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Hereditary clear cell renal cell carcinoma (ccRCC) is a hereditary renal cancer syndrome defined as development of ccRCC in two or more family members without evidence of constitutional chromosome 3 translocation, von Hippel-Lindau disease or other tumor predisposing syndromes associated with ccRCC, such as tuberous sclerosis or Birt-Hogg-Dubbé 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Hereditary clear cell renal cell carcinoma	c0279702	4,300	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=422526	2021-01-23T18:02:37	{"gard": ["9571"], "mesh": ["D002292"], "omim": ["144700"], "icd-10": ["C64"], "synonyms": ["Hereditary clear cell renal cell adenocarcinoma"]}
Hitzig (1959) reported an autosomal dominant form of chronic familial neutropenia. The father, aged 36, a son, aged 8, and a daughter, aged 4, were affected. The blood and marrow findings were similar to those in severe congenital neutropenia (202700), but severe infections were not a feature. Levine (1959) described an affected 14.5-year-old-boy who also showed hyperplastic gingivitis. The father and 2 sibs also had chronic neutropenia. Clubbing of the fingers and hyperglobulinemia were other features. Kirstila et al. (1993) gave a detailed account of the periodontal disease in 3 sibs with neutropenia. The mother had been diagnosed as having neutropenia during her first pregnancy when she was 30 years of age. She had a long history of infections in childhood and adolescence, including recurrent oral ulcerations and severe periodontitis, which led to the loss of all teeth by the age of 22. Cutting and Lang (1964) observed 9 cases of benign chronic neutropenia in 3 generations of a family. The neutropenia was constant. Neutrophil counts returned to normal in adults, but one such person showed the same defect as in children, i.e., reduction in the mitotic pool of neutrophil precursors and in committed stem cells of marrow. Dale et al. (1979) reported a family in which 11 members in 3 generations had chronic neutropenia. In Israel, Djaldetti et al. (1961) collected 11 Jewish families from Yemen with familial neutropenia. Feinaro and Alkan (1968) found 16 Yemenite Jewish persons with neutropenia among 780. Neutropenia was found in 80 of 104 relatives of these 16 persons. No neutrophilia, shift to the left, or morphologic change occurred with intercurrent infection. Eosinophilia was present in 33 of the 80 neutropenics. Berrebi et al. (1987) found a high frequency of leukopenia in Ethiopian Jews and presented evidence of autosomal dominant inheritance. Forbes et al. (1941) noted that neutrophil counts in healthy black sharecroppers in Mississippi were lower than those of white workers living under the same conditions. That black Americans have mean neutrophil counts lower than those of white Americans has been confirmed by Broun et al. (1966), Karayalcin et al. (1972), Orfanakis et al. (1970), Shaper and Lewis (1971), and others. Mason et al. (1979) tested bone marrow granulocyte reserves of 9 black patients with 'benign' neutropenia by measuring the maximum neutrophil increment after the administration of hydrocortisone. They found significantly less increment in these black patients than in control subjects. The black patients studied had neutrophil counts below 2,000 per microliter. Bone marrow aspirates in 4 patients showed normal cellularity and myeloid maturation. Dale et al. (1979) stated that lower neutrophil counts in African and American blacks and in Yemenite Jews are of little or no clinical consequence. Holmes and Thompson (1988) reported affected mother and daughter who also had a fragile site at 10q25. In an admixture study, Nalls et al. (2008) investigated the observation that African Americans have a lower white blood cell count than European Americans. Within a strongly associated locus on chromosome 1q, the strongest association was with a marker known to affect the expression of the Duffy blood group antigen (110700.0002). This variant confers complete protection from Plasmodium vivax infection. Participants who had both copies of the common West African allele had a mean WBC of 4.9 (standard deviation 1.3); participants who had both common European alleles had a mean WBC of 7.1 (standard deviation 1.3). This variant explained approximately 20% of population variation in WBC. Limbs \- Finger clubbing Inheritance \- Autosomal dominant form \- recessive forms more frequent Lab \- Hyperglobulinemia Heme \- Neutropenia Mouth \- Recurrent oral ulcerations \- Hyperplastic gingivitis Teeth \- Periodontitis \- Early tooth loss ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	NEUTROPENIA, CHRONIC FAMILIAL	c3665676	4,301	omim	https://www.omim.org/entry/162700	2019-09-22T16:37:24	{"mesh": ["C535815"], "omim": ["162700"], "synonyms": ["Alternative titles", "LEUKOPENIA, BENIGN FAMILIAL"]}
Cranberry Root Rot (CRR) is a disease in cranberries that can cause a decline in yield. ## Contents * 1 Hosts and symptoms * 2 Disease cycle * 3 Management * 4 References ## Hosts and symptoms[edit] It is categorized by a decline in vine density, and more severe cases can result in dieback of vines over larger areas[1]. A reduction in root mass can also cause secondary symptoms associated with nutrient deficiency[2]. Symptoms can also mirror drought stress, such as chlorosis and wilting[3]. The disease infects the root tissue, limiting its ability to take up water and nutrients, causing these secondary symptoms. ## Disease cycle[edit] CRR is usually caused by Phytophthora cinnamomi, but other Phytophthora pathogens may be responsible as well.[4]. Phytophthora pathogens are a oomycetes, which indicates that water plays an important role in their lifecycle. The root tissue is infected by the zoospores, the motile life stage of the pathogen, which possess two flagella. The pathogen will eventually produce sporangia, if conditions are favorable, which will produce additional zoospores. Under unfavorable conditions, the pathogen will produce asexual chlamydospores which are more resistant to desiccation and cold conditions than the mycelium of the pathogen. Once the conditions become favorable once more, the chlamydospore will produce a sporangium. The sporangia will release zoospores, continuing the lifecycle of the pathogen[2] ## Management[edit] The most important aspect of CRR management is proper drainage[2]. Proper drainage will decrease survivability of the pathogen enough that it will not likely progress to disease. The spread of the pathogen relies on the mobility of the zoospores, which swim using flagella, so limiting soil moisture decreases the ability of zoospores to swim through the soil water. Presence of the inoculum alone is generally not enough to induce disease symptoms, as Phytophthora inoculum is commonly present in irrigation water[5]. Environmental controls, like transitioning from drip irrigation to sprinklers and care to not overwater has been shown to help in other Vaccinium species[6] ## References[edit] 1. ^ Pozdnyakova, Larisa; Oudemans, Peter; Hughes, Marilyn; Gimenez, Daniel. "Estimation of Spatial and Spectral Properties of Phytophthora Root Rot and Its Effects on Cranberry Yield". Computers and Electronics in Agriculture. 37: 57–70. 2. ^ a b c Oudemans, James. "Management of Phytophthora Root and Runner Rot in Cranberry" (PDF). Rutgers Cooperative Extension. 3. ^ "Phytophthora Root Rot of Trees and Shrubs". Missouri Botanical Garden. 4. ^ Polashock, James; Vaiciunas, Jennifer; Oudemans, Peter (1 July 2005). "Identification of a New Phytophthora Species Causing Root and Runner Rot of Cranberry in New Jersey". Phytopathology. 95: 1237–1243. 5. ^ Oudemans, Peter. "Phytophthora species associated with cranberry root rot and surface irrigation water in New Jersey". Plant Disease. 83: 251–258. 6. ^ Bryla, David; Linderman, Robert. "Implications of Irrigation Method and Amount of Water Application on Phytophthora and Pythium Infection and Severity of Root Rot in Highbush Blueberry". HortScience. 42: 1463–1467. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Cranberry root rot	None	4,302	wikipedia	https://en.wikipedia.org/wiki/Cranberry_root_rot	2021-01-18T18:49:10	{"wikidata": ["Q104177884"]}
A rare, genetic, progeroid syndrome disorder characterized by a prematurely aged appearance (including lipoatrophy, thin, translucent skin, sparse, thin hair, and skeletal muscle atrophy), delayed tooth eruption, keloid-like lesions on pressure regions, and skeletal abnormalities including marked acroosteolysis, brachydactyly with small hands and feet, kyphoscoliosis, osteopenia, and progressive joint contractures in the fingers and toes. Craniofacial features include a thin calvarium, delayed closure of the anterior fontanel, flat occiput, shallow orbits, malar hypoplasia and narrow nose. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Acroosteolysis-keloid-like lesions-premature aging syndrome	c1866182	4,303	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=363665	2021-01-23T18:43:03	{"gard": ["4276"], "mesh": ["C536653"], "omim": ["601812"], "umls": ["C1866182"], "icd-10": ["E34.8"], "synonyms": ["Premature aging syndrome, Penttinen type"]}
Stocks (1922-23) made a distinction between facial tic (or habit spasm), which is a movement of a coordinated group of facial muscles not entirely beyond the control of the will and not occurring during sleep, and facial spasm, which is usually confined to the muscles supplied by the facial nerve or one branch thereof. The 18-year-old proband in Stocks' Polish family had rapid clonic spasm of the levator menti muscle between the chin and lower lip. The involvement was said to be limited to that muscle in other affected members of the family also. Cold and excitement aggravated the condition. Hellsing's family (1930) showed more extensive involvement, and anisocoria and depressed tendon reflexes were noted. Considerable confusion exists between facial spasm and trembling chin (190100). It seems possible that the families of Stocks and of Goldsmith are ones of trembling chin and Hellsing's one of facial spasm. Misc \- Worsened by cold and excitement Eyes \- Anisocoria Neuro \- Facial nerve spasm \- Depressed tendon reflexes 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	FACIAL SPASM	c0278151	4,304	omim	https://www.omim.org/entry/134300	2019-09-22T16:41:15	{"omim": ["134300"]}
Hallidie-Smith and Olsen (1968) described a girl and her 2 affected brothers. Mitral regurgitation was present. The parents were not related. Cardiac \- Mitral regurgitation \- Endocardial fibroelastosis \- Cardiomyopathy Inheritance \- Autosomal recessive Vascular \- Coarctation of abdominal aorta ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	ENDOCARDIAL FIBROELASTOSIS AND COARCTATION OF ABDOMINAL AORTA	c1856971	4,305	omim	https://www.omim.org/entry/226100	2019-09-22T16:28:24	{"mesh": ["C565592"], "omim": ["226100"]}
Anaplastic astrocytoma Micrograph of an anaplastic astrocytoma. H&E stain. SpecialtyNeurosurgery Anaplastic astrocytoma is a rare WHO grade III type of astrocytoma, which is a type of cancer of the brain. In the United States, the annual incidence rate for Anaplastic astrocytoma is 0.44 per 100,000 people [1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathology * 4 Treatment * 5 Prognosis * 6 References * 7 External links ## Signs and symptoms[edit] Initial presenting symptoms most commonly are headache, depressed mental status, focal neurological deficits, and/or seizures.[2] The growth rate and mean interval between onset of symptoms and diagnosis is approximately 1.5–2 years but is highly variable,[2] being intermediate between that of low-grade astrocytomas and glioblastomas.[2] Seizures are less common among patients with anaplastic astrocytomas compared to low-grade lesions.[2] ## Causes[edit] Most high-grade gliomas occur sporadically or without identifiable cause.[3] However, a small proportion (less than 5%) of persons with malignant astrocytoma has a definite or suspected hereditary predisposition.[4] The main hereditary predispositions are mainly neurofibromatosis type I, Li-Fraumeni syndrome, hereditary nonpolyposis colorectal cancer and tuberous sclerosis.[3] Anaplastic astrocytomas have also been associated with previous exposure to vinyl chloride and to high doses of radiation therapy to the brain.[3] ## Pathology[edit] Anaplastic astrocytomas fall under the category of high grade gliomas (WHO grade III-IV), which are pathologically undifferentiated gliomas that carry a poor clinical prognosis. Unlike glioblastomas (WHO grade IV), anaplastic astrocytomas lack vascular proliferation and necrosis on pathologic evaluation.[5] Compared to grade II tumors, anaplastic astrocytomas are more cellular, demonstrate more atypia, and mitoses are seen. ## Treatment[edit] The standard initial treatment is to remove as much of the tumor as possible without worsening neurologic deficits. Radiation therapy has been shown to prolong survival and is a standard component of treatment. There is no proven benefit to adjuvant chemotherapy or supplementing other treatments for this kind of tumor. Although temozolomide is effective for treating recurrent anaplastic astrocytoma, its role as an adjuvant to radiation therapy has not been fully tested. Quality of life after treatment depends heavily on the area of the brain that housed the tumor. In many cases, patients with anaplastic astrocytoma may experience various types of paralysis, speech impediments, difficulties planning and skewed sensory perception. Most cases of paralysis and speech difficulties can be rehabilitated with speech, occupational, physical, and vision therapy. ## Prognosis[edit] The age-standardized 5-year relative survival rate is 23.6%.[6] Patients with this tumor are 46 times more likely to die than matched members of the general population.[6] It is important to note that prognosis across age groups is different especially during the first three years post-diagnosis. When the elderly population is compared with young adults, the excess hazard ratio (a hazard ratio that is corrected for differences in mortality across age groups) decreases from 10.15 to 1.85 at 1 to 3 years, meaning that the elderly population are much more likely to die in the first year post-diagnosis when compared to young adults (aged 15 to 40), but after three years, this difference is reduced markedly.[6] Typical median survival for anaplastic astrocytoma is 2–3 years. Secondary progression to glioblastoma multiforme is common. Radiation, younger age, female sex, treatment after 2000, and surgery were associated with improved survival in AA patients.[7] ## References[edit] 1. ^ "Malignant astrocytomas - Epidemiology". 2. ^ a b c d Astrocytoma at eMedicine 3. ^ a b c Children's Hospital Boston > Anaplastic Astrocytoma. Archived 2010-07-06 at the Wayback Machine Retrieved on August 2010 4. ^ Malignant astrocytomas By Edward J Dropcho MD. Contributing editor: Dr. Dropcho. Originally released November 11, 1996; last updated December 7, 2009 5. ^ "Anaplastic astrocytoma". 6. ^ a b c Smoll NR, Hamilton B (2014). "Incidence and relative survival of anaplastic astrocytomas". Neuro-Oncology. 0 (10): 1–8. doi:10.1093/neuonc/nou053. PMC 4165416. PMID 24723565. 7. ^ Nuño M, Birch K, Mukherjee D, Sarmiento JM, Black KL, Patil CG (Sep 2013). "Survival and prognostic factors of anaplastic gliomas". Neurosurgery. 73 (3): 458–65. doi:10.1227/01.neu.0000431477.02408.5e. PMID 23719055.CS1 maint: multiple names: authors list (link) ## External links[edit] Classification D * v * t * e Tumours of the nervous system Endocrine Sellar: * Craniopharyngioma * Pituicytoma Other: * Pinealoma CNS Neuroepithelial (brain tumors, spinal tumors) Glioma Astrocyte * Astrocytoma * Pilocytic astrocytoma * Pleomorphic xanthoastrocytoma * Subependymal giant cell astrocytoma * Fibrillary astrocytoma * Anaplastic astrocytoma * Glioblastoma multiforme Oligodendrocyte * Oligodendroglioma * Anaplastic oligodendroglioma Ependyma * Ependymoma * Subependymoma Choroid plexus * Choroid plexus tumor * Choroid plexus papilloma * Choroid plexus carcinoma Multiple/unknown * Oligoastrocytoma * Gliomatosis cerebri * Gliosarcoma Mature neuron * Ganglioneuroma: Ganglioglioma * Retinoblastoma * Neurocytoma * Dysembryoplastic neuroepithelial tumour * Lhermitte–Duclos disease PNET * Neuroblastoma * Esthesioneuroblastoma * Ganglioneuroblastoma * Medulloblastoma * Atypical teratoid rhabdoid tumor Primitive * Medulloepithelioma Meninges * Meningioma * Hemangiopericytoma Hematopoietic * Primary central nervous system lymphoma PNS: * Nerve sheath tumor * Cranial and paraspinal nerves * Neurofibroma * Neurofibromatosis * Neurilemmoma/Schwannoma * Acoustic neuroma * Malignant peripheral nerve sheath tumor Other * WHO classification of the tumors of the central nervous system Note: Not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastasis). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Anaplastic astrocytoma	c0334579	4,306	wikipedia	https://en.wikipedia.org/wiki/Anaplastic_astrocytoma	2021-01-18T18:40:43	{"gard": ["5860"], "mesh": ["D001254"], "umls": ["C0334579"], "icd-10": ["C71"], "orphanet": ["251589"], "wikidata": ["Q486092"]}
## Description Pontine tegmental cap dysplasia (PTCD) refers to a neurologic condition characterized by a distinct pattern of hindbrain malformations apparent on brain imaging. The abnormalities affect the pons, medulla, and cerebellum. In neuroradiologic studies, the ventral side of the pons is flattened, whereas there is vaulting ('capping') of the dorsal pontine border into the fourth ventricle. Affected individuals show a variety of neurologic deficits, most commonly sensorineural deafness, impaired cranial nerve function, and variable psychomotor retardation (summary by Barth et al., 2007). Clinical Features Barth et al. (2007) reported 4 unrelated children with a neurologic disorder associated with a similar brainstem and cerebellar malformation on brain MRI. The patients, aged 2 to 7 years, had sensorineural deafness with poor or no speech, variably delayed psychomotor development, and inability to walk or delayed and unstable walking with ataxia. Three had deficits of cranial nerve VII, 2 had oculomotor abnormalities, and 2 had a swallowing disorder. Three had mental retardation, but 1 had an IQ of 94. One had seizures and no purposeful movements. Variable skeletal anomalies were also present, particularly vertebral abnormalities. Brain MRI showed hypoplasia and flattening of the ventral pons combined with a dorsal 'cap-like' vault projecting from the pontine tegmentum into the fourth ventricle. There was hypoplasia of the middle cerebellar peduncles, and abnormal shape and orientation of the superior cerebellar peduncles, resulting in the impression of the molar tooth sign. There was also hypoplasia of the cerebellar vermis and absence or alteration of the inferior olivary nucleus. Diffusion tensor imaging in 1 patient showed an ectopic transverse fiber bundle at the site of the pontine tegmentum and complete absence of transverse fibers in the ventral pons. The findings were suggestive of an embryonic defect in axonal growth and guidance, resulting in the loss of ventral pontine neurons. Jissendi-Tchofo et al. (2009) reported 6 unrelated patients with PTCD. All were evaluated as infants for failure to thrive and/or developmental delay. None had a family history of a similar disorder, but 1 boy had an unaffected monozygotic twin brother. All had cranial nerve involvement, most often manifest as sensorineural deafness, but 4 also had involvement of cranial nerves V, VI, or VII. Some had oculomotor abnormalities and absent corneal reflex. All had impaired swallowing and feeding difficulties. Cerebellar signs included ataxia, head titubation, and abnormal movements. Four showed developmental delay, and information on development in the other 2 was not available. Two patients had extracranial skeletal anomalies with hemivertebrae and vertebral segmentation defects. Brain MRI showed ventral pontine hypoplasia with an unusual dorsal pontine cap composed of white matter extending into the fourth ventricle. The middle cerebellar peduncles were diminished in size, the superior cerebellar peduncles were somewhat lateral in 2 patients, and the inferior cerebellar peduncles were very small or could not be identified. There was also hypoplasia of the cerebellar vermis and hemispheres. The corpus callosum was also abnormal, either thin or dysmorphic, in all patients. Diffusion tensor imaging in 1 patient showed absent decussation of the superior and middle cerebral peduncles and fibers to the pontine nuclei and an abnormal transverse bundle of axons crossing the midline at the dorsal pons. Jissendi-Tchofo et al. (2009) noted similarities to the patients reported by Barth et al. (2007) and also postulated a defect in axonal guidance or neuronal migration. Briguglio et al. (2011) reported 3 unrelated adolescent patients with PTCD. All presented at birth with hypotonia and multiple cranial nerve abnormalities, including sensorineural deafness, decreased corneal sensation, ptosis, abnormal eye movements, facial palsy, and feeding and swallowing difficulties. The feeding and swallowing difficulties improved with age. They had delayed psychomotor development and showed ataxia and hyperreflexia. One patient had seizures. Brain imaging showed a hypoplastic pons, small cerebellum with dysplastic vermis, and focal bulging of the pontine tegmentum into the fourth ventricle. There were abnormalities of the cerebellar peduncles resembling the molar tooth sign, and absence of the lateral bulging of the medulla, perhaps due to absence of the olivary nuclei. Diffusion tensor imaging of 2 patients showed that the pontine cap was a bundle of transversely oriented ectopic fibers. The decussation of the superior cerebellar peduncles was not present. Neuropsychologic assessment showed mild to moderate cognitive impairment, language impairment, and defects in visuospatial tasks. Two had mild behavioral problems, including emotional fragility, attention problems, and easy frustration. High-resolution SNP array analysis did not reveal any pathogenic copy number variants in the patients. Inheritance None of the patients with PTCD reported by Barth et al. (2007), Jissendi-Tchofo et al. (2009), or Briguglio et al. (2011) had a family history of the disorder; all showed sporadic occurrence of the phenotype. However, 1 of the male patients reported by Jissendi-Tchofo et al. (2009) had an unaffected monozygotic twin brother. Molecular Genetics ### Exclusion Studies In 4 patients with PTCD, Barth et al. (2007) excluded mutations in the coding regions of the DCC (120470) and NTN1 (601614) genes. These genes were chosen for study because homozygous loss of these genes in mice results in axonal guidance defects. INHERITANCE \- Isolated cases GROWTH Other \- Failure to thrive HEAD & NECK Head \- Head titubations Face \- Facial palsy Ears \- Deafness, sensorineural Eyes \- Oculomotor apraxia \- Abnormal ocular movements \- Strabismus \- Nystagmus \- Ptosis \- Decreased corneal sensation \- Corneal abrasions Mouth \- Chewing difficulties RESPIRATORY \- Aspiration due to orofacial incoordination CHEST Ribs Sternum Clavicles & Scapulae \- Rib fusion (variable) ABDOMEN Gastrointestinal \- Swallowing difficulties \- Poor feeding SKELETAL Spine \- Scoliosis \- Hemivertebrae \- Vertebral abnormalities MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Head titubations \- Facial palsy \- Mental retardation (in most) \- No motor skills acquired (in some) \- Ataxia \- Abnormal movements \- Poor or absent speech \- Seizures (in some) \- Dysmetria \- Hyperreflexia (in some) \- Ankle clonus (in some) \- Cranial nerve dysfunction \- Brain MRI shows flattening of the ventral pons \- Hypoplastic corpus callosum (in some) \- Absence of the inferior olives \- Hypoplastic or absent middle cerebellar peduncles \- Decussation of the superior cerebellar peduncles \- Abnormal 'cap' on the dorsal pons extending into the fourth ventricle \- Ectopic dorsal pontine transverse bundle of fibers forms the 'cap' Behavioral Psychiatric Manifestations \- Behavioral abnormalities \- Emotional fragility \- Easily frustrated MISCELLANEOUS \- Variable phenotype and severity \- Feeding difficulties, including aspiration, ameliorate with age ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	PONTINE TEGMENTAL CAP DYSPLASIA	c3541340	4,307	omim	https://www.omim.org/entry/614688	2019-09-22T15:54:31	{"omim": ["614688"], "orphanet": ["269229"], "synonyms": ["PTCD"]}
For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000. Clinical Features Kannabiran et al. (2012) described a large Indian family in which 14 of 34 individuals studied had retinitis pigmentosa. Age at presentation ranged from 16 to 65 years, and in most cases the initial symptoms consisted of night blindness associated with blurred vision. Fundus examination revealed a range of features, including degeneration of the retinal pigment epithelium (RPE) to varying extents, arterial attenuation, disc pallor, and pigment migration. Electroretinography (ERG) showed diminished or extinguished responses. The central retina was relatively less involved in most of the affected individuals, as suggested by good visual acuities and fundus appearance, with peripheral visual field loss and severe peripheral retinal involvement. Mapping Kannabiran et al. (2012) genotyped 34 members of a large 4-generation Indian family segregating autosomal dominant retinitis pigmentosa (RP) for microsatellite markers located in proximity to known loci for autosomal dominant retinal dystrophy phenotypes, and obtained a maximum lod score of 2.9 (theta = 0) for marker D6S262 on chromosome 6q23. Fine mapping with additional markers yielded 2 markers, D6S457 and D6S1656, with maximum lod scores of 3.8 (theta = 0). Haplotype analysis in this family indicated a disease-cosegregating region of 28 cM (34 Mb). Kannabiran et al. (2012) stated that the mapped interval contained more than 100 genes, among which there were no known RP genes. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Night blindness \- Blurred vision \- Good visual acuity \- Degeneration of retinal pigment epithelium (relatively less involvement of central retina) \- Arterial attenuation \- Disc pallor \- Pigment migration \- Diminished or extinguished responses on electroretinography MISCELLANEOUS \- Age at onset ranges from 16 years to 65 years ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	RETINITIS PIGMENTOSA 63	c0035334	4,308	omim	https://www.omim.org/entry/614494	2019-09-22T15:55:05	{"doid": ["0110385"], "mesh": ["D012174"], "omim": ["614494"], "orphanet": ["791"]}
Dermatophytid SpecialtyDermatology Dermatophytids are fungus-free disseminated skin lesions resulting from induced sensitization in patients with ringworm infections.[1]:301 The most common dermatophytid is an inflammation in the hands resulting from a fungus infection of the feet. Dermatophytids normally disappear when the primary ringworm infection is treated.[citation needed]Dermatophytids may resemble erythema nodosum.[citation needed] ## Contents * 1 See also * 2 Notes * 3 References * 4 External links ## See also[edit] * Candidid * Skin lesion ## Notes[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. ## References[edit] * The Merck Manual, Twelfth Edition, 1972, p. 1451 ## External links[edit] Classification D * ICD-10: L30.2 * v * t * e Dermatitis and eczema Atopic dermatitis * Besnier's prurigo Seborrheic dermatitis * Pityriasis simplex capillitii * Cradle cap Contact dermatitis (allergic, irritant) * plants: Urushiol-induced contact dermatitis * African blackwood dermatitis * Tulip fingers * other: Abietic acid dermatitis * Diaper rash * Airbag dermatitis * Baboon syndrome * Contact stomatitis * Protein contact dermatitis Eczema * Autoimmune estrogen dermatitis * Autoimmune progesterone dermatitis * Breast eczema * Ear eczema * Eyelid dermatitis * Topical steroid addiction * Hand eczema * Chronic vesiculobullous hand eczema * Hyperkeratotic hand dermatitis * Autosensitization dermatitis/Id reaction * Candidid * Dermatophytid * Molluscum dermatitis * Circumostomy eczema * Dyshidrosis * Juvenile plantar dermatosis * Nummular eczema * Nutritional deficiency eczema * Sulzberger–Garbe syndrome * Xerotic eczema Pruritus/Itch/ Prurigo * Lichen simplex chronicus/Prurigo nodularis * by location: Pruritus ani * Pruritus scroti * Pruritus vulvae * Scalp pruritus * Drug-induced pruritus * Hydroxyethyl starch-induced pruritus * Senile pruritus * Aquagenic pruritus * Aquadynia * Adult blaschkitis * due to liver disease * Biliary pruritus * Cholestatic pruritus * Prion pruritus * Prurigo pigmentosa * Prurigo simplex * Puncta pruritica * Uremic pruritus Other * substances taken internally: Bromoderma * Fixed drug reaction * Nummular dermatitis * Pityriasis alba * Papuloerythroderma of Ofuji [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Dermatophytid	c0343041	4,309	wikipedia	https://en.wikipedia.org/wiki/Dermatophytid	2021-01-18T19:08:04	{"umls": ["C0343041"], "icd-10": ["L30.2"], "wikidata": ["Q5262708"]}
"Alzheimer" redirects here. For other uses, see Alzheimer (disambiguation). Progressive, neurodegenerative disease characterized by memory loss Alzheimer's disease Other namesAlzheimer disease, Alzheimer's Comparison of a normal aged brain (left) and the brain of a person with Alzheimer's (right). Characteristics that separate the two are pointed out. Pronunciation * ˈaltshʌɪməz SpecialtyNeurology SymptomsDifficulty in remembering recent events, problems with language, disorientation, mood swings[1][2] Usual onsetOver 65 years old[3] DurationLong term[2] CausesPoorly understood[1] Risk factorsGenetics, head injuries, depression, hypertension[1][4] Diagnostic methodBased on symptoms and cognitive testing after ruling out other possible causes[5] Differential diagnosisNormal aging[1] MedicationAcetylcholinesterase inhibitors, NMDA receptor antagonists (small benefit)[6] PrognosisLife expectancy 3–9 years[7] Frequency29.8 million (2015)[2][8] DeathsFor all dementias 1.9 million (2015)[9] Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a neurodegenerative disease that usually starts slowly and gradually worsens over time.[1][2] It is the cause of 60–70% of cases of dementia.[1][2] The most common early symptom is difficulty in remembering recent events.[1] As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioural issues.[1][2] As a person's condition declines, they often withdraw from family and society.[1] Gradually, bodily functions are lost, ultimately leading to death.[10] Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.[7][11] The cause of Alzheimer's disease is poorly understood.[1] About 70% of the risk is believed to be inherited from a person's parents, with many genes usually involved.[4] Other risk factors include a history of head injuries, depression, and hypertension.[1] The disease process is associated with amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain.[4] A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes.[5] Initial symptoms are often mistaken for normal ageing.[1] Examination of brain tissue is needed for a definite diagnosis.[4] Mental and physical exercise, and avoiding obesity may decrease the risk of AD; however, evidence to support these recommendations is weak.[4][12] There are no medications or supplements that have been shown to decrease risk.[13] No treatments stop or reverse its progression, though some may temporarily improve symptoms.[2] Affected people increasingly rely on others for assistance, often placing a burden on the caregiver.[14] The pressures can include social, psychological, physical, and economic elements.[14] Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes.[15] Behavioural problems or psychosis due to dementia are often treated with antipsychotics, but this is not usually recommended, as there is little benefit and an increased risk of early death.[16][17] As of 2015, there were approximately 29.8 million people worldwide with AD[8] with about 50 million as of 2020.[2] It most often begins in people over 65 years of age, although 4–5% of cases are early-onset Alzheimer's.[3] It affects about 6% of people 65 years and older.[1] In 2015, all forms of dementia resulted in about 1.9 million deaths.[9] The disease is named after German psychiatrist and pathologist Alois Alzheimer, who first described it in 1906.[18] In developed countries, AD is one of the most financially costly diseases.[19][20] ## Contents * 1 Signs and symptoms * 1.1 Pre-dementia * 1.2 Early * 1.3 Moderate * 1.4 Advanced * 2 Causes * 2.1 Genetic * 2.2 Cholinergic hypothesis * 2.3 Amyloid hypothesis * 2.4 Osaka mutation * 2.5 Tau hypothesis * 2.6 Other hypotheses * 3 Pathophysiology * 3.1 Neuropathology * 3.2 Biochemistry * 3.3 Disease mechanism * 4 Diagnosis * 4.1 Criteria * 4.2 Techniques * 5 Prevention * 5.1 Medication * 5.2 Lifestyle * 5.3 Diet * 6 Management * 6.1 Medications * 6.2 Psychosocial intervention * 6.3 Caregiving * 7 Prognosis * 8 Epidemiology * 9 History * 10 Society and culture * 10.1 Social costs * 10.2 Caregiving burden * 10.3 Media * 11 Research directions * 11.1 Medication * 11.2 Behavioral prevention * 11.3 Possible transmission * 11.4 Infections * 11.5 Imaging * 11.6 Diagnosis * 12 References * 13 Further reading * 14 External links ## Signs and symptoms Stages of Alzheimer's disease[21] Effects of ageing on memory but not AD * Forgetting things occasionally * Misplacing items sometimes * Minor short-term memory loss * Not remembering exact details Early stage Alzheimer's * Not remembering episodes of forgetfulness * Forgets names of family or friends * Changes may only be noticed by close friends or relatives * Some confusion in situations outside the familiar Middle stage Alzheimer's * Greater difficulty remembering recently learned information * Deepening confusion in many circumstances * Problems with sleep * Trouble determining their location Late stage Alzheimer's * Poor ability to think * Problems speaking * Repeats same conversations * More abusive, anxious, or paranoid The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment. Stages of atrophy in Alzheimer's. ### Pre-dementia The first symptoms are often mistakenly attributed to ageing or stress.[22] Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of AD.[23] These early symptoms can affect the most complex activities of daily living.[24] The most noticeable deficit is short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.[23][25] Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD.[23] Apathy and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease.[26][27] The preclinical stage of the disease has also been termed mild cognitive impairment (MCI).[25] This is often found to be a transitional stage between normal ageing and dementia. MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed "amnestic MCI" and is frequently seen as a prodromal stage of Alzheimer's disease.[28] ### Early In people with AD, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems.[29] AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories.[30][31] Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language.[29][32] In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately.[29][32][33] While performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties (apraxia) may be present, but they are commonly unnoticed.[29] As the disease progresses, people with AD can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities.[29] ### Moderate Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living.[29] Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost.[29][33] Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases.[29] During this phase, memory problems worsen, and the person may fail to recognise close relatives.[29] Long-term memory, which was previously intact, becomes impaired.[29] Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving.[29] Sundowning can also appear.[34] Approximately 30% of people with AD develop illusionary misidentifications and other delusional symptoms.[29] Subjects also lose insight of their disease process and limitations (anosognosia).[29] Urinary incontinence can develop.[29] These symptoms create stress for relatives and carers, which can be reduced by moving the person from home care to other long-term care facilities.[29][35] ### Advanced During the final stages, the patient is completely dependent upon caregivers.[29] Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.[29][33] Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.[29] ## Causes Alzheimer's disease is believed to occur when abnormal amounts of proteins, amyloids and possibly tau proteins, form in the brain and begin to encroach upon the organ's cells. The resultant plaque disrupts normal function and chemistry, and leads to a significant deficit of neurotransmitters, resulting in a progressive loss of brain function.[36] As for why these protein 'malfunctions' occur in the first place, the ultimate cause is poorly understood, and subject to ongoing research and speculation. The cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic differences have been identified.[37][38] Several competing hypotheses exist trying to explain the cause of the disease. ### Genetic The genetic heritability of Alzheimer's disease (and memory components thereof), based on reviews of twin and family studies, ranges from 49% to 79%.[39] Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65.[40] This form of the disease is known as early onset familial Alzheimer's disease. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins PSEN1 and PSEN2.[41] Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques.[42] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels.[43] Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.[44] Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD, in which environmental and genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE).[45][46] Between 40 and 80% of people with AD possess at least one APOEε4 allele.[46] The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes.[40] Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, certain Nigerian populations do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.[47][48] Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield.[40][41] More recent genome-wide association studies (GWAS) have found 19 areas in genes that appear to affect the risk.[49] These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SLC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP.[49] Alleles in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer's disease.[50][51] A suggested mechanism of action is that in some variants in TREM2, white blood cells in the brain are no longer able to control the amount of beta amyloid present. Many single-nucleotide polymorphisms (SNPs) are associated with Alzheimer's, with a 2018 study adding 30 SNPs by differentiating AD into 6 categories, including memory, language, visuospatial, and executive functioning.[52] ### Cholinergic hypothesis The oldest hypothesis, on which most currently available drug therapies are based, is the cholinergic hypothesis,[53] which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective.[54] ### Amyloid hypothesis In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease.[55][56] Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age.[57][58] Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.[59] Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.[60] An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.[61] Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication.[62] One receptor for Aβ oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer's disease.[63] In 2009, this hypothesis was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The hypothesis holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by ageing-related processes in later life to cause the neuronal withering of Alzheimer's disease.[64] N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21).[64] DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function. ### Osaka mutation A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP.[65] This mutation and its association with Alzheimer's disease was first reported in 2008.[66] This mutation is known as the Osaka mutation. Only homozygotes with this mutation develop Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form amyloid fibrils suggesting that it is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all usual pathologies of Alzheimer's disease. ### Tau hypothesis In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells. The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade.[56] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.[67] When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.[68] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.[69] ### Other hypotheses An inflammatory hypothesis is that AD is caused by a self-perpetuating progressive inflammation in the brain culminating in neurodegeneration.[70] A possible role of chronic periodontal infection[70] and the gut microbiota has been suggested.[71] A neurovascular hypothesis stating that poor functioning of the blood–brain barrier may be involved has been proposed.[72] Spirochete infections have also been linked to dementia.[73][74] The cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in AD, though it remains unclear whether this is produced by or causes the changes in proteins. These ions affect and are affected by tau, APP, and APOE,[75] and their dysregulation may cause oxidative stress that may contribute to the pathology.[76][77][78][79][80] The quality of some of these studies has been criticised,[81][82] and the link remains controversial.[83] The majority of researchers do not support a causal connection with aluminium.[82] Smoking is a significant AD risk factor.[84] Systemic markers of the innate immune system are risk factors for late-onset AD.[85] There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.[86] One hypothesis posits that dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which then causes amyloid production and tau hyper-phosphorylation as a side effect.[87][88] Retrogenesis is a medical hypothesis about the development and progress of Alzheimer's disease proposed by Barry Reisberg in the 1980s.[89] The hypothesis is that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with AD go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter.[90] Likewise the hypothesis is, that as infants go through states of cognitive development, people with AD go through the reverse process of progressive cognitive impairment.[89] Reisberg developed the caregiving assessment tool known as "FAST" (Functional Assessment Staging Tool) which he says allows those caring for people with AD to identify the stages of disease progression and that provides advice about the kind of care needed at each stage.[89][91] The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with CD, while a 2018 review found an association with several types of dementia including AD.[92][93] ## Pathophysiology Histopathologic images of Alzheimer's disease, in the CA3 area of the hippocampus, showing an amyloid plaque (top right), neurofibrillary tangles (bottom left), and granulovacuolar degeneration (bottom center) ### Neuropathology Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[94] Degeneration is also present in brainstem nuclei like the locus coeruleus.[95] Studies using MRI and PET have documented reductions in the size of specific brain regions in people with AD as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.[96][97] Both Aβ plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD,[98] especially in the hippocampus.[99] Plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of people with AD have a greater number of them in specific brain regions such as the temporal lobe.[100] Lewy bodies are not rare in the brains of people with AD.[101] ### Biochemistry Main article: Biochemistry of Alzheimer's disease Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD. Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by plaque accumulation of abnormally folded amyloid beta protein and tau protein in the brain.[102] Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (Aβ). Aβ is a fragment from the larger amyloid precursor protein (APP). APP is a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival, and post-injury repair.[103][104] In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments.[105] One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as senile plaques.[98][106] AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.[107] Pathogenic tau can also cause neuronal death through transposable element dysregulation.[108] ### Disease mechanism Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of AD is not known.[109][110] The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis).[111] It is also known that Aβ selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.[112] Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response.[113] There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.[114] Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in AD.[115][116] ## Diagnosis PET scan of the brain of a person with AD showing a loss of function in the temporal lobe Alzheimer's disease is usually diagnosed based on the person's medical history, history from relatives, and behavioural observations. The presence of characteristic neurological and neuropsychological features and the absence of alternative conditions is supportive.[117][118] Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia.[119] Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease.[120] Assessment of intellectual functioning including memory testing can further characterise the state of the disease.[22] Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.[121] ### Criteria The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984,[121] extensively updated in 2007.[122] These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation.[123] Eight intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.[124][125] ### Techniques Neuropsychological screening tests can help in the diagnosis of AD. In the tests, people are instructed to copy drawings similar to the one shown in the picture, remember words, read, and subtract serial numbers. Neuropsychological tests such as the mini–mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis. More comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.[126][127] Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from other diseases processes, including other causes of dementia. Further neurological examinations are crucial in the differential diagnosis of AD and other diseases.[22] Interviews with family members are also utilised in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease, over time, of the person's mental function.[128] A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits.[129] Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.[130] Supplemental testing provides extra information on some features of the disease or is used to rule out other diagnoses. Blood tests can identify other causes for dementia than AD[22]—causes which may, in rare cases, be reversible.[131] It is common to perform thyroid function tests, assess B12, rule out syphilis, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals (e.g., lead, mercury) and anaemia. (It is also necessary to rule out delirium). Psychological tests for depression are employed, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment,[132] or even the cause.[133][134] Due to low accuracy, the C-PIB-PET scan is not recommended to be used as an early diagnostic tool or for predicting the development of Alzheimer's disease when people show signs of mild cognitive impairment (MCI).[135] The use of 18F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is also not supported by evidence.[136] ## Prevention Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found. There is no definitive evidence to support that any particular measure is effective in preventing AD.[13] Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. Epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities, among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can help to prevent AD.[13] ### Medication Cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and worsened course of AD.[137][138] Blood pressure medications may decrease the risk.[139] Statins, which lower cholesterol however, have not been effective in preventing or improving the course of the disease.[140][141][142] Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought in 2007 to be associated with a reduced likelihood of developing AD.[143] Evidence also suggested the notion that NSAIDs could reduce inflammation related to amyloid plaques, but trials were suspended due to high adverse events.[13] No prevention trial has been completed.[13] They do not appear to be useful as a treatment, but as of 2011[update] were thought to be candidates as presymptomatic preventives.[144] Hormone replacement therapy in menopause, although previously used, may increase the risk of dementia.[145] ### Lifestyle People who engage in intellectual activities such as reading books (but not newspapers[146]), playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's disease.[147] This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations.[147] Education delays the onset of AD syndrome without changing the duration of the disease.[148] Learning a second language even later in life seems to delay the onset of Alzheimer's disease.[149] Physical activity is also associated with a reduced risk of AD.[148] Physical exercise is associated with decreased rate of dementia.[150] Physical exercise is also effective in reducing symptom severity in those with Alzheimer's disease.[151] ### Diet People who maintain a healthy, Japanese, or Mediterranean diet have a reduced risk of AD.[152] A Mediterranean diet may improve outcomes in those with the disease.[153] Those who eat a diet high in saturated fats and simple carbohydrates (mono- and disaccharide) have a higher risk.[154] The Mediterranean diet's beneficial cardiovascular effect has been proposed as the mechanism of action.[155] Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomised controlled trials.[152] There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD.[152] There is tentative evidence that caffeine may be protective.[156] A number of foods high in flavonoids such as cocoa, red wine, and tea may decrease the risk of AD.[157][158] Reviews on the use of vitamins and minerals have not found enough consistent evidence to recommend them. This includes vitamin A,[159][160] C,[161][162] the alpha-tocopherol form of vitamin E,[163] selenium,[164] zinc,[165][166] and folic acid with or without vitamin B12.[167] Evidence from one randomized controlled trial indicated that the alpha-tocopherol form of vitamin E may slow cognitive decline, this evidence was judged to be "moderate" in quality.[163] Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline.[168] Omega-3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA), do not appear to benefit people with mild to moderate Alzheimer's disease.[169][170] Curcumin as of 2010[update] had not shown benefit in people even though there is tentative evidence in animals.[171] There was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia.[172] As of 2008[update] there was no concrete evidence that cannabinoids are effective in improving the symptoms of AD or dementia;[173] however, some research into endocannabinoids looked promising.[174] ## Management There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving. ### Medications Three-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms Molecular structure of memantine, a medication approved for advanced AD symptoms Five medications are currently used to treat the cognitive problems of AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is an NMDA receptor antagonist. The benefit from their use is small.[175][176][177] No medication has been clearly shown to delay or halt the progression of the disease. Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease.[178] Acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons.[179] There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease,[180][176][175] and some evidence for their use in the advanced stage.[175] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[181] The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses.[182] Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.[180] Glutamate is an excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.[183] Memantine is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate.[183][184] Memantine has been shown to have a small benefit in the treatment of moderate to severe Alzheimer's disease.[185] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[186] The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[187] Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with Alzheimer's disease, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline.[188] When used in the long-term, they have been shown to associate with increased mortality.[189] Stopping antipsychotic use in this group of people appears to be safe.[190] ### Psychosocial intervention Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behaviour-, emotion-, cognition- or stimulation-oriented approaches. Research on efficacy is unavailable and rarely specific to AD, focusing instead on dementia in general.[191] Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning,[192] but can help to reduce some specific problem behaviours, such as incontinence.[193] There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.[194][195] Music therapy is effective in reducing behavioural and psychological symptoms.[196] Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. A Cochrane review has found no evidence that this is effective.[197] Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired people adjust to their illness.[191] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. A 2018 review of the effectiveness of RT found that effects were inconsistent, small in size and of doubtful clinical significance, and varied by setting.[198] Simulated presence therapy (SPT) is based on attachment theories and involves playing a recording with voices of the closest relatives of the person with Alzheimer's disease. There is partial evidence indicating that SPT may reduce challenging behaviours.[199] Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate senses. There is no evidence to support the usefulness of these therapies.[200][201] The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining, is the reduction of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person to ease the understanding of the person about its surroundings and his or her place in them. On the other hand, cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities,[202] although in some studies these effects were transient and negative effects, such as frustration, have also been reported.[191] Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities. Stimulation has modest support for improving behaviour, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the change in the person's routine.[191] ### Caregiving Further information: Caregiving and dementia Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving is essentially the treatment and must be carefully managed over the course of the disease. During the early and moderate stages, modifications to the living environment and lifestyle can increase patient safety and reduce caretaker burden.[203][204] Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labelling of household items to cue the person with the disease or the use of modified daily life objects.[191][205][206] If eating becomes problematic, food will need to be prepared in smaller pieces or even pureed.[207] When swallowing difficulties arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members.[208][209] The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with AD or their caregivers.[191] As the disease progresses, different medical issues can appear, such as oral and dental disease, pressure ulcers, malnutrition, hygiene problems, or respiratory, skin, or eye infections. Careful management can prevent them, while professional treatment is needed when they do arise.[210][211] During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of hospice.[212] ## Prognosis Disability-adjusted life year for Alzheimer and other dementias per 100,000 inhabitants in 2004. No data ≤ 50 50–70 70–90 90–110 110–130 130–150 150–170 170–190 190–210 210–230 230–250 ≥ 250 The early stages of Alzheimer's disease are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living, especially in the late stages of the disease.[29] Life expectancy of people with AD is reduced.[213] Following diagnosis it typically ranges from three to ten years.[213] Fewer than 3% of people live more than fourteen years.[214] Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival.[215][216][217] While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger.[218] Men have a less favourable survival prognosis than women.[214][219] Pneumonia and dehydration are the most frequent immediate causes of death brought by AD, while cancer is a less frequent cause of death than in the general population.[219] ## Epidemiology Rates after age 65[220] Age New affected per thousand person-years 65–69 3 70–74 6 75–79 9 80–84 23 85–89 40 90– 69 Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person-time at risk (usually number of new cases per thousand person-years); while prevalence is the total number of cases of the disease in the population at any given time. Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person-years for all dementias and 5–8 for AD,[220][221] which means that half of new dementia cases each year are AD. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every five years after the age of 65, the risk of acquiring the disease approximately doubles, increasing from 3 to as much as 69 per thousand person years.[220][221] There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than 85.[221][222] In the United States, the risk of dying from Alzheimer's disease is 26% higher among the non-Hispanic white population than among the non-Hispanic black population, whereas the Hispanic population has a 30% lower risk than the non-Hispanic white population.[223] Deaths per million persons in 2012 due to dementias including Alzheimer's disease 0–4 5–8 9–10 11–13 14–17 18–24 25–45 46–114 115–375 376–1266 Prevalence of AD in populations is dependent upon different factors including incidence and survival. Since the incidence of AD increases with age, it is particularly important to include the mean age of the population of interest. In the United States, Alzheimer prevalence was estimated to be 1.6% in 2000 both overall and in the 65–74 age group, with the rate increasing to 19% in the 75–84 group and to 42% in the greater than 84 group.[224] Prevalence rates in less developed regions are lower.[225] The World Health Organization estimated that in 2005, 0.379% of people worldwide had dementia, and that the prevalence would increase to 0.441% in 2015 and to 0.556% in 2030.[226] Other studies have reached similar conclusions.[225] Another study estimated that in 2006, 0.40% of the world population (range 0.17–0.89%; absolute number 26.6 million, range 11.4–59.4 million) were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by 2050.[227] ## History Alois Alzheimer's patient Auguste Deter in 1902. Hers was the first described case of what became known as Alzheimer's disease. The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia.[18] It was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he called Auguste D. He followed her case until she died in 1906, when he first reported publicly on it.[228] During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[18] The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D.[229] He included Alzheimer's disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published on 15 July, 1910.[230] For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on AD concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility that they had different causes.[231] This eventually led to the diagnosis of Alzheimer's disease independent of age.[232] The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used to describe those who were younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.[233] ## Society and culture See also: Alzheimer's disease organisations ### Social costs Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for society in Europe and the United States,[19][20] while their costs in other countries such as Argentina,[234] and South Korea,[235] are also high and rising. These costs will probably increase with the ageing of society, becoming an important social problem. AD-associated costs include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost productivity of both patient and caregiver.[20] Numbers vary between studies but dementia costs worldwide have been calculated around $160 billion,[236] while costs of Alzheimer's disease in the United States may be $100 billion each year.[20] The greatest origin of costs for society is the long-term care by health care professionals and particularly institutionalisation, which corresponds to 2/3 of the total costs for society.[19] The cost of living at home is also very high,[19] especially when informal costs for the family, such as caregiving time and caregiver's lost earnings, are taken into account.[237] Costs increase with dementia severity and the presence of behavioural disturbances,[238] and are related to the increased caregiving time required for the provision of physical care.[237] Therefore, any treatment that slows cognitive decline, delays institutionalisation or reduces caregivers' hours will have economic benefits. Economic evaluations of current treatments have shown positive results.[20] ### Caregiving burden Further information: Caregiving and dementia The role of the main caregiver is often taken by the spouse or a close relative.[239] Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical or economic aspects.[14][240][241] Home care is usually preferred by people with AD and their families.[242] This option also delays or eliminates the need for more professional and costly levels of care.[242][243] Nevertheless, two-thirds of nursing home residents have dementias.[191] Dementia caregivers are subject to high rates of physical and mental disorders.[244] Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the carer being a spouse, demanding behaviours of the cared person such as depression, behavioural disturbances, hallucinations, sleep problems or walking disruptions and social isolation.[245][246] Regarding economic problems, family caregivers often give up time from work to spend 47 hours per week on average with the person with AD, while the costs of caring for them are high. Direct and indirect costs of caring for an Alzheimer's patient average between $18,000 and $77,500 per year in the United States, depending on the study.[237][239] Cognitive behavioural therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.[14][247] ### Media Main article: Alzheimer's disease in the media AD has been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch;[248] The Notebook (2004), based on Nicholas Sparks' 1996 novel of the same name;[249] A Moment to Remember (2004); Thanmathra (2005);[250] Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name;[251] Away from Her (2006), based on Alice Munro's short story "The Bear Came over the Mountain";[252] Still Alice (2014), about a Columbia University professor who has early onset Alzheimer's disease, based on Lisa Genova's 2007 novel of the same name and featuring Julianne Moore in the title role. Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love's Farewell (2007), both featuring Malcolm Pointon.[253][254][255] It has also been portrayed in music by the Caretaker in Everywhere at the End of Time. ## Research directions ### Medication In the decade 2002–2012, 244 compounds were assessed in Phase I, Phase II, or Phase III trials, and only one of these (memantine) received FDA approval (though others were still in the pipeline).[256] Solanezumab and aducanumab failed to show effectiveness in people who already had Alzheimer's symptoms.[257] One area of clinical research is focused on treating the underlying disease pathology. Reduction of beta-amyloid levels is a common target of compounds[258] (such as apomorphine) under investigation. Immunotherapy or vaccination for the amyloid protein is one treatment modality under study.[259] Unlike preventive vaccination, the putative therapy would be used to treat people already diagnosed. It is based upon the concept of training the immune system to recognise, attack, and reverse deposition of amyloid, thereby altering the course of the disease.[260] An example of such a vaccine under investigation was ACC-001,[261][262] although the trials were suspended in 2008.[263] Another similar agent is bapineuzumab, an antibody designed as identical to the naturally induced anti-amyloid antibody.[264] However, immunotherapeutic agents have been found to cause some concerning adverse drug reactions, such as amyloid-related imaging abnormalities.[265] Other approaches are neuroprotective agents, such as AL-108,[266] and metal-protein interaction attenuation agents, such as PBT2.[267] A TNFα receptor-blocking fusion protein, etanercept has showed encouraging results.[268] In 2008, two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride, a drug that inhibits tau aggregation,[269][270] and dimebon, an antihistamine.[271] The consecutive phase-III trial of dimebon failed to show positive effects in the primary and secondary endpoints.[272][273][274] Work with methylthioninium chloride showed that bioavailability of methylthioninium from the gut was affected by feeding and by stomach acidity, leading to unexpectedly variable dosing.[275] A new stabilised formulation, as the prodrug LMTX, is in phase-III trials (in 2014).[276] In early 2017, a trial of verubecestat, which inhibits the beta-secretase protein responsible for creating beta-amyloid protein was discontinued as an independent panel found "virtually no chance of finding a positive clinical effect".[277] In 2018 and 2019, more trials, including aducanumab which reduced amyloid beta concentrations, failed, leading some to question the validity of the amyloid hypothesis.[278][279] However, in October 2019, an analysis of another dataset found that aducanumab may reduce clinical decline in people with early Alzheimer's disease and the Biogen company may seek regulatory approval again.[280] The senescence accelerated mouse (SAMP8) is an Alzheimer's disease (AD) animal model in which amyloid precursor protein (APP) is overproduced. The mice develops early memory disturbances and alters the blood–brain barrier, which causes a decreased expulsion of amyloid-β protein from the brain. It has a marked increase in oxidative stress in the brain. Medications that reduce oxidative stress have been shown to improve memory. Treatments that reduce amyloid-β (antisense to APP and antibodies to amyloid-β) not only improve memory but also reduce oxidative stress. It has been shown that the initial deviations in lipid peroxidative damage favor mitochondrial dysfunction as being a trigger for amyloid-β overproduction in this AD mouse strain. This process begets increased amyloid-beta, which further damages mitochondria.[281] ### Behavioral prevention Research on the effects of meditation on preserving memory and cognitive functions is at an early stage.[282] A 2015 review suggests that mindfulness-based interventions may prevent or delay the onset of mild cognitive impairment and Alzheimer's disease.[283] ### Possible transmission Rare cases of possible transmission between people are being studied,[284] e.g. to growth hormone patients.[285] ### Infections The herpes simplex virus HSV-1 has been found in the same areas as amyloid plaques.[286] This suggested the possibility that AD could be treated or prevented with antiviral medication.[286][287] Studies of antivirals in cell cultures have shown promising results.[288] Fungal infection of AD brain has also been described.[289] This hypothesis was proposed by the microbiologist L. Carrasco when his group found statistical correlation between disseminated mycoses and AD.[290] Further work revealed that fungal infection is present in different brain regions of AD patients, but not in the control individuals.[291][292] A fungal infection explains the symptoms observed in AD patients. The slow progression of AD fits with the chronic nature of some systemic fungal infections, which can be asymptomatic and thus, unnoticed and untreated.[291] The fungal hypotheses are also compatible with some other established AD hypotheses, like the amyloid hypothesis, that can be explained as an immune system response to an infection in the CNS,[293][294][295] as found by R. Moir and R. Tanzi in mouse and worm models of AD. ### Imaging This section needs to be updated. Please update this article to reflect recent events or newly available information. Last update: from PMID 28072381 and PMID 28259856 (April 2018) Of the many medical imaging techniques available, single photon emission computed tomography (SPECT) appears to be superior in differentiating Alzheimer's disease from other types of dementia, and this has been shown to give a greater level of accuracy compared with mental testing and medical history analysis.[296] Advances have led to the proposal of new diagnostic criteria.[22][122] PiB PET remains investigational, but a similar PET scanning radiopharmaceutical called florbetapir, containing the longer-lasting radionuclide fluorine-18, is a diagnostic tool in Alzheimer's disease.[297][298] Amyloid imaging is likely to be used in conjunction with other markers rather than as an alternative.[299] Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive than other imaging methods currently under study.[300] In 2011, an FDA panel voted unanimously to recommend approval of florbetapir.[301] The imaging agent can help to detect Alzheimer's brain plaques.[302] A negative scan indicates sparse or no plaques, which is not consistent with a diagnosis of AD.[303] ### Diagnosis Emphasis in Alzheimer's research has been placed on diagnosing the condition before symptoms begin.[304] A number of biochemical tests have been developed to enable earlier detection. Some such tests involve the analysis of cerebrospinal fluid for beta-amyloid, total tau protein and phosphorylated tau181P protein concentrations.[305] Because drawing CSF can be painful, repeated draws are avoided. 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JAMA. 305 (3): 275–83. doi:10.1001/jama.2010.2008. PMC 7041965. PMID 21245183. 303. ^ "Amyvid". Community register of medicinal products for human use. European Community. 17 January 2013. Retrieved 18 April 2018. 304. ^ Chong MS, Sahadevan S (September 2005). "Preclinical Alzheimer's disease: diagnosis and prediction of progression". The Lancet. Neurology. 4 (9): 576–79. doi:10.1016/s1474-4422(05)70168-x. PMID 16109364. S2CID 45448888. 305. ^ a b Sharma N, Singh AN (July 2016). "Exploring Biomarkers for Alzheimer's Disease". Journal of Clinical and Diagnostic Research (Review). 10 (7): KE01–06. doi:10.7860/JCDR/2016/18828.8166. PMC 5020308. PMID 27630867. 306. ^ Montagne A, Barnes SR, Sweeney MD, et al. (January 2015). "Blood-brain barrier breakdown in the aging human hippocampus". Neuron. 85 (2): 296–302. doi:10.1016/j.neuron.2014.12.032. PMC 4350773. PMID 25611508. 307. ^ Nation DA, Sweeney MD, Montagne A, et al. (February 2019). "Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction". Nature Medicine. 25 (2): 270–276. doi:10.1038/s41591-018-0297-y. PMC 6367058. PMID 30643288. 308. ^ Montagne A, Nation DA, Sagare AP, et al. (May 2020). "APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline". Nature. 581 (7806): 71–76. Bibcode:2020Natur.581...71M. doi:10.1038/s41586-020-2247-3. PMC 7250000. PMID 32376954. ## Further reading Library resources about Alzheimer's Disease * * * Resources in your library * Resources in other libraries * Irvine K, Laws KR, Gale TM, Kondel TK (2012). "Greater cognitive deterioration in women than men with Alzheimer's disease: a meta analysis". Journal of Clinical and Experimental Neuropsychology (Meta-analysis). 34 (9): 989–98. doi:10.1080/13803395.2012.712676. PMID 22913619. S2CID 28300240. * Harilal S, Jose J, Parambi DG, Kumar R, Mathew GE, Uddin MS, et al. (September 2019). "Advancements in nanotherapeutics for Alzheimer's disease: current perspectives". The Journal of Pharmacy and Pharmacology. 71 (9): 1370–1383. doi:10.1111/jphp.13132. PMID 31304982. S2CID 196616758. ## External links Wikimedia Commons has media related to Alzheimer's disease. Classification D * ICD-10: G30, F00 * ICD-9-CM: 331.0, 290.1 * OMIM: 104300 * MeSH: D000544 * DiseasesDB: 490 External resources * MedlinePlus: 000760 * eMedicine: neuro/13 * Patient UK: Alzheimer's disease * GeneReviews: NBK1161 * Scholia: Q11081 * Alzheimer's disease at Curlie * 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 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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 Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica 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Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Amyloidosis Common amyloid forming proteins * AA * ATTR * Aβ2M * AL * Aβ/APP * AIAPP * ACal * APro * AANF * ACys * ABri Systemic amyloidosis * AL amyloidosis * AA amyloidosis * Aβ2M/Haemodialysis-associated * AGel/Finnish type * AA/Familial Mediterranean fever * ATTR/Transthyretin-related hereditary Organ-limited amyloidosis Heart AANF/Isolated atrial Brain * Familial amyloid neuropathy * ACys+ABri/Cerebral amyloid angiopathy * Aβ/Alzheimer's disease Kidney * AApoA1+AFib+ALys/Familial renal Skin * Primary cutaneous amyloidosis * Amyloid purpura Endocrine Thyroid ACal/Medullary thyroid cancer Pituitary APro/Prolactinoma Pancreas AIAPP/Insulinoma AIAPP/Diabetes mellitus type 2 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Alzheimer's disease	c0002395	4,310	wikipedia	https://en.wikipedia.org/wiki/Alzheimer%27s_disease	2021-01-18T19:03:47	{"gard": ["10254"], "mesh": ["D000544"], "umls": ["C0002395"], "wikidata": ["Q11081"]}
