlineplus	https://medlineplus.gov/genetics/condition/proopiomelanocortin-deficiency/	2021-01-27T08:25:21	{"gard": ["10823"], "mesh": ["C565726"], "omim": ["609734"], "synonyms": []}
Colic in horses is defined as abdominal pain,[1] but it is a clinical symptom rather than a diagnosis. The term colic can encompass all forms of gastrointestinal conditions which cause pain as well as other causes of abdominal pain not involving the gastrointestinal tract. The most common forms of colic are gastrointestinal in nature and are most often related to colonic disturbance. There are a variety of different causes of colic, some of which can prove fatal without surgical intervention. Colic surgery is usually an expensive procedure as it is major abdominal surgery, often with intensive aftercare. Among domesticated horses, colic is the leading cause of premature death.[2] The incidence of colic in the general horse population has been estimated between 4[2] and 10[3] percent over the course of the average lifespan. Clinical signs of colic generally require treatment by a veterinarian. The conditions that cause colic can become life-threatening in a short period of time.[4] ## Contents * 1 Pathophysiology * 1.1 Simple obstruction * 1.2 Strangulating obstruction * 1.3 Non-strangulating infarction * 1.4 Inflammation or ulceration of the gastrointestinal tract * 2 Types * 2.1 Gas and spasmodic colic * 2.2 Impaction * 2.2.1 Pelvic flexure impaction * 2.2.2 Ileal impaction and ileal hypertrophy * 2.2.3 Sand impaction * 2.2.4 Cecal impaction * 2.2.5 Gastric impaction * 2.2.6 Small colon impaction * 2.2.7 Large colon impaction * 2.2.8 Enteroliths and fecaliths * 2.3 Displacement * 2.4 Torsion and volvulus * 2.5 Intussusception * 2.6 Entrapment * 2.6.1 Epiploic foramen entrapment * 2.6.2 Mesenteric rent entrapment * 2.7 Inflammatory and ulcerative conditions * 2.7.1 Proximal enteritis * 2.7.2 Colitis * 2.7.3 Gastric ulceration * 2.7.4 Right dorsal colitis * 2.8 Tumors * 2.8.1 Strangulating pedunculated lipoma * 2.8.2 Other cancers * 2.9 Ileus * 2.10 Parasites * 2.10.1 Ascarids (roundworms) * 2.10.2 Tapeworms * 2.10.3 Cyathostomes * 2.10.4 Large strongyles * 2.11 Foal colic * 2.11.1 Meconium impactions * 2.11.2 Lethal white syndrome * 2.11.3 Congenital abnormalities * 2.11.4 Infectious organisms * 2.12 Herniation * 2.12.1 Inguinal herniation * 2.12.2 Umbilical herniation * 2.12.3 Diaphragmatic herniation * 2.13 Toxins * 2.14 Uterine tears and torsions * 2.15 Other causes that may show clinical signs of colic * 3 Diagnosis * 3.1 History * 3.2 Physical examination * 3.3 Rectal examination * 3.4 Nasogastric intubation * 3.5 Auscultation * 3.6 Abdominal ultrasound * 3.7 Abdominocentesis (belly tap) * 3.8 Abdominal distension * 3.9 Fecal examination * 3.10 Radiography, gastroscopy, and laparoscopy * 3.10.1 Radiography * 3.10.2 Gastroscopy * 3.10.3 Laparoscopy * 3.11 Rectal biopsy * 4 Clinical signs * 4.1 General * 5 Medical management * 5.1 Analgesia and sedation * 5.2 Nasogastric intubation and gastric decompression * 5.3 Fluid support * 5.4 Intestinal lubricants and laxatives * 5.5 Nutritional support * 5.6 Endotoxemia prevention * 5.7 Case-specific drug treatment * 6 Surgical intervention * 6.1 Survival rates * 6.2 Adhesion formation * 6.3 Post-operative care * 7 Prevention * 8 References * 9 Further reading * 10 External links ## Pathophysiology[edit] Colic can be divided broadly into several categories: 1. excessive gas accumulation in the intestine (gas colic) 2. simple obstruction 3. strangulating obstruction 4. non-strangulating infarction 5. inflammation of the gastrointestinal tract (enteritis, colitis) or the peritoneum (peritonitis) 6. ulceration of the gastrointestinal mucosa These categories can be further differentiated based on location of the lesion and underlying cause (See Types of colic). ### Simple obstruction[edit] Further information: § Impaction This is characterised by a physical obstruction of the intestine, which can be due to impacted food material, stricture formation, or foreign bodies. The primary pathophysiological abnormality caused by this obstruction is related to the trapping of fluid within the intestine oral to the obstruction. This is due to the large amount of fluid produced in the upper gastrointestinal tract, and the fact that this is primarily re-absorbed in parts of the intestine downstream from the obstruction. The first problem with this degree of fluid loss from circulation is one of decreased plasma volume, leading to a reduced cardiac output, and acid-base disturbances. The intestine becomes distended due to the trapped fluid and gas production from bacteria. It is this distension, and subsequent activation of stretch receptors within the intestinal wall, that leads to the associated pain. With progressive distension of the intestinal wall, there is occlusion of blood vessels, firstly the less rigid veins, then arteries. This impairment of blood supply leads to hyperemia and congestion, and ultimately to ischaemic necrosis and cellular death. The poor blood supply also has effects on the vascular endothelium, leading to an increased permeability which first leaks plasma and eventually blood into the intestinal lumen. In the opposite fashion, gram-negative bacteria and endotoxins can enter the bloodstream, leading to further systemic effects.[5] ### Strangulating obstruction[edit] Further information: § Torsion and volvulus, § Intussusception, § Entrapment, § Strangulating pedunculated lipoma, and § Herniation Strangulating obstructions have all the same pathological features as a simple obstruction, but the blood supply is immediately affected. Both arteries and veins may be affected immediately, or progressively as in simple obstruction. Common causes of strangulating obstruction are intussusceptions, torsion or volvulus, and displacement of intestine through a hole, such as a hernia, a mesenteric rent, or the epiploic foramen.[6] ### Non-strangulating infarction[edit] Further information: § Large strongyles In a non-strangulating infarction, blood supply to a section of intestine is occluded, without any obstruction to ingesta present within the intestinal lumen. The most common cause is infection with Strongylus vulgaris larvae, which primarily develop within the cranial mesenteric artery. ### Inflammation or ulceration of the gastrointestinal tract[edit] Further information: § Ileus, equine proximal enteritis, § Toxins, and equine gastric ulcer syndrome Inflammation along any portion of the GI tract can lead to colic. This leads to pain and possibly stasis of peristalsis (Ileus), which can cause excessive accumulation of fluid in the gastrointestinal tract. This is a functional rather than mechanical blockage of the intestine, but like the mechanical blockage seen with simple obstructions, it can have serious effects including severe dehydration. Inflammation of the bowel may lead to increased permeability and subsequent endotoxemia. The underlying cause of inflammation may be due to infection, toxin, or trauma, and may require special treatment in order to resolve the colic. Ulceration of the mucosal surface occurs very commonly in the stomach (gastric ulceration), due to damage from stomach acid or alteration in protective mechanisms of the stomach, and is usually not life-threatening. The right dorsal colon may also develop ulceration, usually secondary to excessive NSAID use, which alters the homeostatic balance of prostaglandins that protect the mucosa. ## Types[edit] This list of types of colic is not exhaustive but details some of the types which may be encountered. ### Gas and spasmodic colic[edit] Gas colic, also known as tympanic colic, is the result of gas buildup within the horse's digestive tract due to excessive fermentation within the intestines or a decreased ability to move gas through it.[7] It is usually the result of a change in diet, but can also occur due to low dietary roughage levels, parasites (22% of spasmodic colics are associated with tapeworms),[8] and anthelminthic administration.[7][9] This gas buildup causes distention and increases pressure in the intestines, causing pain.[7] Additionally, it usually causes an increase in peristaltic waves, which can lead to painful spasms of the intestine, producing subsequent spasmodic colic. The clinical signs of these forms of colic are generally mild, transient,[9] and respond well to spasmolytic medications, such as buscopan, and analgesics. Gas colics usually self-correct,[9] but there is the risk of subsequent torsion (volvulus) or displacement of the bowel due to gas distention, which causes this affected piece of bowel to rise upward in the abdomen.[7] Abdominal distention may occasionally be seen in adult horses in the flank region, if the cecum or large colon is affected.[7] Foals, however, may show signs of gas within the small intestines with severe abdominal distention.[7] ### Impaction[edit] #### Pelvic flexure impaction[edit] This is caused by an impaction of food material (water, grass, hay, grain) at a part of the large bowel known as the pelvic flexure of the left colon where the intestine takes a 180 degree turn and narrows. Impaction generally responds well to medical treatment, usually requiring a few days of fluids and laxatives such as mineral oil,[10] but more severe cases may not recover without surgery. If left untreated, severe impaction colic can be fatal. The most common cause is when the horse is on box rest and/or consumes large volumes of concentrated feed, or the horse has dental disease and is unable to masticate properly. This condition could be diagnosed on rectal examination by a veterinarian. Impactions are often associated with the winter months because horses do not drink as much water and eat drier material (hay instead of grass), producing drier intestinal contents that are more likely to get stuck.[9] #### Ileal impaction and ileal hypertrophy[edit] The ileum is the last part of the small intestine that ends in the cecum. Ileal impaction can be caused by obstruction of ingesta. Coastal Bermuda hay is associated with impactions in this most distal segment of the small intestine,[11][12] although it is difficult to separate this risk factor from geographic location, since the southeastern United States has a higher prevalence of ileal impaction and also has regional access to coastal Bermuda hay.[13] Other causes can be obstruction by ascarids (Parascaris equorum), usually occurring at 3–5 months of age right after deworming, and tapeworms (Anoplocephala perfoliata), which have been associated with up to 81% of ileal impactions[8][13] (See Ascarids). Horses show intermittent colic, with moderate to severe signs and with time, distended small intestinal loops on rectal.[13] Although most ileal impactions will sometimes pass without intervention, those present for 8–12 hours will cause fluid to back up, leading to gastric reflux, which is seen in approximately 50% of horses that require surgical intervention.[10][13] Diagnosis is usually made based on clinical signs, presence of reflux, rectal exam, and ultrasound. Often the impaction can not be felt on rectal due to distended small intestinal loops that block the examiner.[13] Those impactions that are unresponsive to medical management, which includes IV fluids and removal of reflux,[10] may be treated using a single injection into the ileum with 1 liter of carboxymethylcellulose, and then massaging the ileum.[14] This allows the impaction to be treated without actually cutting into the ileum. Prognosis for survival is good.[13] Ileal hypertrophy occurs when the circular and longitudinal layers of the ileal intestinal wall hypertrophy, and can also occur with jejunal hypertrophy. The mucosa remains normal, so malabsorption is not expected to occur in this disease.[13] Ileal hypertrophy may be idiopathic, with current theories for such cases including neural dysfunction within the intestinal wall secondary to parasite migration, and increased tone of the ileocecal valve which leads to hypertrophy of the ileum as it tries to push contents into the cecum.[13] Hypertrophy may also occur secondary to obstruction, especially those that have had surgery for an obstruction that required an anastomosis.[13] Hypertrophy gradually decreases the size of the lumen, resulting in intermittent colic, and in approximately 45% of cases includes weight loss of 1–6 month duration and anorexia.[13] Although rectal examination may display a thickened ileal wall, usually the diagnosis is made at surgery, and an ileocecal or jejunocecal anastomosis is made to allow intestinal contents to bypass the affected area.[13] If surgery and bypass is not performed, there is a risk of rupture, but prognosis is fair with surgical treatment.[13] #### Sand impaction[edit] This is most likely to occur in horses that graze sandy or heavily grazed pastures leaving only dirt to ingest. Foals, weanlings, and yearlings are most likely to ingest sand, and are therefore most commonly seen with sand colic.[15] The term sand also encompasses dirt. The ingested sand or dirt most commonly accumulates in the pelvic flexure,[9] but may also occur in the right dorsal colon and the cecum of the large intestines. The sand can cause colic signs similar to other impactions of the large colon, and often causes abdominal distention[15] As the sand or dirt irritates the lining of the bowel it can cause diarrhea. The weight and abrasion of the sand or dirt causes the bowel wall to become inflamed and can cause a reduction in colonic motility and, in severe cases, leads to peritonitis. Diagnosis is usually made by history, environmental conditions, auscultation of the ventral abdomen, radiographs, ultrasound, or fecal examination (See Diagnosis).[15] Historically, medical treatment of the problem is with laxatives such as liquid paraffin or oil and psyllium husk. More recently veterinarians treat cases with specific synbiotic (pro and prebiotic) and psyllium combinations. Psyllium is the most effective medical treatment.[15] It works by binding to the sand to help remove it, although multiple treatments may be required.[9] Mineral oil is mostly ineffective since it floats on the surface of the impaction, rather than penetrating it.[15] Horses with sand or dirt impaction are predisposed to Salmonella infection and other GI bacteria, so antibiotics are often added to help prevent infection.[15] Medical management usually resolves the colic, but if improvement doesn't occur within a few hours then surgery must be performed to flush the colon of any sand, which procedure that has a 60–65% survival rate.[15] Horses that are not treated, or treated too late after the onset of clinical signs, are at risk of death.[15] Horses should not be fed directly on the ground in areas where sand, dirt and silt are prevalent,[15] although small amounts of sand or dirt may still be ingested by grazing. Management to reduce sand intake and prophylactic treatments with sand removal products are recommended by most veterinarians. Such prophylaxis includes feeding a pelleted psyllium for one week every 4–5 weeks.[15] Longer duration of treatment will result in gastrointestinal flora changes and the psyllium to be broken down and ineffective for sand clearance. Other methods include feeding the horse before turnout, and turning the horses out in the middle of the day so they are more likely to stand in the shade rather than graze.[15] #### Cecal impaction[edit] Only 5%[16] of large intestinal impactions at referral hospital involve the cecum. Primary cecal impactions usually consist of dry feed material, with the horse slowly developing clinical signs over several days.[13] Secondary cecal impactions may occur post-surgery, orthopedic or otherwise, and the cecum does not function properly. Horses usually show clinical signs 3–5 days post general anesthesia, including decreased appetite, decreased manure production, and gas in the cecum which can be auscultated.[17] The cecum quickly distends due to fluid and gas accumulation, often leading to rupture within 24–48 hours if not corrected.[10] This impaction may be missed since decreased manure production can be attributed secondarily to surgery, and often rupture occurs before severe signs of pain.