Low blood volume This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (June 2009) (Learn how and when to remove this template message) Hypovolemia Other namesOligemia, hypovolaemia, oligaemia, hypovolæmia, volume depletion SpecialtyEmergency medicine Symptomsheadache, fatigue, nausea, profuse sweating, dizziness Hypovolemia, also known as volume depletion or volume contraction, is a state of abnormally low extracellular fluid in the body.[1] This may be due to either a loss of both salt and water or a decrease in blood volume.[2][3] Hypovolemia refers to the loss of extracellular fluid and should not be confused with dehydration.[4] Hypovolemia is caused by a variety of events, but these can be simplified into two categories: those that are associated with kidney function and those that are not.[5] The signs and symptoms of hypovolemia worsen as the amount of fluid lost increases.[6] Immediately or shortly after mild fluid loss, one may experience headache, fatigue, weakness, dizziness or thirst (as in blood transfusion, diarrhea, vomiting). Untreated hypovolemia or excessive and rapid losses of volume may lead to hypovolemic shock.[7] Signs and symptoms of hypovolemic shock include increased heart rate, low blood pressure, pale or cold skin, and altered mental status. When these signs are seen, immediate action should be taken to restore the lost volume. ## Contents * 1 Signs and symptoms * 2 Causes * 2.1 Kidney * 2.2 Other * 3 Pathophysiology * 4 Diagnosis * 4.1 Investigation * 4.2 Stages * 5 Treatment * 5.1 Field care * 5.2 Hospital treatment * 6 History * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Signs and symptoms of hypovolemia progress with increased loss of fluid volume.[5] Early symptoms of hypovolemia include headache, fatigue, weakness, thirst, and dizziness. The more severe signs and symptoms are often associated with hypovolemic shock. These include oliguria, cyanosis, abdominal and chest pain, hypotension, tachycardia, cold hands and feet, and progressively altering mental status. ## Causes[edit] The causes of hypovolemia can be characterized into two categories:[5] ### Kidney[edit] * Loss of body sodium and consequent intravascular water (due to impaired reabsorption of salt and water in the tubules of the kidneys) * Osmotic diuresis: the increase in urine production due to an excess of osmotic (namely glucose and urea) load in the tubules of the kidneys * Overuse of pharmacologic diuretics * Impaired response to hormones controlling salt and water balance (see mineralocorticoids) * Impaired kidney function due to tubular injury or other diseases ### Other[edit] * Loss of bodily fluids due to: * Gastrointestinal losses; e.g. vomiting and diarrhea * Skin losses; e.g. excessive sweating and burns * Respiratory losses; e.g. hyperventilation (breathing fast) * Build up of fluid in empty spaces (third spaces) of the body due to: * Acute pancreatitis * Intestinal obstruction * Increase in vascular permeability * Hypoalbuminemia * Loss of blood (external or internal bleeding or blood donation[8]) ## Pathophysiology[edit] Pathophysiology of hypovolemia The signs and symptoms of hypovolemia are primarily due to the consequences of decreased circulating volume and a subsequent reduction in the amount of blood reaching the tissues of the body.[9] In order to properly perform their functions, tissues require the oxygen transported in the blood.[10] A decrease in circulating volume can lead to a decrease in bloodflow to the brain, resulting in headache and dizziness. Baroreceptors in the body (primarily those located in the carotid sinuses and aortic arch) sense the reduction of circulating fluid and send signals to the brain to increase sympathetic response (see also: baroreflex).[11] This sympathetic response is to release epinephrine and norepinephrine, which results in peripheral vasoconstriction (reducing size of blood vessels) in order to conserve the circulating fluids for organs vital to survival (i.e. brain and heart). Peripheral vasoconstriction accounts for the cold extremities (hands and feet), increased heart rate, increased cardiac output (and associated chest pain). Eventually, there will be less perfusion to the kidneys, resulting in decreased urine output.[citation needed] ## Diagnosis[edit] See also: Shock index Hypovolemia can be recognized by a fast heart rate, low blood pressure,[12] and the absence of perfusion as assessed by skin signs (skin turning pale) and/or capillary refill on forehead, lips and nail beds. The patient may feel dizzy, faint, nauseated, or very thirsty. These signs are also characteristic of most types of shock.[13] In children, compensation can result in an artificially high blood pressure despite hypovolemia (a decrease in blood volume). Children typically are able to compensate (maintain blood pressure despite hypovolemia) for a longer period than adults, but deteriorate rapidly and severely once they are unable to compensate (decompensate).[14] Consequently, any possibility of internal bleeding in children should be treated aggressively.[15][16] Signs of external bleeding should be assessed, noting that individuals can bleed internally without external blood loss or otherwise apparent signs.[16] There should be considered possible mechanisms of injury that may have caused internal bleeding, such as ruptured or bruised internal organs. If trained to do so and if the situation permits, there should be conducted a secondary survey and checked the chest and abdomen for pain, deformity, guarding, discoloration or swelling. Bleeding into the abdominal cavity can cause the classical bruising patterns of Grey Turner's sign (bruising along the sides) or Cullen's sign (around the navel).[17] ### Investigation[edit] In a hospital, physicians respond to a case of hypovolemic shock by conducting these investigations: * Blood tests: U+Es/Chem7, full blood count, glucose, blood type and screen * Central venous catheter * Arterial line * Urine output measurements (via urinary catheter) * Blood pressure * SpO2 oxygen saturation monitoring ### Stages[edit] Untreated hypovolemia can lead to shock (see also: hypovolemic shock). Most sources state that there are 4 stages of hypovolemia and subsequent shock;[18] however, a number of other systems exist with as many as 6 stages.[19] The 4 stages are sometimes known as the "Tennis" staging of hypovolemic shock, as the stages of blood loss (under 15% of volume, 15–30% of volume, 30–40% of volume and above 40% of volume) mimic the scores in a game of tennis: 15, 15–30, 30–40 and 40.[20] It is basically the same as used in classifying bleeding by blood loss. The signs and symptoms of the major stages of hypovolemic shock include:[21][22] Stage 1 Stage 2 Stage 3 Stage 4 Blood loss Up to 15% (750 mL) 15–30% (750–1500 mL) 30–40% (1500–2000 mL) Over 40% (over 2000 mL) Blood pressure Normal (Maintained by vasoconstriction) Increased diastolic BP Systolic BP < 100 Systolic BP < 70 Heart rate Normal Slight tachycardia (> 100 bpm) Tachycardia (> 120 bpm) Extreme tachycardia (> 140 bpm) with weak pulse Respiratory rate Normal Increased (> 20) Tachypneic (> 30) Extreme tachypnea Mental status Normal Slight anxiety, restless Altered, confused Decreased LOC, lethargy, coma Skin Pale Pale, cool, clammy Increased diaphoresis Extreme diaphoresis; mottling possible Capillary refill Normal Delayed Delayed Absent Urine output Normal 20–30 mL/h 20 mL/h Negligible ## Treatment[edit] ### Field care[edit] The most important step in treatment of hypovolemic shock is to identify and control the source of bleeding.[23] Medical personnel should immediately supply emergency oxygen to increase efficiency of the patient's remaining blood supply. This intervention can be life-saving.[24] The use of intravenous fluids (IVs) may help compensate for lost fluid volume, but IV fluids cannot carry oxygen the way blood does—however, researchers are developing blood substitutes that can. Infusing colloid or crystalloid IV fluids also dilutes clotting factors in the blood, increasing the risk of bleeding. Current best practice allow permissive hypotension in patients suffering from hypovolemic shock,[25] both avoid overly diluting clotting factors and avoid artificially raising blood pressure to a point where it "blows off" clots that have formed.[26][27] ### Hospital treatment[edit] Fluid replacement is beneficial in hypovolemia of stage 2, and is necessary in stage 3 and 4.[21] See also the discussion of shock and the importance of treating reversible shock while it can still be countered. The following interventions are carried out: * IV access * Oxygen as required * Fresh frozen plasma or blood transfusion * Surgical repair at sites of bleeding Vasopressors (such as dopamine and noradrenaline) should generally be avoided, as they may result in further tissue ischemia and don't correct the primary problem. Fluids are the preferred choice of therapy.[28] ## History[edit] In cases where loss of blood volume is clearly attributable to bleeding (as opposed to, e.g., dehydration), most medical practitioners prefer the term exsanguination for its greater specificity and descriptiveness, with the effect that the latter term is now more common in the relevant context.[29] ## See also[edit] * Hypervolemia * Non-pneumatic anti-shock garment * Polycythemia, an increase of the hematocrit level, with the "relative polycythemia" being a decrease in the volume of plasma * Volume status ## References[edit] 1. ^ McGee S (2018). Evidence-based physical diagnosis. Philadelphia, PA: Elsevier. ISBN 978-0-323-39276-1. OCLC 959371826. "The term hypovolemia refers collectively to two distinct disorders: (1) volume depletion, which describes the loss of sodium from the extracellular space (i.e., intravascular and interstitial fluid) that occurs during gastrointestinal hemorrhage, vomiting, diarrhea, and diuresis; and (2) dehydration, which refers to the loss of intracellular water (and total body water) that ultimately causes cellular desiccation and elevates the plasma sodium concentration and osmolality." 2. ^ "Hypovolemia definition - MedicineNet - Health and Medical Information Produced by Doctors". Medterms.com. 2012-03-19. Retrieved 2015-11-01. 3. ^ "Hypovolemia \| definition of hypovolemia by Medical dictionary". Medical-dictionary.thefreedictionary.com. Retrieved 2015-11-01. 4. ^ Bhave G, Neilson EG (August 2011). "Volume depletion versus dehydration: how understanding the difference can guide therapy". American Journal of Kidney Diseases. 58 (2): 302–9. doi:10.1053/j.ajkd.2011.02.395. PMC 4096820. PMID 21705120. 5. ^ a b c Jameson, J. Larry; Kasper, Dennis L.; Longo, Dan L.; Fauci, Anthony S.; Hauser, Stephen L.; Loscalzo, Joseph, eds. (2018-08-13). Harrison's principles of internal medicine (20th ed.). New York: McGraw-Hill Education. ISBN 9781259644030. OCLC 1029074059. 6. ^ "Hypovolemic shock: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2019-09-02. 7. ^ Kolecki P (October 13, 2016). "Hypovolemic Shock". Medscape. 8. ^ Danic B, Gouézec H, Bigant E, Thomas T (June 2005). "[Incidents of blood donation]". Transfusion Clinique et Biologique (in French). 12 (2): 153–9. doi:10.1016/j.tracli.2005.04.003. PMID 15894504. 9. ^ Taghavi S, Askari R (2019), "Hypovolemic Shock", StatPearls, StatPearls Publishing, PMID 30020669, retrieved 2019-09-02 10. ^ Carreau A, El Hafny-Rahbi B, Matejuk A, Grillon C, Kieda C (June 2011). "Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia". Journal of Cellular and Molecular Medicine. 15 (6): 1239–53. doi:10.1111/j.1582-4934.2011.01258.x. PMC 4373326. PMID 21251211. 11. ^ Armstrong M, Moore RA (2019). "Physiology, Baroreceptors". StatPearls. StatPearls Publishing. PMID 30844199. Retrieved 2019-09-02. 12. ^ "Stage 3: Compensated Shock". Archived from the original on 2010-06-11. 13. ^ Alpert JS, Ewy GA (2002). Manual of Cardiovascular Diagnosis and Therapy. Lippincott Williams & Wilkins. p. 101. ISBN 978-0-7817-2803-4. 14. ^ Henry MC, Stapleton ER, Edgerly D (26 July 2011). EMT Prehospital Care. Jones & Bartlett Publishers. pp. 471–. ISBN 978-0-323-08533-5. 15. ^ Assuma Beevi (31 August 2012). Pediatric Nursing Care Plans. JP Medical Ltd. pp. 47–. ISBN 978-93-5025-868-2. 16. ^ a b Clement I (20 May 2013). Textbook on First Aid and Emergency Nursing. Jaypee Brothers Publishers. pp. 113–. ISBN 978-93-5025-987-0. 17. ^ Blaber A, Harris G (1 October 2011). Assessment Skills For Paramedics. McGraw-Hill Education. pp. 83–. ISBN 978-0-335-24199-6. 18. ^ Hudson, Kristi. "Hypovolemic Shock - 1 Nursing CE". Archived from the original on 2009-06-06. 19. ^ "Stage 1: Anticipation stage (a new paradigm)". Archived from the original on 2010-01-16. 20. ^ Greaves I, Porter K, Hodgetts T, et al., eds. (2006). Emergency Care: A Textbook for Paramedics. Elsevier Health Sciences. p. 229. ISBN 9780702025860. 21. ^ a b Agabegi ED, Steven S A (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 978-0-7817-7153-5. 22. ^ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C., eds. (2015). Robbins and Cotran pathologic basis of disease. Illustrated by Perkins, James A. (9th ed.). Philadelphia, PA: Saunders. ISBN 9781455726134. OCLC 879416939. 23. ^ Bulger, E. M.; et al. (2014). "An evidence-based prehospital guideline for external hemorrhage control: American College of Surgeons Committee on Trauma". Prehospital Emergency Care. 18 (2): 163–173. doi:10.3109/10903127.2014.896962. PMID 24641269. S2CID 15742568. 24. ^ Takasu, A.; Prueckner, S.; Tisherman, S. A.; Stezoski, S. W.; Stezoski, J.; Safar, P. (2000). "Effects of increased oxygen breathing in a volume controlled hemorrhagic shock outcome model in rats". Resuscitation. 45 (3): 209–220. doi:10.1016/s0300-9572(00)00183-0. PMID 10959021. 25. ^ "Permissive Hypotension". Trauma.Org. 1997-08-31. Archived from the original on 2013-11-27. Retrieved 2015-11-01. 26. ^ Kennamer M, American Academy of Orthopaedic Surgeons (AAOS) (30 September 2013). Intravenous Therapy for Prehospital Providers. Jones & Bartlett Publishers. pp. 63–. ISBN 978-1-4496-4204-4. 27. ^ de Franchis R, Dell'Era A (25 January 2014). Variceal Hemorrhage. Springer Science & Business Media. pp. 113–. ISBN 978-1-4939-0002-2. 28. ^ Nordin, A. J.; Mäkisalo, H.; Höckerstedt, K. A. (1996-08-31). "Failure of dobutamine to improve liver oxygenation during resuscitation with a crystalloid solution after experimental haemorrhagic shock". The European Journal of Surgery = Acta Chirurgica. Pubmed-NCBI. 162 (12): 973–979. Retrieved 2017-11-21. 29. ^ Geeraedts LM, Kaasjager HA, van Vugt AB, Frölke JP (January 2009). "Exsanguination in trauma: A review of diagnostics and treatment options". Injury. 40 (1): 11–20. doi:10.1016/j.injury.2008.10.007. PMID 19135193. ## External links[edit] Classification D * ICD-10: E86, R57.1, T81.1 * ICD-9-CM: 276.52 * MeSH: D020896 * DiseasesDB: 29217 External resources * MedlinePlus: 000167 * v * t * e Shock Distributive * Septic shock * Neurogenic shock * Anaphylactic shock * Toxic shock syndrome Obstructive * Abdominal compartment syndrome Low volume * Hemorrhage * Hypovolemia * Osmotic shock Other * Spinal shock * Cryptic shock * Vasodilatory shock * v * t * e Disorders of volume state Volume contraction * dehydration * hypovolemia Hypervolemia * Edema * Anasarca * Cerebral edema * Pulmonary edema * Angioedema * Lymphedema Other * Cause of fluid collection * Exudate * Transudate * By site * Hydrothorax * Ascites * Hydrosalpinx * Hyperemia * v * t * e Symptoms and signs relating to the circulatory system Chest pain * Referred pain * Angina * Levine's sign Auscultation * Heart sounds * Split S2 * S3 * S4 * Gallop rhythm * Heart murmur * Systolic * Functional murmur * Still's murmur * Diastolic * Pulmonary insufficiency * Graham Steell murmur * Continuous * Carey Coombs murmur * Mitral insufficiency * Presystolic murmur * Pericardial friction rub * Heart click * Bruit * carotid Pulse * Tachycardia * Bradycardia * Pulsus paradoxus * doubled * Pulsus bisferiens * Pulsus bigeminus * Pulsus alternans Other * Palpitations * Apex beat * Cœur en sabot * Jugular venous pressure * Cannon A waves * Hyperaemia * Shock * Cardiogenic * Obstructive * Hypovolemic * Distributive * See further Template:Shock Cardiovascular disease Aortic insufficiency * Collapsing pulse * De Musset's sign * Duroziez's sign * Müller's sign * Austin Flint murmur * Mayne's sign Other endocardium * endocarditis: Roth's spot * Janeway lesion/Osler's node * Bracht–Wachter bodies Pericardium * Cardiac tamponade/Pericardial effusion: Beck's triad * Ewart's sign Other * rheumatic fever: * Anitschkow cell * Aschoff body * EKG * J wave * Gallavardin phenomenon Vascular disease Arterial * aortic aneurysm * Cardarelli's sign * Oliver's sign * pulmonary embolism * Right heart strain * radial artery sufficiency * Allen's test * pseudohypertension * thrombus * Lines of Zahn * Adson's sign * arteriovenous fistula * Nicoladoni sign Venous * Friedreich's sign * Caput medusae * Kussmaul's sign * Trendelenburg test * superior vena cava syndrome * Pemberton's sign [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Hypovolemia	c0546884	4,311	wikipedia	https://en.wikipedia.org/wiki/Hypovolemia	2021-01-18T18:44:34	{"mesh": ["D020896"], "umls": ["C0546884"], "icd-9": ["276.52"], "icd-10": ["T81.1", "E86", "R57.1"], "wikidata": ["Q1320276"]}
Peutz-Jeghers syndrome (PJS) is an inherited condition that is associated with an increased risk of growths along the lining of the gastrointestinal tract (called hamartomatous polyps) and certain types of cancer. Most affected people also have characteristic dark blue to dark brown macules around the mouth, eyes, and nostrils; near the anus (perianal); and on the inside of the cheeks (buccal mucosa). PJS is caused by changes (mutations) in the STK11 gene and is inherited in an autosomal dominant manner. Management typically includes high-risk screening for associated polyps and cancers. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Peutz-Jeghers syndrome	c0031269	4,312	gard	https://rarediseases.info.nih.gov/diseases/7378/peutz-jeghers-syndrome	2021-01-18T17:58:21	{"mesh": ["D010580"], "omim": ["175200"], "umls": ["C0031269"], "orphanet": ["2869"], "synonyms": ["Polyposis, hamartomatous intestinal", "PJS", "Polyps-and-spots syndrome", "Peutz Jeghers polyposis", "Periorificial lentiginosis syndrome", "Lentiginosis, perioral"]}
A neurodevelopmental teratologic syndrome due to prenatal exposure to toluene. The disease is characterized by prematurity, low birth weight, dysmorphic features (short palpebral fissures, deep set eyes, low set ears, mid-facial hypoplasia, flat nasal bridge, thin upper lip, micrognathia, spatulate fingertips and small fingernails), central nervous system dysfunctions (intellectual disability, microcephaly, language impairment, hyperactivity, visual dysfunction) and postnatal growth delay. Prenatal exposure to toluene occurs as a result of incidental occupational exposure or solvent abuse during pregnancy. The features of toluene embryopathy often overlap with those seen in fetal alcohol 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Toluene embryopathy	c2931737	4,313	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1920	2021-01-23T17:32:04	{"mesh": ["C538114"], "icd-10": ["Q86.8"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive peripheral neuropathy with or without impaired intellectual development (PNRIID) is caused by homozygous or compound heterozygous mutation in the MCM3AP gene (603294) on chromosome 21q22. Description Autosomal recessive peripheral neuropathy with or without impaired intellectual development is an early childhood-onset neurologic disorder characterized by slowly progressive distal motor impairment resulting in gait difficulties, often with loss of ambulation, and difficulties using the hands in most patients. Most affected individuals also have impaired intellectual development, although some have normal cognition. Electrophysiologic testing and sural nerve biopsy are most compatible with an axonal motor neuropathy; some patients may show signs of demyelination. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis (summary by Ylikallio et al., 2017). Clinical Features Schuurs-Hoeijmakers et al. (2013) reported a Dutch brother and sister, born of unrelated parents, with mildly impaired intellectual development, progressive polyneuropathy, cerebellar ataxia, ptosis, saccadic eye movements, hypotonia, and facial dysmorphism. The family was ascertained from a cohort of 19 nonconsanguineous families with intellectual disability that underwent exome sequencing. Ylikallio et al. (2017) reported 9 patients from 5 unrelated families of various ethnic origins with a complex neurologic disorder beginning in infancy or early childhood. The patients ranged in age from 3 to 28 years. Initial features included hypotonia and mildly delayed motor development with most patients achieving walking by age 2 years, although 2 unrelated patients achieved walking at age 4 years. Almost all patients lost independent ambulation between 10 and 24 years and became wheelchair-bound. All patients had evidence of a sensorimotor peripheral neuropathy, and most had distal muscle atrophy and weakness and impaired distal sensation associated with decreased or absent lower limb reflexes. Electrophysiologic studies were consistent with an axonal neuropathy in most patients, but 2 brothers, born of consanguineous Turkish parents (family T), had nerve conduction studies (NCV) suggestive of a demyelinating neuropathy. Sural nerve biopsies, performed in some patients, showed loss of myelinated axons. Seven of 9 patients had mild to moderate intellectual disability with learning difficulties and often with delayed speech, but several could read and attend special schools. Brain imaging, performed in 7 patients, was normal in 4, but showed mildly increased signal intensities in the temporal lobe in 2 patients and mild ventriculomegaly and small white matter cysts in a third. Two sisters in 1 family (family C) had obesity and primary ovarian failure. Additional uncommon features, seen only in a single patient or a few patients, included extensor plantar responses, short stature, microtia with hearing impairment, strabismus, amblyopia, hypotonia, seizures, scoliosis, and distal contractures. One patient was ventilator-dependent at age 14. Karakaya et al. (2017) reported 4 patients from 3 unrelated families with early-onset autosomal recessive peripheral neuropathy. An 8-year-old girl, born of consanguineous Kurdish parents (family A), had delayed motor development, gait difficulties, ophthalmoplegia, and strabismus. She was able to walk at age 4 years. Physical examination showed distal muscle atrophy and weakness of the upper and lower limbs, absent reflexes, and scoliosis. Nerve conduction studies were consistent with an axonal sensorimotor neuropathy. In a second family, 2 adult sisters, born of consanguineous Iranian parents (family B), developed distal muscle atrophy and weakness in the upper and lower limbs at age 10 to 13 years. They had thenar atrophy, mild wasting of the intrinsic hand muscles, and distal spinal muscular atrophy resulting in hand weakness, writing difficulty, and claw hands. Both also had pes cavus with Achilles tendon shortness, difficulty walking with frequent falls and abnormal gait, and loss of the ability to run. Electrophysiologic studies showed low motor NCVs with normal sensory NCVs. Hearing, vision, and cognition were normal. The last patient was a 13-year-old girl who showed global developmental delay from infancy and later developed progressive distal motor impairment in childhood with difficulty walking. She had mild intellectual disability. Other features included arched feet and kyphosis. NCV was consistent with an axonal sensorimotor neuropathy, and sural nerve biopsy showed mild chronic axonal neuropathy with mild loss of large diameter axons. Kennerson et al. (2018) reported 3 sibs, born of consanguineous Lebanese parents, with early-onset autosomal recessive peripheral neuropathy. The patients were young adults at the time of the report, but developed slowly progressive distal muscle weakness of the upper and lower limbs between ages 6 and 10 years after early normal motor development. In the teenage years, all had foot drop, wrist and finger drop, marked distal muscle atrophy, and decreased sensation to pain and temperature; vibration and proprioception were normal. The patients remained ambulatory. Electrophysiologic studies showed absent or markedly reduced compound motor action potentials and decreased motor conduction velocities, although sensory studies were basically normal. All 3 patients became obese, and 2 developed type 2 diabetes mellitus. One sib developed psychosis with catatonia, but cognition level was not reported. Inheritance The transmission pattern of PNRIID in the families reported by Ylikallio et al. (2017) was consistent with autosomal recessive inheritance. Molecular Genetics In a Dutch brother and sister, born of unrelated parents, with mild intellectual disability, Schuurs-Hoeijmakers et al. (2013) identified a homozygous missense mutation in the MCM3AP gene (E915K; 603294.0001) affecting a highly conserved residue in the Sac3 domain. The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was present in less than 1% of dbSNP (build 134) samples and in less than 1% of 672 in-house exomes. DNA from the parents was not available for segregation analysis. Schuurs-Hoeijmakers et al. (2013) noted that the MCM3AP gene is expressed in the brain or in neuronal tissue. In 9 patients from 5 unrelated families with PNRIID, Ylikallio et al. (2017) identified homozygous or compound heterozygous mutations in the MCM3AP gene (see, e.g., 603294.0002-603294.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patients in 4 families were compound heterozygous for a missense mutation affecting a conserved residue and a frameshift, nonsense, or splice site mutation, predicted to result in a loss of function or to be subjected to nonsense-mediated mRNA decay. Fibroblasts derived from 1 patient (family F) showed significantly decreased levels of MCM3AP mRNA and protein levels of 20% compared to controls, whereas fibroblasts from the affected individual in family A showed a milder decrease in protein levels at about 85% of controls. Patient cells did not show a deficit in DNA repair. Ylikallio et al. (2017) postulated that the mutations resulted in a partial or complete loss of protein function, possibly leading to abnormal nuclear retention of mRNAs that are crucial for neuronal function. In 4 patients from 3 unrelated families with PNRIID, Karakaya et al. (2017) identified homozygous or compound heterozygous mutations in the MCM3AP gene (see, e.g., 603294.0006 and 603294.0007). The mutations were found by targeted sequencing of a gene panel and confirmed by Sanger sequencing. Segregation studies confirmed recessive inheritance in 2 of the families. Functional studies of the variants and studies of patient cells were not performed, but 2 families carried homozygous missense mutations in the Sac 3 domain, and the third family was compound heterozygous for a nonsense and a frameshift mutation. Two families were consanguineous and of Kurdish and Iranian descent, respectively. In 3 sibs of Lebanese ethnicity with PNRIID, Kennerson et al. (2018) identified a homozygous missense mutation in the Sac3 domain of the MCM3AP gene (L870S; 603294.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (in some patients) Weight \- Obesity (in some patients) HEAD & NECK Eyes \- Strabismus \- Abnormal eye movements (in some patients) \- Ophthalmoplegia (in some patients) Mouth \- High arched palate SKELETAL \- Distal contractures Spine \- Scoliosis Hands \- Clawed hands Feet \- Foot deformities \- Foot drop MUSCLE, SOFT TISSUES \- Hypotonia \- Distal muscle weakness, neurogenic \- Distal muscle atrophy, neurogenic NEUROLOGIC Central Nervous System \- Impaired intellectual development, mild (in most patients) \- Speech delay \- Learning difficulties \- Delayed motor development \- Unsteady gait \- Loss of ambulation Peripheral Nervous System \- Sensorimotor peripheral neuropathy, primarily axonal \- Distal sensory impairment, mild (in some patients) \- Hyporeflexia \- Areflexia \- Loss of myelinated axons seen on sural nerve biopsy \- Axonal neuropathy \- Demyelinating neuropathy (in some patients) ENDOCRINE FEATURES \- Premature ovarian failure (1 family) MISCELLANEOUS \- Onset in infancy or first decade \- Slowly progressive \- Variable phenotype and severity MOLECULAR BASIS \- Caused by mutation in the minichromosome maintenance 3-associated protein gene (MCM3AP, 603294.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	PERIPHERAL NEUROPATHY, AUTOSOMAL RECESSIVE, WITH OR WITHOUT IMPAIRED INTELLECTUAL DEVELOPMENT	None	4,314	omim	https://www.omim.org/entry/618124	2019-09-22T15:43:33	{"omim": ["618124"]}
X-linked dominant condition characterised by neurological and retinal abnormalities Not to be confused with Aicardi–Goutières syndrome. Aicardi syndrome Other namesAgenesis of corpus callosum with chorioretinal abnormality[1] This condition is inherited in an X-linked dominant manner. SpecialtyMedical genetics Aicardi syndrome is a rare genetic malformation syndrome characterized by the partial or complete absence of a key structure in the brain called the corpus callosum, the presence of retinal abnormalities, and seizures in the form of infantile spasms.[2] Aicardi syndrome is theorized to be caused by a defect on the X chromosome as it has thus far only been observed in girls or in boys with Klinefelter syndrome. Confirmation of this theory awaits the discovery of a causative gene. Symptoms typically appear before a baby reaches about 5 months of age.[citation needed] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 History * 8 References * 9 External links ## Signs and symptoms[edit] Children are most commonly identified with Aicardi syndrome before the age of five months. A significant number of girls are products of normal births and seem to be developing normally until around the age of three months, when they begin to have infantile spasms. The onset of infantile spasms at this age is due to closure of the final neural synapses in the brain, a stage of normal brain development[citation needed]. A number of tumors have been reported in association with Aicardi syndrome: choroid plexus papilloma (the most common), medulloblastoma, gastric hyperplastic polyps, rectal polyps, soft palate benign teratoma, hepatoblastoma, parapharyngeal embryonal cell cancer, limb angiosarcoma and scalp lipoma.[3] ## Genetics[edit] Almost all reported cases of Aicardi syndrome have been in girls. The few boys that have been identified with Aicardi syndrome have proved to have 47 chromosomes including an XXY sex chromosome complement, a condition called Klinefelter syndrome.[citation needed] All cases of Aicardi syndrome are thought to be due to new mutations. No person with Aicardi syndrome is known to have transmitted the X-linked gene responsible for the syndrome to the next generation.[citation needed] ## Diagnosis[edit] Aicardi syndrome is typically characterized by the following triad of features - however, one of the "classic" features being missing does not preclude a diagnosis of Aicardi Syndrome, if other supporting features are present.[4] 1. Partial or complete absence of the corpus callosum in the brain (agenesis of the corpus callosum); 2. Eye abnormalities known as "lacunae" of the retina that are quite specific to this disorder; optic nerve coloboma; and 3. The development in infancy of seizures that are called infantile spasms. Other types of defects of the brain such as microcephaly, polymicrogyria, porencephalic cysts and enlarged cerebral ventricles due to hydrocephalus are also common in Aicardi syndrome. ## Treatment[edit] Treatment of Aicardi syndrome primarily involves management of seizures and early/continuing intervention programs for developmental delays.[citation needed]Additional comorbidities and complications sometimes seen with Aicardi syndrome include porencephalic cysts and hydrocephalus, and gastro-intestinal problems. Treatment for porencephalic cysts and/or hydrocephalus is often via a shunt or endoscopic fenestration of the cysts, though some require no treatment. Placement of a feeding tube, fundoplication, and surgeries to correct hernias or other gastrointestinal structural problems are sometimes used to treat gastro-intestinal issues.[citation needed] ## Prognosis[edit] The prognosis varies widely from case to case, depending on the severity of the symptoms. However, almost all people reported with Aicardi syndrome to date have experienced developmental delay of a significant degree, typically resulting in mild to moderate to profound intellectual disability. The age range of the individuals reported with Aicardi syndrome is from birth to the mid-40s. There is no cure for this syndrome.[citation needed] ## Epidemiology[edit] Worldwide prevalence of Aicardi syndrome is estimated at several thousand, with approximately 900 cases reported in the United States.[5] ## History[edit] This disorder was first recognized as a distinct syndrome in 1965 by Jean Aicardi, a French pediatric neurologist and epileptologist.[6][4] ## References[edit] 1. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Aicardi syndrome". www.orpha.net. Retrieved 17 June 2019. 2. ^ Rosser, Tena (1 October 2003). "Aicardi Syndrome". Archives of Neurology. 60 (10): 1471–3. doi:10.1001/archneur.60.10.1471. PMID 14568821. 3. ^ Sijmons, Rolf H (2008). "Encyclopaedia of tumour-associated familial disorders. Part I: from AIMAH to CHIME syndrome". Hereditary Cancer in Clinical Practice. 6 (1): 22–57. doi:10.1186/1897-4287-6-1-22. PMC 2735164. PMID 19706204. 4. ^ a b Aicardi, Jean (January 1999). "Aicardi Syndrome: Old and New Findings" (PDF). International Pediatrics. 14 (1): 5–8. 5. ^ Kroner, Barbara L.; Preiss, Liliana R.; Ardini, Mary-Anne; Gaillard, William D. (29 January 2008). "New Incidence, Prevalence, and Survival of Aicardi Syndrome From 408 Cases". Journal of Child Neurology. 23 (5): 531–535. doi:10.1177/0883073807309782. PMID 18182643. S2CID 28004201. 6. ^ Aicardi J, Lefebvre J, Lerique-Koechlin A. A new syndrome: spasm in flexion, callosal agenesis, ocular abnormalities. Electroenceph Clin Neurophysiol 1965; 19: 609–610 ## External links[edit] * GeneReviews/NCBI/NIH/UW entry on Aicardi Syndrome * OMIM entries on Aicardi syndrome Classification D * ICD-10: Q04.0 * ICD-9-CM: 742.2 * OMIM: 304050 * MeSH: D058540 * DiseasesDB: 29761 * SNOMED CT: 80651009 External resources * MedlinePlus: 001664 * eMedicine: ped/58 * GeneReviews: Aicardi Syndrome * Orphanet: 50 * v * t * e X-linked disorders X-linked recessive Immune * Chronic granulomatous disease (CYBB) * Wiskott–Aldrich syndrome * X-linked severe combined immunodeficiency * X-linked agammaglobulinemia * Hyper-IgM syndrome type 1 * IPEX * X-linked lymphoproliferative disease * Properdin deficiency Hematologic * Haemophilia A * Haemophilia B * X-linked sideroblastic anemia Endocrine * Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy * KAL1 Kallmann syndrome * X-linked adrenal hypoplasia congenita Metabolic * Amino acid: Ornithine transcarbamylase deficiency * Oculocerebrorenal syndrome * Dyslipidemia: Adrenoleukodystrophy * Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency * Pyruvate dehydrogenase deficiency * Danon disease/glycogen storage disease Type IIb * Lipid storage disorder: Fabry's disease * Mucopolysaccharidosis: Hunter syndrome * Purine–pyrimidine metabolism: Lesch–Nyhan syndrome * Mineral: Menkes disease/Occipital horn syndrome Nervous system * X-linked intellectual disability: Coffin–Lowry syndrome * MASA syndrome * Alpha-thalassemia mental retardation syndrome * Siderius X-linked mental retardation syndrome * Eye disorders: Color blindness (red and green, but not blue) * Ocular albinism (1) * Norrie disease * Choroideremia * Other: Charcot–Marie–Tooth disease (CMTX2-3) * Pelizaeus–Merzbacher disease * SMAX2 Skin and related tissue * Dyskeratosis congenita * Hypohidrotic ectodermal dysplasia (EDA) * X-linked ichthyosis * X-linked endothelial corneal dystrophy Neuromuscular * Becker's muscular dystrophy/Duchenne * Centronuclear myopathy (MTM1) * Conradi–Hünermann syndrome * Emery–Dreifuss muscular dystrophy 1 Urologic * Alport syndrome * Dent's disease * X-linked nephrogenic diabetes insipidus Bone/tooth * AMELX Amelogenesis imperfecta No primary system * Barth syndrome * McLeod syndrome * Smith–Fineman–Myers syndrome * Simpson–Golabi–Behmel syndrome * Mohr–Tranebjærg syndrome * Nasodigitoacoustic syndrome X-linked dominant * X-linked hypophosphatemia * Focal dermal hypoplasia * Fragile X syndrome * Aicardi syndrome * Incontinentia pigmenti * Rett syndrome * CHILD syndrome * Lujan–Fryns syndrome * Orofaciodigital syndrome 1 * Craniofrontonasal dysplasia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Aicardi syndrome	c0175713	4,315	wikipedia	https://en.wikipedia.org/wiki/Aicardi_syndrome	2021-01-18T18:36:22	{"gard": ["5764"], "mesh": ["D058540"], "umls": ["C0175713"], "icd-9": ["742.2"], "orphanet": ["50"], "wikidata": ["Q403463"]}
Ileal neuroendocrine tumor is a rare, primary, malignant, epithelial neoplasm of the small intestine arising from enterochromaffin cells in the ileum (usually the terminal ileum). Clinical behavior depends on the histologic grade, but initially it is generally characterized by vague abdominal symptoms (cramping, bloating, diarrhea) with insidious onset, although sometimes it could present with signs of bowel obstruction/perforation or gastrointestinal bleeding. Diagnosis in advanced stages with regional or distant spread is common, but signs of carcinoid syndrome (flushing, sweating, diarrhea) are usually not apparent until hepatic metastasis has occurred. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Ileal neuroendocrine tumor	c4525628	4,316	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100078	2021-01-23T18:03:55	{"synonyms": ["Ileal neuroendocrine neoplasm"]}
A number sign (#) is used with this entry because primary ciliary dyskinesia-20 (CILD20) is caused by homozygous or compound heterozygous mutation in the CCDC114 gene (615038) on chromosome 19q13. Description CILD20 is an autosomal recessive ciliopathy characterized by infantile onset of chronic sinopulmonary infections resulting from immotile cilia and defective clearance. Patients may also have situs inversus or cardiac anomalies. Electron microscopy of respiratory epithelial cells shows absence of the outer dynein arms. Unlike other forms of CILD, patients with CILD20 do not appear to be infertile. For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see 244400. Clinical Features Onoufriadis et al. (2013) reported a large multigenerational consanguineous family from Volendam, North Holland, in which 8 individuals had primary ciliary dyskinesia. Eight additional patients with this disorder from 7 other families were also ascertained. Affected individuals presented with early neonatal respiratory symptoms, including cough, shortness of breath, pneumonia, increased mucus production, chronic respiratory infections, recurrent otitis media, atelectasis, and bronchiectasis. Six (38%) of patients had situs-related abnormalities, either complete left-right organ reversal or isolated thoracic/abdominal complications. Two had complex heart malformations. Patient respiratory epithelial cells showed abnormal ciliary motility with static cilia or few cilia with stiff, slow, twitching or flickering movement, and transmission electron microscopy showed loss of the outer dynein arms. There was also a decrease in expression of DNAH5 (603335) in patient cilia. Although infertility is usually associated with CILD, 5 affected individuals had offspring, and fertility problems were not noted. Sperm analysis of 1 patient showed normal count and motility. Knowles et al. (2013) reported 6 patients from 4 families with CILD20. All patients had respiratory symptoms, but none had situs inversus, and infertility was not reported. Electron microscopic analysis of patient cells showed absence of the outer dynein arms. Patient nasal epithelial cells showed complete ciliary immotility in most cells, with some cells showing stiff and dyskinetic cilia. Inheritance The transmission pattern of CILD20 in the families reported by Onoufriadis et al. (2013) and Knowles et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics In affected members of a large multigenerational family from an isolated region of North Holland with primary ciliary dyskinesia-20, Onoufriadis et al. (2013) identified a homozygous mutation in the CCDC114 gene (742G-A; 615038.0001), demonstrated to result in a frameshift and premature termination. The mutation was identified by exome sequencing of 2 individuals, segregated with the disorder, and was also found in 8 patients from 7 additional families from this region. A second homozygous truncating mutation (615038.0002) was identified in a woman from the U.K. with a similar phenotype. Simultaneously and independently, Knowles et al. (2013) identified homozygous and compound heterozygous mutations in the CCDC114 gene (615038.0001 and 615038.0002-615038.0005) in 6 patients from 4 families with CILD20. All carried the 742G-A transition on at least 1 allele, and all shared a common haplotype surrounding that mutation. Population Genetics Onoufriadis et al. (2013) reported 9 families with CILD20 from Volendam, a small fishing village in North Holland that has been genetically isolated for geographic and religious reasons since the 15th century. All affected individuals were homozygous for the same mutation (742G-A; 615038.0001), and haplotype analysis indicated a founder effect. However, the mutation was estimated to have occurred prior to the founding of the Volendam village in 1462. Knowles et al. (2013) also observed a founder effect among 6 CILD patients with the 742G-A allele. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Otitis media, recurrent Nose \- Sinusitis, recurrent \- Rhinorrhea CARDIOVASCULAR Heart \- Dextrocardia (in some patients) \- Complex cardiac malformations (in some patients) RESPIRATORY \- Respiratory insufficiency due to defective ciliary clearance \- Respiratory infections, recurrent \- Cough Lung \- Pneumonia, recurrent \- Atelectasis \- Bronchiectasis ABDOMEN \- Situs inversus (in some patients) GENITOURINARY Internal Genitalia (Male) \- Normal fertility LABORATORY ABNORMALITIES \- Respiratory epithelial show lack of ciliary movement or abnormal movement \- Electron microscopy of patient respiratory cells shows loss of ciliary outer dynein arms \- Decreased nasal nitric oxide MISCELLANEOUS \- Onset in early infancy MOLECULAR BASIS \- Caused by mutation in the coiled-coil domain-containing protein 114 gene (CCDC114, 615038.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	CILIARY DYSKINESIA, PRIMARY, 20	c0022521	4,317	omim	https://www.omim.org/entry/615067	2019-09-22T15:53:16	{"doid": ["0110625"], "mesh": ["D007619"], "omim": ["244400", "615067"], "orphanet": ["244"], "synonyms": ["Alternative titles", "PCD", "CILIARY DYSKINESIA, PRIMARY, 20, WITH OR WITHOUT SITUS INVERSUS"], "genereviews": ["NBK1122"]}
Terminal osseous dysplasia-pigmentary defects syndrome is characterised by malformation of the hands and feet, pigmentary skin lesions on the face and scalp and digital fibromatosis. ## Epidemiology It has been described in 18 females, six of whom came from four different generations of the same family. ## Clinical description Phenotypic expression is very heterogeneous. In the majority of patients, the bone dysplasia is limited to the hands and feet but shortening and/or bowing of the bones of the arms and legs has been reported in severe cases. The pigmentary lesions and digital fibromatosis appear a few months after birth. ## Etiology The causative gene remains unknown. ## Genetic counseling The syndrome is transmitted as an in utero male-lethal X-linked dominant trait, explaining the large number of miscarriages reported in the affected families. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Terminal osseous dysplasia-pigmentary defects syndrome	c1846129	4,318	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=88630	2021-01-23T17:42:31	{"mesh": ["C564554"], "omim": ["300244"], "umls": ["C1846129"], "icd-10": ["Q87.2"]}
A number sign (#) is used with this entry because multiple endocrine neoplasia type I (MEN1) is caused by heterozygous mutation in the MEN1 gene (613733) on chromosome 11q13. Description Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant disorder characterized by varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary, with 94% penetrance by age 50. Less commonly associated tumors include foregut carcinoids, lipomas, angiofibromas, thyroid adenomas, adrenocortical adenomas, angiomyolipomas, and spinal cord ependymomas. Except for gastrinomas, most of the tumors are nonmetastasizing, but many can create striking clinical effects because of the secretion of endocrine substances such as gastrin, insulin, parathyroid hormone, prolactin, growth hormone, glucagon, or adrenocorticotropic hormone (summary by Chandrasekharappa et al., 1997). Familial isolated hyperparathyroidism (see 145000) occasionally results from the incomplete expression of MEN1 (summary by Simonds et al., 2004). ### Genetic Heterogeneity of Multiple Endocrine Neoplasia Other forms of multiple endocrine neoplasia include MEN2A (171400) and MEN2B (162300), both of which are caused by mutation in the RET gene (164761), and MEN4 (610755), which is caused by mutation in the CDKN1B gene (600778). Clinical Features Underwood and Jacobs (1963) identified an affected father, son, and daughter. Hypoglycemia was the presenting manifestation in all 3. In addition to islet cell adenomas, the father had bronchial carcinoma and hyperparathyroidism (145000) from parathyroid adenomas. The son and daughter had been followed from childhood as cases of idiopathic epilepsy unresponsive to anticonvulsive therapy. Guida et al. (1966) described pituitary adenoma and duodenal carcinoid in patients with this condition. Bronchial carcinoid was described as a feature of the disorder by Williams and Celestin (1962). Some kindreds (e.g., Ballard et al., 1964; Wermer, 1954) have a high frequency of severe peptic ulcer disease with islet cell tumors, whereas other kindreds (e.g., Johnson et al., 1967) are devoid of peptic disease. Bilateral pheochromocytomas occur in MEN2A and MEN2B and pancreatic islet cell tumors in MEN1. Tateishi et al. (1978) described a patient with both forms of endocrine neoplasia. They also reviewed 14 reported cases of MEN with features overlapping MEN I and II. For example, 7 patients with acromegaly (102200) due to pituitary adenoma had pheochromocytoma, 2 with Sipple syndrome (MEN2A) had pituitary adenoma, and so on. Prosser et al. (1979) found 4 patients in 3 unrelated families who had prolactin-secreting pituitary adenomas. Farid et al. (1980) observed 4 kindreds in the Burin Peninsula of Newfoundland, whose ancestors came from the same small community in the British Isles, with hyperparathyroidism and prolactinoma, but no documented pancreatic tumors. Two kindreds had carcinoid tumors at unusual sites, either thymus or peripheral lung parenchyma. In contrast to the benign course of the prolactinomas and the primary hyperparathyroidism, 2 persons with thymic carcinoid died from metastatic disease. Bear et al. (1985) referred to the disorder in these families as MEN1-Burin (see 613733.0016). Hershon et al. (1983) described a phenotypically similar but unrelated kindred from the Pacific Northwest, in which 6 of 7 living affected members had prolactinomas and none had pancreatic islet tumors. Farid (1994) reported that the Burin Peninsula families were in fact related. All 4 families had ancestors who lived in the Harbor Breton region a century earlier and all affected members of the 4 families carried the same PYGM (608455) allele segregating with the disorder. Petty et al. (1994) demonstrated by linkage studies that the gene in both the Newfoundland kindreds and the kindred from the Pacific Northwest mapped to 11q in the same region as the MEN1 gene. No recombinants were seen with PYGM in either kindred, but the PYGM allele associated with the disease was different in the 2 kindreds. The Zollinger-Ellison syndrome (ZES) may present purely as hyperparathyroidism. For example, 1 member of the family described as having hereditary hyperparathyroidism by Cutler et al. (1964) was later reported to have a malignant schwannoma, pituitary adenomas, multiple pancreatic islet cell adenomas, and multiple adrenocortical adenomas. Snyder et al. (1972) reported 5 families and noted the previously described association of lipomas. The Zollinger-Ellison syndrome is merely hypergastrinism and may have causes other than MEN I. For example, Long et al. (1980) reported the Zollinger-Ellison syndrome with ectopic production of gastrin by a mucinous cystadenoma of the ovary. McCarthy (1982) distinguished 2 common forms of the Zollinger-Ellison syndrome: the sporadic and usually malignant type, seen most often in later life, and the genetic variety that occurs as part of MEN I. Stacpoole et al. (1981) observed a family in which 3 persons had A-cell pancreatic tumors (glucagonomas) as part of MEN I. Two had the classic glucagonoma syndrome with skin rash, glucose intolerance, and hypoaminoacidemia. Administered secretin and somatostatin gave anomalous metabolic responses. Bahn et al. (1986) reported 25-year-old monozygotic twins with MEN I who had impressive differences in expression of the disorder. One had epigastric pain and diarrhea at presentation; was found to have primary hyperparathyroidism, Zollinger-Ellison syndrome, Cushing disease, and hyperprolactinemia; and underwent hypophysectomy. The second twin was asymptomatic but had primary hyperparathyroidism and hyperprolactinemia. A large, histologically benign pituitary adenoma 'that invaded dura and bone' was removed by a transsphenoidal approach 2 days after parathyroidectomy. Maton et al. (1986) suggested that the Cushing syndrome is more common in patients with the Zollinger-Ellison syndrome than previously reported, occurring in 8% of all cases. Three of 16 patients with the Zollinger-Ellison syndrome and MEN1 had the Cushing syndrome due to pituitary overproduction of ACTH. In all sporadic cases of ZES, Cushing syndrome was due to ectopic production of ACTH by the gastrinoma. Gaitan et al. (1993) described mother and daughter who, in addition to other manifestations of MEN1, had Cushing disease due to ACTH-secreting tumors. Yu et al. (1999) reported on the long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors in whom the excess hormone state was controlled. They studied 212 patients with Zollinger-Ellison syndrome. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up of 13.8 years (range, 0.1 to 31 years). Death had occurred in 31% of patients, all from non-acid-related causes. One-half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushing syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. Yu et al. (1999) concluded that in ZES, gastrinoma growth is the main single determinant of long-term survival, with 50% of patients dying a gastrinoma-related death and none an acid-related death. Bordi et al. (2001) identified carcinoid tumors in the antropyloric mucosa of 4 patients with MEN1/Zollinger-Ellison syndrome, accounting for 8.7% of 46 patients with this condition examined by endoscopy and histology. In contrast, no tumors were found in the antral biopsies from 124 cases of sporadic ZES (p less than 0.001), indicating a prominent role for the MEN1 gene defects in tumor development. Immunohistochemically, the tumors did not express the hormones produced by antral endocrine cells (gastrin, somatostatin, serotonin). In contrast, 2 of them were diffusely immunoreactive for the isoform 2 of the vesicular monoamine transporter (VMAT2; 193001), a marker specific for the gastric nonantral enterochromaffin-like (ECL) cells. In 1 of these patients, a second antral VMAT2-positive carcinoid was seen 21 months after the first diagnosis. The authors concluded that the antral mucosa is an additional tissue that may harbor endocrine tumors in MEN1 syndrome. These tumors did not express the phenotype of normal antral endocrine cells and, in at least 2 cases, were identified as ectopic ECL cell carcinoids. Skogseid et al. (1992) reviewed adrenocortical lesions in 31 MEN I patients. In 12 (37%), they found adrenal enlargement, which was bilateral in 7. One person developed unilateral adrenocortical carcinoma manifested by rapid adrenal expansion, feminization, and an abnormal urinary steroid profile after 4 years of observation for bilateral minor adrenal enlargement. In the other patients, adrenal enlargement was not associated with ascertainable biochemical disturbances in the hypothalamic-pituitary-adrenocortical axis. Pancreatic endocrine tumors were significantly overrepresented in the patients with adrenal lesions, being present in all 12. In agreement with findings in sporadic cases, the MEN1 adrenocortical carcinoma showed loss of constitutional heterozygosity for alleles at 17p, 13q, 11p, and 11q. The benign adrenal lesions retained heterozygosity for the MEN1 locus at 11q13. Skogseid et al. (1992) concluded that the pituitary-independent adrenocortical proliferation is not the result of the primary lesion in MEN I but may represent a secondary phenomenon, perhaps related to the pancreatic endocrine tumor. Verges et al. (2002) analyzed data on pituitary adenomas in 324 MEN1 patients from a French and Belgian multicenter study. Data on pituitary disease were compared with those from 110 non-MEN1 patients with pituitary adenomas, matched for age, year of diagnosis, and follow-up period. In the authors' MEN1 series, pituitary disease occurred in 136 of 324 (42%), less frequently than hyperparathyroidism (95%, p less than 0.001) and endocrine enteropancreatic tumors (54%, p less than 0.01). Mean age of onset of pituitary tumors was 38.0 +/- 15.3 years (range, 12 to 83 years). Pituitary disease was associated with hyperparathyroidism in 90% of cases, with enteropancreatic tumors in 47%, with adrenal tumors in 16%, and with thoracic neuroendocrine tumors in 4%. Pituitary disease was the initial lesion of MEN1 in 17% of all MEN1 patients. MEN1 pituitary adenomas were significantly more frequent in women than in men (50% vs 31%, p less than 0.001). Eighty-five percent of MEN1-related pituitary lesions were macroadenomas, including 32% of invasive cases. Among secreting adenomas, hormonal hypersecretion was normalized, after treatment, in only 42%, with a median follow-up of 11.4 years. No correlation was found between the type of MEN1 germline mutation and the presence or absence of pituitary adenoma. The authors concluded that their study shows that pituitary adenomas occur in 42% of cases and are characterized by a larger size and a more aggressive presentation than without MEN1. Darling et al. (1997) performed a complete cutaneous evaluation on 32 consecutive patients with established diagnoses of MEN1. They observed multiple facial angiofibromas in 88%, collagenomas in 72%, cafe-au-lait macules in 38%, lipomas in 34%, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% of these individuals. Darling et al. (1997) noted that there is considerable overlap between the cutaneous findings in MEN1 and those in tuberous sclerosis (see 191100). However, facial angiofibromas in MEN1 tend to be smaller and fewer and to occur in different areas (upper lip and vermilion border) in comparison to those seen in tuberous sclerosis. Darling et al. (1997) suggested that these cutaneous findings may be helpful in presymptomatic diagnosis of MEN1 patients. Schussheim et al. (2001) reviewed new clinical features of MEN1. These included multiple facial angiofibromas, previously considered pathognomonic for tuberous sclerosis; these had been reported in approximately 90% of MEN1 patients, with 50% having 5 or more. MEN1-related angiofibromas differ from those associated with tuberous sclerosis in that they are smaller, fewer, and located on the upper lip and vermilion border of the lip, areas that appear to be spared in tuberous sclerosis patients. Collagenomas had also been identified in more than 70% of MEN1 cases. These lesions can be subtle, and diagnosis might require consultation and biopsy by a dermatologist. Lipomas, both cutaneous and visceral, had been described in up to one-third of MEN1 patients compared with 6% of controls. This moderately high prevalence of lipoma in the general population made it difficult to use this lesion as a marker for MEN1 disease. In contrast to pheochromocytoma in MEN2 (171400), pheochromocytoma occurring in association with MEN1 is rare. In all cases the tumors were unilateral, and it was malignant in only one patient. Leiomyomas had been observed in patients with MEN1. Adrenal cortical lesions were common in MEN1, occurring in up to 40% of patients. The majority of these tumors were bilateral, hyperplastic, and nonfunctional, and caused minimal morbidity; however, tumors that cause hypercortisolemia and hyperaldosteronism had been reported. Thyroid tumors, which include follicular adenomas, goiters, and carcinoma, had long been observed in more than 25% of MEN1 patients. Asgharian et al. (2004) prospectively assessed the frequency and sensitivity/specificity of various cutaneous criteria for MEN1 in 110 consecutive patients with gastrinomas with or without MEN1. All patients had hormonal and functional studies to determine MEN1 status, dermatologic evaluation, and tumor imaging studies. Combinations of the occurrence of angiofibromas, collagenomas, and lipomas were analyzed. The combination criterion of more than 3 angiofibromas or any collagenoma had the highest sensitivity (75%) and specificity (95%). Asgharian et al. (2004) concluded that this diagnostic criterion has greater sensitivity for MEN1 than pituitary or adrenal disease and has comparable sensitivity to hyperparathyroidism reported in some studies of patients with MEN1 with gastrinoma. Hao et al. (2004) examined 2 large kindreds with a MEN1 variant that were followed up for 20 to 30 years, with MEN1 tumors in 30 members. Cases from the 2 kindreds had parathyroid adenomas (93%), pituitary tumors (40%) (always prolactinoma), and enteropancreatic endocrine tumors (27%). The latter included insulinoma (10%) and nonfunctioning islet tumor (7%), but only 10% gastrinoma. Compared with prior large series, this lower prevalence of gastrinoma (10% vs 42%, p less than 0.01) and higher prevalence of prolactinoma (40% vs 22%, p less than 0.01) defined this variant. DNA showed no characteristic MEN1 mutation in these 2 kindreds. ### Reviews Wolfe and Jensen (1987) reviewed diagnosis and treatment of the Zollinger-Ellison syndrome. For a review of MEN1, see Thakker (1998). Guo and Sawicki (2001) reviewed the various clinical manifestations of MEN1 syndrome, potential mechanisms of MEN1 tumorigenesis, and mutations associated with MEN and sporadic endocrine tumors. Clinical Management Brandi et al. (2001) authored a consensus statement covering the diagnosis and management of MEN1 and MEN2, including important contrasts between them. The most common tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of enteropancreatic hormones, except insulin. The roles for surgery of most enteropancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. Biochemical Features Brandi et al. (1986) cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with type I MEN. Whereas normal plasma stimulated incorporation of labeled thymidine to the same extent as did plasma-free culture medium, the plasma from the patients increased mitogenic activity 2400% over the control value. Bovine parathyroid cells were stimulated to proliferation, whereas plasma from normal subjects inhibited proliferation of the bovine parathyroid cells. The mitogenic activity had an apparent molecular weight of 50,000 to 55,000. Inheritance MEN I is an autosomal dominant disorder. Chandrasekharappa et al. (1997) suggested that affected individuals inherit one altered copy of the MEN1 gene from an affected parent, but the tumors lose the remaining copy (the wildtype allele) as a somatic event. Thus, the inheritance pattern is autosomal dominant, but the mechanism of tumorigenesis is recessive. Mapping Bale et al. (1987, 1989) studied linkage with multiple markers in a single large kindred with MEN I. INT2 (164950), which is located at 11q13, was found to be closely linked to MEN1. In studies of 3 families, Thakker et al. (1989) established linkage with INT2; peak lod score = 3.30 at theta = 0.00. Larsson et al. (1988) mapped the MEN1 locus to chromosome 11 by demonstrating linkage to a DNA probe derived from the PYGM locus (608455), which, in turn, has been mapped to 11q13-qter. By comparing constitutional and tumor tissue genotypes of insulinomas from 2 brothers who had inherited the disorder from their mother, Larsson et al. (1988) demonstrated loss of the linked locus in tumor tissue. Tumors in both showed loss of 1 constitutional allele at all informative loci on chromosome 11. The informative markers extended from HRAS1, located at 11p15.5, to APOA1 (107680), located at 11q13. (Larsson et al. (1988) quoted a paper in press indicating that the APOA1 locus is in band q23.) In 3 families, the authors observed a total maximum lod score of 4.37 at theta = 0.00. Larsson et al. (1989) and Nordenskjold et al. (1989) both provided linkage data for markers at 11q13 with multiple endocrine neoplasia type I. Nakamura et al. (1989) identified 6 closely linked markers in the vicinity of 11q13 which are useful for identification of carriers in MEN I families. The target region containing the gene was narrowed to about 12 cM. Friedman et al. (1989) and Thakker et al. (1989) demonstrated loss of heterozygosity (LOH) for chromosome 11 alleles in parathyroid tumors from patients with MEN I. Friedman et al. (1989) found such loss in 10 of 16 tumors from 14 patients. In 7 of 10 tumors, the subregion of loss was less than the full length of chromosome 11 but always included 1 copy of the MEN I locus. Bale et al. (1989) studied the DNA from 66 tumors removed from patients with MEN I. They demonstrated allelic loss of chromosome 11 RFLPs in 10 of 16 parathyroid tumors from MEN I patients and in 9 of 34 sporadic parathyroid adenomas. The smallest consistent region of loss was between INT2 and D11S149. Bystrom et al. (1990) showed that the pathogenesis of MEN1-associated parathyroid lesions involves unmasking of a recessive mutation at the disease locus and that sporadic primary hyperparathyroidism shares the same mechanisms. By examination of allele losses in MEN1-associated lesions, they defined deletions of chromosome 11 and mapped the MEN1 locus to a small region within 11q13, telomeric to PYGM. Richard et al. (1991) created a high-resolution radiation hybrid map of the proximal long arm of chromosome 11 containing the MEN1 and BCL1 (168461) gene loci. By statistical analysis of the cosegregation of markers in radiation hybrids, they arrived at the following most likely order of loci: C1NH (606860)--OSBP (167040)--CD5 (153340)/CD20(112210)--PGA (169710)--FTH1 (134770)--COX8 (123870)--PYGM--SEA (165110)--KRN1 (148021)--HSTF1 (164980)/INT2--GST3 (134660)--PPP1A (176875). They suggested that the localization of the protooncogene SEA between PYGM and INT2, 2 markers that flank MEN1, makes SEA a potential candidate for the MEN1 locus. The positions of PPP1A and GST3 are such that neither is likely to be directly involved in CLL (151400) or MEN1. Fujimori et al. (1992) placed the MEN1 locus within an 8-cM region between D11S480 and D11S546. Larsson et al. (1992) found that 13 marker systems tested with 17 DNA probes were located within a region on chromosome 11 spanning a 14% meiotic recombination region, with the MEN1 locus in the middle: based on meiotic crossovers, 4 systems were on the telomeric side and 4 on the centromeric side of MEN1. The remaining 5 were closely linked to MEN1, with no crossovers in their set of 6 families including 59 affected persons. The calculated accuracy of prediction of MEN1 was more than 99.5% when 3 of the marker systems were informative. Sawicki et al. (1992) reported loss of heterozygosity on chromosome 11 in 5 of 11 sporadic gastrinomas. Four of these tumors had LOH for markers flanking the MEN1 region. LOH on chromosome 11 had previously been found in 3 types of tumors that occur in patients with the MEN I syndrome: sporadic pituitary adenomas, sporadic and familial parathyroid neoplasms, and pancreatic endocrine tumors including insulinoma, glucagonoma, vasointestinal peptide tumor, and nonfunctional tumors. Although gastrinomas account for the majority of both sporadic and familial pancreatic endocrine tumors, LOH had not previously been demonstrated for this form. Courseaux et al. (1996) used a combination of methods to refine maps of the approximately 5-Mb region of 11q13 that includes MEN1. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel. The location of MEN1 was narrowed to a 2-Mb region beginning centromeric to COX8 and extending to approximately CAPN1. Guru et al. (1997) mapped and sequenced the MEN1 genomic region. They produced a precisely ordered map of 33 transcribed genes within this 2-Mb region. The European Consortium on MEN1 (1997) constructed a 1.2-Mb sequence-ready contig encompassing the MEN1 region. They described 3 gene clusters, including the central cluster which contains the MEN1 gene. From a comparative mapping analysis of 10q and the pericentric region of 11q in the human and mouse chromosome 19, Rochelle et al. (1992) concluded that the murine homolog of the MEN1 locus may lie in the proximal segment of chromosome 19. By FISH, Guru et al. (1999) mapped the mouse Men1 gene to chromosome 19 in a region showing homology of synteny to human chromosome 11q13. Molecular Genetics Chandrasekharappa et al. (1997) identified several MEN1 candidate genes in a previously identified minimal interval on 11q13. Chandrasekharappa et al. (1997) identified mutations in one of these genes, designated MEN1, in 14 probands from 15 families. Twelve different heterozygous mutations (613733.0001-613733.0012) were identified (5 frameshift, 3 nonsense, 2 missense, and 2 in-frame deletions). Most of the mutations predicted loss of function of the protein, consistent with a tumor suppressor mechanism. Lemmens et al. (1997) independently identified the MEN1 gene, which they had designated SCG2, and found 9 different heterozygous mutations in 10 unrelated MEN1 families. Agarwal et al. (1997) extended their mutation analysis to 34 more unrelated familial MEN1 probands (to a total of 50 kindreds) and to 2 related disorders, sporadic MEN1 and familial hyperparathyroidism (145000). In 8 of 11 cases of sporadic MEN1, they found heterozygous germline MEN1 mutations (e.g., 613733.0014); such mutations were found in 47 of 50 familial MEN1 probands. They proved that the mutation was new in 1 case of sporadic MEN1. Among the familial MEN1 cases, 8 mutations were observed more than once. In all, 40 different mutations (32 familial and 8 sporadic) were distributed across the MEN1 gene. A predicted loss of function of the encoded menin protein supported the prediction that MEN1 is a tumor suppressor gene. No MEN1 germline mutations were found in 5 probands with familial hyperparathyroidism, suggesting that this disorder is often caused by mutation in another gene. In affected members of the 4 families with MEN1 from the Burin peninsula in Newfoundland, who were previously described by Farid et al. (1980) and Bear et al. (1985), Olufemi et al. (1998) identified a mutation in the MEN1 gene (613733.0016). Bassett et al. (1998) investigated 63 unrelated MEN1 kindreds (195 affected and 396 unaffected members) for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. They identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice site mutation, and 6 missense mutations) that were scattered throughout the coding region, together with 6 polymorphisms that had heterozygosity frequencies of 2 to 44%. More than 10% of the mutations arose de novo, and 4 mutation hotspots accounted for more than 25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected more than 85% of the mutations. MEN1 mutant-gene carrier status was detected in 201 individuals (155 affected and 46 unaffected). By analysis of these cases, they defined the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. The number of disease alleles and the frequent occurrence of de novo mutations, often at hotspots with short repeat sequences, suggested that haplotype analysis is of limited use for the diagnosis of MEN1. Tanaka et al. (1998) studied germline mutations of the MEN1 gene in 5 cases of familial and 4 cases of sporadic multiple endocrine neoplasia type I, 6 cases in 3 independent pedigrees of familial pituitary adenoma without MEN1, and 3 cases of familial primary hyperparathyroidism in Japanese patients. Eight different types of germline mutations in all 9 MEN1 cases were distributed in exons 2, 3, 7, and 10 and intron 7 of the MEN1 gene. Loss of heterozygosity (LOH) on 11q13 was detected in all 9 tumors of the cases with microsatellite analysis. No germline mutation of the MEN1 gene was detected in 3 pedigrees of familial pituitary adenoma and 3 cases of familial primary hyperparathyroidism. LOH on 11q13 was detected in 2 cases in 1 pedigree of familial pituitary adenoma, and 1 of them showed a heterozygous somatic mutation of the MEN1 gene. No LOH on 11q13 was detected in 3 cases of familial primary hyperparathyroidism. The authors concluded that the loss of function of MEN1 causes familial or sporadic MEN1, but does not cause familial primary hyperparathyroidism or most familial pituitary adenoma without MEN1. Both alleles of the MEN1 gene at 11q13 are mutated in the majority of MEN1 tumors. Hessman et al. (2001) performed a genomewide LOH screening of 23 pancreatic lesions, 1 duodenal tumor, and 1 thymic carcinoid from 13 MEN1 patients. Multiple allelic deletions were found. Fractional allelic loss varied from 6 to 75% (mean 31%). All pancreatic tumors displayed LOH on chromosome 11, whereas the frequency of losses for chromosomes 3, 6, 8, 10, 18, and 21 was over 30%. Different lesions from individual patients had discrepant patterns of LOH. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells, whereas other chromosomal loci were deleted in portions of the analyzed tumor. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. Fractional allelic loss did not correlate to malignancy or to tumor size. The authors concluded that MEN1 pancreatic tumors fail to maintain DNA integrity and demonstrate signs of chromosomal instability. Lipomatous tumors are known to occur in a relatively high proportion of patients with MEN1. By fluorescence in situ hybridization analysis of lipomas from 2 patients with MEN1, Vortmeyer et al. (1998) demonstrated deletion of 1 MEN1 allele in 53% of cells examined from case 1 and in 63% of cells examined from case 2. In both cases, both MEN1 gene copies were visualized in normal cellular constituents. Giraud et al. (1998) studied a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors. They screened for MEN1 germline mutations by heteroduplex and sequence analysis of the gene-coding region of the MEN1 gene and its untranslated exon 1. Germline MEN1 alterations were identified in 47 of 54 (87%) MEN1 families, in 9 of 11 (82%) isolated MEN1 patients, and in only 6 of 19 (31.5%) atypical MEN1-related inherited cases. They characterized 52 distinct mutations in a total of 62 MEN1 germline alterations. Truncating mutations, frameshifts and nonsense mutations, accounted for 35 of the 52 alterations. No genotype/phenotype correlation could be made. Age-related penetrance was estimated to be more than 95% over age 30 years. No MEN1 germline mutations were found in 7 of 54 (13%) MEN1 families. Teh et al. (1998) performed MEN1 mutation analysis in 55 MEN1 families from 7 countries, 13 isolated MEN1 cases without family history of the disease, 8 acromegaly families, and 4 familial isolated hyperparathyroidism (FIHP) families. Mutations were identified in samples from 27 MEN1 families and 9 isolated cases. The 22 different mutations were distributed across most of the 9 translated exons and included 11 frameshift, 6 nonsense, 2 splice site, and 2 missense mutations, and 1 in-frame deletion. Among the 19 Finnish MEN1 probands, a 1466del12 (613733.0032) mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases, indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was identified in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common 'warm' spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case, 1 mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved, and that additional families of these types need to be analyzed. Sato et al. (1998) studied 8 unrelated Japanese families. These included 5 with familial MEN1, 2 with sporadic MEN1, and 1 with familial hyperparathyroidism. Six different mutations were identified, including 1 missense mutation, 3 deletions, and 2 nonsense mutations. In 1 proband with familial MEN1, no mutation was identified. In Spain, Cebrian et al. (1999) studied 10 unrelated MEN1 kindreds by a complete sequencing analysis of the entire MEN1 gene. Mutations were identified in 9 of them: 5 deletions, 1 insertion, 2 nonsense mutations, and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations had been described; the other 7 were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype. The observation of LOH involving 11q13 in MEN1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the '2-hit' model of hereditary cancer. The second hit in MEN1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur. Pannett and Thakker (2001) searched for other mechanisms, such as intragenic deletions or point mutations that inactivate the MEN1 gene, in 6 MEN1 tumors (4 parathyroid tumors, 1 insulinoma, and 1 lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883, and PYGM centromerically and D11S449 and D11S913 telomerically. They found 4 somatic mutations, which consisted of 2 missense mutations and 2 frameshift mutations, in 2 parathyroid tumors, 1 insulinoma, and 1 lipoma. The authors concluded that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by the Knudson '2-hit' hypothesis. Perren et al. (2007) hypothesized that monohormonal endocrine cell clusters observed in MEN1 patients are small neoplasms with loss of heterozygosity of the MEN1 locus. Loss of one MEN1 allele was found in all 27 microadenomas and 19 of 20 (95%) monohormonal endocrine cell clusters. By contrast, it was absent in islets and ductal or acinar structures. Perren et al. (2007) concluded that the frequent presence of single nonneoplastic insulin cells in microadenomas and the occurrence of microadenomas in islets suggest an islet origin of microadenomas. Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development. By exhaustive sequence analysis of probands belonging to 170 unrelated MEN1 families collected through a French clinical network, Wautot et al. (2002) identified 165 mutations located in coding parts of the MEN1 gene, which represented 114 distinct MEN1 germline alterations. The mutations, which were spread over the entire coding sequence, included 56 frameshifts, 23 nonsense, 27 missense, and 8 deletion or insertion in-frame mutations. These mutations were included in a MEN1 locus-specific database available on the Internet together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Taken together, most missense and in-frame MEN1 genomic alterations affected 1 or all domains of menin interacting with JUND (165162), SMAD3, and nuclear factor kappa-B (NFKB1; 164011), 3 major effectors in transcription and cell growth regulation. No correlation was observed between genotype and MEN1 phenotype. Turner et al. (2002) ascertained 34 unrelated MEN1 probands and performed DNA sequence analysis. They identified 17 different mutations in 24 probands: 2 nonsense, 2 missense, 2 in-frame deletions, 5 frameshift deletions, 1 frameshift deletion-insertion, 3 frameshift insertions, 1 donor splice site mutation, and a G-to-A transition that resulted in a novel acceptor splice site in IVS4 (613733.0024). The IVS4 mutation was found in 7 unrelated families, and the tumors in these families varied considerably, indicating a lack of genotype-phenotype correlation. However, this IVS4 mutation is the most frequently occurring germline MEN1 mutation, accounting for approximately 10% of all mutations, and together with 5 others at codons 83-84, 118-119 (613733.0025), 209-211 (613733.0026), 418 (613733.0027), and 516 (613733.0028) accounts for 36.6% of all mutations. In 3 members of a Japanese family with MEN1 and a predisposition to insulinoma, Okamoto et al. (2002) identified a heterozygous germline mutation in exon 4 of the MEN1 gene (613733.0030). Chi square analysis of 72 MEN1 patients with or without germline mutations in exon 4 and with or without insulinomas showed a significant difference (p = 0.0022), suggesting a possible correlation between insulinoma development and mutations in exon 4 where JunD binding occurs. Park et al. (2003) investigated 5 Korean families with MEN1, 1 family with familial isolated hyperparathyroidism and 1 family with familial pituitary adenoma. Four germline mutations were identified in 5 typical MEN1 families. All of these mutations led to truncated proteins or a change in the amino acids of the functional domains. No MEN1 germline mutations were detected in the 2 families with FIHP or familial pituitary adenoma. Using church records and MEN1 family information for the 2 founder MEN1 mutations in Northern Finland, 1466del12 (613733.0032) and 1657insC (613733.0033), Ebeling et al. (2004) traced back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and found 67 probable carriers born between 1728 and 1929, among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age of death of affected males was 61.1 years versus 65.8 years for unaffected males, and for affected females was 67.2 years versus 67.7 years for unaffected females. The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex matched life expectancy estimates derived from Finnish national statistics. The authors concluded that obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 years. Lemos and Thakker (2008) provided a detailed review of the clinical aspects and molecular genetics of MEN1. The majority of the 1,336 mutations reported to date are predicted to result in truncated forms of menin and are scattered throughout the gene. There were no apparent genotype/phenotype correlations. ### Familial Primary Isolated Hyperparathyroidism, MEN1 Variant In a Caucasian English family in which 7 family members from 2 generations had primary isolated hyperparathyroidism (see 145000), Teh et al. (1998) found that affected members had a germline missense mutation in the MEN1 gene (613733.0020). This appeared to be the first study to demonstrate that familial isolated primary hyperparathyroidism can occur as a variant of MEN1. The pattern of transmission was autosomal dominant with high penetrance. Clinically, the hyperparathyroidism ran a rather mild course, as evidenced by 2 affected subjects who declined surgery and yet developed no obvious complications. Pathologically, the multiglandular parathyroid disease was consistent with that of MEN1. In 2 individuals, Teh et al. (1998) demonstrated loss of heterozygosity (LOH) in the parathyroid tumors, consistent with the Knudson 2-hit model. In a 61-year-old Japanese woman and 2 of her sons, aged 38 and 33 years, all with hyperparathyroidism due to parathyroid adenomas. Fujimori et al. (1998) identified a missense mutation in the MEN1 gene (613733.0021). Warner et al. (2004) screened 22 unrelated patients with FIHP for mutations in the MEN1, CASR (601199) and HRPT2 (CDC73; 607393) genes. They identified 5 patients with MEN1 mutations, 4 with CASR mutations, and none with HRPT2 mutations. All 9 patients in whom mutations were found had multiglandular hyperparathyroidism. The patients with CASR mutations did not have biochemical findings of hypocalciuric hypercalcemia. Warner et al. (2004) recommended MEN1 and CASR genotyping in patients with multiglandular FIHP, regardless of urinary calcium excretion. ### MEN1 Somatic Mutations Heppner et al. (1997) found somatic mutation of the MEN1 gene in 21% of parathyroid tumors not associated with MEN1, representing 54% of parathyroid tumors with 11q13 LOH. The authors suggested that parathyroid tumor formation in kindreds with somatic mutation of MEN1 may be initiated by germline mutation of an unidentified tumor suppressor gene or oncogene. The finding of somatic mutation (613733.0013) in a single tumor from a member of such a kindred indicated that somatic MEN1 gene mutation may also contribute to tumorigenesis in such individuals. Previous studies had found frequent 11q13 LOH in sporadic tumors as follows: gastrinoma (45%), insulinoma (19%), anterior pituitary gland tumors (3 to 30%), carcinoid tumors (78%), thyroid follicular tumors (15%), and aldosteronomas (36%). Heppner et al. (1997) suggested that many of these tumors likewise may have MEN1 somatic mutations. Carling et al. (1998) used microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons to study the MEN1 gene in 49 parathyroid lesions of patients with nonfamilial primary hyperparathyroidism. Allelic loss at 11q13 was detected in 13 tumors, 6 of which had previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of these mutations were predicted to encode a nonfunctional menin protein, consistent with a tumor suppressor mechanism. While the clinical and biochemical characteristics of hyperparathyroidism were apparently unrelated to LOH at 11q13 and the MEN1 gene mutations, the demonstration of LOH and MEN1 gene mutations in small parathyroid adenomas of patients who had slight hypercalcemia and normal serum parathyroid hormone (168450) levels suggested that altered MEN1 gene function may also be important for the development of mild sporadic primary hyperparathyroidism. Farnebo et al. (1998) screened 45 sporadic tumors from 40 patients for alterations involving the MEN1 gene. Thirteen tumors showed LOH at 11q13, and in 6 of these cases, a somatic mutation of the MEN1 gene was detected. In tumors without LOH, no mutations were detected. The mutations consisted of 3 small deletions, 1 insertion, and 2 missense mutations that had not been reported in MEN1 patients or parathyroid tumors previously. Using mRNA in situ hybridization, the expression of the MEN1 gene was studied. The authors concluded that there was no difference in MEN1 expression between normal and tumor tissue, and that their findings of inactivating mutations in tumors with LOH at 11q13 confirmed the role of the MEN1 tumor suppressor gene in a subset of sporadic parathyroid tumors. By comparative genomic hybridization, Farnebo et al. (1999) screened DNAs from 44 parathyroid tumors from 26 sporadic cases, 10 cases previously given irradiation to the neck, and 8 familial cases for sequence copy number alterations. In the sporadic adenomas, commonly occurring minimal regions of loss could be defined to chromosome 11 (38%), 15q15-qter (27%), and 1p34-pter (19%), whereas gains preferentially involved 19p13.2-pter (15%) and 7pter-qter (12%). Multiple aberrations were found in sporadic tumors with a somatic mutation and/or LOH of the MEN1 gene. The irradiation-associated tumors also showed multiple comparative genomic hybridization alterations and frequent losses of 11q (50%), and subsequent analysis of the MEN1 gene demonstrated mutations in 4 of 8 cases (50%). The majority of these alterations were found in tumors with confirmed involvement of the MEN1 gene, in agreement with a role of the MEN1 gene in genomic stability. The authors concluded that the frequent occurrence of MEN1 mutations in irradiation-associated parathyroid tumors suggests that inactivation of the MEN1 gene is an important genetic alteration involved in the development of parathyroid tumors in post-irradiation patients. Prezant et al. (1998) screened the complete coding sequence of the MEN1 gene for mutations in 45 sporadic anterior pituitary tumors, including 14 hormone-secreting tumors and 31 nonsecreting tumors, by dideoxy fingerprinting and sequence analysis. No pathogenic sequence changes were found in the MEN1 coding region. The MEN1 gene was expressed in 43 of these tumors with sufficient RNA, including 1 tumor with LOH for several polymorphic markers on chromosomal region 11q13. Also, both alleles were expressed in 19 tumors in which the constitutional DNA was heterozygous for intragenic polymorphisms. The authors concluded that inactivation of the MEN1 tumor suppressor gene, by mutation or by imprinting, does not appear to play a prominent role in sporadic pituitary adenoma pathogenesis. Heppner et al. (1999) studied whether somatic inactivation of the MEN1 gene contributes to the pathogenesis of sporadic adrenocortical neoplasms. Thirty-three tumors and cell lines were screened for mutations throughout the MEN1 open reading frame and adjacent splice junctions. No mutations were detected within the MEN1 coding region. The authors concluded that somatic mutations within the MEN1 coding region do not occur commonly in sporadic adrenocortical tumors, although the majority of adrenocortical carcinomas exhibited 11q13 LOH. To investigate the role of the MEN1 gene in sporadic lipomas, Vortmeyer et al. (1998) analyzed 6 sporadic tumors. In 1 case, SSCP analysis and subsequent sequencing revealed a 4-bp deletion in exon 2 (613733.0017). This deletion was present only in the tumor tissue, and not in the normal tissue from the same patient. To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, Kjellman et al. (1999) screened a panel of 60 tumors (39 carcinomas and 21 adenomas) for loss of heterozygosity. The vast majority of LOH detected was in the carcinomas involving chromosomes 2, 4, 11, and 18; little was found in the adenomas. The Carney complex (160980) and the MEN1 loci on 2p16 and 11q13, respectively, were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-cM region that is separate from the Carney complex locus. LOH for PYGM was detected in all 8 informative carcinomas and in 2 of 14 adenomas. Of the cases analyzed in detail, 13 of 27 (11 carcinomas and 2 adenomas) showed LOH on chromosome 11, and these were selected for MEN1 mutation analysis. In 6 cases a common polymorphism was found, but no mutation was detected. The authors concluded that LOH in 2p16 was strongly associated with the malignant phenotype, and LOH in 11q13 occurred frequently in carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome. Hibernomas are benign tumors of brown fat, frequently characterized by aberrations of chromosome band 11q13. Gisselsson et al. (1999) analyzed chromosome 11 changes in 5 hibernomas in detail by metaphase fluorescence in situ hybridization. In all cases, complex rearrangements leading to loss of chromosome 11 material were found. Deletions were present not only in those chromosomes that were shown to be rearranged by G-banding, but in 4 cases also in the ostensibly normal homologs, resulting in homozygous loss of several loci. Among these, the MEN1 gene was most frequently deleted. In addition to the MEN1 deletions, heterozygous loss of a second region, approximately 3 Mb distal to MEN1, was found in all 5 cases, adding to previous evidence for a second tumor suppressor locus in 11q13. Tahara et al. (2000) analyzed 81 parathyroid glands from 22 Japanese uremic patients for allelic loss on chromosomal arm 11q13 DNA using 3 flanking markers (PYGM, 608455; D11S4946; and D11S449), and for mutations of the MEN1-coding exons by PCR-based SSCP analysis and sequencing. Allelic loss on 11q13 was observed in 6 glands (7%), and 1 of 6 demonstrated a previously unrecognized somatic frameshift deletion in MEN1. They inferred that this mutation would result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and pathologic characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations. The authors concluded that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited. Sato et al. (2001) reported a male patient with adult-onset, hypophosphatemic osteomalacia who had been treated with 1-alpha-hydroxyvitamin D3 and oral phosphate for 13 years when tertiary hyperparathyroidism developed. Sequence analysis of the coding exons of the MEN1 gene revealed somatic MEN1 mutations in 2 of the 4 hyperplastic parathyroid glands, accompanied by loss of heterozygosity at the 11q13 locus in 1 gland. These findings suggested that the repeated increase in serum phosphate concentrations for a prolonged period may be related to tumorigenesis of the parathyroid gland. Animal Model Chedid et al. (1988) described hereditary pituitary prolactinomas in the rat. It was thought to be an autosomal dominant characteristic with incomplete penetrance and a greater incidence in males. To examine the role of MEN1 in tumor formation, Crabtree et al. (2001) generated a mouse model through homologous recombination of the mouse homolog Men1. Homozygous null mice died in utero at embryonic days 11.5 to 12.5, whereas heterozygous mice developed features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets showed a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas were frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary were seen by 16 months. All of the tumors tested showed loss of the wildtype Men1 allele, further supporting the role of MEN1 as a tumor suppressor gene. Most tumor suppressor genes show a widespread pattern of expression, yet individuals with germline, heterozygous loss of function of such genes develop tumors in a restricted set of tissues. To investigate the paradox of tissue-specific tumor phenotype in MEN1, Scacheri et al. (2004) bred mice homozygous for an Men1 gene with exons 3-8 flanked by loxP sites to transgenic mice expressing cre from the albumin promoter. This strategy allowed them to generate mice with homozygous deletion of the Men1 gene in liver, a tissue not normally predisposed to developing tumors in humans or mice with heterozygous MEN1 loss-of-function mutations. Livers that were completely null for menin expression appeared entirely normal and remained tumor free until late adulthood. These results narrowed the possible mechanisms of tissue specificity in MEN1. Busygina et al. (2004) generated a null allele of Mnn1, the Drosophila homolog of the MEN1 gene, and showed that homozygous inactivation resulted in morphologically normal flies that are hypersensitive to ionizing radiation and 2 DNA crosslinking agents (nitrogen mustard and cisplatinum). The spectrum of agents to which mutant flies were sensitive and analysis of the molecular mechanisms of this sensitivity suggested a defect in nucleotide excision repair. Drosophila Mnn1 mutants had an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats (LATS1; 603473), which is a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. Busygina et al. (2004) concluded that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA1 (113705) and MSH2 (609309) genes. History Wermer first reported 'his' syndrome in 1954, and Zollinger and Ellison 'theirs' in 1955 (see Wermer, 1954; Zollinger and Ellison, 1955). The Zollinger-Ellison syndrome of intractable peptic ulcer with pancreatic islet adenoma is a facet of multiple endocrine adenomatosis. Recognition that the 2 eponymic syndromes are one subsequently occurred (Lulu et al., 1968), with multiple endocrine neoplasia type I (MEN1) as the preferred designation. On the basis of studies of 8 affected members of a family, Vance et al. (1972) suggested that the primary genetic lesion in endocrine adenomatosis is one that leads to neoplasia and hyperfunction of the islets of Langerhans and that the other endocrine tumors arise as secondary effects of hypersecretion of islet hormones. Brandi et al. (1986) concluded that primary hyperparathyroidism in familial MEN type I may have a humoral cause. Since the mitogenic factor persists after parathyroidectomy, it evidently is not secreted by the hyperplastic glands themselves. It did not seem to be identical to any of the well-recognized circulating growth factors, nor did it have similar mitogenic effects on pancreatic or pituitary cells in vitro, despite the presence of islet cell and pituitary tumors in some of the same patients. Curiously, Brandi et al. (1986) did not detect a parathyroid mitogenic factor in patients with MEN II who also had hyperparathyroidism. Schimke (1986) suggested: 'Considered within the framework of a 2-step model, the general event in the multiple endocrine neoplasia syndromes may be an abnormality of a plasma-membrane receptor in the affected endocrine glands. The somatic mutation may involve derepression of a primitive gene coding for a protein that promotes the growth of endocrine glands.' The 'primitive gene' might be an oncogene. This would represent a rather different 2-mutation theory than the one that applies to retinoblastoma (180200) and Wilms tumor (194070). In this case the mutations are presumably at different loci. INHERITANCE \- Autosomal dominant ABDOMEN Gastrointestinal \- Intractable peptic ulcer \- Diarrhea \- Zollinger-Ellison syndrome \- Esophagitis SKIN, NAILS, & HAIR Skin \- Subcutaneous lipomas \- Facial angiofibromas \- Collagenomas \- Cafe-au-lait macules \- Confetti-like hypopigmented macules \- Multiple gingival papules ENDOCRINE FEATURES \- Pancreatic islet cell adenoma \- Parathyroid adenoma \- Pituitary adenoma \- Adrenocortical adenomas \- Cushing syndrome \- Prolactinoma \- Glucagonoma \- Insulinoma \- Vasointestinal peptide tumor \- Gastrinoma \- Acromegaly \- Thyroid disease NEOPLASIA \- Carcinoid tumors LABORATORY ABNORMALITIES \- Elevated ACTH \- Abnormal secretin test \- Elevated gastrin concentration \- Hypercalcemia \- Hypoglycemia \- Elevated PTH (parathyroid hormone) MOLECULAR BASIS \- Caused by mutations in the menin gene (MEN1, 131100.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	MULTIPLE ENDOCRINE NEOPLASIA, TYPE I	c0025267	4,319	omim	https://www.omim.org/entry/131100	2019-09-22T16:41:45	{"doid": ["10017"], "mesh": ["D018761"], "omim": ["131100"], "icd-9": ["258.01"], "icd-10": ["E31.21"], "orphanet": ["652"], "synonyms": ["Alternative titles", "MEN I", "ENDOCRINE ADENOMATOSIS, MULTIPLE", "MEA I", "WERMER SYNDROME"], "genereviews": ["NBK1538"]}
This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (April 2016) (Learn how and when to remove this template message) Post-schizophrenic depression SpecialtyPsychiatry Post-schizophrenic depression is a "depressive episode arising in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms may still be present."[1] Someone that suffers from post-schizophrenic depression experiences both symptoms of depression and can also continue showing mild symptoms of schizophrenia. Unfortunately, depression is a common symptom found in patients with schizophrenia and can fly under the radar for years before others become aware of its presence in a patient.[1] However, very little research has been done on the subject, meaning there are few answers to how it should be systematically diagnosed, treated, or what course the illness will take.[2] Some scientists would entirely deny the existence of post-schizophrenic depression, insisting it is a phase in schizophrenia as a whole. As of late, post-schizophrenic depression has become officially recognized as a syndrome and is considered a sub-type of schizophrenia. ## Contents * 1 Symptoms * 2 Causes * 3 Suicide * 4 Treatment * 5 References * 6 External links ## Symptoms[edit] Because the nature of acute schizophrenia is similar to depression, it is difficult to differentiate normal levels of depression in patients with schizophrenia from depressive levels in post-schizophrenic depression. "Prominent subjectively low mood, suggesting depression, and prominent blunting of affect, suggesting negative symptoms, are the two features which are most helpful in differentiating [schizophrenia and depression]."[1] A number of researchers believe that depression is actually a symptom of schizophrenia that has been hidden by the psychosis.[3] However, symptoms usually arise after the first psychotic episodes if they will arise at all.[4] Officially, diagnosing post-schizophrenia depression in a patient requires for the patient to be experiencing a depressive episode of either short or long term following the overcoming of schizophrenia. The patient must still demonstrate some schizophrenic symptoms but those symptoms must no longer be the focus of the illness. Typically, the depressive symptoms are not severe enough to be classified as a severe depressive episode.[5] Formally, diagnosis entails the patient having had schizophrenia within the past year, a number of schizophrenic symptoms, and depression being present for two weeks or more.[5] Mild schizophrenic signs may be withdrawing socially, agitation or hostility, and irregular sleep such as in the case of insomnia and hypersomnia. ## Causes[edit] There is no clear cause to how certain patients with schizophrenia develop post-schizophrenic depression while others may surpass this stage. However, there are a few theories as to possible causes. Those suffering from post-schizophrenic depression often suffer from social isolation due to their illness, which may increase depression levels.[6] There is strong evidence of stigma-related isolation against those suffering from mental illnesses in a variety of societies, especially those with schizophrenia as they are often viewed as dangerous and unpredictable.[6] Because of this isolation and studies linking social isolation and depression, it is possible that patients under these stigmas eventually develop post-schizophrenic depression.[7] Depression in patients with schizophrenia may also be caused by substance abuse, which is fairly common among those suffering from schizophrenia, as depressants such as alcohol and cannabis can relax the patient.[8] Furthermore, with what little information is currently known about post-schizophrenic depression, the onset may be caused by not giving patients with schizophrenia antipsychotic medications.[9] After being taken off of antipsychotic medication, schizophrenic patients' antidepressant medication had to be increased, while those under antipsychotic medication reported suffering fewer depressive symptoms, further giving reason to believe that a lack of antipsychotic medication in earlier stages of schizophrenia may lead to post-schizophrenic depression.[10] However, some psychology professionals still push for the reduction of neuroleptic drugs, as there is a popular belief that post-schizophrenic depression is caused by neuroleptic treatment.[3] Therapists are also believed to engage the depression in people with schizophrenia, having given too much psychotherapy after the patient had overcome their schizophrenic symptoms.[3] Schizophrenia itself should not be overlooked as a key player in causing post-schizophrenic depression, though. A study done over a two-year time period shadowing patients with schizophrenia and monitoring their depression was unable to locate possible triggers such as the ones previously listed, so it is possible the nature of schizophrenia itself is the primary cause of post-schizophrenic depression.[11] ## Suicide[edit] Those suffering from post-schizophrenic depression are also commonly at risk for suicidal tendencies.[1] There is a trend correlated between suicide and post-schizophrenic depression according to Mulholland and Cooper's research in "The Symptoms of Depression in Schizophrenia and its Management." Furthermore, depression and schizophrenia have both been studied individually to try to determine if there is a correlation, and research has indicated that there is a very strong tendency for people with depression or schizophrenia to attempt suicide.[12] Statistically, out of all patients suffering from schizophrenia, "10%...commit suicide. Depressed patients with schizophrenia are at a particularly high risk for suicide the first few months after diagnosis and after hospital discharge."[13] Risk factors increasing the chance of suicide are, from highest to lowest, previous depressive orders, previous suicide attempts, drug abuse, and several other factors.[14] Surprisingly, the suicide risk actually decreased with the presence of hallucinations.[14] The ICD-10 Classification of Mental and Behavioural Disorders officially recognizes suicide as being a prominent aspect of post-schizophrenic depression. Because of this drastic increase in suicide, it can be difficult to study post-schizophrenic depression as many of its victims tragically take their own lives. ## Treatment[edit] For a number of years, scholars debated amongst themselves whether or not antipsychotic drugs had a tendency to increase depression or simply help the patient manage their mental illness. However, conclusive evidence points to antipsychotic drugs actually helping patients with their depression while simultaneously assisting in the suppression of schizophrenic episodes.[10] Specifically risperidone, olanzapine, quetiapine, fluphenazine, haloperidol, and L-sulpiride have done the best in drug trials pertaining to people with schizophrenia.[13] Along with antipsychotic drugs, post-schizophrenic patients may receive antidepressants to actively treat the depression.[4] Drugs are certainly not the only answer, though. At the base of both depression and schizophrenia, social withdrawal is a shared symptom between the two. People suffering from schizophrenia require a strong support system to be healthy, just as is the case with the rest the human population. The opportunity to become a working citizen is another way to ward off depression in patients with schizophrenia, helping them create social ties and a feeling of accomplishment.[1] ## References[edit] 1. ^ a b c d e Mulholland, Ciaran; Cooper, Stephen (1 May 2000). "The symptoms of depression in schizophrenia and its management". Advances in Psychiatric Treatment. 6 (3): 169–177. doi:10.1192/apt.6.3.169. 2. ^ Jeczmien, P; Levkovitz, Y; Weizman, A; Carmel, Z (August 2001). "Post-psychotic depression in schizophrenia". The Israel Medical Association Journal. 3 (8): 589–92. PMID 11519384. 3. ^ a b c "Post-schizophrenic depression". Annales Médico-Psychologiques. Jun 1975. 4. ^ a b Ivanets, NN; Kinkul'kina, MA (2008). "Depression in schizophrenia". Vestnik Rossiiskoi Akademii Medistinskikh Nauk (10): 55–63. PMID 19140400. 5. ^ a b The ICD-10 Classification of Mental and Behavioural Disorders. World Health Organization. 6. ^ a b Nordt, C.; Rossler, W.; Lauber, C. (2006). "Attitudes of mental health professionals toward people with schizophrenia and major depression". Schizophrenia Bulletin. 32 (4): 709–714. doi:10.1093/schbul/sbj065. PMC 2632277. PMID 16510695. 7. ^ Crisp, Arthur H.; Gelder, Michael G.; Rix, Susannah; Meltzer, Howard I.; Rowlands, Olwen J. (July 2000). "Stigmatisation of people with mental illnesses". The British Journal of Psychiatry. 177: 4–7. doi:10.1192/bjp.177.1.4. PMID 10945080. 8. ^ Mauri, MC; Volonteri, LS; De Gaspari, IF; Colasanti, A; Brambilla, MA; Cerruti, L (2006). "Substance abuse in first-episode schizophrenic patients: A retrospective study". Clinical Practice and Epidemiology in Mental Health. 2: 4. doi:10.1186/1745-0179-2-4. PMC 1435752. PMID 16556300. 9. ^ "Outpatient maintenance of chronic schizophrenic patients with long-term fluphenazine: double-blind placebo trial". British Medical Journal. 1973. 10. ^ a b "Dysphoric and depressive symptoms in chronic schizophrenia". Schizophrenia Research. 1989. 11. ^ Johnson, D. (1981). "Studies of depressive symptoms in schizophrenia". British Journal of Psychiatry. 139 (2): 89–101. doi:10.1192/bjp.139.2.89. PMID 7030447. 12. ^ Schwartz-Stav, Osnat (7 April 2006). "Depressive, suicidal behaviour and insight in adolescents with schizophrenia". European Child & Adolescent Psychiatry. 15 (6): 352–359. doi:10.1007/s00787-006-0541-8. PMID 16604378. 13. ^ a b Samuel, Siris (August 2012). "Treating 'depression' in patients with schizophrenia". Current Psychiatry. 14. ^ a b Hawton, Keith; Sutton, Lesley; Haw, Camilla; Sinclair, Julia; Deeks, Jonathan J. (June 2005). "Schizophrenia and suicide: systematic review of risk factors". The British Journal of Psychiatry. 187: 9–20. doi:10.1192/bjp.187.1.9. PMID 15994566. ## External links[edit] Classification D * ICD-10: F20.4 * ICD-10-CM: F32.89 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Post-schizophrenic depression	c0338808	4,320	wikipedia	https://en.wikipedia.org/wiki/Post-schizophrenic_depression	2021-01-18T18:31:23	{"icd-10": ["F20.4"], "wikidata": ["Q3208285"]}