[13] Horses are most at risk for this type of impaction if surgery is greater than 1 hour in length, or if inadequate analgesia is provided postoperatively.[13] Diagnosis is usually made by rectal palpation. Treatment includes fluid therapy and analgesics, but surgery is indicated if there is severe distention of the cecum or if medical therapy does not improve the situation.[13] Surgery includes typhlotomy, and although cecal bypass has been performed in the past to prevent reoccurrence, a recent study suggests it is not necessary.[18] Surgery has a good prognosis, although rupture can occur during surgical manipulation.[13][16] The cause of cecal impactions are not known.[10] Cecal impassion should be differentiated from large colon impaction via rectal, since cecal impaction has a high risk of rupture even before developing severe pain.[13] Overall prognosis is 90%, regardless of medical or surgical treatment, but rupture does occur, often with no warning.[13] #### Gastric impaction[edit] Gastric impactions are relatively rare,[19] and occur when food is not cleared at the appropriate rate. It is most commonly associated with ingestion of foods that swell after eating or feeds that are coarse (bedding or poor quality roughage), poor dental care, poor mastication, inadequate drinking, ingestion of a foreign object, and alterations in the normal function of the stomach. Persimmons, which form a sticky gel in the stomach, and haylage, have both been associated with it,[10][20] as has wheat, barley, mesquite beans, and beet pulp.[13] Horses usually show signs of mild colic that is chronic, unresponsive to analgesics, and may include signs such as dysphagia, ptyalism, bruxism, fever, and lethargy,[19][20] although severe colic signs may occur.[13] Signs of shock may be seen if gastric rupture has occurred.[19] Usually, the impaction must be quite large before it presents symptoms,[10] and may be diagnosed via gastroscopy or ultrasound, although rectal examinations are unhelpful.[20] Persimmon impaction is treated with infusions of Coca-Cola.[21] Other gastric impactions are often resolves with enteral fluids.[10] Quick treatment generally produces a favorable prognosis.[20] #### Small colon impaction[edit] Small colon impactions represent a small number of colics in the horse, and are usually caused by obstruction from fecaliths, enteroliths, and meconium.[22] Horses usually present with standard colic signs (pawing, flank watching, rolling) in 82% of horses, and occasionally with diarrhea (31%), anorexia (30%), straining (12%), and depression (11%), and rectal examination will reveal firm loops of small colon or actually palpable obstruction in the rectum.[22] Impactions are most common in miniature horses, possibly because they do not masticate their feed as well,[10] and during the fall and winter.[22] Medical management includes the aggressive use of fluids, laxatives and lubricants, and enemas, as well as analgesics and anti-inflammatories. However, these impactions often require surgical intervention, and the surgeon will empty the colon either by enterotomy or by lubricants and massage.[10] Surgical intervention usually results in longer recovery time at the hospital. Prognosis is very good, and horses treated with surgical treatment had a survival with return to athletic function rate of 91%, while 89% of the medically managed horses returned to previous use.[22] #### Large colon impaction[edit] Large colon impactions typically occur at the pelvic flexure and right dorsal colon,[13] two areas where the lumen of the intestine narrows. Large colon impactions are most frequently seen in horses that have recently had a sudden decrease in exercise, such as after a musculoskeletal injury.[13] They are also associated in the practice of twice daily feeding of grain meals, which causes a short-lived but significant secretion of fluid into the lumen of the intestine, resulting in a 15% decrease in plasma volume (hypovolemia of the circulatory system) and the subsequent activation of the renin–angiotensin–aldosterone system. Aldosterone secretion activates absorption of fluid from the colon, decreasing the water content of the ingesta and increasing risk of impaction.[17] Amitraz has also been associated with large colon impaction, due to alterations in motility and retention of intestinal contents, which causes further absorption of water and dehydration of ingesta.[13] Other possible factors include poor dental care, course roughage, dehydration, and limited exercise.[13] Horses with a large colon impaction usually have mild signs that slowly get worse if the impaction does not resolve, and can produce severe signs. Diagnosis is often made by rectal palpation of the mass, although this is not always accurate since a portion of the colon is not palpable on rectal. Additional sections of intestines may be distended if there is fluid backup. Manure production decreases, and if passed, is usually firm, dry and mucus covered.[13] Horses are treated with analgesics, fluid therapy, mineral oil, dactyl sodium sulfosuccinate (DSS), and/or epsom salts. Analgesics usually can control the abdominal discomfort, but may become less efficacious over time if the impaction does not resolve.[13] Persistent impactions may require fluids administered both intravenously and orally via nasogastric tube, at a rate 2–4 times the maintenance for the animal.[13] Feed is withheld. Horses that do not improve or become very painful, or those that have large amounts of gas distention, are recommended to undergo surgery to remove the impaction via enterotomy of the pelvic flexure.[13][17] Approximately 95% of horses that undergo medical management, and 58% of surgical cases, survive.[17] #### Enteroliths and fecaliths[edit] Enteroliths in horses are round 'stones' of mineral deposits, usually of ammonium magnesium phosphate (struvite)[17] but sometimes of magnesium vivainite and some amounts of sodium, potassium, sulfur and calcium,[13] which develop within the horse's gastrointestinal tract. They can form around a piece of ingested foreign material, such as a small nidus of wire or sand (similar to how an oyster forms a pearl).[9] When they move from their original site they can obstruct the intestine, usually in the right dorsal and transverse colon, but rarely in the small colon.[17] They may also cause mucosal irritation or pain when they move within the gastrointestinal tract. Enteroliths are not a common cause of colic, but are known to have a higher prevalence in states with a sandy soil or an abundance of alfalfa hay is fed, such as California,[12][17] a state where 28% of surgical colics are due to enteroliths.[13] Alfalfa hay is thought to increase the risk due to the high protein content in the hay, which would likely elevate ammonia nitrogen levels within the intestine.[13] They may be more common in horses with diets high in magnesium,[17] and are also seen more often in Arabians, Morgans, American Saddlebreds, miniature horses, and donkeys, and usually occur in horses older than four years of age.[13][17] Horses with enteroliths typically have chronic, low-grade, recurring colic signs, which may lead to acute colic and distention of the large colon after occlusion of the lumen occurs. These horse may also have had a history of passing enteroliths in their manure.[17] Level of pain is related to the degree of luminal occlusion.[13] Abdominal radiographs can confirm the diagnosis, but smaller enteroliths may not be visible. In rare instances, enteroliths may be palpated on rectal examination, usually if they are present in the small colon.[13][17] Once a horse is diagnosed with colic due to an enterolith, surgery is necessary to remove it, usually by pelvic flexure enterotomy and sometimes an additional right dorsal colon enterotomy,[13] and fully resolve the signs of colic.[23] Horses will usually present a round enterolith if it is the only one present, while multiple enteroliths will usually have flat sides, a clue to the surgeon to look for more stones.[17] The main risk of surgery is rupture of the colon (15% of cases), and 92% of horses that are recovered survive to at least one year from their surgery date.[17] Fecaliths are hard formations of ingest that obstruct the GI tract, and may require surgery to resolve. These are most commonly seen in miniature horses, ponies, and foals.[23] ### Displacement[edit] A displacement occurs when a portion of the large colon—usually the pelvic flexure—moves to an abnormal location. There are four main displacements described in equine medicine: 1. Left dorsal displacement (nephrosplenic entrapment): the pelvic flexure moves dorsally towards the nephrosplenic space. This space is found between the spleen, the left kidney, the nephrosplenic ligament (which runs between the spleen and kidney), and the body wall.[24] In some cases, the bowel become entrapped over the nephrosplenic ligament. LDD accounts for 6-8% of all colics.[24] 2. Right dorsal displacement: the colon moves between the cecum and body wall. 3. The pelvic flexure retroflexes towards the diaphragm 4. The colon develops a 180-degree volvulus, which may or may not occlude the vasculature of the organ. The cause of displacement is not definitively known, but one explanation is that the bowel becomes abnormally distended with gas (from excessive fermentation of grain, a change in the microbiota secondary to antibiotic use, or a buildup of gas secondary to impaction) which results in a shift in the bowel to an abnormal position.[25] Because much of the bowel is not anchored to the body wall, it is free to move out of position. Displacement is usually diagnosed using a combination of findings from the rectal exam and ultrasonography. Many displacements (~96% of LDD, 64% of RDD)[25] resolve with medical management that includes fluids (oral or intravenous) to rehydrate the horse and soften any impaction that may be present. Systemic analgesics, antispasmodics, and sedation are often used to keep the horse comfortable during this time. Horses with left dorsal displacement are sometimes treated with exercise and/or phenylephrine—a medication that causes contracture of the spleen and may allow the bowel to slip off the nephrosplenic ligament. At times anesthesia and a rolling procedure, in which the horse is placed in left lateral recumbency and rolled to right lateral recumbency while jostling, can also be used to try to shift the colon off of the nephrosplenic ligament. Displacements that do not respond to medical therapy require surgery, which generally has a very high success rate (80–95%).[25] Reoccurrence can occur with all types of displacements: 42% of horses with RDD, 46% of horses with retroflexion, 21% of those with volvulus, and 8% of those with LDD had reoccurrence of colic.[25] LDD may be prevented by closing the nephrosplenic space with sutures,[24] although this does not prevent other types of displacements from occurring in that same horse. ### Torsion and volvulus[edit] A volvulus is a twist along the axis of the mesentery, a torsion is a twist along the longitudinal axis of the intestine.[17] Various parts of the horse's gastrointestinal tract may twist upon themselves. It is most likely to be either small intestine or part of the colon. Occlusion of the blood supply means that it is a painful condition causing rapid deterioration and requiring emergency surgery. Volvulus of the large colon usually occurs where the mesentery attaches to the body wall, but may also occur at the diaphragmatic or sternal flexures, with rotations up to 720 degrees reported.[13] It is most commonly seen in postpartum mares, usually presents with severe signs of colic that are refractory to analgesic administration, and horses often lie in dorsal recumbency.[9][13] Abdominal distention is common due to strangulation and rapid engorgement of the intestine with gas, which then can lead to dyspnea as the growing bowel pushes against the diaphragm and prevents normal ventilation.[13] Additionally, compression can place pressure on the caudal vena cava, leading to pooling of blood and hypovolemia.[13] However, horses may not have a high heart rate, presumably due to increased vagal tone.[13] Rectal palpation will demonstrate a severely gas distended colon, and the examiner may not be able to push beyond the brim of the pelvis due to the obstruction.[13] The colon may be irreversibly damaged in as little as 3–4 hours from the initial time of the volvulus, so immediate surgical correction is required.[13] The surgeon works to correct the volvulus and then removes any damaged colon. 95% of the colon may be resected, but often the volvulus damages more than this amount, requiring euthanasia.[13] Plasma lactate levels can help predict survival rates, with an increased survival seen in horses with a lactate below 6.0 mmol/L.[13] Prognosis is usually poor, with a survival rate of approximately 36% of horses with a 360 degree volvulus, and 74% of those with a 270 degree volvulus, and a reoccurrence rate of 5–50%.[13] Complications post-surgery include hypoproteinemia, endotoxic shock, laminitis, and DIC.[13] Small intestinal volvulus is thought to be caused by a change in local peristalsis, or due to a lesion that the mesentery may twist around (such as an ascarid impaction), and usually involves the distal jejunum and ileum.w It is one of the most common causes of small intestinal obstruction in foals, possibly because of a sudden change to a bulkier foodstuff.[17] Animals present with acute and severe signs of colic, and multiple distended loops of small intestine, usually seen radiographically in a foal.[17] Small intestinal volvulus often occurs secondary to another disease process in adult horses, where small intestinal obstruction causes distention and then rotation around the root of the mesentery.[17] Surgery is required to resect nonviable sections of bowel, and prognosis is correlated to the length of bowel involved, with animals with greater than 50% of small intestinal involvement having a grave prognosis.[17] ### Intussusception[edit] Intussusception is a form of colic in which a piece of intestine "telescopes" within a portion of itself because a section is paralyzed, so the motile section pushes itself into the non-motile section.[9] It most commonly occurs at the ileocecal junction[9] and requires urgent surgery. It is almost always associated with parasitic infections, usually tapeworms,[8][9][17] although small masses and foreign bodies may also be responsible,[17] and is most common in young horses usually around 1 year of age.[17] Ileocecal intussusception may be acute, involving longer (6–457 cm) segments of bowel, or chronic involving shorter sections (up to 10 cm in length). Horses with the acute form of colic usually have a duration of colic less than 24 hours long, while chronic cases have mild but intermittent colic. Horses with the chronic form tend to have better prognosis. Rectal examination reveals a mass at the base of the cecum in 50% of cases.[17] Ultrasound reveals a very characteristic "target" pattern on cross-section. Abdominocentesis results can vary, since the strangulated bowel is trapped within the healthy bowel, but there are usually signs of obstruction, including reflux and multiple loops of distended small intestine felt on rectal.[17] Surgery is required for intussusception. Reduction of the area is usually ineffective due to swelling, so jejunojejunal intussusceptions are resected and ileocolic intussusceptions are resected as far distally as possible and a jejunocecal anatomosis is performed.[17] ### Entrapment[edit] #### Epiploic foramen entrapment[edit] On rare occasions, a piece of small intestine (or rarely colon) can become trapped through the epiploic foramen into the omental bursa.[9] The blood supply to this piece of intestine is immediately occluded and surgery is the only available treatment.[23] This type of colic has been associated with cribbers,[9][23] possibly due to changes in abdominal pressure, and in older horses, possibly because the foramen enlarges as the right lobe of the liver atrophies with age, although it has been seen in horses as young as 4 months old.[17] Horses usually present with colic signs referable to small intestinal obstruction. During surgery, the foramen can not be enlarged due to the risk of rupture of the vena cava or portal vein, which would result in fatal hemorrhage. Survival is 74–79%, and survival is consistently correlated with abdominocentesis findings prior to surgery.[13] #### Mesenteric rent entrapment[edit] The mesentery is a thin sheet attached to the entire length of intestine, enclosing blood vessels, lymph nodes, and nerves. Occasionally, a small rent (hole) can form in the mesentery, through which a segment of bowel can occasionally enter. As in epiploic foramen entrapment, the bowel first enlarges, since arteries do not occlude as easily as veins, which causes edema (fluid buildup).[9] As the bowel enlarges, it becomes less and less likely to be able to exit the site of entrapment. Colic signs are referable to those seen with a strangulating lesion, such as moderate to severe abdominal pain, endotoxemia, decrease gut sounds, distended small intestine on rectal, and nasogastric reflux.[13] This problem requires surgical correction. Survival for mesenteric rent entrapment is usually lower than other small intestinal strangulating lesions, possibly due to hemorrhage, difficulty correcting the entrapment, and the length of intestine commonly involved, with <50% of cases surviving until discharge.[13] ### Inflammatory and ulcerative conditions[edit] #### Proximal enteritis[edit] Main article: Equine proximal enteritis Proximal enteritis, also known as anterior enteritis or duodenitis-proximal jejunitis (DPJ), is inflammation of the duodenum and upper jejunum. It is potentially caused by infectious organisms, such as Salmonella and Clostridial species, but other possible contributing factors include Fusarium infection or high concentrate diets.[13] The inflammation of the intestine leads to large secretions of electrolytes and fluid into its lumen, and thus large amounts of gastric reflux, leading to dehydration and occasionally shock.[13] Signs include acute onset of moderate to severe pain, large volumes orange-brown and fetid gastric reflux, distended small intestine on rectal examination, fever, depression, increased heart rate and respiratory rate, prolonged CRT, and darkened mucous membranes.[13] Pain level usually improves after gastric decompression. It is important to differentiate DPI from small intestinal obstruction, since obstruction may require surgical intervention. This can be difficult, and often requires a combination of clinical signs, results from the physical examination, laboratory data, and ultrasound to help suggest one diagnosis over the other, but a definitive diagnosis can only be made with surgery or on necropsy.[17] DPI usually is managed medically with nasogastric intubation every 1–2 hours to relieve gastric pressure secondary to reflux,[17][26] and aggressive fluid support to maintain hydration and correct electrolyte imbalances. Horses are often withheld food for several days. Use of anti-inflammatory, anti-endotoxin, anti-microbial, and prokinetic drugs are common with this disease. Surgery may be needed to rule out obstruction or strangulation,[26] and in cases that are long-standing to perform a resection and anastomosis of the diseased bowel.[17] Survival rates for DPJ are 25–94%, and horses in the southeast United States appear to be more severely affected.[13] #### Colitis[edit] Colitis is inflammation of the colon. Acute cases are medical emergencies as the horse rapidly loses fluid, protein, and electrolytes into the gut, leading to severe dehydration which can result in hypovolemic shock and death. Horses generally present with signs of colic before developing profuse, watery, fetid diarrhea. Both infectious and non-infectious causes for colitis exist. In the adult horse, Salmonella, Clostridium difficile, and Neorickettsia risticii (the causative agent of Potomac Horse Fever) are common causes of colitis. Antibiotics, which may lead to an altered and unhealthy microbiota, sand, grain overload, and toxins such as arsenic and cantharidin can also lead to colitis. Unfortunately, only 20–30% of acute colitis cases are able to be definitively diagnosed.[27] NSAIDs can cause slower-onset of colitis, usually in the right dorsal colon (see Right dorsal colitis). Treatment involves administration of large volumes of intravenous fluids, which can become very costly. Antibiotics are often given if deemed appropriate based on the presumed underlying cause and the horse's CBC results. Therapy to help prevent endotoxemia and improve blood protein levels (plasma or synthetic colloid administration) may also be used if budgetary constraints allow. Other therapies include probiotics and anti-inflammatory medication. Horses that are not eating well may also require parenteral nutrition. Horses usually require 3–6 days of treatment before clinical signs improve.[28] Due to the risk of endotoxemia, laminitis is a potential complication for horses suffering from colitis, and may become the primary cause for euthanasia. Horses are also at increased risk of thrombophlebitis.[29] #### Gastric ulceration[edit] Main article: Equine gastric ulcer syndrome Horses form ulcers in the stomach fairly commonly, a disease called equine gastric ulcer syndrome. Risk factors include confinement, infrequent feedings, a high proportion of concentrate feeds, such as grains, excessive non-steroidal anti-inflammatory drug use,[12] and the stress of shipping and showing. Gastric ulceration has also been associated with the consumption of cantharidin beetles in alfalfa hay which are very caustic when chewed and ingested. Most ulcers are treatable with medications that inhibit the acid producing cells of the stomach. Antacids are less effective in horses than in humans, because horses produce stomach acid almost constantly, while humans produce acid mainly when eating. Dietary management is critical. Bleeding ulcers leading to stomach rupture are rare. #### Right dorsal colitis[edit] Long-term use of NSAIDs can lead to mucosal damage of the colon, secondary to decreased levels of homeostatic prostaglandins. Mucosal injury is usually limited to the right dorsal colon, but can be more generalized. Horses may display acute or chronic intermittent colic, peripheral edema secondary to protein losing enteropathy, decreased appetite, and diarrhea. Treatment involves decreasing the fiber levels of the horse's diet by reducing grass and hay, and placing the horse on an easily digestible pelleted feed until the colon can heal. Additionally, the horse may be given misoprostol, sucralfate, and psyllium to try to improve mucosal healing, as well as metronidazole to reduce inflammation of the colon. ### Tumors[edit] #### Strangulating pedunculated lipoma[edit] Benign fatty tumors[12] known as lipomas can form on the mesentery. As the tumor enlarges, it stretches the connective tissue into a stalk which can wrap around a segment of bowel, typically small intestine, cutting off its blood supply.[9] The tumor forms a button that latches onto the stalk of the tumor, locking it on place, and requiring surgery for resolution.[3] Surgery involves cutting the stalk of the tumor, untwisting the bowel, and removing bowel that is no longer viable.[17] If the colic is identified and taken to surgery quickly, there is a reasonable rate of success of 50–78%.[17] This type of colic is most commonly associated with ponies, and aged geldings, 10 years and older, probably because of fat distribution in this group of animals.[17][23] #### Other cancers[edit] Cancers (neoplasia) other than lipoma are relatively rare causes of colic. Cases have been reported with intestinal cancers including intestinal lymphosarcoma, leiomyoma, and adenocarcinoma, stomach cancers such as squamous cell carcinoma, and splenic lymphosarcoma.[12] Gastric squamous cell carcinoma is most often found in the non-glandular region of the stomach of horses greater than 5 years of age, and horses often present with weight loss, anorexia, anemia, and ptyalism.[19] Gastric carcinoma is usually diagnosed via gastroscopy, but may sometimes be felt on rectal if they have metastasized to the peritoneal cavity. Additionally, laparoscopy can also diagnose metastasized cancer, as can presence of neoplastic cells on abdominocentesis.[19] Often the signs of intestinal neoplasia are non-specific, and include weight loss and colic, usually only if obstruction of the intestinal lumen occurs.[17] ### Ileus[edit] Ileus is the lack of motility of the intestines, leading to a functional obstruction. It often occurs postoperatively following any type of abdominal surgery, and 10–50% of all cases of surgical colic will develop this complication,[2] including 88% of horses with a strangulating obstructions and 41% of all colics with a large intestinal lesion.[6] The exact cause is unknown, but is suspected to be due to inflammation of the intestine, possibly a result of manipulation by the surgeon,[2] and increased sympathetic tone.[6][13] It has a high fatality rate of 13–86%.[2] Ileus diagnosed based on several criteria:[2] 1. Nasogastric reflux: 4 liters or greater in a single intubation, or greater than 2 liters of reflex over more than one intubation 2. A heart rate greater than 40 bpm 3. Signs of colic, which may vary from mild to severe 4. Distended small intestine, based on rectal or abdominal ultrasound findings. On ultrasound, ileus presents as more than 3 loops of distended small intestine, with a lack of peristaltic waves.[6] This form of colic is usually managed medically. Because there is no motility, intestinal contents back up into the stomach. Therefore, periodic decompression of the stomach though nasogastric intubation is essential to prevent rupture.[2] Horses are monitored closely following abdominal surgery, and a sudden increase in heart rate indicates the need to check for nasogastric reflux, as it is an early indication of postoperative ileus.[13] The horse is placed on intravenous fluids to maintain hydration and electrolyte balance and prevent hypovolemic shock,[13] and rate of fluids is calculated based on daily maintenance requirement plus fluid lose via nasogastric reflux. Motility is encouraged by the use of prokinetic drugs such as erythromycin, metoclopramide, bethanechol and lidocaine, as well as through vigorous walking, which has also been shown to have a beneficial effect on GI motility.[2] Lidocaine is especially useful, as it not only encourages motility, but also has anti-inflammatory properties and may ameliorate some post-operative pain.[13] Metoclopramide has been shown to reduce reflux and hospital stay, but does has excitatory effects on the central nervous system.[13] Anti-inflammatory drugs are used to decrease inflammation of the GI tract, which is thought to be the underlying cause of the disease, as well as to help control any absorption of LPS in cases of endotoxemia since the substance decreases motility.[13] However, care must be taken when giving these drugs, as NSAIDs have been shown to alter intestinal motility.[13] Large intestinal ileus is most commonly seen in horses following orthopedic surgery, but its risk is also increased in cases where post-operative pain is not well-controlled, after long surgeries, and possibly following ophthalmologic surgeries.[13] It is characterized by decreased manure output (<3 piles per day), rather than nasogastric reflux, as well as decreased gut sounds, signs of colic, and the occasional impaction of the cecum or large colon.[13] Cecal impactions can be fatal, so care must be taken to monitor the horse for large intestinal ileus after orthopedic surgery, primarily by watching for decreased manure production. Decreased intestinal motility can also be the result of drugs such as Amitraz, which is used to kill ticks and mites.[12] Xylazine, detomidine, and butorphanol also reduce motility, but will not cause colic if appropriately administered.[12] ### Parasites[edit] #### Ascarids (roundworms)[edit] Occasionally there can be an obstruction by large numbers of roundworms. This is most commonly seen in young horses as a result of a very heavy infestation of Parascaris equorum that can subsequently cause a blockage and rupture of the small intestine. Rarely, dead worms will be seen in reflux.[13] Deworming heavily infected horses may cause a severe immune reaction to the dead worms, which can damage the intestinal wall and cause a fatal peritonitis. Veterinarians often treat horses with suspected heavy worm burdens with corticosteroids to reduce the inflammatory response to the dead worms. Blockages of the small intestine, particularly the ileum, can occur with Parascaris equorum and may well require colic surgery to remove them manually.[13] Large roundworm infestations are often the result of a poor deworming program.[30] Horses develop immunity to parascarids between 6 months age and one year and so this condition is rare in adult horses. Prognosis is fair unless the foal experiences hypovolemia and septic shock, with a survival rate of 33%.[13] #### Tapeworms[edit] Tapeworms at the junction of the cecum have been implicated in causing colic. The most common species of tapeworm in the equine is Anoplocephala perfoliata. However, a 2008 study in Canada indicated that there is no connection between tapeworms and colic, contradicting studies performed in the UK.[31] #### Cyathostomes[edit] Acute diarrhea can be caused by cyathostomes or "small Strongylus-type" worms that are encysted as larvae in the bowel wall, particularly if large numbers emerge simultaneously. The disease most frequently occurs in winter time. Pathological changes of the bowel reveal a typical "pepper and salt" color of the large intestines. Animals suffering from cyathostominosis usually have a poor deworming history. There is now a lot of resistance to fenbendazole in the UK.[32] #### Large strongyles[edit] Large strongyle worms, most commonly Strongylus vulgaris, are implicated in colic secondary to non-strangulating infarction of the cranial mesenteric artery supplying the intestines, most likely due to vasospasm.[12][13] Usually the distal small intestine and the large colon are affected, but any segment supplied by this artery can be compromised.[13] This type of colic has become relatively rare with the advent of modern anthelminthics.[12] Clinical signs vary based on the degree of vascular compromise and the length of intestine that is affected, and include acute and severe colic seen with other forms of strangulating obstruction, so diagnosis is usually made based on anthelminthic administration history although may be definitively diagnosed during surgical exploratoration.[13] Treatment includes typical management of colic signs and endotoxemia, and the administration of aspirin to reduce the risk of thrombosis, but surgery is usually not helpful since lesions are often patchy and may be located in areas not easily resected.[13] ### Foal colic[edit] #### Meconium impactions[edit] Meconium, or the first feces produced by the foal, is a hard pelleted substance.[33] It is normally passed within the first 24 hours of the foal's life, but may become impacted in the distal colon or rectum.[33] Meconium impaction is most commonly is seen in foals 1–5 days of age,[12] and is more common in miniature foals[34] and in colts more than fillies (possibly because fillies have a wider pelvis).[33] Foals will stop suckling, strain to defecate (presents as an arched back and lifted tail), and may start showing overt signs of colic such as rolling and getting up and down. In later stages, the abdomen will distend as it continues to fill with gas and feces.[33] Meconium impactions are often diagnosed by clinical signs, but digital examination to feel for impacted meconium, radiographs, and ultrasound may also be used. Treatment for meconium impaction typically involves the use of enemas, although persistent cases may require mineral oil or IV fluids. It is possible to tell that the meconium has passed when the foal begins to produce a softer, more yellow manure. Although meconium impactions rarely cause perforation, and are usually not life-threatening, foals are at risk of dehydration and may not get adequate levels of IgG due to decreased suckling and not enough ingestion of colostrum. Additionally, the foals will eventually bloat, and will require surgical intervention. Surgery in a foal can be especially risky due to immature immune system and low levels of ingested colostrum. #### Lethal white syndrome[edit] Lethal white syndrome, or ileocolonic aganglionosis, will result in meconium impaction since the foal does not have adequate nerve innervation to the large intestine, in essence, a nonfunctioning colon. Foals that are homozygous for the frame overo gene, often seen in Paint horse heritage, will develop the condition. They present with signs of colic within the first 12 hours after birth, and die within 48 hours due to constipation. This syndrome is not treatable.