A common discoloration of tissue in the mouth Amalgam tattoo Other namesLocalized argyrosis,[1] focal argyrosis[2][nb 1] Amalgam tattoo in upper labial sulcus in an edentulous individual, left behind after teeth have been lost/extracted SpecialtyDentistry Amalgam tattoo is a grey, blue or black area of discoloration on the mucous membranes of the mouth, typically on the gums of the lower jaw. It is a healthcare caused lesion, due to entry of dental amalgam into the soft tissues. It is common, painless, and benign, but it can be mistaken for melanoma. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 Notes * 8 References * 9 External links ## Signs and symptoms[edit] Granular deposits of silver sulfide along elastic fibers of the connective tissue of the oral mucosa. Low chronic inflammatory changes in the form of a lymphocytic aggregate (bottom right) Silver sulfide deposits are found in proximity to small vessels in the oral mucosa Silver sulfide deposits in the surrounding area of skeletal muscle fibers of the oral mucosa Amalgam tattoo usually occurs on the mandibular gingiva, often in an area in which an apicoectomy ("root-end filling") with amalgam was carried out.[3]:138 After the gingiva, the alveolar mucosa and the buccal mucosa are the next most common sites, although any mucosal site in the mouth is possible.[1] It is painless, and appears as a blue-black or grey discolored macule on the surface of the mucosa.[3]:138[4]:330[5]:183 The borders of the tattoo are variable, and may be well defined, irregular or diffuse.[1] ## Causes[edit] Amalgam tattoo is caused by implantation of amalgam into the tissues.[5]:183 It may occur in several ways: * During placement of an amalgam filling,[5]:183 e.g. if abrasions on the mucosa are present which allow entry of amalgam dust[1] * Shortly after placement of an amalgam filling, e.g. amalgam particles can contaminate dental floss and lead to linear amalgam tattoos in between the teeth, especially if flossing is carried out immediately after placement of an amalgam filling with a mesial or distal aspect[1] * Polishing of an amalgam filling * The pressure from high speed turbine dental drills can be enough to force amalgam particles into soft tissue,[1] as may occur when an old amalgam filling is being removed * When a tooth with an amalgam filling is extracted,[5]:183 e.g. broken bits of amalgam filling falling into an extraction socket unnoticed[1] * When an amalgam filling is placed in the same appointment as a tooth extracted, as may occur in "quadrant dentistry" * Apicectomies are common causes of amalgam tattoo, since the amalgam is being placed inside the alveolus and the soft tissues are replaced on top[1] Over time, the amalgam particles embedded in the soft tissues corrode.[5]:183 Macrophages take up the exogenous particles, and the silver in amalgam leads to staining of collagen fibers.[5]:183 A similar appearance can be caused by implantation of graphite (e.g. from pencil leads), and is sometimes termed a graphite tattoo, although this is less common than tattooing with amalgam.[3]:138 ## Diagnosis[edit] The diagnosis is clinical.[3]:138 Amalgam tattoo can be distinguished from other causes of localized oral pigmentation because it does not change significantly in size or color,[3]:138 although it may appear to slowly enlarge for several months after the initial implantation of the metal particles.[1][5]:183 Some amalgam tattoos appear radio-opaque on radiographs (i.e. they show up on x-rays),[3]:138 although in many cases amalgam tattoos have no radiographic features since the responsible particle(s) of amalgam are very small even though clinically the area of discolored mucosa is much larger.[1] If necessary, the diagnosis can be confirmed histologically by excisional biopsy, which excludes nevi and melanomas.[3]:138 If a biopsy is taken, the histopathologic appearance is:[1] * Pigmented fragments of metal within connective tissue * Staining of reticulin fibers with silver salts * A scattered arrangement of large, dark, solid fragments or a fine, black or dark brown granules * Large particles may be surrounded by chronically inflamed fibrous tissue * Smaller particles surrounded by more significant inflammation, which may be granulomatous or a mixture of lymphocytes and plasma cells ## Prevention[edit] Theoretically, routine use of a dental dam during dental procedures which involve amalgam should reduce the risk of amalgam tattoo.[1] ## Treatment[edit] No treatment is required since the lesion is entirely benign. Some suggest that amalgam tattoos are best surgically excised so as to ensure the lesion does not represent a melanoma.[3]:138 Others say that excision should only be carried out if there is any doubt over the diagnosis, and that amalgam tattoos are managed by simple reassurance about the nature of the lesion.[4]:330 For example, if radio-opaque particles are demonstrated on the x-ray, biopsy is unnecessary.[1] ## Epidemiology[edit] Amalgam tattoo is found in up to 1% of people in the general population.[6] It is the most common cause of solitary or focal pigmentation of the oral mucosa.[6] ## Notes[edit] 1. ^ Argyrosis is an uncommon synonym of argyria, a condition caused by excessive exposure to silver, where the skin and mucous membranes are discolored blue or black. Some have criticized these as inappropriate synonyms for amalgam tattoo since silver is just one of several components of dental amalgam (See Neville 2001) ## References[edit] 1. ^ a b c d e f g h i j k l m Neville BW, Damm DD, Allen CA, Bouquot JE (2002). Oral & maxillofacial pathology (2nd ed.). Philadelphia: W.B. Saunders. pp. 269–272. ISBN 0721690033. 2. ^ Richard C.K. Jordan; Michael A.O. Lewis (2004). A color handbook of oral medicine. New York: Thieme. p. 131. ISBN 9781588902740. 3. ^ a b c d e f g h Scully, Crispian (2013). Oral and maxillofacial medicine : the basis of diagnosis and treatment (3rd ed.). Edinburgh: Churchill Livingstone/Elsevier. ISBN 9780702049484. 4. ^ a b Athanasios Kalantzis; Crispian Scully (2005). Oxford handbook of dental patient care (2nd ed.). New York: Oxford University Press. ISBN 9780198566236. 5. ^ a b c d e f g Paul Coulthard; et al. (2008). Master dentistry (2nd ed.). Edinburgh: Churchill Livingstone/Elsevier. ISBN 9780443068966. 6. ^ a b Martin S. Greenberg; Michael Glick; Jonathan A. Ship (2008). Burket's oral medicine (11th ed.). Hamilton, Ont.: BC Decker. p. 124. ISBN 9781550093452. ## External links[edit] Classification D * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Amalgam tattoo	c0399493	4,321	wikipedia	https://en.wikipedia.org/wiki/Amalgam_tattoo	2021-01-18T19:00:50	{"wikidata": ["Q16242812"]}
A rare soft tissue sarcoma characterized by a lesion in the deep soft tissues of the proximal extremities and limb girdles, composed of malignant chondroblast-like cells arranged in cords, clusters, or networks, and an abundant myxoid matrix. The tumor is typically encased by a pseudocapsule and divided into multiple nodules by fibrous septa. Patients present with a soft tissue mass which can be painful and may ulcerate the skin or restrict range of motion if located next to joints. Despite prolonged survival, local recurrence and metastasis are frequent. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Extraskeletal myxoid chondrosarcoma	c1275278	4,322	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=209916	2021-01-23T18:28:31	{"mesh": ["C563195"], "omim": ["612237"], "umls": ["C1275278"], "icd-10": ["C49.9"]}
Horseshoe kidney SpecialtyNephrology Horseshoe kidney, also known as ren arcuatus (in Latin), renal fusion or super kidney, is a congenital disorder affecting about 1 in 500 people that is more common in men, often asymptomatic, and usually diagnosed incidentally.[1][2] In this disorder, the patient's kidneys fuse together to form a horseshoe-shape during development in the womb. The fused part is the isthmus of the horseshoe kidney. The abnormal anatomy can affect kidney drainage resulting in increased frequency of kidney stones and urinary tract infections as well as increase risk of certain renal cancers.[1] Fusion abnormalities of the kidney can be categorized into two groups: horseshoe kidney and crossed fused ectopia. The 'horseshoe kidney' is the most common renal fusion anomaly.[3] ## Contents * 1 Signs and symptoms * 1.1 Associated conditions * 2 Etiology * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 Epidemiology * 7 Notable cases * 8 References * 9 External links ## Signs and symptoms[edit] Axial CT image of the abdomen showing a horseshoe kidney. Although often asymptomatic, the most common presenting symptom of patients with a horseshoe kidney is abdominal or flank pain. However, presentation is often non-specific.[1] Approximately a third of patients with horseshoe kidneys remain asymptomatic throughout their entire life with over 50% of patients having no medical issues related to their renal fusion when followed for a 25 year period.[1] As a result, it is estimated that approximately 25% of patients with horseshoe kidneys are diagnosed incidentally with ultrasound or CT imaging.[1] ### Associated conditions[edit] Patients with a horseshoe kidney can develop sequelae related to the abnormal anatomy and present with symptoms related to them. The general categories a horseshoe kidney may increase the risk for fall under the following categories: * Kidney obstruction – commonly causes ureteropelvic junction obstruction (UPJ)[1] which is a blockage at the area where the ureter connects to the renal pelvis. This can lead to urinary stasis which can promote infection and stone formation.[4] * Kidney infections – associated with vesicoureteral reflux (present in approximately 50% of all patients with renal fusion) which is an abnormal reflux of urine back into the ureters that increases risk of urinary tract infections.[1] * Kidney stones – deviant orientation of kidneys combined with slow urine flow and kidney obstruction may increase the risk of developing kidney stones. Treatment is further complicated if patient possesses aberrant skeletal anatomy.[5] It is estimated approximately 36% of patients with horseshoe kidneys will develop kidney stones.[6] * Kidney cancer – increased frequency of certain renal cancers such as transitional cell tumors, Wilms tumors, and carcinoid tumors.[1] * Heart abnormalities – ventricular septal defect[7] * Neurological abnormalities - encephalocoele, myelomeningocoele, spina bifida[7] * Skeletal abnormalities - kyphosis, scoliosis, hemeivertebra, and micrognathia.[7] * Genitourinary abnormalities - septate vagina, bicornuate uterus, hypospadias, undescended testis, adult polycystic kidney disease, and more than two kidneys.[7] * Genetic abnormalities - Turner syndrome, Down syndrome, Patau syndrome, Edward syndrome, oro-cranial-digital syndrome[7] Intravenous pyelogram showing horseshoe kidney. ## Etiology[edit] There have been several proposed factors that may contribute to the development of a horseshoe kidney. Different exposures to the developing fetus such as different teratogens (e.g. thalidomide, ethanol, ACE inhibitors, cocaine, gentamycin, corticosteroids, NSAIDs, and vitamin A) have been hypothesized.[1][2][8] Impairment of a developing embryo's nephrogenic cell migration or abnormal migration of the kidneys due to fetal structural abnormalities is another potential factor.[1][2] However, no definitive genetic cause has been identified.[1][8] ## Pathophysiology[edit] Kidneys are normally located in the retroperitoneal space between the T12 and L3 vertebrae after ascending from the pelvis during development to rest underneath the adrenal glands.[1] In patients with this condition, the horseshoe kidney ascent is commonly arrested by the inferior mesenteric artery due to the central fusion of the kidneys.[9] However, this is present in only 40% of cases, and, in 20% of cases, the fused kidney remains in the pelvis.[1] Its ascension may also be restricted by its own renal artery.[10] Additionally, during normal development, the kidneys undergo a 90 degree medial rotation while ascending. However, due to the renal fusion, this rotation is impaired resulting in abnormal placement of the ureters. This in turn can lead to urinary stasis and drainage issues.[1] Furthermore, approximately 70% of kidneys in normal individuals are supplied by a single renal artery with the remaining 30% having embryonic collateral or accessory arteries.[1] With horseshoe kidneys, the majority are supplied by derivatives of the abdominal aorta or common illiac arteries depending on the final position of the kidneys.[1][11] ## Diagnosis[edit] Horseshoe kidneys are commonly diagnosed incidentally on abdominal imaging. The diagnosis can be made with many different imaging modalities such as ultrasound, intravenous pyelogram, CT, and MRI.[1] Common features that can be found on imaging include: * Midline symmetrical fusion (present in 90% of cases) or lateral asymmetric fusion (present in 10% of cases) of the lower poles[12] * Position of fused kidneys are lower than normal with incomplete medial rotation[12] * Renal pelvis and ureters are positioned more anteriorly and ventrally cross the isthmus[12][4] * Isthmus that may be positioned below the inferior mesenteric artery[12] * Variant arterial supply that can originate from the abdominal aorta or common illiac arteries[1][11][12] * Lower poles of kidney that extend ventromedially and may be poorly defined[13] ## Treatment[edit] Symphysiotomy, which involves separating the fused isthmus in order to release the kidneys, used to be a recommended treatment for this condition but has fallen out of favor due to complications and minimal benefit.[1][14] Furthermore, kidneys can remain in their original abnormal location after the surgery.[1][15] Instead, management focuses on treating the sequelae should the patient become symptomatic. While treatment typically does not differ from that of patients with normal kidney anatomy,[16] kidney stones can warrant a different approach. Extracorporeal shockwave lithotripsy, a possible treatment for kidney stones, can be less effective in patients with horseshoe kidneys due to the abnormal anatomy causing difficulties with localizing the energy to the stones. Also, due to the kidney obstruction that can commonly occur with this renal fusion, clearance of the resulting stone fragments can also be impaired.[1] For this reason, prior to any treatment with shockwave lithotripsy, a UPJ obstruction must first be ruled out as it significantly impair successful treatment.[4] For stones that are less than 1.5 cm, ureteroscopy and shockwave lithotripsy can be first utilized.[4] For stones larger than 1.5 cm or when previous treatment has failed, the stones can instead be removed through a minimally invasive procedure known as percutaneous nephrolithotomy.[4] Compared to patients with normal kidneys, patients with horseshoe kidneys who undergo treatment with percutaneous nephrolithotomy experience no difference in complications or stone clearance.[4] Patients will also typically require imaging before any abdominal surgery as the vascular supply to the abnormal kidney can be highly variable between patients.[1] Additionally, the horseshoe kidneys can have a close association with colon which can increase risk of bowel injury.[1] ## Epidemiology[edit] There is an incidence of 1 in every 500 individuals within a normal population.[1][2] Males are more likely to develop a horseshoe kidney with a preponderance of 2:1.[1][2] Certain genetic diseases can predispose patients to developing a horseshoe kidney: * Edwards Syndrome: 67%[1][2][17][18] * Turner Syndrome: 14-20%[1][2][19][20] * Down Syndrome: <1%[1][2][21] ## Notable cases[edit] * Mel Gibson is affected with this condition.[22] * Sam Kinison, an American comedian, also had this condition.[23] * Robert Rowan a member of the Anglican clergy was afflicted by the condition. ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Kirkpatrick JJ, Leslie SW (2018). Horseshoe Kidney. StatPearls. StatPearls Publishing. PMID 28613757. Retrieved 2019-01-16. 2. ^ a b c d e f g h Taghavi K, Kirkpatrick J, Mirjalili SA (October 2016). "The horseshoe kidney: Surgical anatomy and embryology". Journal of Pediatric Urology. 12 (5): 275–280. doi:10.1016/j.jpurol.2016.04.033. PMID 27324557. 3. ^ Glodny B, Petersen J, Hofmann KJ, Schenk C, Herwig R, Trieb T, et al. (January 2009). "Kidney fusion anomalies revisited: clinical and radiological analysis of 209 cases of crossed fused ectopia and horseshoe kidney". BJU International. 103 (2): 224–35. doi:10.1111/j.1464-410X.2008.07912.x. PMID 18710445. 4. ^ a b c d e f Wein, Alan J.; Kavoussi, Louis R.; Partin, Alan W.; Peters, Craig Andrew (2015-10-23). Campbell-Walsh Urology (Eleventh ed.). Philadelphia, PA. ISBN 9780323263740. OCLC 931870910. 5. ^ Jung M, Rai A, Wang L, Puttmann K, Kukreja K, Koh CJ (October 2018). "Nephrolithiasis in a 17-Year-Old Male With Seckel Syndrome and Horseshoe Kidneys: Case Report and Review of the Literature". Urology. 120: 241–243. doi:10.1016/j.urology.2018.05.023. PMID 29894776. 6. ^ Pawar AS, Thongprayoon C, Cheungpasitporn W, Sakhuja A, Mao MA, Erickson SB (January 2018). "Incidence and characteristics of kidney stones in patients with horseshoe kidney: A systematic review and meta-analysis". Urology Annals. 10 (1): 87–93. doi:10.4103/UA.UA_76_17. PMC 5791465. PMID 29416282. 7. ^ a b c d e Shah HU, Ojili V (2017). "Multimodality imaging spectrum of complications of horseshoe kidney". The Indian Journal of Radiology & Imaging. 27 (2): 133–140. doi:10.4103/ijri.IJRI_298_16. PMC 5510309. PMID 28744072. 8. ^ a b Woolf AS, Winyard PJ, Hermanns MH, Welham SJ (2003). "Maldevelopment of the human kidney and lower urinary tract: an overview.". In Vize PD, Woolf AS, Bard JB (eds.). In The kidney. Academic Press. pp. 377–393. doi:10.1016/b978-012722441-1/50023-3. ISBN 9780127224411. 9. ^ Oktem H, Gozil R, Calguner E, Bahcelioglu M, Mutlu S, Kurkcuoglu A, et al. (2008). "Morphometric study of a horseshoe kidney". Medical Principles and Practice. 17 (1): 80–3. doi:10.1159/000109596. PMID 18059107. 10. ^ Suwannakhan A, Meemon K (2019-05-28). "Horseshoe kidney with extrarenal calyces and malformed renal vessels". European Journal of Anatomy. 20 (4): 355–359. 11. ^ a b Natsis K, Piagkou M, Skotsimara A, Protogerou V, Tsitouridis I, Skandalakis P (August 2014). "Horseshoe kidney: a review of anatomy and pathology". Surgical and Radiologic Anatomy. 36 (6): 517–26. doi:10.1007/s00276-013-1229-7. PMID 24178305. S2CID 7889789. 12. ^ a b c d e Gutiérrez M (2013). "Renal anomalies of position, shape and fusion: radiographic analysis" (PDF). Revista de la Federación Ecuatoriana de Radiología. 6: 24–30. 13. ^ Nahm AM, Ritz E (November 1999). "Horseshoe kidney". Nephrology, Dialysis, Transplantation. 14 (11): 2740–1. doi:10.1093/ndt/14.11.2740. PMID 10534525. 14. ^ Oderda M, Calleris G, Allasia M, Dalmasso E, Falcone M, Catti M, et al. (February 2017). "Robot-assisted laparoscopic pyeloplasty in a pediatric patient with horseshoe kidney: surgical technique and review of the literature". Urologia. 84 (1): 55–60. doi:10.5301/uro.5000188. PMID 27516351. S2CID 25468419. 15. ^ Pitts WR, Muecke EC (June 1975). "Horseshoe kidneys: a 40-year experience". The Journal of Urology. 113 (6): 743–6. doi:10.1016/S0022-5347(17)59571-3. PMID 1152146. 16. ^ Al Otay A, Sarhan O, El-Tholoth HS, Alhelaly A, Al Akrash H, Al Ghanbar M, et al. (July 2018). "Different managements of horseshoe kidney stones, any difference in the outcome?". Urology Annals. 10 (3): 287–290. doi:10.4103/UA.UA_116_17. PMC 6060601. PMID 30089987. 17. ^ "Renal Pathology". Retrieved 2008-11-26. 18. ^ Cereda A, Carey JC (October 2012). "The trisomy 18 syndrome". Orphanet Journal of Rare Diseases. 7 (1): 81. doi:10.1186/1750-1172-7-81. PMC 3520824. PMID 23088440. 19. ^ Kleta R, Brämswig JH (July 2000). "Horseshoe kidney and Turner syndrome". Nephrology, Dialysis, Transplantation. 15 (7): 1094. doi:10.1093/ndt/15.7.1094-b. PMID 10862660. 20. ^ Ranke MB, Saenger P (July 2001). "Turner's syndrome". Lancet. 358 (9278): 309–14. doi:10.1016/S0140-6736(01)05487-3. PMID 11498234. S2CID 42096888. 21. ^ Niamien-Attai C, Bacchetta J, Ranchin B, Sanlaville D, Cochat P (October 2017). "[Renal abnormalities in Down syndrome: A review]". Archives de Pédiatrie. 24 (10): 1013–1018. doi:10.1016/j.arcped.2017.07.014. PMID 28893484. 22. ^ Parkinson. "Mel Gibson Interview - part one". BBC. 23. ^ Paget ET. "Autopsy Report: Sam Kinison" (PDF). Autopsy Files. ## External links[edit] Classification D * ICD-10: Q63.1 * ICD-9-CM: 753.3 * DiseasesDB: 6020 External resources * eMedicine: article/441510 article/378396 * v * t * e Congenital malformations and deformations of urinary system Abdominal Kidney * Renal agenesis/Potter sequence, Papillorenal syndrome * cystic * Polycystic kidney disease * Meckel syndrome * Multicystic dysplastic kidney * Medullary sponge kidney * Horseshoe kidney * Renal ectopia * Nephronophthisis * Supernumerary kidney * Pelvic kidney * Dent's disease * Alport syndrome Ureter * Ectopic ureter * Megaureter * Duplicated ureter Pelvic Bladder * Bladder exstrophy Urethra * Epispadias * Hypospadias * Posterior urethral valves * Penoscrotal transposition Vestigial Urachus * Urachal cyst * Urachal fistula * Urachal sinus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Horseshoe kidney	c0221353	4,323	wikipedia	https://en.wikipedia.org/wiki/Horseshoe_kidney	2021-01-18T18:29:47	{"gard": ["2739"], "mesh": ["D000069337"], "icd-9": ["753.3"], "icd-10": ["Q63.1"], "orphanet": ["3029"], "wikidata": ["Q1634033"]}
A number sign (#) is used with this entry because of evidence that neovascular inflammatory vitreoretinopathy (VRNI) is caused by heterozygous mutation in the CAPN5 gene (602537) on chromosome 11q14. Description Autosomal dominant neovascular inflammatory vitreoretinopathy is a blinding disorder that shares some clinical features with retinitis pigmentosa (see 268000), uveitis, and proliferative diabetic retinopathy (see 603933). Features include prominent ocular inflammation; vascular dropout, large spots of hyperpigmentation, and neovascularization of the peripheral and posterior retina; vitreous hemorrhage; and retinal detachment (summary by Sheffield et al., 1992). Clinical Features Bennett et al. (1990) studied a large 6-generation family of northern European ancestry segregating autosomal dominant inflammatory eye disease. There were 28 affected individuals, the condition was present in every generation, and there was at least 1 documented male-to-male transmission. The youngest age at which symptoms developed was 16 years; most affected individuals remained asymptomatic until their third or fourth decade. The first signs of disease included vitreous cells, minimal far-peripheral arteriolar closure and pigmentation, and selective reduction in the b-wave of the electroretinogram (ERG). In middle age, more prominent anterior and posterior inflammation, progressive vascular closure with neovascularization of the far peripheral retina or optic disc, vitreous hemorrhage, tractional retinal detachment, fluorescein leakage in the posterior pole and midperiphery, and cystoid macular edema develop. By 60 years of age, cataracts, marked progressive neovascularization, and tractional retinal detachment were observed, and anterior segment neovascularization developed. Cystoid macular edema, vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma caused profound visual loss in some patients. The ERG was extinguished late in the disease. Mahajan et al. (2012) studied 2 families segregating autosomal dominant neovascular inflammatory vitreoretinopathy and noted that the phenotype was very similar to that described by the pedigree described by Bennett et al. (1990). Affected members exhibited noninfectious uveitis, early loss of the b-wave on electroretinography, pigmentary retinal degeneration, cystoid macular edema, retinal and iris neovascularization, vitreous hemorrhage, epiretinal membrane formation, proliferative vitreoretinopathy, retinal detachment, cataract, neovascular glaucoma, and ultimately phthisis and complete blindness. Both pedigrees were consistent with autosomal dominant inheritance with complete penetrance. Mapping Sheffield et al. (1992) established close linkage of VRNI to markers that map to 11q13. In a single large pedigree, linkage analysis with the closest marker, D11S527, demonstrated a maximum lod of 6.29 with no recombinants. Stone et al. (1992) reported that they had found 34 affected members in this pedigree, that no recombinants were found between the disease phenotype and D11S527, and that multipoint analysis yielded a maximum lod score of 11.9 centered on this marker. Another inherited retinal dystrophy, Best macular dystrophy (VMD; 153700), also maps to 11q13. However, Sheffield et al. (1992) stated that the 2 diseases appear to be at least 10 cM apart. Mahajan et al. (2012) genotyped 2 unrelated families segregating autosomal dominant neovascular inflammatory vitreoretinopathy and confirmed linkage to the 11q13 locus. Haplotype analysis was suggestive of an ancestral relationship between 1 of the families (ADNIV-2) and the original (ADNIV-1) family described by Bennett et al. (1990). Recombination events in 1 of the families (ADNIV-3) narrowed the critical interval to 6.5 Mb between D11S4139 and D11S1789; high resolution SNP genotyping of ADNIV-1 and ADNIV-3 further reduced the interval to 6 Mb between SNP rs879380 and D11S1789. Pathogenesis Proliferative vitreoretinopathy is characterized by the development of epi- and subretinal fibrocellular membranes containing modified retinal pigment epithelial (RPE) cells among others. Priglinger et al. (2003) found that tissue transglutaminase (190196) was present and functionally active in proliferative vitreoretinopathy membranes. The amount and activity of tissue transglutaminase appeared to be related to the differentiation state of the RPE cells and their stimulation by TGFB2 (190220), a growth factor known to be increased in the vitreous of proliferative vitreoretinopathy. Molecular Genetics Mahajan et al. (2012) performed whole-exome sequencing in the family with autosomal dominant neovascular inflammatory vitreoretinopathy originally reported by Bennett et al. (1990) (ADNIV-1) and identified a heterozygous missense mutation in the CAPN5 gene (R243L; 602537.0001) that segregated fully with disease. Sequencing of CAPN5 in 2 additional ADNIV families revealed that affected members of family ADNIV-2 carried the same heterozygous R243L mutation, whereas affected individuals from family ADNIV-3 were heterozygous for an adjacent missense mutation (L244P; 602537.0002). The mutations segregated with disease in each family and were not found in 272 ethnically matched controls or in the dbSNP or 1000 Genomes Project databases. Animal Model Saika et al. (2007) determined the effects of Smad7 (602932) gene transfer in the prevention of fibrogenic responses by the retinal pigment epithelium, a major cause of proliferative vitreoretinopathy after retinal detachment in mice. In a retinal detachment-induced proliferative vitreoretinopathy in a mouse model, Smad7 gene transfer inhibited TGFB2/Smad signaling in ARPE19 cells and expression of collagen type I and TGFB1 but had no effect on their basal levels. In vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and of the fibrogenic response to epithelial-mesenchymal transition by the retinal pigment epithelium. Saika et al. (2007) concluded that Smad7 gene transfer suppressed fibrogenic responses to TGFB2 by retinal pigment epithelial cells in vitro and in vivo. Wert et al. (2015) generated transgenic mice expressing human CAPN5(R243L) only in the retina and observed a clinical, histologic, and molecular phenotype consistent with human VRNI and uveitis. The fundi of the transgenic mice showed enhanced autofluorescence and pigment changes indicative of reactive retinal pigment epithelial cells and photoreceptor degeneration. Electroretinography of mutant mouse eyes revealed a selective loss of the b-wave, indicating an inner-retina signaling defect. Histologic analysis of mutant mouse eyes showed protein extravasation from dilated vessels into the anterior chamber and vitreous, vitreous inflammation, vitreous and retinal fibrosis, and retinal degeneration. Analysis of gene expression changes in the hCAPN5(R243L) mouse retina demonstrated upregulation of several markers, including members of the Toll-like receptor pathway, chemokines, and cytokines, indicative of both an innate and adaptive immune response. Noting that many forms of uveitis share phenotypic characteristics of VRNI, Wert et al. (2015) suggested that this mouse model might have therapeutic testing utility for VRNI and uveitis patients. Eyes \- Neovascular inflammatory vitreoretinopathy \- Blindness \- Prominent ocular inflammation \- Retinal vascular dropout \- Large hyperpigmented retinal spots \- Neovascularization of peripheral and posterior retina \- Vitreous hemorrhage \- Retinal detachment Lab \- Distinct b-wave abnormality on electrooculography Inheritance \- Autosomal dominant (11q13) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY	c0242852	4,324	omim	https://www.omim.org/entry/193235	2019-09-22T16:31:55	{"mesh": ["D018630"], "omim": ["193235"], "orphanet": ["329211"], "synonyms": ["VITREORETINOPATHY, NEOVASCULAR INFLAMMATORY, AUTOSOMAL DOMINANT", "Alternative titles", "PROLIFERATIVE VITREORETINOPATHY", "ADNIV"]}