[34][35] #### Congenital abnormalities[edit] Atresia coli and atresia ani can also present as meconium impaction. The foal is missing the lumen of its distal colon or anus, respectively, and usually show signs of colic within 12–24 hours. Atresia coli is usually diagnosed with barium contrast studies, in which foals are given barium, and then radiographed to see if and where the barium is trapped. Atresia ani is simply diagnosed with digital examination by a veterinarian. Both situations requires emergency surgery to prevent death, and often still has a poor prognosis for survival with surgical correction. #### Infectious organisms[edit] Clostridial enterocolitis due to infection by Clostridium perfringens is most commonly seen in foals under 3 months of age. Clostridial toxins damage the intestine, leading to dehydration and toxemia. Foals usually present with signs of colic, decreased nursing, abdominal distention, and diarrhea which may contain blood. Diagnosis is made with fecal culture, and while some foals do not require serious intervention, others need IV fluids, antibiotics, and aggressive treatment, and may still die. Other bacterial infections that may lead to enterocolitis include Salmonella, Klebsiella, Rhodococcus equi, and Bacteroides fragilis.[34] Parasitic infection, especially with threadworms (Strongyloides westeri) and ascarids (Parascaris equorum) can produce signs of colic in foals (See Ascarids). Other conditions that may lead to signs of colic in foals include congenital abnormalities, gastric ulcers (see Gastric ulceration), which may lead to gastric perforation and peritonitis, small intestine volvulus, and uroabdomen secondary to urinary bladder rupture.[34] ### Herniation[edit] #### Inguinal herniation[edit] Inguinal hernias are most commonly seen in Standardbred and Tennessee Walking Horse stallions due, likely due to a breed prevalence of a large inguinal ring,[13] as well as Saddlebred and Warmblood breeds.[12] Inguinal hernias in adult horses are usually strangulating (unlike foals, which are usually non-strangulating). Stallions usually display acute signs of colic, and a cool, enlarged testicle on one side.[17] Hernias are classified as either indirect, in which the bowel remains in the parietal vaginal tunic, or direct, in which case it ruptures through the tunic and goes subcutaneously. Direct hernias are seen most commonly in foals, and usually congenital. Indirect hernias may be treated by repeated manual reduction, but direct hernias often require surgery to correct.[17] The testicle on the side of resection will often require removal due to vascular compromise, although prognosis for survival is good (75%)[13] and the horse may be used for breeding in the future.[17] #### Umbilical herniation[edit] Although umbilical hernias are common in foals, strangulation is rare, occurring only 4% of the time and usually involving the small intestine.[17] Rarely, the hernia will only involve part of the intestinal wall (termed a Richter's hernia), which can lead to an enterocutaneous fistula.[13] Strangulating umbilical hernias will present as enlarged, firm, warm, and painful with colic signs. Foals usually survive to discharge.[17] #### Diaphragmatic herniation[edit] Diaphragmatic hernias are rare in horses, accounting for 0.3% of colics.[17] Usually the small intestine herniates through a rent in the diaphragm, although any part of the bowel may be involved. Hernias are most commonly acquired, not congenital, with 48% of horses having a history of recent trauma, usually through during parturition, distention of the abdomen, a fall, or strenuous exercise, or direct trauma to the chest.[17] Congenital hernias occur most commonly in the most ventral part of the diaphragm, while acquired hernias are usually seen at the junction of the muscular and tendinous sections of the diaphragm.[17] Clinical signs usually are similar to an obstruction, but occasionally decreased lung sounds may be heard in one section of the chest, although dyspnea is only seen in approximately 18% of horses.[17] Ultrasound and radiography may both be used to diagnose diaphragmatic herniation. ### Toxins[edit] Ingested toxins are rarely a cause of colic in the horse. Toxins that can produce colic signs include organophosphates, monensin, and cantharidin.[12] Additionally, overuse of certain drugs such as NSAIDs may lead to colic signs (See Gastric ulceration and Right dorsal colitis).[12] ### Uterine tears and torsions[edit] Uterine tears often occur a few days post parturition. They can lead to peritonitis and require surgical intervention to fix.[23] Uterine torsions can occur in the third trimester, and while some cases may be corrected if the horse in anesthetized and rolled, others require surgical correction.[23] ### Other causes that may show clinical signs of colic[edit] Strictly speaking, colic refers only to signs originating from the gastrointestinal tract of the horse. Signs of colic may be caused by problems other than the GI-tract e.g. problems in the liver, ovaries, spleen, urogenital system, testicular torsion, pleuritis, and pleuropneumonia. Diseases which sometimes cause symptoms which appear similar to colic include uterine contractions, laminitis, and exertional rhabdomyolysis.[12] Colic pain secondary to kidney disease is rare.[12] ## Diagnosis[edit] Many different diagnostic tests are used to diagnose the cause of a particular form of equine colic, which may have greater or lesser value in certain situations. The most important distinction to make is whether the condition is managed medically or surgically. If surgery is indicated, then it must be performed as soon as possible, as delay is a dire prognostic indicator.[26] ### History[edit] A thorough history is always taken, including signalment (age, sex, breed), recent activity, diet and recent dietary changes, anthelmintic history, if the horse is a cribber, fecal quality and when it was last passed, and any history of colic. The most important factor is time elapsed since onset of clinical signs, as this has a profound impact on prognosis. Additionally, a veterinarian will need to know any drugs given to the horse, their amount, and the time they were given, as those can help with the assessment of the colic progression and how it is responding to analgesia.[36] ### Physical examination[edit] Heart rate rises with progression of colic, in part due to pain, but mainly due to decreased circulating volume secondary to dehydration, decreased preload from hypotension, and endotoxemia.[37] The rate is measured over time, and its response to analgesic therapy ascertained. A pulse that continues to rise in the face of adequate analgesia is considered a surgical indication.[26] Mucous membrane color can be assessed to appreciate the severity of haemodynamic compromise. Pale mucous membranes may be caused by decreased perfusion (as with shock), anemia due to chronic blood loss (seen with GI ulceration), and dehydration.[37][38] Pink or cyanotic (blue) membrane colors are associated with a greater chance of survival (55%).[38] Dark red, or "injected", membranes reflect increased perfusion, and the presence of a "toxic line" (a red ring over the top of the teeth where it meets the gum line, with pale or gray mucous membranes) can indicate endotoxemia.[36] Both injected mucous membranes and the presence of a toxic line correlate to a decreased likelihood of survival, at 44%.[38] Capillary refill time is assessed to determine hydration levels and highly correlates to perfusion of the bowel.[38] A CRT of < 2 seconds has a survival rate of 90%, of 2.5–4 seconds a survival rate of 53%, and > 4 seconds a survival rate of 12%.[38] Laboratory tests can be performed to assess the cardiovascular status of the patient. Packed cell volume (PCV) is a measure of hydration status, with a value 45% being considered significant. Increasing values over repeated examination are also considered significant. The total protein (TP) of blood may also be measured, as an aid in estimating the amount of protein loss into the intestine. Its value must be interpreted along with the PCV, to take into account the hydration status. When laboratory tests are not available, hydration can be crudely assessed by tenting the skin of the neck or eyelid, looking for sunken eyes, depression, high heart rate, and feeling for tackiness of the gums.[37] Jugular filling and quality of the peripheral pulses can be used to approximate blood pressure.[26] Capillary refill time (CRT) may be decreased early in the colic, but generally prolongs as the disease progresses and cardiovascular status worsens.[39] Percent Dehydration Heart rate Mucous membrane quality CRT Time skin tent holds Other 5% Normal Moist to slightly tacky < 2 seconds 1–3 seconds Decrease in urine production 8% 40-60 bpm Tacky Usually 2–3 seconds 3–5 seconds Decrease in blood pressure 10-12% 60+ bpm Dry Usually > 4 seconds 5+ seconds Decrease in jugular fill and quality of peripheral pulses; sunken eyes present [17] Weight and body condition score (BCS) is important when evaluating a horse with chronic colic, and a poor BCS in the face of good quality nutrition can indicate malabsorptive and maldigestive disorders.[40] Rectal temperature can help ascertain if an infectious or inflammatory cause is to blame for the colic, which is suspected if the temperature if >103F. Temperature should be taken prior to rectal examination, as the introduction of air will falsely lower rectal temperature.[37] Coolness of extremities can indicate decreased perfusion secondary to endotoxemia. Elevated respiratory rate can indicate pain as well as acid-base disturbances.[37] A rectal examination, auscultation of the abdomen, and nasogastric intubation should always occur in addition to the basic physical exam. ### Rectal examination[edit] Rectal examinations are a cornerstone of colic diagnosis, as many large intestinal conditions can be definitively diagnosed by this method alone. Due to the risk of harm to the horse, a rectal examination is performed by a veterinarian.[41] Approximately 40% of the gastrointestinal tract can be examined by rectal palpation, although this can vary based on the size of the horse and the length of the examiner's arm.[41] Structures that can be identified include the aorta, caudal pole of the left kidney, nephrosplenic ligament, caudal border of the spleen, ascending colon (left dorsal and ventral, pelvic flexure), the small intestine if distended (it is not normally palpable on rectal), the mesenteric root, the base of the cecum and the medial cecal band, and rarely the inguinal rings.[41] The location within the colon is identified based on size, presence of sacculations, number of bands, and if fecal balls are present.[41] Displacements, torsions, strangulations, and impactions may be identified on rectal examination.[41] Other non-specific findings, such as dilated small intestinal loops, may also be detected, and can play a major part in determining if surgery is necessary. Thickness of the intestinal walls may indicate infiltrative disease or abnormal muscular enlargement.[40] Roughening of the serosal surface of the intestine can occur secondary to peritonitis.[40] Horses that have had gastrointestinal rupture may have gritty feeling and free gas in the abdominal cavity.[42] Surgery is usually suggested if rectal examination finds severe distention of any part of the GI tract, a tight cecum or multiple tight loops of small intestine, or inguinal hernia.[26] However, even if the exact cause can not be determined on rectal, significant abnormal findings without specific diagnosis can indicate the need for surgery.[41] Rectal examinations are often repeated over the course of a colic to monitor the GI tract for signs of change. Rectals are a risk to the practitioner, and the horse is ideally examined either in stocks or over a stall door to prevent kicking, with the horse twitched, and possibly sedated if extremely painful and likely to try to go down.[41] Buscopan is sometimes used to facilitate rectal examination and reduce the risk of tears, because it decreases the smooth muscle tone of the gastrointestinal tract, but can be contraindicated and will produce a very rapid heart rate. Because the rectum is relatively fragile, the risk of rectal tears is always present whenever an examination is performed. Severe rectal tears often result in death or euthanasia.[41] However, the diagnostic benefits of a rectal examination almost always outweigh these risks. ### Nasogastric intubation[edit] Passing a nasogastric tube (NGT) is useful both diagnostically and therapeutically. A long tube is passed through one of the nostrils, down the esophagus, and into the stomach. Water is then pumped into the stomach, creating a siphon, and excess fluid and material (reflux) is pulled off the stomach. Healthy horses will often have less than 1 liter removed from the stomach;[39] any more than 2 litres of fluid is considered to be significant. Horses are unable to vomit or regurgitate, therefore nasogastric intubation is therapeutically important for gastric decompression. A backup of fluid in the gastrointestinal tract will cause it to build up in the stomach, a process that can eventually lead to stomach rupture, which is inevitably fatal.[36] Backing up of fluid through the intestinal tract is usually due to a downstream obstruction, ileus, or proximal enteritis, and its presence usually indicates a small intestinal disease.[26][36] Generally, the closer the obstruction is to the stomach, the greater amount of gastric reflux will be present.[36] Approximately 50% of horses with gastric reflux require surgery.[26] ### Auscultation[edit] Auscultation of the abdomen is subjective and non-specific, but can be useful.[37] Auscultation typically is performed in a four-quadrant approach: 1. Upper flank, right side: corresponds to the cecum 2. Caudoventral abdomen, right side: corresponds to the colon 3. Upper flank, left side: corresponds to the small intestine 4. Caudoventral abdomen, left side: corresponds to colon Each quadrant should ideally be listened to for 2 minutes. Gut sounds (borborygmi) correlate to motility of the bowel, and care should be taken to note intensity, frequency, and location.[37] Increased gut sounds (hyper-motility) may be indicative of spasmodic colic. Decreased sound, or no sound, may be suggestive of serious changes such as ileus or ischemia,[39] and persistence of hypomotile bowel often suggests the need for surgical intervention.[26] Gut sounds that occur concurrently with pain may indicate obstruction of the intestinal lumen.[39] Sounds of gas can occur with ileus, and those of fluid are associated with diarrhea which may occur with colitis.[39] Sand may sometimes be heard on the ventral midline, presenting a typical "waves on the beach" sound in a horse with sand colic after the lower abdomen is forcefully pushed with a fist.[15] Abdominal percussion ("pinging") can sometimes be used to determine if there is gas distention in the bowel.[37] This may be useful to help determine the need for trocarization, either of the cecum or the colon.[39] ### Abdominal ultrasound[edit] Ultrasound is a useful diagnostic tool for colics. Ultrasound provides visualization of the thoracic and abdominal structures, and can sometimes rule out or narrow down a diagnosis. Information that may be gleaned from ultrasonographic findings include the presence of sand, distention, entrapment, strangulation, intussusception, and wall thickening of intestinal loops, as well as diagnose nephrosplenic entrapment, peritonitis, abdominal tumors, and inguinal or scrotal hernias.[23][26] Abdominal ultrasound requires an experienced operator to accurately diagnose the cause of colic.[23] It may be applied against the side of the horse, as well as transrectally.[39] Sand presents as a homogenous gray and allows the ultrasound waves to penetrate deep. It is distinguishable from feces, which is less homogenous, and gas colic, which does not allow the operator to see pass the gas. Additionally, the sand usually "sparkles" on ultrasound if it moves. Sand is best diagnosed using a 3.5 megahertz probe.[15] Horses with gastrointestinal rupture will have peritoneal fluid accumulation, sometimes with debris, visible on ultrasound.[42] Horses with peritonitis will often have anechoic fluid, or material in between visceral surfaces. Differentiation between proximal enteritis and small intestinal obstruction is important to ensure correct treatment, and can be assisted with the help of ultrasound. Horses with small intestinal obstruction will usually have an intestinal diameter of -10 cm with a wall thickness of 3-5mm. Horses with proximal enteritis usually have an intestinal diameter that is narrower, but wall thickness is often greater than 6mm,[17] containing a hyperechoic or anechoic fluid, with normal, increased, or decreased peristalsis.[13] However, obstructions that have been present for some time may present with thickened walls and distention of the intestine.[13] Horses experiencing intussusception may have a characteristic "bullseye" appearance of intestine on ultrasound, which is thickened, and distended intestine proximal to the affected area.[39] Those experiencing nephrosplenic entrapment will often have ultrasonographic changes including an inability to see the left kidney and/or tail of the spleen.[39] ### Abdominocentesis (belly tap)[edit] Abdominocentesis, or the extraction of fluid from the peritoneum, can be useful in assessing the state of the intestines. Normal peritoneal fluid is clear, straw-colored, and of serous consistency, with a total nucleated cell count of less than 5000 cells/microliter (24–60% which are neutrophils) and a total protein of 2.5 g/dL.[17] Abdominocentesis allows for the evaluation of red and white blood cells, hemoglobin concentration, protein levels, and lactate levels. A high lactate in abdominal fluid suggests intestinal death and necrosis, usually due to strangulating lesion, and often indicates the need for surgical intervention.[26][43] A strangulating lesion may produce high levels of red blood cells, and a serosanguinous fluid containing blood and serum.[9] White blood cell levels may increase if there is death of intestine that leads to leakage of intestinal contents, which includes high levels of bacteria, and a neutrophil to monocyte ratio greater than or equal to 90% is suggestive of a need for surgery.[26] "High" nucleated cell counts (15,000–800,000 cells/microliter depending on the disease present) occur with horses with peritonitis or abdominal abscesses.[17] The protein level of abdominal fluid can give information as to the integrity of intestinal blood vessels. High protein (> 2.5 mg/dL) suggests increased capillary permeability associated with peritonitis, intestinal compromise, or blood contamination.[17] Horses with gastrointestinal rupture will have elevated protein the majority of the time (86.4%) and 95.7% will have bacteria present.[42] Occasionally, with sand colic, it is possible to feel the sand with the tip of the needle.[15] Clinical analysis is not necessarily required to analyze the fluid. Simple observation of color and turbidity can be useful in the field. * Sanguinous fluid indicates an excess of red blood cells or hemoglobin, and may be due to leakage of the cells through a damaged intestinal wall, splenic puncture during abdominocentesis, laceration of abdominal viscera, or contamination from a skin capillary.[17] * Cloudy fluid is suggestive of an increased number of cells or protein. * White fluid indicates chylous effusion.[17] * Green fluid indicates either gastrointestinal rupture or enterocentesis,[17] and a second sample should be drawn to rule out the latter. Gastrointestinal rupture produces a color change in peritoneal fluid in 85.5% of cases.[42] * Colorless (dilute) peritoneal fluid, especially in large quantities, can indicate ascites or uroperitoneum (urine in the abdomen).[17] * Large amount of fluid can indicate acute peritonitis.[17] ### Abdominal distension[edit] Any degree of abdominal distension is usually indicative of a condition affecting the large intestines, as distension of structures upstream of here would not be large enough to be visible externally. Abdominal distention may indicate the need for surgical intervention, especially if present with severe signs of colic, high heart rate, congested mucous membranes, or absent gut sounds.[23] ### Fecal examination[edit] The amount of feces produced, and its character can be helpful, although as changes often occur relatively distant to the anus, changes may not be seen for some time. In areas where sand colic is known to be common, or if the history suggests it may be a possibility, faeces can be examined for the presence of sand, often by mixing it in water and allowing the sand to settle out over 20 minutes.[15] However, sand is sometimes present in a normal horse's feces, so the quantity of sand present must be assessed. Testing the feces for parasite load may also help diagnose colic secondary to parasitic infection.[40] ### Radiography, gastroscopy, and laparoscopy[edit] #### Radiography[edit] Radiographs (x-rays) are sometimes used to look for sand[15] and enteroliths. Due to the size of the adult horse's abdomen, it requires a powerful machine that is not available to all practitioners. Additionally, the quality of these images is sometimes poor.[40] #### Gastroscopy[edit] Gastroscopy, or endoscopic evaluation of the stomach, is useful in chronic cases of colic suspected to be caused by gastric ulcers, gastric impactions, and gastric masses.[40] A 3-meter scope is required to visualize the stomach of most horses, and the horse must be fasted prior to scoping. #### Laparoscopy[edit] Laparoscopy involves inserting a telescoping camera approximately 1 cm in diameter into the horse's abdomen, through a small incision, to visualize the gastrointestinal tract. It may be performed standing or under general anesthesia, and is less invasive than an exploratory celiotomy (abdominal exploratory surgery).[40] ### Rectal biopsy[edit] Rectal biopsy is rarely performed due to its risks of abscess formation, rectal perforation and peritonitis, and because it requires a skilled clinical to perform. However, it can be useful in cases of suspected intestinal cancer, as well as some inflammatory diseases (such as IBD) and infiltrative diseases, like granulomatous enteritis.[40][44] ## Clinical signs[edit] Clinical signs of colic are usually referable to pain, although the horse may appear depressed rather than painful in cases of necrosis (tissue death) of the gastrointestinal tract, inflammation of the intestines, endotoxemia, or significant dehydration.[45] Pain levels are often used to determine the need for surgery (See Surgical intervention). Horses are more likely to require surgery if they display severe clinical signs that can not be controlled by the administration of analgesics and sedatives, or have persistent signs that require multiple administrations of such drugs.[26] Heart rate is often used as a measure of the animal's pain level and a heart rate >60 bpm is more likely to require surgery.[23] However, this measure can be deceiving in the early stages of a severe colic, when the horse may still retain a relatively low rate.[26] Additionally, pain tolerance of the individual must be taken into account, since very stoic animals with severe cases of colic may not show adequate levels of pain to suggest the need for surgery.[9] High heart rates (>60 bpm), prolonged capillary refill time (CRT), and congested mucous membranes suggest cardiovascular compromise and the need for more intense management.[26] Decreased or absent gut sounds often suggest the need for surgical intervention if prolonged.[9][26][46] A horse showing severe clinical signs, followed by a rapid and significant improvement, may have experienced gastrointestinal perforation.[45] While this releases the pressure that originally caused so much discomfort for the horse, it results in a non-treatable peritonitis that requires euthanasia. Soon after this apparent improvement, the horse will display signs of shock, including an elevated heart rate, increased capillary refill time, rapid shallow breathing, and a change in mucous membrane color. It may also be pyretic, act depressed, or become extremely painful.[42] Gas distention usually produces mild clinical signs, but in some cases leads to severe signs due to pressure and tension on the mesentery.[45] Simple obstructions often present with a slightly elevated heart rate (<60 bpm) but normal CRT and mucous membrane color.[9] Strangulating obstructions are usually extremely painful, and the horse may have abdominal distention, congested mucous membranes, altered capillary refill time, and other signs of endotoxemia.[9] ### General[edit] * Elevated body temperature: most commonly associated with medically managed colics such as enteritis, colitis, peritonitis, and intestinal rupture[26][37] * Elevated heart rate[26] * Elevated respiratory rate[46] * Increased capillary refill time[26] * Change in mucous membrane (gum) color (See Physical examination)[26][36] * Change in the degree of gut sounds (See Auscultation)[9][26][46] * Pawing[45][46] * Increased attention toward the abdomen, including flank watching (turning of the head to look at the abdomen and/or hind quarters), nipping, biting, or kicking[9][45][46] * Repeatedly lying down and rising, which may become violent when the colic is severe[45] * Rolling, especially when not followed by shaking after standing, and which may become violent when the colic is severe (thrashing)[45][46] * Sweating[45] * Change in activity level: lethargy, pacing, or a constant shifting of weight when standing[9][45] * Change in feces: decreased fecal output or a change in consistency[45] * Repeated flehmen response * Stretching, abnormal posturing,[7][45] or frequent attempts to urinate[15] * Groaning[45][46] * Bruxism[19][34] * Excess salivation (ptyalism)[10] * Excessive yawning[15] * Loss of appetite[45] * Abdominal distention[23] * Dorsal recumbency in foals[45] * Poor coat or weight loss (chronic colic)[45] ## Medical management[edit] Colic may be managed medically or surgically. Severe clinical signs often suggest the need for surgery, especially if they can not be controlled with analgesics.[26] Immediate surgical intervention may be required, but surgery can be counter-indicated in some cases of colic, so diagnostic tests are used to help discover the cause of the colic and guide the practitioner in determining the need for surgery (See Diagnosis). The majority of colics (approximately 90%)[9] can be successfully managed medically. ### Analgesia and sedation[edit] The intensity of medical management is dependent on the severity of the colic, its cause, and the financial capabilities of the owner. At the most basic level, analgesia and sedation is administered to the horse. The most commonly used analgesics for colic pain in horses are NSAIDs, such as flunixin meglumine, although opioids such as butorphanol may be used if the pain is more severe.[39] Butrophanol is often given with alpha-2 agonists such as xylazine and detomidine to prolong the analgesic effects of the opioid.[39] Early colic signs may be masked with the use of NSAIDs, so some practitioners prefer to examine the horse before they are given by the owner. ### Nasogastric intubation and gastric decompression[edit] Nasogastric intubation, a mainstay of colic management, is often repeated multiple times until resolution of clinical signs, both as a method of gastric reflux removal and as a way to directly administer fluids and medication into the stomach. Reflux must be removed periodically to prevent distention and possible rupture of the stomach, and to track reflux production, which aids in monitoring the progression of the colic. Its use is especially important in the case of strangulating obstruction or enteritis, since both of these cause excessive secretion of fluid into the intestine, leading to fluid back-up and distention of the stomach. Nasogastric intubation also has the benefit of providing pain relief resulting from gastric distention.[39] ### Fluid support[edit] Fluids are commonly given, either orally by nasogastric tube or by intravenous catheter, to restore proper hydration and electrolyte balance. In cases of strangulating obstruction or enteritis, the intestine will have decreased absorption and increased secretion of fluid into the intestinal lumen, making oral fluids ineffective and possibly dangerous if they cause gastric distention and rupture.[39] This process of secretion into the intestinal lumen leads to dehydration, and these horse require large amounts of IV fluids to prevent hypotension and subsequent cardiovascular collapse. Fluid rates are calculated by adding the fluid lost during each collection of gastric reflux to the daily maintenance requirement of the horse. Due to the fact that horses absorb water in the cecum and colon, the IV fluid requirement of horses with simple obstruction is dependent on the location of the obstruction. Those that are obstructed further distally, such as at the pelvic flexure, are able to absorb more oral fluid than those obstructed in the small intestine, and therefore require less IV fluid support. Impactions are usually managed with fluids for 3–5 days before surgery is considered.[39] Fluids are given based on results of the physical examination, such as mucous membrane quality, PCV, and electrolyte levels.[39] Horses in circulatory shock, such as those suffering from endotoxemia, require very high rates of IV fluid administration. Oral fluids via nasogastric tube are often given in the case of impactions to help lubricate the obstruction. Oral fluids should not be given if significant amounts of nasogastric reflux are obtained.[39] Access to food and water will often be denied to allow careful monitoring and administration of what is taken in by the horse. ### Intestinal lubricants and laxatives[edit] In addition to fluid support, impactions are often treated with intestinal lubricants and laxatives to help move the obstruction along. Mineral oil is the most commonly used lubricant for large colon impactions, and is administered via nasogastric tube, up to 4 liters once or twice daily.[39] It helps coat the intestine, but is not very effective for severe impactions or sand colic since it may simply bypass the obstruction.[39] Mineral oil has the added benefit of crudely measuring GI transit time, a process which normally takes around 18 hours,[9] since it is obvious when it is passed. The detergent dioctyl sodium sulfosuccinate (DDS) is also commonly given in oral fluids. It is more effective in softening an impaction than mineral oil,[39] and helps stimulate intestinal motility,[9] but can inhibit fluid absorption from the intestine and is potentially toxic so is only given in small amounts, two separate times 48 hours apart.[39] Epsom salts are also useful for impactions, since they act both as an osmotic agent, to increase fluid in the GI tract, and as a laxative, but do run the risk of dehydration and diarrhea.[39] Strong laxatives are not recommended for treating impactions.[39] ### Nutritional support[edit] Horses are withheld feed when colic signs are referable to gastrointestinal disease. In long-standing cases, parenteral nutrition may be instituted. Once clinical signs improve, the horse will slowly be re-fed (introduced back to its normal diet), while being carefully monitored for pain. ### Endotoxemia prevention[edit] Endotoxemia is a serious complication of colic and warrants aggressive treatment. Endotoxin (lipopolysaccharide) is released from the cell wall of gram-negative bacteria when they die. Normally, endotoxin is prevented from entering systemic circulation by the barrier function of the intestinal mucosa, antibodies and enzymes which bind and neutralize it and, for the small amount that manages to enter the blood stream, removal by Kupffer cells in the liver.