## Clinical Features Kleiner and Holmes (1980) described 2 brothers with bilateral hallux varus. The propositus had clinodactyly of both fifth fingers. Radiographs showed that the first metatarsals and phalanges of both great toes were broad, short, and misshapen. His younger brother had preaxial polysyndactyly of the great toes. Radiographs showed broad, short, and misshapen first metatarsals, duplication of the proximal phalanges, and triplication of the distal phalanges on the right foot and duplication on the left. Neither brother had any other malformations. The parents were not related and showed no skeletal abnormality. Inheritance Kleiner and Holmes (1980) could not establish a pattern of inheritance in the family they reported but considered autosomal dominant inheritance unlikely. INHERITANCE \- Autosomal recessive SKELETAL Feet \- Hallux varus \- Preaxial polysyndactyly \- Broad great toes \- Duplication or triplication of phalanges ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	HALLUX VARUS AND PREAXIAL POLYSYNDACTYLY	c1856197	4,325	omim	https://www.omim.org/entry/234280	2019-09-22T16:27:13	{"mesh": ["C536885"], "omim": ["234280"], "orphanet": ["2110"]}
A number sign (#) is used with this entry because type A1 brachydactyly is caused by heterozygous mutation in the Indian hedgehog gene (IHH; 600726) on chromosome 2q35. Description In the classification of the brachydactylies, the analysis by Bell (1951) proved highly useful. The type A brachydactylies of Bell have the shortening confined mainly to the middle phalanges. In the A1 type, the middle phalanges of all the digits are rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short. ### Genetic Heterogeneity of Brachydactyly Type A1 BDA1B (607004) has been mapped to chromosome 5. BDA1C (615072) is caused by mutation in the GDF5 gene (601146) on chromosome 20q11. BDA1D (616849) is caused by mutation in the BMPR1B gene (603248) on chromosome 4q22. Clinical Features This trait has the distinction of being the first in man to be interpreted in mendelian dominant terms, by Farabee (1903). Haws and McKusick (1963) followed up on Farabee's family. The subjects were short of stature. Type A1 brachydactyly was present in the women of 3 successive generations, who also had ankylosis of the thumbs, which was not accompanied by synostosis on x-ray, and mental retardation (Piussan et al., 1983); see 188201. Stiff thumbs also occur with the C.S. Lewis type of symphalangism (185650). Drinkwater (1908, 1912, 1914) performed a comprehensive study of families with BDA1 and concluded that the shortness of the phalanges was attributable to absence of the epiphyses, short shaft of the bone, and premature closure of the epiphyses, when present. He noted that affected individuals tended to be of shorter stature in adulthood. Mapping By 2-point linkage analysis and haplotype analysis in 2 large Chinese kindreds with BDA1, Yang et al. (2000) mapped a BDA1 locus to 2q35-q36. Different haplotypes within the defined region were found in the 2 families, suggesting that they were not related. ### Genetic Heterogeneity Kirkpatrick et al. (2003) presented evidence suggesting a third locus for brachydactyly type A1: an affected family did not show linkage to chromosome 5p13 and did not have mutations in the IHH gene on chromosome 2. Lacombe et al. (2010) reported a 3-generation family in which 5 individuals had an osteochondrodysplasia including brachydactyly type A1, short humerus, and other skeletal anomalies. The phenotype was transmitted in an autosomal dominant pattern. Molecular analysis excluded mutations in the IHH and GDF5 (601146) genes. The proband was a male infant with short humeri, bowing of the radii, short ulnas, short and broad metacarpals, short and broad second to fifth middle phalanges, and short metatarsals. He also had a pseudarthrosis at the proximal ulna, proximal accessory ossification centers at the metacarpals, and metaphyseal irregularities of the proximal femurs. The mother had short arms, radial angulation of the forearms, and brachydactyly of hands and feet with short metacarpals and metatarsals, and short second phalanges of the hands. She had an affected brother, who had the same skeletal phenotype including BDA1, short humeri, pseudarthrosis-like aspect of the proximal part of the ulna and a proximal accessory ossification center of the ulna in infancy, as well as triphalangeal thumbs. Finally, the maternal grandmother of the proband had the same osseous dysplasia with brachydactyly, short first metacarpal and short middle phalanges (BDA1), short humerus, and bowing of the radius with hypoplasia of the proximal part of the ulna. A brother of hers was similarly affected. All had normal mental status. Two of the affected individuals had hearing loss, but it was not clear if this was an independent trait. Molecular Genetics Studying 2 families with multiple affected members, Mastrobattista et al. (1995) excluded the following candidate genes: HOXD (see 142980), MSX1 (142983), MSX2 (123101), FGF1 (131220), and FGF2 (134920). Affected members of 1 of the families reported by Mastrobattista et al. (1995) were found by Kirkpatrick et al. (2003) to have a mutation in the Indian hedgehog gene (600726.0007). The family was of Mexican descent. Gao et al. (2001) identified 3 heterozygous missense mutations in the region encoding the amino-terminal signaling domain of Indian hedgehog (600726.0001-600726.0003) in all affected members of 3 large, unrelated Chinese families. The 3 mutant amino acids, which are conserved across diverse vertebrates and invertebrates, are thought to be adjacent on the surface of IHH. McCready et al. (2002) studied descendants of the first and third brachydactylous families reported by Drinkwater (1908, 1914) and showed that although they were not known to be related, they shared a common mutation within the IHH gene (D100N; 600726.0004). The family reported by Farabee (1903) and the first kindred reported by Drinkwater (1908) had been thought to be related, but no connection between the families could be established by Haws and McKusick (1963). McCready et al. (2005) identified the D100N mutation of the IHH gene in descendants of the family described by Farabee (1903). Using 16 markers spanning the IHH locus, they identified a common haplotype between this family and the 2 kindreds studied by Drinkwater (1908, 1914) and McCready et al. (2002), suggesting a common founder. In affected members of a 5-generation Chinese family with brachydactyly type A1, Liu et al. (2006) identified a heterozygous mutation in the IHH gene (600726.0008). Radiographic analysis of affected individuals showed unaffected proximal phalanges of the thumb and no apparent anomalies of the feet. In affected members of a large 4-generation Chinese family with brachydactyly, Zhu et al. (2007) identified heterozygosity for the D100N mutation of the IHH gene and demonstrated a haplotype different than the previously published Farabee-Drinkwater common haplotype (McCready et al., 2005), suggesting that the mutation arose independently in this family. The hands of the affected family members were broad, and there was shortening of all digits; x-ray examination revealed that the defects were mainly confined to the middle phalanges and metacarpals. In affected members of a Dutch family with mild brachydactyly type A1, Lodder et al. (2008) identified a heterozygous deletion in the IHH gene (600276.0009), resulting in an in-frame deletion of residue glu95, which was predicted to be located on the edge of a groove important for the interaction between IHH and PTCH1 (601309). Lodder et al. (2008) noted that this was the first reported deletion in the IHH gene, but that this residue has been reported to be affected in other patients with the disorder (see, e.g., G95K; 600726.0001). History Julia Bell (1879-1979) died 3 months after her 100th birthday (Obituary, 1979). INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature SKELETAL Hands \- Short broad hands \- Short to absent middle phalanges \- Short distal phalanges \- Thin metacarpals with broad epiphyses \- Absent distal interphalangeal creases \- Clinodactyly (2nd, 3rd, 4th fingers) \- Short, broad proximal phalanx of thumb \- Thin proximal phalanges with broad epiphyses \- Proportionate shortening of all digits \- Terminal symphalangism Feet \- Short proximal phalanx of halluces SKIN, NAILS, & HAIR Skin \- Absent distal interphalangeal creases MISCELLANEOUS \- Allelic to acrocapitofemoral dysplasia ( 607778 ) \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutations in the Indian hedgehog gene (IHH, 600726.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	BRACHYDACTYLY, TYPE A1	c1862151	4,326	omim	https://www.omim.org/entry/112500	2019-09-22T16:44:07	{"doid": ["0110964"], "mesh": ["C537088"], "omim": ["112500"], "orphanet": ["93388"], "synonyms": ["Alternative titles", "FARABEE-TYPE BRACHYDACTYLY"]}
GATAD2B-associated neurodevelopmental disorder (GAND) affects the way the brain develops. Symptoms of GAND include moderate to severe intellectual disability, poor speech development, and large head size. Other signs and symptoms may include low muscle tone in children (childhood hypotonia), feeding problems, heart problems and shared facial features. Because so few cases have been described in the medical literature, it is difficult to know how this condition changes over time. GAND is caused by a GATAD2B gene that is absent or not working correctly. It usually occurs in a family for the first time due to a new genetic change (de novo) and may be inherited in an autosomal dominant pattern. GAND is diagnosed based on the symptoms, a 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	GATAD2B-associated neurodevelopmental disorder	c3554448	4,327	gard	https://rarediseases.info.nih.gov/diseases/12815/gatad2b-associated-neurodevelopmental-disorder	2021-01-18T18:00:22	{"omim": ["615074"], "orphanet": ["363686"], "synonyms": ["Severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome"]}
A number sign (#) is used with this entry because the phenotype is caused by mutation in the mitochondrially-encoded tRNA-glu gene (MTTE; 590025). Clinical Features Worsfold et al. (1973) described a kindred in which persons in 4 generations showed a myopathy with expression ranging from subclinical to moderately severe weakness and wasting clinically resembling facioscapulohumeral dystrophy (158900), but which on ultrastructural grounds had been designated a 'mitochondrial myopathy' (Hudgson et al., 1972; Johnson et al., 1973). In vitro oxidative phosphorylation by mitochondria showed reduced or absent respiratory control. Greatly increased muscle lipid, in the form of triglyceride, was demonstrated. Mechler et al. (1981) studied further the family reported by Hudgson et al. (1972). By inference, the disorder could be traced through 6 generations. Although the authors considered autosomal dominant inheritance with variable expression and incomplete penetrance likely, mitochondrial inheritance could not be excluded because full-blown disease was transmitted only by females. A male with a fully affected mother showed subclinical myopathy and all 3 of his children (1 male, 2 females) had subclinical myopathy; this was the only instance of male transmission in the kindred. Diabetes mellitus was present in 8 members with myopathy, and 2 of the 8 also had cerebellar ataxia. Mechler et al. (1981) concluded that the myopathy, cerebellar disorder, and diabetes may all be manifestations of a single underlying metabolic defect. Sengers et al. (1984) provided an extensive review of mitochondrial myopathies. McFarland et al. (2004) provided more information and follow-up of 7 members of the family originally reported by Hudgson et al. (1972). The most severely affected man had onset at age 14 years of insulin-dependent diabetes mellitus, dysarthria, and ataxia. Although he complained of fatigue since adolescence, he did not have muscle weakness or myalgia until his forties. Other features included weakness of the orbicularis oculi muscles and severe peripheral vascular disease with motor and sensory neuropathy. Other affected family members exhibited various combinations of proximal myopathy, ataxia, diabetes mellitus, and weakness of the orbicularis muscles. Muscle biopsy showed histologic features of mitochondrial disease with variation in fiber diameter, interstitial fibrosis, fat accumulation, and subsarcolemmal aggregates of mitochondria. Cultured fibroblasts showed a severe reduction in complex I activity. Hao et al. (1995) reported a 29-year-old man with progressive muscle weakness, especially of the neck and limbs, and exercise intolerance since the age of 27 years. Gait was normal except for mild difficulty walking on heels. Tendon reflexes were hypoactive in the arms, but brisk in the legs, with bilateral Babinski signs. Muscle biopsy showed many ragged-red fibers, most of which showed cytochrome c oxidase deficiency. Electron microscopy showed an increased number of abnormal mitochondria with disorganized and vacuolated cristae and paracrystalline inclusions. At age 29 years, the patient was also found to have diabetes mellitus. He reported increased strength after insulin injections, and physical examination confirmed his subjective assessment. Hanna et al. (1995) reported a family with a variety of clinical features including congenital myopathy, mental retardation, cerebellar ataxia, and diabetes mellitus. Both the proband, a 28-year-old man, and his sister had congenital myopathy and mental retardation, and subsequently developed cerebellar ataxia. Their mother was well until age 45 years when she developed diabetes mellitus, limb weakness, and exercise intolerance. Other family members had either adult-onset diabetes mellitus with muscle weakness or diabetes mellitus alone. The authors emphasized the variable phenotype. Molecular Genetics In a patient with adult-onset myopathy and diabetes mellitus, Hao et al. (1995) identified a heteroplasmic mutation in the MTTE gene (14709T-C; 590025.0001). In the family originally reported by Hudgson et al. (1972) with IDDM and myopathy, McFarland et al. (2004) identified the 14709T-C mtDNA mutation. The mutation was homoplasmic in almost all tissues from the most severely affected patient and in the muscle tissue from another affected family member. Other members had high percentages of heteroplasmy (80 to 94% mutant load). One asymptomatic family member was homoplasmic for the mutation in white blood cells. INHERITANCE \- Mitochondrial HEAD & NECK Face \- Facial weakness Eyes \- Weakness of orbicularis oculi muscles MUSCLE, SOFT TISSUES \- Myopathy, proximal \- Proximal muscle weakness \- Proximal muscle wasting \- Hypotonia \- EMG shows myopathic changes \- Muscle biopsy shows ragged-red fibers with decreased COX activity \- Decreased activity of complex I and complex IV \- Muscle shows lipid accumulation \- Electron microscopy shows abnormal mitochondria with disorganized and vacuolated cristae \- Mitochondria show paracrystalline inclusions NEUROLOGIC Central Nervous System \- Delayed motor development \- Intellectual delay \- Cerebellar ataxia \- Dysarthria \- Hyporeflexia ENDOCRINE FEATURES \- Diabetes mellitus, insulin-dependent \- Diabetes mellitus, noninsulin-dependent LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Variable age at onset (birth to adult) \- Highly variable clinical phenotype MOLECULAR BASIS \- Caused by mutation in the mitochondrial tRNA-glutamic acid gene (MTTE, 590025.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	MITOCHONDRIAL MYOPATHY WITH DIABETES	c1839028	4,328	omim	https://www.omim.org/entry/500002	2019-09-22T16:16:57	{"mesh": ["C564026"], "omim": ["500002"], "orphanet": ["2596"], "synonyms": ["Alternative titles", "MITOCHONDRIAL MYOPATHY, LIPID TYPE"]}
A number sign (#) is used with this entry because X-linked thrombocytopenia with beta-thalassemia (XLTT) is caused by mutation in the gene encoding GATA-binding protein-1 (GATA1; 305371) on chromosome Xp11. Description XLTT is an X-linked recessive hematologic disorder characterized by variable thrombocytopenia, hemolytic anemia, splenomegaly, and abnormalities in hemoglobin chain synthesis (summary by Ciovacco et al., 2008 and Millikan et al., 2011). Clinical Features Thompson et al. (1977) described an unusual family in which 4 and possibly 5 males in multiple generations had splenomegaly and petechiae, moderate thrombocytopenia, prolonged bleeding time due to platelet dysfunction, reticulocytosis and unbalanced (hemo)globin chain synthesis resembling that of beta-thalassemia minor. Minor defects (reticulocytosis, globin synthesis imbalance) were found in some females. The female progenitor was white, but her ethnic extraction was not specified. No linkage to Xg was demonstrated. Tubman et al. (2007) reported a family in which 3 affected males had thrombocytopenia, increased mean platelet volume, mild microcytosis, and increased red cell distribution consistent with X-linked inheritance. Peripheral blood smear showed so-called 'gray platelets' with decreased alpha-granules (see 139090). One male studied had a mild beta-thalassemia-like phenotype on hemoglobin electrophoresis. The proband was a 1-year-old girl with normal platelet count and no bleeding history who had 2 populations of platelets on peripheral blood smear: one normal and the other large, agranular, and pale. ### Clinical Variability Phillips et al. (2007) reported a 3-year-old boy with XLTT and anemia who presented with a photosensitive bullous dermatosis and was found to have hirsutism, splenomegaly, and increased uroporphyrin with decreased UROS (606938) activity (21% of normal). Although these features were consistent with a clinical diagnosis of congenital erythropoietic porphyria (CEP; 263700), sequencing of the UROS gene was negative. Laboratory studies showed microcytic anemia with increased reticulocytes, thrombocytopenia, increased fetal hemoglobin (59.5%), and beta-thalassemia. Bone marrow biopsy was hypercellular with dyserythropoiesis, nuclear bridging, and occasional multinucleated red cells. Megakaryocytes were decreased in number. He underwent a stem cell transplant, which was successful. The mother had had multiple first-trimester spontaneous abortions, but no signs of porphyria. The grandmother had chronic anemia and thrombocytopenia. Molecular Genetics Yu et al. (2002) identified an arg216-to-gln mutation in the N finger of GATA1 (R216Q; 305371.0006) in the family with X-linked thrombocytopenia with beta-thalassemia reported by Thompson et al. (1977). Tubman et al. (2007) identified an R216Q substitution in affected members of a family with a mild bleeding disorder, thrombocytopenia, and large agranular platelets characteristic of the so-called 'gray platelet syndrome.' In a letter, Balduini et al. (2007) stated that the family reported by Tubman et al. (2007) had a phenotype consistent with XLTT and that the classification as 'X-linked gray platelet syndrome' is a misnomer risking confusion in the literature. They noted that deficiency of platelet alpha-granules can be a feature of XLTT. In response, the original authors (Neufeld et al., 2007) agreed that the disorder in the family may be classified as an example of a unique disorder, i.e., XLTT, but endorsed its classification as 'a unique kind of GPS, inherited in X-linked fashion, with platelets indistinguishable by experts from autosomal GPS (at the light microscope and ultrastructure level).' Genotype/Phenotype Correlations In a 3-year-old boy with XLTT, anemia, and clinical features reminiscent of congenital erythropoietic porphyria, Phillips et al. (2007) identified a hemizygous mutation in the GATA1 gene (R216W; 305371.0010). The GATA1 gene regulates expression of UROS in developing erythrocytes, which explained the decreased UROS activity and features of porphyria in this patient. The R216W mutation affects the same residue as that reported by Yu et al. (2002) (R216Q; 305371.0006) in an XLTT family with a less severe phenotype. Phillips et al. (2007) postulated that the larger, more hydrophobic tryptophan in their family would affect GATA1 binding to the UROS promoter more significantly than the smaller glutamine described by Yu et al. (2002). The striking fetal hemoglobin in the patient reported by Phillips et al. (2007) also suggested a role for GATA1 in globin chain switching. INHERITANCE \- X-linked recessive HEAD & NECK Nose \- Epistaxis ABDOMEN Spleen \- Splenomegaly SKIN, NAILS, & HAIR Skin \- Petechiae \- Easy bruisability \- Photosensitivity bullous dermatitis (1 patient) Hair \- Hirsutism (1 patient) HEMATOLOGY \- Thrombocytopenia \- Prolonged bleeding time \- Increased alpha/beta globin ratio in reticulocytes \- Reticulocytosis \- Imbalanced hemoglobin chain synthesis \- Elevated HbA(2) \- Elevated HbF \- Bone marrow biopsy shows increased numbers of normal to small megakaryocytes \- Enlarged platelets \- Platelets have decreased alpha-granules \- Decreased platelet function \- Normal platelet aggregation studies \- Hemolytic anemia (variable) \- Dyserythropoiesis in bone marrow (1 patient) \- Decreased number of small megakaryocytes (1 patient) \- Mild reticulocytosis in carrier females \- Low-normal platelet count in carrier females LABORATORY ABNORMALITIES \- Decreased UROS activity (1 patient) MISCELLANEOUS \- Three unrelated families have been reported (last curated June 2012) MOLECULAR BASIS \- Caused by mutation in the GATA-binding protein 1 gene (GATA1, 305371.0006 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	THROMBOCYTOPENIA WITH BETA-THALASSEMIA, X-LINKED	c1839161	4,329	omim	https://www.omim.org/entry/314050	2019-09-22T16:17:08	{"mesh": ["C564050"], "omim": ["314050"], "orphanet": ["231393"], "synonyms": ["Alternative titles", "THROMBOCYTOPENIA, PLATELET DYSFUNCTION, HEMOLYSIS, AND IMBALANCED GLOBIN SYNTHESIS", "XLTT"], "genereviews": ["NBK1364"]}
A rare renal disease occurring in the setting of a systemic IgG4 related disease (IgG4-RD). The disorder is characterized by a fibrosing tubulointerstitial nephritis consisting of predominantly IgG4+ plasma cells with/without glomerulonephritis, mass lesions, enlarged kidneys and hydronephrosis. ## Epidemiology The disease prevalence is unknown. ## Clinical description The clinical manifestations include tubulointerstitial nephritis (TIN) and membranous glomerulonephritis with or without TIN. Other glomerular disease is reported (IgA nephropathy, membranoproliferative glomerulonephritis, mesangioproliferative glomerulonephritis). Radiological abnormalities include mass lesions and diffusely enlarged kidneys. Presentation may be on routine imaging, with acute or chronic kidney disease, or with nephrosis depending on underlying lesion. Hydronephrosis may occur due to obstruction from IgG4-related retroperitoneal fibrosis. Other extra renal manifestations of IgG4-RD may also be present (e.g. salivary glands, hepatobiliary system, lungs). ## Etiology The etiology is unknown. ## Diagnostic methods The disease is diagnosed with characteristic imaging and renal biopsy findings (lymphocytic infiltration with predominantly IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis). Diagnostic criteria have been outlined. ## Differential diagnosis The differential diagnosis depends on presentation. For example, the differential for presentation with TIN includes: medications, autoimmune disease (e.g. Sjogren's syndrome, Sarcoid), malignancy (e.g. lymphoproliferative disease), and infection (e.g. Tuberculosis). ## Management and treatment Not supported by randomized controlled trials. Lymphocytic infiltration is usually quickly responsive to steroids. Steroid sparing agents are required/used in some patients. ## Prognosis Relapse is common, and progressive renal impairment can occur, including the need for renal replacement therapy. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	IgG4-related kidney disease	None	4,330	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=449395	2021-01-23T18:09:39	{"icd-10": ["N11.8"]}
Human autoimmune disease This article is about the most common type of lupus. For the broader group of diseases known as "lupus", see Lupus erythematosus. "SLE" redirects here. For other uses, see Lupus (disambiguation) and SLE (disambiguation). Lupus Other namesSystemic lupus erythematosus (SLE) Young woman with the typical butterfly rash found in lupus Pronunciation * /sɪˈstɛmɪk ˈluːpəs ˌɛrɪθiːməˈtoʊsəs/ (listen) sih-STEM-ik LOOP-əs ERR-i-thee-mə-TOH-səs SpecialtyRheumatology SymptomsPainful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, red rash[1] Usual onset15–45 years of age[1][2] DurationLong term[1] CausesUnclear[1] Diagnostic methodBased on symptoms and blood tests[1] MedicationNSAIDs, corticosteroids, immunosuppressants, hydroxychloroquine, methotrexate[1] Prognosis15 year survival ~80%[3] Frequency2–7 per 10,000[2] Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body.[1] Symptoms vary between people and may be mild to severe.[1] Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face.[1] Often there are periods of illness, called flares, and periods of remission during which there are few symptoms.[1] The cause of SLE is not clear.[1] It is thought to involve genetics together with environmental factors.[4] Among identical twins, if one is affected there is a 24% chance the other one will be as well.[1] Female sex hormones, sunlight, smoking, vitamin D deficiency, and certain infections are also believed to increase the risk.[4] The mechanism involves an immune response by autoantibodies against a person's own tissues.[1] These are most commonly anti-nuclear antibodies and they result in inflammation.[1] Diagnosis can be difficult and is based on a combination of symptoms and laboratory tests.[1] There are a number of other kinds of lupus erythematosus including discoid lupus erythematosus, neonatal lupus, and subacute cutaneous lupus erythematosus.[1] There is no cure for SLE.[1] Treatments may include NSAIDs, corticosteroids, immunosuppressants, hydroxychloroquine, and methotrexate.[1] Although corticosteroids are rapidly effective, long term use results in side effects.[5] Alternative medicine has not been shown to affect the disease.[1] Life expectancy is lower among people with SLE.[6] SLE significantly increases the risk of cardiovascular disease with this being the most common cause of death.[4] With modern treatment about 80% of those affected survive more than 15 years.[3] Women with lupus have pregnancies that are higher risk but are mostly successful.[1] Rate of SLE varies between countries from 20 to 70 per 100,000.[2] Women of childbearing age are affected about nine times more often than men.[4] While it most commonly begins between the ages of 15 and 45, a wide range of ages can be affected.[1][2] Those of African, Caribbean, and Chinese descent are at higher risk than white people.[4][2] Rates of disease in the developing world are unclear.[7] Lupus is Latin for "wolf": the disease was so-named in the 13th century as the rash was thought to appear like a wolf's bite.[8] ## Contents * 1 Signs and symptoms * 1.1 Skin * 1.2 Muscles and bones * 1.3 Blood * 1.4 Heart * 1.5 Lungs * 1.6 Kidneys * 1.7 Neuropsychiatric * 1.8 Eyes * 1.9 Reproductive * 1.10 Systemic * 2 Causes * 2.1 Genetics * 2.2 Drug reactions * 2.3 Non-systemic forms of lupus * 3 Pathophysiology * 3.1 Cell death signaling * 3.2 Clearance deficiency * 3.3 Germinal centers * 3.4 Anti-nRNP autoimmunity * 3.5 Others * 4 Diagnosis * 4.1 Laboratory tests * 4.2 Diagnostic criteria * 4.2.1 Criteria * 4.2.2 Criteria for individual diagnosis * 5 Treatment * 5.1 Medications * 5.1.1 Disease-modifying antirheumatic drugs * 5.1.2 Immunosuppressive drugs * 5.1.3 Analgesia * 5.1.4 Intravenous immunoglobulins (IVIGs) * 5.2 Lifestyle changes * 5.3 Kidney transplantation * 5.4 Antiphospholipid syndrome * 5.5 Management of pregnancy * 6 Prognosis * 7 Epidemiology * 7.1 Ethnicity * 7.2 Sex * 7.3 Changing rate of disease * 8 History * 8.1 Etymology * 8.2 Classical period * 8.3 Neoclassical period * 8.4 Modern period * 9 Research * 10 See also * 11 References * 12 External links ## Signs and symptoms Common symptoms of SLE[9] SLE is one of several diseases known as "the great imitator" because it often mimics or is mistaken for other illnesses.[10] SLE is a classical item in differential diagnosis,[11] because SLE symptoms vary widely and come and go unpredictably. Diagnosis can thus be elusive, with some people having unexplained symptoms of SLE for years. Common initial and chronic complaints include fever, malaise, joint pains, muscle pains, and fatigue. Because these symptoms are so often seen in association with other diseases, these signs and symptoms are not part of the diagnostic criteria for SLE. When occurring in conjunction with other signs and symptoms, however, they are considered suggestive.[12] While SLE can occur in both males and females, it is found far more often in women, and the symptoms associated with each sex are different.[6] Females tend to have a greater number of relapses, a low white blood cell count, more arthritis, Raynaud's phenomenon, and psychiatric symptoms. Males tend to have more seizures, kidney disease, serositis (inflammation of tissues lining the lungs and heart), skin problems, and peripheral neuropathy.[13] ### Skin As many as 70% of people with lupus have some skin symptoms. The three main categories of lesions are chronic cutaneous (discoid) lupus, subacute cutaneous lupus, and acute cutaneous lupus. People with discoid lupus may exhibit thick, red scaly patches on the skin. Similarly, subacute cutaneous lupus manifests as red, scaly patches of skin but with distinct edges. Acute cutaneous lupus manifests as a rash. Some have the classic malar rash (commonly known as the butterfly rash) associated with the disease.[14] This rash occurs in 30 to 60% of people with SLE.[15] Hair loss, mouth and nasal ulcers, and lesions on the skin are other possible manifestations.[16] ### Muscles and bones The most commonly sought medical attention is for joint pain, with the small joints of the hand and wrist usually affected, although all joints are at risk. More than 90 percent of those affected will experience joint or muscle pain at some time during the course of their illness.[17] Unlike rheumatoid arthritis, lupus arthritis is less disabling and usually does not cause severe destruction of the joints. Fewer than ten percent of people with lupus arthritis will develop deformities of the hands and feet.[17] People with SLE are at particular risk of developing osteoarticular tuberculosis.[18] A possible association between rheumatoid arthritis and SLE has been suggested,[19] and SLE may be associated with an increased risk of bone fractures in relatively young women.[20] ### Blood Anemia is common in children with SLE[21] and develops in about 50% of cases.[22] Low platelet count and white blood cell count may be due to the disease or a side effect of pharmacological treatment. People with SLE may have an association with antiphospholipid antibody syndrome[23] (a thrombotic disorder), wherein autoantibodies to phospholipids are present in their serum. Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged partial thromboplastin time (which usually occurs in hemorrhagic disorders) and a positive test for antiphospholipid antibodies; the combination of such findings have earned the term "lupus anticoagulant-positive". Another autoantibody finding in SLE is the anti-cardiolipin antibody, which can cause a false positive test for syphilis.[citation needed] ### Heart SLE may cause pericarditis—inflammation of the outer lining surrounding the heart, myocarditis—inflammation of the heart muscle, or endocarditis—inflammation of the inner lining of the heart. The endocarditis of SLE is non-infectious, and is also called (Libman–Sacks endocarditis). It involves either the mitral valve or the tricuspid valve. Atherosclerosis also occurs more often and advances more rapidly than in the general population.[24][25] ### Lungs SLE can cause pleuritic pain as well as inflammation of the pleurae known as pleurisy, which can rarely give rise to shrinking lung syndrome involving a reduced lung volume.[26][27] Other associated lung conditions include pneumonitis, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, and pulmonary hemorrhage. ### Kidneys Painless passage of blood or protein in the urine may often be the only presenting sign of kidney involvement. Acute or chronic renal impairment may develop with lupus nephritis, leading to acute or end-stage kidney failure. Because of early recognition and management of SLE with immunosuppressive drugs or corticosteroids,[28] end-stage renal failure occurs in less than 5%[29][30] of cases; except in the black population, where the risk is many times higher. The histological hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities.[31] This finding is due to immune complex deposition along the glomerular basement membrane, leading to a typical granular appearance in immunofluorescence testing. ### Neuropsychiatric Further information: Neuropsychiatric systemic lupus erythematosus Neuropsychiatric syndromes can result when SLE affects the central or peripheral nervous system. The American College of Rheumatology defines 19 neuropsychiatric syndromes in systemic lupus erythematosus.[32] The diagnosis of neuropsychiatric syndromes concurrent with SLE (now termed as NPSLE),[33] is one of the most difficult challenges in medicine, because it can involve so many different patterns of symptoms, some of which may be mistaken for signs of infectious disease or stroke.[34] A common neurological disorder people with SLE have is headache,[35] although the existence of a specific lupus headache and the optimal approach to headache in SLE cases remains controversial.[36] Other common neuropsychiatric manifestations of SLE include cognitive dysfunction, mood disorder, cerebrovascular disease,[35] seizures, polyneuropathy,[35] anxiety disorder, psychosis, depression, and in some extreme cases, personality disorders.[37] Steroid psychosis can also occur as a result of treating the disease.[33] It can rarely present with intracranial hypertension syndrome, characterized by an elevated intracranial pressure, papilledema, and headache with occasional abducens nerve paresis, absence of a space-occupying lesion or ventricular enlargement, and normal cerebrospinal fluid chemical and hematological constituents.[38] More rare manifestations are acute confusional state, Guillain–Barré syndrome, aseptic meningitis, autonomic disorder, demyelinating syndrome, mononeuropathy (which might manifest as mononeuritis multiplex), movement disorder (more specifically, chorea), myasthenia gravis, myelopathy, cranial neuropathy and plexopathy. Neurological disorders contribute to a significant percentage of morbidity and mortality in people with lupus.[39] As a result, the neural side of lupus is being studied in hopes of reducing morbidity and mortality rates.[32] One aspect of this disease is severe damage to the epithelial cells of the blood–brain barrier. In certain regions, depression affects up to 60% of women with SLE.[40] ### Eyes Eye involvement is seen in up to one-third of people. The most common diseases are dry eye syndrome and secondary Sjögren's syndrome, but episcleritis, scleritis, retinopathy (more often affecting both eyes than one), ischemic optic neuropathy, retinal detachment, and secondary angle-closure glaucoma may occur. In addition, the medications used to treat SLE can cause eye disease: long-term glucocorticoid use can cause cataracts and secondary open-angle glaucoma, and long-term hydroxychloroquine treatment can cause vortex keratopathy and maculopathy.[41] ### Reproductive Further information: Systemic lupus erythematosus and pregnancy While most pregnancies have positive outcomes there is a greater risk of adverse events occurring during pregnancy.[42] SLE causes an increased rate of fetal death in utero and spontaneous abortion (miscarriage). The overall live-birth rate in people with SLE has been estimated to be 72%.[43] Pregnancy outcome appears to be worse in people with SLE whose disease flares up during pregnancy.[44] Neonatal lupus is the occurrence of SLE symptoms in an infant born from a mother with SLE, most commonly presenting with a rash resembling discoid lupus erythematosus, and sometimes with systemic abnormalities such as heart block or enlargement of the liver and spleen.[45] Neonatal lupus is usually benign and self-limited.[45] ### Systemic Fatigue in SLE is probably multifactorial and has been related to not only disease activity or complications such as anemia or hypothyroidism, but also to pain, depression, poor sleep quality, poor physical fitness and lack of social support.[46][47] ## Causes SLE is presumably caused by a genetic susceptibility coupled with an environmental trigger which results in defects in the immune system. One of the factors associated with SLE is vitamin D deficiency.[48] ### Genetics SLE does run in families, but no single causal gene has been identified. Instead, multiple genes appear to influence a person's chance of developing lupus when triggered by environmental factors. HLA class I, class II, and class III genes are associated with SLE, but only classes I and II contribute independently to increased risk of SLE.[49] Other genes which contain risk variants for SLE are IRF5, PTPN22, STAT4,[50] CDKN1A,[51] ITGAM, BLK,[50] TNFSF4 and BANK1.[52] Some of the susceptibility genes may be population specific.[50] Genetic studies of the rates of disease in families supports the genetic basis of this disease with a heritability of >66%.[53] Identical (monozygotic) twins were found to share susceptibility to the disease at >35% rate compared to fraternal (dizygotic) twins and other full siblings who only showed a 2–5% concordance in shared inheritance.[53] Since SLE is associated with many genetic regions, it is likely an oligogenic trait, meaning that there are several genes that control susceptibility to the disease.[54] SLE is regarded as a prototype disease due to the significant overlap in its symptoms with other autoimmune diseases.[55] ### Drug reactions Drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being treated for a long-term illness. Drug-induced lupus mimics SLE. However, symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped. More than 38 medications can cause this condition, the most common of which are procainamide, isoniazid, hydralazine, quinidine, and phenytoin.[56][11] ### Non-systemic forms of lupus Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed by biopsy of rash on the face, neck, scalp or arms. Approximately 5% of people with DLE progress to SLE.[57] ## Pathophysiology SLE is triggered by environmental factors that are unknown. In SLE, the body's immune system produces antibodies against itself, particularly against proteins in the cell nucleus. These antibody attacks are the immediate cause of SLE.[11][58][59] SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response with potential type II involvement.[60] Reticulate and stellate acral pigmentation should be considered a possible manifestation of SLE and high titers of anti-cardiolipin antibodies, or a consequence of therapy.