[5] Endotoxemia occurs when there is an overgrowth and secondary die-off of gram negative bacteria, releasing mass quantities of endotoxin. This is especially common when the mucosal barrier is damaged, as with ischemia of the GI tract secondary to a strangulating lesion or displacement.[5] Endotoxemia produces systemic effects such as cardiovascular shock, insulin resistance, and coagulation abnormalities.[3][39] Fluid support is essential to maintain blood pressure, often with the help of colloids or hypertonic saline. NSAIDs are commonly given to reduce systemic inflammation. However, they decrease the levels of certain prostaglandins that normally promote healing of the intestinal mucosa, which subsequently increases the amount of endotoxin absorbed. To counteract this, NSAIDs are sometimes administered with a lidocaine drip, which appears to reduce this particular negative effect.[5] Flunixin may be used for this purpose at a dose lower than that used for analgesia, so can be safely given to a colicky horse without risking masking signs that the horse requires surgery.[39] Other drugs that bind endotoxin, such as polymyxin B and Bio-Sponge, are also often used.[5] Polymixin B prevents endotoxin from binding to inflammatory cells, but is potentially nephrotoxic, so should be used with caution in horses with azotemia, especially neonatal foals. Plasma may also be given with the intent of neutralizing endotoxin.[39] Laminitis is a major concern in horses suffering from endotoxemia. Ideally, prophylactic treatment should be provided to endotoxic horses, which includes the use of NSAIDs, DMSO, icing of the feet, and frog support.[3] Horses are also sometimes administered heparin, which is thought to reduce the risk of laminitis by decreasing blood coagulability and thus blood clot formation in the capillaries of the foot.[5] ### Case-specific drug treatment[edit] Specific causes of colic are best managed with certain drugs. These include: * Spasmolytic agents, most commonly Buscopan, especially in the case of gas colic.[6] * Pro-motility agents: metoclopramide, lidocaine, bethanechol, and erythromycin are used in cases of ileus.[2] * Anti-inflammatories are often used in the case of enteritis or colitis. * Anti-microbials may be administered if an infectious agent is suspected to be the underlying cause of colic. * Phenylephrine: used in cases of nephrosplenic entrapment to contract the spleen, and is followed by light exercise to try to shift the displaced colon back into its normal position.[39] * Psyllium may be given via nasogastric tube to treat sand colic. * Anthelminthics for parasitic causes of colic. ## Surgical intervention[edit] Surgery poses significant expense and risks, including peritonitis, the formation of adhesions, complications secondary to general anesthesia, injury upon recovery of the horse which may require euthanasia, dehiscence, or infection of the incisional site. Additionally, surgical cases may develop post-operative ileus which requires further medical management.[2] However, surgery may be required to save the life of the horse, and 1–2% of all colics require surgical intervention.[3] If a section of intestine is significantly damaged, it may need to be removed (resection) and the healthy parts reattached together (anastomosis). Horses may have up to 80% of their intestines removed and still function normally, without needing a special diet.[9] ### Survival rates[edit] In the case of colics requiring surgery, survival rates are best improved by quick recognition of colic and immediate surgical referral, rather than waiting to see if the horse improves, which only increases the extent of intestinal compromise.[3] Survival rates are higher in surgical cases that do not require resection and anastomosis. 90% of large intestinal colic surgeries that are not due to volvulus, and 20–80% of large colon volvuluses, are discharged; while 85–90% of non strangulating small intestinal lesions, and 65–75% of strangulating intestinal lesions are discharged.[3] 10–20% of small intestinal surgical cases require a second surgery, while only 5% of large intestinal cases do so.[3] Horses that survive colic surgery have a high rate of return to athletic function. According to one study, approximately 86% of horses discharged returned to work, and 83.5% returned to same or better performance.[3] ### Adhesion formation[edit] Adhesions, or scar tissue between various organs that are not normally attached within the abdomen, may occur whenever an abdominal surgery is performed. It is often seen secondary to reperfusion injury where there is ischemic bowel or after intestinal distention.[13][47] This injury causes neutrophils to move into the serosa and mesothelium to be lost, which the body then attempts to repair using fibrin and collagen, leading to adhesion formation between adjacent tissues with either fibrinous or fibrous material.[13] Adhesions may encourage a volvulus, as the attachment provides a pivot point, or force a tight turn between two adjacent loops that are now attached, leading to partial obstruction. For this reason, clinical signs vary from silent lesions to acute obstruction,[13] encouraging future colics including intestinal obstruction or strangulation,[48] and requiring further surgery and risk of adhesion.[6] Generally, adhesions form within the first two months following surgery.[13] Adhesions occur most commonly in horses with small intestinal disease (22% of all surgical colics), foals (17%), those requiring enterotomy or a resection and anastomosis, or those that develop septic peritonitis.[13] Prevention of adhesions begins with good surgical technique to minimize trauma to the tissue and thus reparative responses by the body. Several drugs and substances are used to try to prevent adhesion formation. Preoperative use of DMSO, a free radical scavenger, potassium penicillin, and flunixin meglumine may be given. The thick intestinal lubricant carboxymethylcellulose[2] is often applied to the GI tract intraoperatively, to decrease trauma from handling by the surgeon and provide a physical barrier between the intestine and adjacent intestinal loops or abdominal organs. It has been shown to double the survival rate of horses, and its use is now a standard practice.[6] Hyaluraonan can also be used to produce a physical barrier.[13] Intraperitoneal unfractionated heparin is sometimes used, since it decreases fibrin formation and thus may decrease fibrinous adhesions.[6] Omentectomy (removal of the omentum) is a quick, simple procedure that also greatly decreases the risk of adhesions, since the omentum is one organ that commonly adheres to the intestines.[6] The abdomen is usually lavaged copiously before the abdomen is sutured closed, and anti-inflammatories are given postoperatively.[3] A laparoscope may be used post-surgery to look for and break down adhesions, however there is risk of additional adhesions forming post-procedure.[48] Encouraging motility post-surgery can also be useful, as it decreases the contact time between tissues.[13] Adhesion-induced colic has a poor prognosis, with a 16% survival rate in one study.[13] ### Post-operative care[edit] Small amounts of food is usually introduced as soon as possible after surgery, usually within 18–36 hours,[36] to encourage motility and reduce the risk of ileus and the formation of adhesions.[2][3] Often horses are stall rested with short bouts of hand walking to encourage intestinal motility.[3] The incision site is carefully monitored for dehiscence, or complete failure of the incision leading to spillage of the abdominal contents out of the incision site,[6] and the horse is not allowed turn-out until the incision has healed, usually after 30 days of stall rest. Abdominal bandages are sometimes used to help prevent the risk of dehiscence.[6] Incisional infection doubles the time required for postoperative care, and dehiscence may lead to intestinal herniation, which reduces the likelihood of return to athletic function.[3] Therefore, antibiotics are given 2–3 days after surgery, and temperature is constantly monitored, to help assess if an infection is present. Antibiotics are not used long-term due to the risk of antimicrobial resistance.[36] The incision usually takes 6 months to reach 80% strength, while intestinal healing following resection and anastomosis is much faster, at a rate to 100% strength in 3 weeks.[3] After the incision has healed adequately, the horse is turned out in a small area for another 2–3 months, and light exercise is added to improve the tone and strength of the abdominal musculature. Weight loss of 75–100 pounds is common after colic surgery, secondary to the decreased function of the gastrointestinal tract and from muscle atrophy that occurs while the horse is rested.[3] This weight is often rapidly replaced. Draft horses tend to have more difficulty post-surgery because they are often under anesthesia for a longer period of time, since they have a greater amount of gastrointestinal tract to evaluate, and their increased size places more pressure on their musculature, which can lead to muscle damage. Miniature horses and fat ponies are at increased risk for hepatic lipidosis post-surgery,[36] a serious complication. ## Prevention[edit] The incidence of colic can be reduced by restricted access to simple carbohydrates[12] including sugars from feeds with excessive molasses, providing clean feed and drinking water, preventing the ingestion of dirt or sand by using an elevated feeding surface, a regular feeding schedule, regular deworming, regular dental care, a regular diet that does not change substantially in content or proportion and prevention of heatstroke. Horses that bolt their feed are at risk of colic, and several management techniques may be used to slow down the rate of feed consumption. Supplementing with previously mentioned form of pysllium fiber may reduce risk of sand colic if in a high-risk area. Most supplement forms are given one week per month and available wherever equine feed is purchased. Turnout is thought to reduce the likelihood of colic, although this has not been proven.[12][49] It is recommended that a horse receive ideally 18 hours of grazing time each day,[49] as in the wild. However, many times this is difficult to manage with competition horses and those that are boarded, as well as for animals that are easy keepers with access to lush pasture and hence at risk of laminitis. Turnout on a dry lot with lower-quality fodder may have similar beneficial effects. ## References[edit] 1. ^ Abutarbush SM, Carmalt JL, Shoemaker RW (September 2005). "Causes of gastrointestinal colic in horses in western Canada: 604 cases (1992 to 2002)". The Canadian Veterinary Journal. 46 (9): 800–5. PMC 1187790. PMID 16231649. 2. ^ a b c d e f g h i j k l Larson, Erica. "Equine Postoperative Ileus Insights". www.thehorse.com. The Horse. Retrieved 4 July 2014. 3. ^ a b c d e f g h i j k l m n o Loving, Nancy. "Equine Colic Management and Long-Term Survival". www.thehorse.com. The Horse. Retrieved 4 July 2014. 4. ^ "10 Tips for Preventing Colic" (PDF). 5. ^ a b c d e f Loving, Nancy. "Endotoxemia Explained". www.thehorse.com. The Horse. Retrieved 4 July 2014. 6. ^ a b c d e f g h i j k Oke, Stacey. "Horse Colic: Surgical and Medical Management". www.thehorse.com. The Horse. Retrieved 4 July 2014. 7. ^ a b c d e f g Moore, James. "Gas Colic". www.thehorse.com. The Horse. Retrieved 4 July 2014. 8. ^ a b c Press Release. "Pfizer Introduces New Daily+ Deworming Program". www.thehorse.com. The Horse. Retrieved 5 July 2014. 9. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa Briggs, Karen. "The Many Faces of Colic". www.thehorse.com. The Horse. Retrieved 4 July 2014. 10. ^ a b c d e f g h i j k Lyons, D.J. Carey. "An Unwanted Impact". www.thehorse.com. The Horse. Retrieved 5 July 2014. 11. ^ Current Therapy in Equine Medicine, 5th ed. Reid Hanson. Chapter 3.13 Ileal Impaction 12. ^ a b c d e f g h i j k l m n o p q White, Nat. "The Epidemiology Of Colic". www.thehorse.com. The Horse. Retrieved 4 July 2014. 13. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt bu bv bw bx by bz ca cb cc cd ce Reed, Stephen M., Waewick M. Bayly, and Debra C. Sellon. (2010). Equine Internal Medicine (Third ed.). St Louis, MO: Saunders. pp. 846–850, 878–891. ISBN 978-1-4160-5670-6.CS1 maint: multiple names: authors list (link) 14. ^ Oke, Stacey. "Colic Surgery and Intestinal Lubricants (AAEP 2010)". www.thehorse.com. The Horse. Retrieved 5 July 2014. 15. ^ a b c d e f g h i j k l m n o p q r King, Marcia. "Dealing with Sand Colic". www.thehorse.com. The Horse. Retrieved 5 July 2014. 16. ^ a b Oke, Stacey. "Cecal Impaction: Surgery Can Make a Difference". www.thehorse.com. The Horse. Retrieved 5 July 2014. 17. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay Smith, Bradford (2002). Large Animal Internal Medicine (3rd ed.). St. Louis, Missouri: Mosby, Inc. pp. 644–47, 650–52, 662–65, 670, 682. ISBN 0-323-00946-8. 18. ^ Plummer AE, Rakestraw PC, Hardy J, Lee RM: Outcomes of medical and surgical treatment of cecal impaction in horses: 114 cases (1999-2004), J Am Vet Med Assoc 231:1378-1385, 2007. 19. ^ a b c d e f Conrad, Sarah. "The Equine Stomach (AAEP 2003:Milne Lecture)". www.thehorse.com. The Horse. Retrieved 5 July 2014. 20. ^ a b c d Larson, Erica. "Gastric Impactions in Horses: A Review". www.thehorse.com. The Horse. Retrieved 5 July 2014. 21. ^ West, Christy. "Horse Vets Say: Hold the Persimmons, Please (AAEP 2009)". www.thehorse.com. The Horse. Retrieved 5 July 2014. 22. ^ a b c d Sellnow, Les. "Small Colon Impactions". www.thehorse.com. The Horse. Retrieved 5 July 2014. 23. ^ a b c d e f g h i j k l Larson, Erica. "Managing Severe Colic in the Field". www.thehorse.com. The Horse. Retrieved 27 June 2020. 24. ^ a b c West, Christy. "Correcting Large Colon Displacement". www.thehorse.com. The Horse. Retrieved 4 July 2014. 25. ^ a b c d Munsterman, Amelia. "Lefts and Rights: Medical Management of Displacements". NAVC Conference 2015. 26. ^ a b c d e f g h i j k l m n o p q r s t u v Larson, Erica (21 February 2012). "Colic in the Horse: When is Surgery Necessary". www.thehorse.com. The Horse. Retrieved 4 July 2014. 27. ^ Merritt AM, Bolton JR, Cimprich R (March 1975). "Differential diagnosis of diarrhoea in horses over six months of age". Journal of the South African Veterinary Association. 46 (1): 73–6. PMID 1177243. 28. ^ Cohen ND, Woods AM (February 1999). "Characteristics and risk factors for failure of horses with acute diarrhea to survive: 122 cases (1990-1996)". Journal of the American Veterinary Medical Association. 214 (3): 382–90. PMID 10023402. 29. ^ Divers TJ (December 2003). "Prevention and treatment of thrombosis, phlebitis, and laminitis in horses with gastrointestinal diseases". The Veterinary Clinics of North America. Equine Practice. 19 (3): 779–90. doi:10.1016/j.cveq.2003.08.002. PMID 14740769. 30. ^ Stephen, Jennifer (2009). The horse professional guide to colic. www.horseprofessional.com 31. ^ Oke, Stacy. "Research Ongoing for Tapeworm, Colic Link." The Horse July 2008: 20. 32. ^ Chandler KJ, Collins MC, Love S (December 2000). "Efficacy of a five-day course of fenbendazole in benzimidazole-resistant cyathostomes". The Veterinary Record. 147 (23): 661–2. doi:10.1136/vr.147.23.661. PMID 11131553. 33. ^ a b c d Cable, Christina. "Foals and Meconium Impaction". www.thehorse.com. The Horse. Retrieved 5 July 2014. 34. ^ a b c d e King, Marcia. "GI Disease in Foals". www.thehorse.com. The Horse. Retrieved 5 July 2014. 35. ^ Finno CJ, Spier SJ, Valberg SJ (March 2009). "Equine diseases caused by known genetic mutations". Veterinary Journal. Elsevier. 179 (3): 336–47. doi:10.1016/j.tvjl.2008.03.016. PMID 18472287. "Ileocolonic aganglionosis, or overo lethal white foal syndrome (OLWS), is an autosomal recessive trait" 36. ^ a b c d e f g h i West, Christy. "Colic in Horses: An Overview for Owners". www.thehorse.com. The Horse. Retrieved 4 July 2014. 37. ^ a b c d e f g h i Bentz, Bradford. "When a Horse Colics: The Physical Examination". www.thehorse.com. The Horse. Retrieved 5 July 2014. 38. ^ a b c d e Loving, Nancy. "Mucous Membranes". www.thehorse.com. The Horse. Retrieved 4 July 2014. 39. ^ 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 "Overview of Colic in Horses". Merck Veterinary Manual. Retrieved 20 July 2014. 40. ^ a b c d e f g h Larson, Erica. "Chronic Colic in Horses: What to Consider". www.thehorse.com. The Horse. Retrieved 4 July 2014. 41. ^ a b c d e f g h Peloso, John. "Rectal Examination of the Colicky Horse". www.thehorse.com. The Horse. Retrieved 4 July 2014. 42. ^ a b c d e Conrad, Sarah. "Gastrointestinal Rupture Clinical Signs (AAEP 2003)". www.thehorse.com. The Horse. Retrieved 5 July 2014. 43. ^ Loving, Nancy. "Changes in Equine Surgical and Postoperative Care, AAEP 2009". www.thehorse.com. The Horse. Retrieved 5 July 2014. 44. ^ Diehl, Nancy. "Protein-losing Enteropathy Diagnosis". www.thehorse.com. The Horse. Retrieved 4 July 2014. 45. ^ a b c d e f g h i j k l m n o Bentz, Bradford. "The Clinical Signs of Equine Colic". www.thehorse.com. The Horse. Retrieved 4 July 2014. 46. ^ a b c d e f g University of Kentucky College of Agriculture, Food, and Environment. "Colic in Horses: General Review". www.thehorse.com. The Horse. Retrieved 4 July 2014.CS1 maint: multiple names: authors list (link) 47. ^ The Horse Staff. "Minimizing Abdominal Adhesions". www.thehorse.com. The Horse. Retrieved 4 July 2014. 48. ^ a b Piscopo, Susan. "Decreasing Abdominal Adhesions". www.thehorse.com. The Horse. Retrieved 4 July 2014. 49. ^ a b Blikslager, Anthony (July 2008). "Avoiding Colic Through Management". The Horse. pp. 47–54. ## Further reading[edit] * The Illustrated Veterinary Encyclopedia for Horsemen Equine Research Inc. * Veterinary Medications and Treatments for Horsemen Equine Research Inc. * Horse Owner's Veterinary Handbook James M. Giffin, M.D. and Tom Gore, D.V.M. * Preventing Colic in Horses Christine King, BVSc, MACVSc ## External links[edit] * [1] Vet advice: Colic in horses * Colic in Horses * The horse professional guide to colic * Colic information sheet * Colic in Horses in the Merck Veterinary Manual [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	Horse colic	None	6,289	wikipedia	https://en.wikipedia.org/wiki/Horse_colic	2021-01-18T19:06:50	{"wikidata": ["Q1569563"]}
A number sign (#) is used with this entry because the skin fragility-woolly hair syndrome is caused by homozygous or compound heterozygous mutation in the desmoplakin gene (DSP; 125647) on chromosome 6p24. Clinical Features Whittock et al. (2002) reported 2 unrelated individuals with an autosomal recessive genodermatosis characterized by focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, and woolly hair with varying degrees of alopecia. They referred to this disorder as skin fragility-woolly hair syndrome (SFWHS). The phenotype of SFWHS is similar to dilated cardiomyopathy with woolly hair and keratoderma (DCWHK; 605676), another recessive disorder due to desmoplakin mutations, but is significantly different in that DCWHK lacks persistent skin fragility with neonatal onset and SFWHS lacks cardiomyopathy. The combination of desmoplakin haploinsufficiency and a missense mutation resulted in a painful keratoderma on the hands and feet with recurrent secondary infection. Occasionally, there was more widespread trauma-induced 'sloughing' of the skin. In contrast to other genodermatoses such as epidermolysis bullosa simplex (see 131800), patients with SFWHS did not appear to improve with age. Unlike other forms of keratoderma, this disorder was disabling, and patients required a wheelchair for mobility. Biochemical Features Immunohistochemistry of skin biopsies from both affected individuals with SFWHS reported by Whittock et al. (2002) revealed that desmoplakin was located not only at the cell periphery but also in the cytoplasm. In addition, electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network. Molecular Genetics In 2 probands with SFWHS, Whittock et al. (2002) performed mutation screening of desmoplakin and demonstrated compound heterozygosity for a nonsense/missense combination of mutations in both patients, cys809 to ter/asn287 to lys (C809X/N287K; see 125647.0004) and gln664 to ter/arg2366 to cys (Q664X/R2366C; see 125647.0006), respectively. Mutations in desmoplakin also cause some cases of the autosomal dominant skin disorder striate palmoplantar keratoderma (see 148700), which is characterized clinically by linear and focal hyperkeratosis of the palms and soles. Whittock et al. (2002) reported that heterozygous carriers of DSP C809X, N287K, Q664X, or R2366C mutations displayed no phenotypic abnormalities. The nonsense mutations C809X and Q664X would be expected to cause nonsense-mediated mRNA decay resulting in haploinsufficiency of desmoplakin. Whittock et al. (2002) concluded that desmoplakin haploinsufficiency can be tolerated in some cases, but that in combination with a missense mutation on the other allele, the consequences are a severe genodermatosis with specific clinical manifestations. INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive CARDIOVASCULAR Heart \- Normal SKIN, NAILS, & HAIR Skin \- Fragility with blistering (neonatal onset) \- Palmoplantar keratosis with erythema and scale \- Hyperkeratotic plaques on trunk and limbs Skin Histology \- Peripheral and cytoplasmic desmoplakin staining (immunohistochemistry) Electron Microscopy \- Acantholysis throughout all layers of the skin \- Focal detachment of desmosomes into the intercellular spaces \- Perinuclear condensation of the suprabasal keratin intermediate filament network Nails \- Nail dystrophy Hair \- Alopecia \- Woolly hair \- Sparse eyelashes \- Sparse eyebrows MOLECULAR BASIS \- Caused by mutations in the desmoplakin gene (DSP, 125647.0004 ) ▲ 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	SKIN FRAGILITY-WOOLLY HAIR SYNDROME	c1843292	6,290	omim	https://www.omim.org/entry/607655	2019-09-22T16:08:52	{"mesh": ["C564359"], "omim": ["607655"], "orphanet": ["293165"], "synonyms": ["Skin fragility-woolly hair-palmoplantar hyperkeratosis syndrome"]}
Ohdo blepharophimosis syndrome (OBS) is a multiple congenital malformation syndrome characterized by blepharophimosis, ptosis, dental hypoplasia, hearing impairment and intellectual disability. ## Epidemiology So far, less than 30 patients have been reported worldwide. ## Clinical description Abnormal ears, microcephaly, and growth retardation have been reported occasionally. Male patients may show cryptorchidism and scrotal hypoplasia. ## Genetic counseling Most reported cases are sporadic, except the original cases of Ohdo who described two affected sisters and a first cousin, favoring autosomal recessive inheritance. Autosomal dominant, X-linked- and mitochondrial inheritance have also been suggested. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Blepharophimosis-intellectual disability syndrome, Ohdo type	c0796094	6,291	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2728	2021-01-23T18:46:50	{"gard": ["3348"], "mesh": ["C536232"], "omim": ["249620"], "umls": ["C0796094", "C2931643"], "icd-10": ["Q87.8"], "synonyms": ["BMRS, Ohdo type", "Blepharophimosis syndrome, Ohdo type", "Ohdo syndrome", "Ohdo-Madokoro-Sonoda syndrome"]}
## Description Familial partial lipodystrophy type 1 (FPLD1), or Kobberling-type lipodystrophy, is characterized by loss of adipose tissue confined to the extremities, with normal or increased distribution of fat on the face, neck, and trunk (Kobberling and Dunnigan, 1986). For a general description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660. Clinical Features Kobberling et al. (1975) reported a woman with complete absence of subcutaneous fat on the arms and legs, well-developed adipose tissue on the trunk and face, severe hyperlipidemia, eruptive xanthomas, insulin-resistant diabetes mellitus with lack of ketoacidosis, hepatomegaly, and increased basal metabolic rate. The patient's mother and sister had the same peculiar appearance and slight hyperlipidemia, but no diabetes mellitus. The authors suggested autosomal dominant inheritance. Johansen et al. (1995) reported a mother and daughter with atrophy of fat in the face, chest, and limbs, and abdominal obesity caused by intraabdominal fat accumulation. The mother had severe insulin resistance and impaired glucose tolerance, whereas the daughter did not. Both had metabolic rates about 30% above normal levels. Herbst et al. (2003) reported 13 patients with FPLD1. All lacked subcutaneous fat in the extremities and gluteal region, but had normal or increased truncal fat. There was normal or increased fat in the face and around the neck. All patients except 1 reported that their body habitus was present in childhood. Other features included hypertension, coronary artery disease, and diabetes. Laboratory studies showed increased total cholesterol, decreased high density lipoprotein, increased triglycerides, and hyperglycemia. Acanthosis nigricans was present in 1 patient with diabetes. None of the patients had polycystic ovary syndrome. Herbst et al. (2003) noted that only women have been reported with FPLD1. None of the patients had mutations in the LMNA (150330) or PPARG (601487) genes. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Normal or increased facial adipose tissue Neck \- Normal or increased adipose tissue around the neck CARDIOVASCULAR Vascular \- Coronary artery disease \- Hypertension \- Prominent superficial veins ABDOMEN Liver \- Hepatomegaly Pancreas \- Pancreatitis, acute SKIN, NAILS, & HAIR Skin \- Xanthomata \- Prominent superficial veins \- Acanthosis nigricans in patients with diabetes MUSCLE, SOFT TISSUES \- Loss of subcutaneous adipose tissue in limbs \- Loss of gluteal adipose tissue \- Increased subcutaneous truncal adipose tissue \- Normal or increased facial and neck adipose tissue METABOLIC FEATURES \- Increased metabolic rate ENDOCRINE FEATURES \- Insulin-resistant diabetes mellitus LABORATORY ABNORMALITIES \- Increased serum lipoproteins \- Increased serum triglycerides \- Increased serum total cholesterol \- Hyperglycemia MISCELLANEOUS \- Onset in childhood \- Only women have been reported \- Inheritance may be X-linked dominant ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 1	c1720859	6,292	omim	https://www.omim.org/entry/608600	2019-09-22T16:07:34	{"doid": ["0070207"], "mesh": ["D052496"], "omim": ["608600"], "orphanet": ["79084"], "synonyms": ["Alternative titles", "LIPODYSTROPHY, FAMILIAL PARTIAL, KOBBERLING TYPE"]}
A number sign (#) is used with this entry because of evidence that the Maroteaux type of spondyloepiphyseal dysplasia is caused by heterozygous mutation in the TRPV4 gene (605427). Clinical Features Doman et al. (1990) used the designation spondyloepiphyseal dysplasia (SED) of Maroteaux for a form of spondyloepiphyseal dysplasia with manifestations limited to the musculoskeletal system and with other features distinguishing it from Morquio syndrome of any type (253000, 253010, 252300), X-linked SED tarda (313400), brachyolmia (113500, 271530, 271630), and spondylometaphyseal dysplasia of Kozlowski (184252). Doman et al. (1990) reported affected father and son, aged 51 and 20 years, respectively, and affected mother and son. The patients were considered normal at birth. Platyspondyly is a feature, but there is no tongue-like deformity of the vertebral bodies in this disorder. Intelligence is normal and there is no clouding of the cornea or mucopolysacchariduria. Both hands and feet are short and stubby. The pelvic inlet is described as having a champagne-glass configuration, unlike the wine-glass-like configuration of the pelvic inlet in patients who have Morquio syndrome. Odontoid hypoplasia was not found. Genu valgum was present. Nishimura et al. (2003) reported a Japanese mother and son and an unrelated 65-year-old man with spondyloepiphyseal dysplasia of Maroteaux. The adults had extremely short stature, brachydactyly, platyspondyly, rectangular vertebral bodies with irregular endplates, epiphyseal hypoplasia of the large joints, and iliac hypoplasia. The man had myeloradiculopathy necessitating neurosurgery. The affected child had short stature and brachydactyly with characteristic spine radiographic findings. None of the patients had mutations in the COL2A1 gene (120140), which excluded a diagnosis of spondyloperipheral dysplasia (271700). Nishimura et al. (2003) suggested that platyspondyly and brachydactyly are much more severe in SED of Maroteaux than in spondyloperipheral dysplasia. Megarbane et al. (2004) reported a patient with characteristic features of spondyloepiphyseal dysplasia of Maroteaux. The 11-year-old girl, who was of normal intelligence, was the only child of nonconsanguineous parents, and appeared normal at birth. Clinical features included short stature, head positioned in hyperextension, mild arched palate, prominent joints, limited elbow movements, hyperextensible wrists and fingers, brachydactyly, broad thorax, pectus carinatum, short trunk, genu valgum, and flat feet. A radiographic skeletal survey revealed generalized osteoporosis, platyspondyly, thoracic kyphoscoliosis, small and square iliac wings, short femoral necks, dysplastic epiphyses, flared metaphyses, and brachydactyly with various carpal, metacarpal, and finger malformations. Megarbane et al. (2004) reviewed features of the 6 previously reported cases and noted that their patient's cervical spine instability and distal joint laxity were unusual, indicating clinical or genetic heterogeneity. Molecular Genetics Nishimura et al. (2010) analyzed the candidate gene TRPV4 (605427) in 6 patients with the Maroteaux type of SED, including 3 previously reported patients (Nishimura et al., 2003; Megarbane et al., 2004), and identified heterozygous mutations in all of them (see, e.g., 605427.0007 and 605427.0018-605427.0021). Nishimura et al. (2010) noted that SED Maroteaux type is thus allelic to several other skeletal dysplasias also caused by heterozygous mutation in TRPV4, including brachyolmia type 3 (113500), spondylometaphyseal dysplasia Kozlowski type (SMDK; 184252), and metatropic dysplasia (MD; 156530), and that the 4 skeletal disorders share many radiographic features, particularly platyspondyly with broad and elongated vertebral bodies that overshadow the vertebral pedicles in anteroposterior radiographs. However, brachydactyly is usually absent or very mild in SMDK, and kyphosis and/or scoliosis develops in childhood in MD but is not seen in patients with the Maroteaux type of SED. Nishimura et al. (2010) noted that genotype/phenotype correlations did not appear to be robust, and suggested that in the presence of a TRPV4 mutation, modulation of the clinical phenotype by other genes and/or by nongenetic factors might occur. Eyes \- No corneal clouding Radiology \- Champagne-glass configuration of pelvic inlet Neuro \- Normal intelligence Inheritance \- Autosomal dominant Limbs \- Short and stubby hands and feet \- Genu valgum Lab \- No mucopolysacchariduria Skel \- Spondyloepiphyseal dysplasia \- Platyspondyly ▲ 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	SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE	c3159322	6,293	omim	https://www.omim.org/entry/184095	2019-09-22T16:34:24	{"mesh": ["C563218"], "omim": ["184095"], "orphanet": ["263482"], "synonyms": ["Alternative titles", "SED, MAROTEAUX TYPE", "PSEUDO-MORQUIO SYNDROME, TYPE 2"], "genereviews": ["NBK201366"]}
Isolated prolactin deficiency is a clear entity (Turkington, 1972) which may be an autosomal recessive trait. The affected females are generally healthy but are unable to nurse following parturition and have no detectable prolactin secretion after stimulation with phenothiazine. Falk (1992), who stated that only 3 cases had previously been reported, described a 36-year-old gravida 2, para 2 who had experienced normal childhood and adolescent development. After spontaneous menarche at age 13, her menses were grossly irregular, for which oral contraceptives were started at age 16. With the help of clomiphene, she conceived at the age of 30 and had an uneventful pregnancy which was followed, however, by failure of lactation during the puerperium. Three years later she again was successfully treated with clomiphene and went through an uncomplicated pregnancy except for the failure to establish lactation. There was no family history of problems with lactation or of irregular or absent menses. In addition to the 2 patients reported by Turkington (1972), Kauppila et al. (1987) reported a woman with puerperal alactogenesis who, despite undetectable immunoactive serum PRL measurements, had 2 normal pregnancies that were conceived without benefit of ovulation-inducing medications. Endocrine \- Isolated prolactin deficiency \- Puerperal lactation failure GU \- Irregular menses \- Variable infertility Lab \- No detectable prolactin secretion after stimulation with phenothiazine Inheritance \- Autosomal recessive ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	PROLACTIN DEFICIENCY, ISOLATED	c0271586	6,294	omim	https://www.omim.org/entry/264110	2019-09-22T16:23:09	{"mesh": ["C562708"], "omim": ["264110"]}
A rare syndrome with combined immunodeficiency characterized by the association of severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells and hepatic veno-occlusive disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Hepatic veno-occlusive disease-immunodeficiency syndrome	c1856128	6,295	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79124	2021-01-23T18:08:42	{"gard": ["10083"], "mesh": ["C537257"], "omim": ["235550"], "umls": ["C1856128"], "icd-10": ["K76.5"], "synonyms": ["VODI syndrome"]}
A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-36 (RP36) is caused by homozygous mutation in the PRCD gene (610598) on chromosome 17q25. For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000. Clinical Features Zangerl et al. (2006) examined a 32-year-old woman from Bangladesh who first noticed difficulty seeing at night as a child. Funduscopic examination revealed optic discs with fairly normal color but markedly attenuated arterioles. Extensive bone-spicule-like pigmentation was present in all 4 quadrants of both eyes, with highest density at the equator, and was admixed with lighter colored deposits at the level of the retinal pigment epithelium. Small patches of geographic atrophy near fixation in both eyes were also observed. ERGs showed no response from either eye under any stimulus condition. The patient was born of first-cousin parents with normal vision and had 4 unaffected sibs, 1 brother who became blind at a young age, and 2 other sibs with uncharacterized vision problems. Nevet et al. (2010) studied 24 individuals with retinitis pigmentosa from a Muslim Arab village with a high degree of inbreeding. Both scotopic and photopic electroretinograms (ERGs) were nonrecordable in all tested individuals, as early as 6 years of age. Typical bone spicule-type pigment deposits were noted in most patients. Additional findings included signs of macular degeneration (macular edema and puckering, macular scarring, and bull's eye maculopathy), optic disc pallor, and cataract. Most patients were also myopic. Mapping Nevet et al. (2010) performed haplotype analysis in a consanguineous family with retinitis pigmentosa from a Muslim Arab village and identified a haplotype of 2 polymorphic marker alleles linked to the PRCD gene on chromosome 17q25.1 that cosegregated with RP in the family. Genetic analysis in 5 additional RP families from the same village showed cosegregation of the PRCD-linked haplotype with the disease in all of them. Molecular Genetics Zangerl et al. (2006) analyzed the PRCD gene in 1,836 patients with RP and other inherited retinal disorders. In a 32-year-old woman from Bangladesh with autosomal recessive RP, they identified homozygosity for a missense mutation in the PRCD gene (C2Y; 610598.0001) that was identical to a mutation observed in dogs with progressive rod-cone degeneration. In an individual from a Muslim Arab village with a high degree of inbreeding, who had RP mapping to the PRCD gene, Nevet et al. (2010) identified homozygosity for a nonsense mutation in the PRCD gene (R22X; 610598.0002). Analysis of 17 additional affected individuals and 28 unaffected relatives from 9 families revealed homozygosity for R22X in all affected individuals but in none of the unaffected family members. The mutation was also found in heterozygosity in 16 of 159 randomly selected adults from the village, indicating a carrier frequency of 10%. No carriers of R22X were detected among 130 unrelated Israeli Muslim Arab controls from Northern Israel, showing that this founder mutation is rare in the surrounding Muslim Arab population. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	RETINITIS PIGMENTOSA 36	c0035334	6,296	omim	https://www.omim.org/entry/610599	2019-09-22T16:04:18	{"doid": ["0110405"], "mesh": ["D012174"], "omim": ["610599"], "orphanet": ["791"], "genereviews": ["NBK1417"]}
Familial pancreatic carcinoma is defined by the presence of pancreatic cancer (PC) in two or more first-degree relatives. ## Epidemiology The annual incidence has been estimated at approximately 1-10/1,000,000, representing 5-10% of all PC cases. ## Clinical description In familial cases, disease onset occurs before 50 years of age, earlier than for the other forms of PC. A high incidence of familial PC has been observed within hereditary syndromes (Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma syndrome, hereditary breast and ovarian cancer syndrome, and hereditary nonpolyposis colorectal cancer; see these terms). Smoking represents a significant risk factor associated with familial PC. PC can arise from the exocrine (95%) or endocrine portions of the pancreas. In 60% of cases it occurs within the head of the pancreas. The main symptoms are non-specific and include pain in the upper abdomen that typically radiates to the back, loss of appetite, significant weight loss and painless jaundice due to bile duct obstruction. As the clinical course is silent, PC often goes undetected until the advanced stages of the disease. In more than 80% of cases, the cancer is either locally advanced or disseminated at the time of diagnosis. A rapid growth pattern, early vascular dissemination, spread to regional lymph nodes, and metastases to distant organs (liver, peritoneum, lungs) are characteristic. PC can also invade the surrounding visceral organs. ## Etiology Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes have been shown to play a role in the etiology of PC. However, they are still not clinically useful for screening or for diagnosing the disease. ## Diagnostic methods Diagnostic methods include ultrasound, contrast-enhanced multidetector computed tomography (MDCT); magnetic resonance (MR) imaging, and integrated positron emission tomography (PET)/computed tomography (CT). Invasive diagnostic techniques are endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound. CA 19-9 is a sensitive tumor serum marker but is not specific. ## Differential diagnosis Differential diagnoses include a wide variety of diseases such as acute and chronic pancreatitis, cholangitis, cholecystitis, cholelithiasis, bile duct tumors and strictures, and gastric cancer and ulcers. ## Management and treatment Surgical resection is the only potentially curative treatment. However, most patients (80%) present with advanced non-resectable tumors. In these cases, chemotherapy (gemcitabine) or radiotherapy, alone or in combination, are alternative treatments, although rather ineffective. ## Prognosis Prognosis is poor (with an overall 5-year survival rate of 5%). Even after complete resection of the tumor, recurrence rates remain high. Patients with a family history of PC should be strongly advised to avoid or cease smoking. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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 pancreatic carcinoma	c2931038	6,297	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1333	2021-01-23T18:45:46	{"gard": ["4206"], "mesh": ["C535837"], "omim": ["260350", "606856", "613347", "613348", "614320"], "umls": ["C2931038"], "icd-10": ["C25"], "synonyms": ["Familial pancreatic cancer"]}
Giant congenital melanocytic nevus is a skin condition characterized by an abnormally dark, noncancerous skin patch (nevus) that is composed of pigment-producing cells called melanocytes. It is present from birth (congenital) or is noticeable soon after birth. The nevus may be small in infants, but it will usually grow at the same rate the body grows and will eventually be at least 40 cm (15.75 inches) across. The nevus can appear anywhere on the body, but it is more often found on the trunk or limbs. The color ranges from tan to black and can become darker or lighter over time. The surface of a nevus can be flat, rough, raised, thickened, or bumpy; the surface can vary in different regions of the nevus, and it can change over time. The skin of the nevus is often dry and prone to irritation and itching (dermatitis). Excessive hair growth (hypertrichosis) can occur within the nevus. There is often less fat tissue under the skin of the nevus; the skin may appear thinner there than over other areas of the body. People with giant congenital melanocytic nevus may have more than one nevus (plural: nevi). The other nevi are often smaller than the giant nevus. Affected individuals may have one or two additional nevi or multiple small nevi that are scattered over the skin; these are known as satellite or disseminated nevi. Affected individuals may feel anxiety or emotional stress due to the impact the nevus may have on their appearance and their health. Children with giant congenital melanocytic nevus can develop emotional or behavior problems. Some people with giant congenital melanocytic nevus develop a condition called neurocutaneous melanosis, which is the presence of pigment-producing skin cells (melanocytes) in the tissue that covers the brain and spinal cord. These melanocytes may be spread out or grouped together in clusters. Their growth can cause increased pressure in the brain, leading to headache, vomiting, irritability, seizures, and movement problems. Tumors in the brain may also develop. Individuals with giant congenital melanocytic nevus have an increased risk of developing an aggressive form of skin cancer called melanoma, which arises from melanocytes. Estimates vary, but it is generally thought that people with giant congenital melanocytic nevus have a 5 to 10 percent lifetime risk of developing melanoma. Melanoma commonly begins in the nevus, but it can develop when melanocytes that invade other tissues, such as those in the brain and spinal cord, become cancerous. When melanoma occurs in people with giant congenital melanocytic nevus, the survival rate is low. Other types of tumors can also develop in individuals with giant congenital melanocytic nevus, including soft tissue tumors (sarcomas), fatty tumors (lipomas), and tumors of the nerve cells (schwannomas). ## Frequency Giant congenital melanocytic nevus occurs in approximately 1 in 20,000 newborns worldwide. ## Causes NRAS gene mutations cause most cases of giant congenital melanocytic nevus. Rarely, mutations in the BRAF gene are responsible for this condition. The proteins produced from these genes are involved in a process known as signal transduction by which signals are relayed from outside the cell to the cell's nucleus. Signals relayed by the N-Ras and BRAF proteins instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). To transmit signals, these proteins must be turned on; when the proteins are turned off, they do not relay signals to the cell's nucleus. The NRAS or BRAF gene mutations responsible for giant congenital melanocytic nevus are somatic, meaning that they are acquired during a person's lifetime and are present only in certain cells. These mutations occur early in embryonic development during the growth and division (proliferation) of cells that develop into melanocytes. Somatic NRAS or BRAF gene mutations cause the altered protein in affected cells to be constantly turned on (constitutively active) and relaying signals. The overactive protein may contribute to the development of giant congenital melanocytic nevus by allowing cells that develop into melanocytes to grow and divide uncontrollably, starting before birth. ### Learn more about the genes associated with Giant congenital melanocytic nevus * BRAF * NRAS ## Inheritance Pattern This condition is generally not inherited but arises from a mutation in the body's cells that occurs after conception. This alteration is called a somatic mutation. A somatic mutation in one copy of the NRAS or BRAF gene is sufficient to cause this disorder. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitor [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens [Diff]: Difference [7d avg]: Average of the last 7 days [per 100k pop]: Deaths per 100,000 population using 10.12 Million as Sweden's total population [Cases per 100k]: Cases per 100,000 county population [Deaths per 100k]: Deaths per 100,000 county population [Percent]: Percent of total in category [Rate]: ICU-care cases per confirmed cases in each category [GER]: Germany [FRA]: France [ITA]: Italy [ESP]: Spain [DEN]: Denmark [SUI]: Switzerland [USA]: United States [COL]: Colombia [KAZ]: Kazakhstan [NED]: Netherlands [LIT]: Lithuania [POR]: Portugal [AUT]: Austria [AUS]: Australia [RUS]: Russia [LUX]: Luxembourg [UKR]: Ukraine [SLO]: Slovenia [GBR]: Great Britain [CZE]: Czech Republic [BEL]: Belgium [CAN]: Canada [DHT]: dihydrotestosterone [IM]: intramuscular injection [SC]: subcutaneous injection [MRIs]: monoamine reuptake inhibitors [GHB]: γ-hydroxybutyric acid [pop.]: population [et al.]: et alia (and others) [a.k.a.]: also known as [mRNA]: messenger RNA *[kDa]: kilodalton	Giant congenital melanocytic nevus	c1842036	6,298	medlineplus	https://medlineplus.gov/genetics/condition/giant-congenital-melanocytic-nevus/	2021-01-27T08:25:36	{"gard": ["2469"], "mesh": ["C536819"], "omim": ["137550"], "synonyms": []}
For a phenotypic description and a discussion of genetic heterogeneity of spondyloarthropathy, see SPDA1 (106300). Mapping Laval et al. (2001) performed a genomewide scan on 185 families containing 255 sib pairs with ankylosing spondylitis (AS). Two-point and multipoint nonparametric linkage analysis identified suggestive linkage with the disease on chromosome 2q (lod scores, 1.6 and 2.5, respectively). To identify major loci controlling clinical manifestations of AS, Brown et al. (2003) performed genomewide linkage analysis on 188 affected sib-pair families containing 454 affected individuals. Heritabilities of the traits studied were as follows: age at symptom onset, 0.33 (p = 0.005); disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 0.49 (p = 0.0001); and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI), 0.76 (p = 0.0000001). No linkage was observed between the MHC (see SPDA1, 106300) and any of the traits studied. Maximum linkage with the BASFI was seen at chromosome 2q (lod = 2.9), and significant or suggestive linkage between other traits and other chromosomal regions was observed. Brown et al. (2003) concluded that these clinical manifestations are largely determined by a small number of genes not encoded within the MHC. Pursuant to the suggestive linkage of AS to chromosome 2q13 (Laval et al., 2001), a region containing the interleukin-1 (IL1; see 147760) family gene cluster, Timms et al. (2004) studied SNPs and haplotypes in the 2q13 region in 227 white British families containing affected sib pairs with AS, 317 parent-offspring trios with AS, and 200 healthy blood donors. They described strong association and transmission of SNPs and haplotypes in the IL1 family gene cluster with AS. Gu et al. (2009) conducted a genomewide scan, followed by fine mapping analysis, on 75 individuals across multiple generations of 3 Han Chinese families with ankylosing spondylitis. Two of the pedigrees shared a 6-cM candidate region for AS on chromosome 2q36.1-q36.3 with a maximum heterogeneity lod score of 12.41 at marker D2S2228 (maximum lod score at that marker for each family individually was 3.26 and 2.13, respectively). The remaining family showed strong linkage to the HLA-B locus (see SPDA1, 106300). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-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	SPONDYLOARTHROPATHY, SUSCEPTIBILITY TO, 3	c2750474	6,299	omim	https://www.omim.org/entry/613238	2019-09-22T15:59:20	{"omim": ["613238"]}

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