[61] People with SLE have intense polyclonal B-cell activation, with a population shift towards immature B cells. Memory B cells with increased CD27+/IgD—are less susceptible to immunosuppression. CD27-/IgD- memory B cells are associated with increased disease activity and renal lupus. T cells, which regulate B-cell responses and infiltrate target tissues, have defects in signaling, adhesion, co-stimulation, gene transcription, and alternative splicing. The cytokines B-lymphocyte stimulator (BLys, also known as B-cell activating factor (BAFF), interleukin 6, interleukin 17, interleukin 18, type I interferons, and tumor necrosis factor α (TNFα) are involved in the inflammatory process and are potential therapeutic targets.[4][62][63] In the complement system low C3 levels are associated with systemic lupus erythematosus[64] ### Cell death signaling * Apoptosis is increased in monocytes and keratinocytes * Expression of Fas by B cells and T cells is increased * There are correlations between the apoptotic rates of lymphocytes and disease activity. * Necrosis is increased in T lymphocytes. Tingible body macrophages (TBMs) – large phagocytic cells in the germinal centers of secondary lymph nodes – express CD68 protein. These cells normally engulf B cells that have undergone apoptosis after somatic hypermutation. In some people with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells. Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells that may have randomly acquired self-specificity through somatic hypermutation.[65] Necrosis, a pro-inflammatory form of cell death, is increased in T lymphocytes, due to mitochondrial dysfunction, oxidative stress, and depletion of ATP.[66] ### Clearance deficiency Clearance deficiency Impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease. This includes deficient phagocytic activity and scant serum components in addition to increased apoptosis. SLE is associated with defects in apoptotic clearance, and the damaging effects caused by apoptotic debris. Early apoptotic cells express “eat-me” signals, of cell-surface proteins such as phosphatidylserine, that prompt immune cells to engulf them. Apoptotic cells also express “find-me” signals, to attract macrophages and dendritic cells. When apoptotic material is not removed correctly by phagocytes, they are captured instead by antigen-presenting cells, which leads to development of antinuclear antibodies.[4] Monocytes isolated from whole blood of people with SLE show reduced expression of CD44 surface molecules involved in the uptake of apoptotic cells. Most of the monocytes and tingible body macrophages (TBMs), which are found in the germinal centres of lymph nodes, even show a definitely different morphology; they are smaller or scarce and die earlier. Serum components like complement factors, CRP, and some glycoproteins are, furthermore, decisively important for an efficiently operating phagocytosis. With SLE, these components are often missing, diminished, or inefficient. Recent research has found an association between certain people with lupus (especially those with lupus nephritis) and an impairment in degrading neutrophil extracellular traps (NETs). These were due to DNAse1 inhibiting factors, or NET protecting factors in people's serum, rather than abnormalities in the DNAse1 itself.[67] DNAse1 mutations in lupus have so far only been found in some Japanese cohorts.[68] The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a progression of the apoptosis process and finally to secondary necrosis of the cells if this ability is disturbed. Necrotic cells release nuclear fragments as potential autoantigens, as well as internal danger signals, inducing maturation of dendritic cells (DCs), since they have lost their membranes' integrity. Increased appearance of apoptotic cells also stimulates inefficient clearance. That leads to maturation of DCs and also to the presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules. Autoimmunity possibly results by the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells. B and T cell tolerance for apoptotic cells is abrogated, and the lymphocytes get activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated. A clearance deficiency in the skin for apoptotic cells has also been observed in people with cutaneous lupus erythematosus (CLE).[69] ### Germinal centers Germinal centres in a person with SLE and controls (schematic). Red: CD68 in tingible body macrophages; black: TUNEL positive apoptotic cells. 1) Healthy donors with florid germinal centres show giant tingible body macrophages (TBM) containing ingested apoptotic cells and no uningested apoptotic cells outside the TBM. 2) People with follicular lymphoma show small tingible body macrophages (TBM) containing few ingested apoptotic cells however, there are no uningested apoptotic cells outside the TBM. 3) Some with SLE (1) show lack of TBM and many uningested apoptotic cells decorating the surfaces of spindle-shaped cell, presumably follicular dendritic cells (SLE 1). 4) Some people with SLE show TBM containing few ingested apoptotic cells and many uningested apoptotic cells outside the TBM (SLE 2). However, about 50 % of people with SLE show rather normal germinal centre. In healthy conditions, apoptotic lymphocytes are removed in germinal centers (GC) by specialized phagocytes, the tingible body macrophages (TBM), which is why no free apoptotic and potential autoantigenic material can be seen. In some people with SLE, buildup of apoptotic debris can be observed in GC because of an ineffective clearance of apoptotic cells. In close proximity to TBM, follicular dendritic cells (FDC) are localised in GC, which attach antigen material to their surface and, in contrast to bone marrow-derived DC, neither take it up nor present it via MHC molecules. Autoreactive B cells can accidentally emerge during somatic hypermutation and migrate into the germinal center light zone. Autoreactive B cells, maturated coincidentally, normally do not receive survival signals by antigen planted on follicular dendritic cells and perish by apoptosis. In the case of clearance deficiency, apoptotic nuclear debris accumulates in the light zone of GC and gets attached to FDC. This serves as a germinal centre survival signal for autoreactive B-cells. After migration into the mantle zone, autoreactive B cells require further survival signals from autoreactive helper T cells, which promote the maturation of autoantibody-producing plasma cells and B memory cells. In the presence of autoreactive T cells, a chronic autoimmune disease may be the consequence. ### Anti-nRNP autoimmunity Anti-nRNP autoantibodies to nRNP A and nRNP C initially targeted restricted, proline-rich motifs. Antibody binding subsequently spread to other epitopes. The similarity and cross-reactivity between the initial targets of nRNP and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading.[70] ### Others Elevated expression of HMGB1 was found in the sera of people and mice with systemic lupus erythematosus, high mobility group box 1 (HMGB1) is a nuclear protein participating in chromatin architecture and transcriptional regulation. Recently, there is increasing evidence HMGB1 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases due to its inflammatory and immune stimulating properties.[71] ## Diagnosis Micrograph showing vacuolar interface dermatitis, as may be seen in SLE. H&E stain. Micrograph of a section of human skin prepared for direct immunofluorescence using an anti-IgG antibody. The skin is from a person with systemic lupus erythematosus and shows IgG deposits at two different places. The first is a bandlike deposit along the epidermal basement membrane ("lupus band test" is positive); the second is within the nuclei of the epidermal cells (antinuclear antibodies are present). ### Laboratory tests Antinuclear antibody (ANA) testing and anti-extractable nuclear antigen (anti-ENA) form the mainstay of serologic testing for SLE. If ANA is negative the disease can be ruled out.[72] Several techniques are used to detect ANAs. The most widely used is indirect immunofluorescence (IF). The pattern of fluorescence suggests the type of antibody present in the people's serum. Direct immunofluorescence can detect deposits of immunoglobulins and complement proteins in the people's skin. When skin not exposed to the sun is tested, a positive direct IF (the so-called lupus band test) is an evidence of systemic lupus erythematosus.[73] ANA screening yields positive results in many connective tissue disorders and other autoimmune diseases, and may occur in normal individuals. Subtypes of antinuclear antibodies include anti-Smith and anti-double stranded DNA (dsDNA) antibodies (which are linked to SLE) and anti-histone antibodies (which are linked to drug-induced lupus). Anti-dsDNA antibodies are highly specific for SLE; they are present in 70% of cases, whereas they appear in only 0.5% of people without SLE.[11] The anti-dsDNA antibody titers also tend to reflect disease activity, although not in all cases.[11] Other ANA that may occur in people with SLE are anti-U1 RNP (which also appears in systemic sclerosis and mixed connective tissue disease), SS-A (or anti-Ro) and SS-B (or anti-La; both of which are more common in Sjögren's syndrome). SS-A and SS-B confer a specific risk for heart conduction block in neonatal lupus.[74] Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and kidney function (disturbed if the kidney is involved), liver enzymes, and complete blood count. The lupus erythematosus (LE) cell test was commonly used for diagnosis, but it is no longer used because the LE cells are only found in 50–75% of SLE cases and they are also found in some people with rheumatoid arthritis, scleroderma, and drug sensitivities. Because of this, the LE cell test is now performed only rarely and is mostly of historical significance.[75] ### Diagnostic criteria Some physicians make a diagnosis on the basis of the American College of Rheumatology (ACR) classification criteria. The criteria, however, were established mainly for use in scientific research including use in randomized controlled trials which require higher confidence levels, so many people with SLE may not pass the full criteria. #### Criteria The American College of Rheumatology (ACR) established eleven criteria in 1982,[76] which were revised in 1997[77] as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individuals and do not do well in that capacity. For the purpose of identifying people for clinical studies, a person has SLE if any 4 out of 11 symptoms are present simultaneously or serially on two separate occasions. 1. Malar rash (rash on cheeks); sensitivity = 57%; specificity = 96%.[78] 2. Discoid rash (red, scaly patches on skin that cause scarring); sensitivity = 18%; specificity = 99%.[78] 3. Serositis: Pleurisy (inflammation of the membrane around the lungs) or pericarditis (inflammation of the membrane around the heart); sensitivity = 56%; specificity = 86% (pleural is more sensitive; cardiac is more specific).[78] 4. Oral ulcers (includes oral or nasopharyngeal ulcers); sensitivity = 27%; specificity = 96%.[78] 5. Arthritis: nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion; sensitivity = 86%; specificity = 37%.[78] 6. Photosensitivity (exposure to ultraviolet light causes rash, or other symptoms of SLE flareups); sensitivity = 43%; specificity = 96%.[78] 7. Blood—hematologic disorder—hemolytic anemia (low red blood cell count), leukopenia (white blood cell count<4000/µl), lymphopenia (<1500/µl), or low platelet count (<100000/µl) in the absence of offending drug; sensitivity = 59%; specificity = 89%.[78] Hypocomplementemia is also seen, due to either consumption of C3[79] and C4 by immune complex-induced inflammation or to congenitally complement deficiency, which may predispose to SLE. 8. Renal disorder: More than 0.5 g per day protein in urine or cellular casts seen in urine under a microscope; sensitivity = 51%; specificity = 94%.[78] 9. Antinuclear antibody test positive; sensitivity = 99%; specificity = 49%.[78] 10. Immunologic disorder: Positive anti-Smith, anti-ds DNA, antiphospholipid antibody, or false positive serological test for syphilis; sensitivity = 85%; specificity = 93%.[78] Presence of anti-ss DNA in 70% of cases (though also positive with rheumatic disease and healthy persons).[80] 11. Neurologic disorder: Seizures or psychosis; sensitivity = 20%; specificity = 98%.[78] Other than the ACR criteria, people with lupus may also have:[81] * fever (over 100 °F/ 37.7 °C) * extreme fatigue * hair loss * fingers turning white or blue when cold (Raynaud's phenomenon) #### Criteria for individual diagnosis Some people, especially those with antiphospholipid syndrome, may have SLE without four of the above criteria, and also SLE may present with features other than those listed in the criteria.[82][83][84] Recursive partitioning has been used to identify more parsimonious criteria.[78] This analysis presented two diagnostic classification trees: 1. Simplest classification tree: SLE is diagnosed if a person has an immunologic disorder (anti-DNA antibody, anti-Smith antibody, false positive syphilis test, or LE cells) or malar rash. It has sensitivity = 92% and specificity = 92%. 2. Full classification tree: Uses 6 criteria. It has sensitivity = 97% and specificity = 95%. Other alternative criteria have been suggested, e.g. the St. Thomas' Hospital "alternative" criteria in 1998.[85] ## Treatment The treatment of SLE involves preventing flares and reducing their severity and duration when they occur. Treatment can include corticosteroids and anti-malarial drugs. Certain types of lupus nephritis such as diffuse proliferative glomerulonephritis require intermittent cytotoxic drugs. These drugs include cyclophosphamide and mycophenolate. Cyclophosphamide increases the risk of developing infections, pancreas problems, high blood sugar, and high blood pressure.[86] Hydroxychloroquine was approved by the FDA for lupus in 1955.[87] Some drugs approved for other diseases are used for SLE 'off-label'. In November 2010, an FDA advisory panel recommended approving belimumab (Benlysta) as a treatment for the pain and flare-ups common in lupus. The drug was approved by the FDA in March 2011.[88][89] ### Medications Due to the variety of symptoms and organ system involvement with SLE, its severity in an individual must be assessed in order to successfully treat SLE. Mild or remittent disease may, sometimes, be safely left untreated. If required, nonsteroidal anti-inflammatory drugs and antimalarials may be used. Medications such as prednisone, mycophenolic acid and tacrolimus have been used in the past. #### Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce the incidence of flares, the progress of the disease, and the need for steroid use; when flares occur, they are treated with corticosteroids. DMARDs commonly in use are antimalarials such as hydroxychloroquine and immunosuppressants (e.g. methotrexate and azathioprine). Hydroxychloroquine is an FDA-approved antimalarial used for constitutional, cutaneous, and articular manifestations. Hydroxychloroquine has relatively few side effects, and there is evidence that it improves survival among people who have SLE.[87] Cyclophosphamide is used for severe glomerulonephritis or other organ-damaging complications. Mycophenolic acid is also used for treatment of lupus nephritis, but it is not FDA-approved for this indication, and FDA is investigating reports that it may be associated with birth defects when used by pregnant women.[90] #### Immunosuppressive drugs In more severe cases, medications that modulate the immune system (primarily corticosteroids and immunosuppressants) are used to control the disease and prevent recurrence of symptoms (known as flares). Depending on the dosage, people who require steroids may develop Cushing's syndrome, symptoms of which may include obesity, puffy round face, diabetes mellitus, increased appetite, difficulty sleeping and osteoporosis. These may subside if and when the large initial dosage is reduced, but long-term use of even low doses can cause elevated blood pressure and cataracts. Numerous new immunosuppressive drugs are being actively tested for SLE. Rather than suppressing the immune system nonspecifically, as corticosteroids do, they target the responses of individual [types of] immune cells. Some of these drugs are already FDA-approved for treatment of rheumatoid arthritis, however due to high-toxicity, its use is limited.[87][91] #### Analgesia Since a large percentage of people with SLE have varying amounts of chronic pain, stronger prescription analgesics (painkillers) may be used if over-the-counter drugs (mainly nonsteroidal anti-inflammatory drugs) do not provide effective relief. Potent NSAIDs such as indomethacin and diclofenac are relatively contraindicated for people with SLE because they increase the risk of kidney failure and heart failure.[87] Pain is typically treated with opioids, varying in potency based on the severity of symptoms. When opioids are used for prolonged periods, drug tolerance, chemical dependency, and addiction may occur. Opiate addiction is not typically a concern since the condition is not likely to ever completely disappear. Thus, lifelong treatment with opioids is fairly common for chronic pain symptoms, accompanied by periodic titration that is typical of any long-term opioid regimen. #### Intravenous immunoglobulins (IVIGs) Intravenous immunoglobulins may be used to control SLE with organ involvement, or vasculitis. It is believed that they reduce antibody production or promote the clearance of immune complexes from the body, even though their mechanism of action is not well understood.[92] Unlike immunosuppressives and corticosteroids, IVIGs do not suppress the immune system, so there is less risk of serious infections with these drugs.[93] ### Lifestyle changes Avoiding sunlight in SLE is critical, since sunlight is known to exacerbate skin manifestations of the disease. Avoiding activities that induce fatigue is also important, since those with SLE fatigue easily and it can be debilitating. These two problems can lead to people becoming housebound for long periods of time. Drugs unrelated to SLE should be prescribed only when known not to exacerbate the disease. Occupational exposure to silica, pesticides, and mercury can also worsen the disease.[62] ### Kidney transplantation Kidney transplants are the treatment of choice for end-stage kidney disease, which is one of the complications of lupus nephritis, but the recurrence of the full disease is common in up to 30% of people.[94] ### Antiphospholipid syndrome Approximately 20% of people with SLE have clinically significant levels of antiphospholipid antibodies, which are associated with antiphospholipid syndrome.[95] Antiphospholipid syndrome is also related to the onset of neural lupus symptoms in the brain. In this form of the disease the cause is very different from lupus: thromboses (blood clots or "sticky blood") form in blood vessels, which prove to be fatal if they move within the blood stream.[82] If the thromboses migrate to the brain, they can potentially cause a stroke by blocking the blood supply to the brain. If this disorder is suspected in people, brain scans are usually required for early detection. These scans can show localized areas of the brain where blood supply has not been adequate. The treatment plan for these people requires anticoagulation. Often, low-dose aspirin is prescribed for this purpose, although for cases involving thrombosis anticoagulants such as warfarin are used.[96] ### Management of pregnancy Further information: Systemic lupus erythematosus and pregnancy While most infants born to mothers who have SLE are healthy, pregnant mothers with SLE should remain under medical care until delivery. Neonatal lupus is rare, but identification of mothers at highest risk for complications allows for prompt treatment before or after birth. In addition, SLE can flare up during pregnancy, and proper treatment can maintain the health of the mother longer. Women pregnant and known to have anti-Ro (SSA) or anti-La antibodies (SSB) often have echocardiograms during the 16th and 30th weeks of pregnancy to monitor the health of the heart and surrounding vasculature.[97] Contraception and other reliable forms of pregnancy prevention is routinely advised for women with SLE, since getting pregnant during active disease was found to be harmful. Lupus nephritis was the most common manifestation. ## Prognosis No cure is available for SLE but there are many treatments for the disease.[1] In the 1950s, most people diagnosed with SLE lived fewer than five years. Today, over 90% now survive for more than ten years, and many live relatively symptom-free. 80–90% can expect to live a normal lifespan.[98] Mortality rates are however elevated compared to people without SLE.[99] Prognosis is typically worse for men and children than for women; however, if symptoms are present after age 60, the disease tends to run a more benign course. Early mortality, within 5 years, is due to organ failure or overwhelming infections, both of which can be altered by early diagnosis and treatment. The mortality risk is fivefold when compared to the normal population in the late stages, which can be attributed to cardiovascular disease from accelerated atherosclerosis, the leading cause of death for people with SLE.[87] To reduce the potential for cardiovascular issues, high blood pressure and high cholesterol should be prevented or treated aggressively. Steroids should be used at the lowest dose for the shortest possible period, and other drugs that can reduce symptoms should be used whenever possible.[87] ## Epidemiology The global rates of SLE are approximately 20–70 per 100,000 people. In females, the rate is highest between 45 and 64 years of age. The lowest overall rate exists in Iceland and Japan. The highest rates exist in the US and France. However, there is not sufficient evidence to conclude why SLE is less common in some countries compared to others; it could be the environmental variability in these countries. For example, different countries receive different levels of sunlight, and exposure to UV rays affects dermatological symptoms of SLE. Certain studies hypothesize that a genetic connection exists between race and lupus which affects disease prevalence. If this is true, the racial composition of countries affects disease, and will cause the incidence in a country to change as the racial makeup changes. In order to understand if this is true, countries with largely homogenous and racially stable populations should be studied to better understand incidence.[2] Rates of disease in the developing world are unclear.[7] The rate of SLE varies between countries, ethnicity, and sex, and changes over time.[100] In the United States, one estimate of the rate of SLE is 53 per 100,000;[100] another estimate places the total affected population at 322,000 to over 1 million (98 to over 305 per 100,000).[101] In Northern Europe the rate is about 40 per 100,000 people.[102] SLE occurs more frequently and with greater severity among those of non-European descent.[101] That rate has been found to be as high as 159 per 100,000 among those of Afro-Caribbean descent.[100] Childhood-onset systemic lupus erythematosus generally presents between the ages of 3 and 15 and is four times more common in girls.[103] While the onset and persistence of SLE can show disparities between genders, socioeconomic status also plays a major role. Women with SLE and of lower socioeconomic status have been shown to have higher depression scores, higher body mass index, and more restricted access to medical care than women of higher socioeconomic statuses with the illness. People with SLE had more self-reported anxiety and depression scores if they were from a lower socioeconomic status.[104] ### Ethnicity There are assertions that race affects the rate of SLE. However, a 2010 review of studies which correlate race and SLE identified several sources of systematic and methodological error, indicating that the connection between race and SLE may be spurious.[105] For example, studies show that social support is a modulating factor which buffers against SLE-related damage and maintains physiological functionality.[105] Studies have not been conducted to determine whether people of different racial backgrounds receive differing levels of social support.[105] If there is a difference, this could act as a confounding variable in studies correlating race and SLE. Another caveat to note when examining studies about SLE is that symptoms are often self-reported. This process introduces additional sources of methodological error. Studies have shown that self-reported data is affected by more than just the patients experience with the disease- social support, the level of helplessness, and abnormal illness-related behaviors also factor into a self-assessment. Additionally, other factors like the degree of social support that a person receives, socioeconomic status, health insurance, and access to care can contribute to an individual's disease progression.[105][106] Racial differences in lupus progression have not been found in studies that control for the socioeconomic status [SES] of participants.[105][107] Studies that control for the SES of its participants have found that non-white people have more abrupt disease onset compared to white people and that their disease progresses more quickly. Non-white patients often report more hematological, serosal, neurological, and renal symptoms. However, the severity of symptoms and mortality are both similar in white and non-white patients. Studies that report different rates of disease progression in late-stage SLE are most likely reflecting differences in socioeconomic status and the corresponding access to care.[105] The people who receive medical care have often accrued less disease-related damage and are less likely to be below the poverty line.[107] Additional studies have found that education, marital status, occupation, and income create a social context which contributes to disease progression.[105] ### Sex SLE, like many autoimmune diseases, affects females more frequently than males, at a rate of about 9 to 1.[6][100] The X chromosome carries immunological related genes, which can mutate and contribute to the onset of SLE. The Y chromosome has no identified mutations associated with autoimmune disease.[108] Hormonal mechanisms could explain the increased incidence of SLE in females. The onset of SLE could be attributed to the elevated hydroxylation of estrogen and the abnormally decreased levels of androgens in females. In addition, differences in GnRH signalling have also shown to contribute to the onset of SLE. While females are more likely to relapse than males, the intensity of these relapses is the same for both sexes.[13] In addition to hormonal mechanisms, specific genetic influences found on the X chromosome may also contribute to the development of SLE. Studies indicate that the X chromosome can determine the levels of sex hormones. A study has shown an association between Klinefelter syndrome and SLE. XXY males with SLE have an abnormal X–Y translocation resulting in the partial triplication of the PAR1 gene region.[109] ### Changing rate of disease The rate of SLE in the United States increased from 1.0 in 1955 to 7.6 in 1974. Whether the increase is due to better diagnosis or to increasing frequency of the disease is unknown.[100] ## History A historical drawing of lupus erythematosus as it was once considered as a non-fatal disfiguring skin disease.[110] The history of SLE can be divided into three periods: classical, neoclassical, and modern. In each period, research and documentation advanced the understanding and diagnosis of SLE, leading to its classification as an autoimmune disease in 1851, and to the various diagnostic options and treatments now available to people with SLE. The advances made by medical science in the diagnosis and treatment of SLE have dramatically improved the life expectancy of a person diagnosed with SLE.[111] ### Etymology There are several explanations ventured for the term lupus erythematosus. Lupus is Latin for "wolf",[112][8] and "erythro" is derived from ερυθρός, Greek for "red." All explanations originate with the reddish, butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks. More likely is that it is derived from the similarity in distribution to lupus vulgaris or chronic facial tuberculosis where the lesions are ragged and punched out and are said to resemble the bite of a wolf. ### Classical period The classical period began when the disease was first recognized in the Middle Ages. The term lupus is attributed to 12th-century Italian physician Rogerius Frugard, who used it to describe ulcerating sores on the legs of people.[113] No formal treatment for the disease existed and the resources available to physicians to help people were limited.[114] ### Neoclassical period The neoclassical period began in 1851 when the skin disease which is now known as discoid lupus was documented by the French physician, Pierre Cazenave. Cazenave termed the illness lupus and added the word erythematosus to distinguish this disease from other illnesses that affected the skin except they were infectious.[115] Cazenave observed the disease in several people and made very detailed notes to assist others in its diagnosis. He was one of the first to document that lupus affected adults from adolescence into the early thirties and that the facial rash is its most distinguishing feature.[116] Research and documentation of the disease continued in the neoclassical period with the work of Ferdinand von Hebra and his son-in-law, Moritz Kaposi. They documented the physical effects of lupus as well as some insights into the possibility that the disease caused internal trauma. Von Hebra observed that lupus symptoms could last many years and that the disease could go "dormant" after years of aggressive activity and then re-appear with symptoms following the same general pattern. These observations led Hebra to term lupus a chronic disease in 1872.[117] Kaposi observed that lupus assumed two forms: the skin lesions (now known as discoid lupus) and a more aggravated form that affected not only the skin but also caused fever, arthritis, and other systemic disorders in people.[118] The latter also presented a rash confined to the face, appearing on the cheeks and across the bridge of the nose; he called this the "butterfly rash". Kaposi also observed those patients who developed the butterfly rash were often afflicted with another disease such as tuberculosis, anemia, or chlorisis which often caused death.[116] Kaposi was one of the first people to recognize what is now termed systemic lupus erythematosus in his documentation of the remitting and relapsing nature of the disease and the relationship of skin and systemic manifestations during disease activity.[119] The 19th century's research into lupus continued with the work of Sir William Osler who, in 1895, published the first of his three papers about the internal complications of erythema exudativum multiforme. Not all the patient cases in his paper had SLE but Osler's work expanded the knowledge of systemic diseases and documented extensive and critical visceral complications for several diseases including lupus.[116] Noting that many people with lupus had a disease that not only affected the skin but many other organs in the body as well, Osler added the word "systemic" to the term lupus erythematosus to distinguish this type of disease from discoid lupus erythematosus.[120] Osler's second paper noted that reoccurrence is a special feature of the disease and that attacks can be sustained for months or even years. Further study of the disease led to a third paper, published in 1903, documenting afflictions such as arthritis, pneumonia, the inability to form coherent ideas, delirium, and central nervous system damage as all affecting patients diagnosed with SLE.[116] ### Modern period The modern period, beginning in 1920, saw major developments in research into the cause and treatment of discoid and systemic lupus. Research conducted in the 1920s and 1930s led to the first detailed pathologic descriptions of lupus and demonstrated how the disease affected the kidney, heart, and lung tissue.[121] A major breakthrough was made in 1948 with the discovery of the LE cell (the lupus erythematosus cell—a misnomer, as it occurs with other diseases as well). Discovered by a team of researchers at the Mayo Clinic, they discovered that the white blood cells contained the nucleus of another cell that was pushing against the white's cell proper nucleus.[122] Noting that the invading nucleus was coated with antibody that allowed it to be ingested by a phagocytic or scavenger cell, they named the antibody that causes one cell to ingest another the LE factor and the two nuclei cell result in the LE cell.[123] The LE cell, it was determined, was a part of an anti-nuclear antibody (ANA) reaction; the body produces antibodies against its own tissue. This discovery led to one of the first definitive tests for lupus since LE cells are found in approximately 60% of all people diagnosed with lupus.[124] The LE cell test is rarely performed as a definitive lupus test today as LE cells do not always occur in people with SLE and can occur in individuals with other autoimmune diseases. Their presence can be helpful in establishing a diagnosis but no longer indicates a definitive SLE diagnosis. The discovery of the LE cell led to further research and this resulted in more definitive tests for lupus. Building on the knowledge that those with SLE had auto-antibodies that would attach themselves to the nuclei of normal cells, causing the immune system to send white blood cells to fight off these "invaders", a test was developed to look for the anti-nuclear antibody (ANA) rather than the LE cell specifically. This ANA test was easier to perform and led not only to a definitive diagnosis of lupus but also many other related diseases. This discovery led to the understanding of what is now known as autoimmune diseases.[125] To ensure that the person has lupus and not another autoimmune disease, the American College of Rheumatology (ACR) established a list of clinical and immunologic criteria that, in any combination, point to SLE. The criteria include symptoms that the person can identify (e.g. pain) and things that a physician can detect in a physical examination and through laboratory test results. The list was originally compiled in 1971, initially revised in 1982, and further revised and improved in 2009.[126] Medical historians have theorized that people with porphyria (a disease that shares many symptoms with SLE) generated folklore stories of vampires and werewolves, due to the photosensitivity, scarring, hair growth, and porphyrin brownish-red stained teeth in severe recessive forms of porphyria (or combinations of the disorder, known as dual, homozygous, or compound heterozygous porphyrias).[127] Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. 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Retrieved 8 May 2019. ## External links Classification D * ICD-10: M32 * ICD-9-CM: 710.0 * OMIM: 152700 * MeSH: D008180 * DiseasesDB: 12782 External resources * MedlinePlus: 000435 * eMedicine: med/2228 emerg/564 * Patient UK: Lupus * Lupus at Curlie * The dictionary definition of lupus at Wiktionary * Media related to Systemic lupus erythematosus at Wikimedia Commons * Systemic Lupus Erythematosus at National Institute of Arthritis and Musculoskeletal and Skin Diseases * Biology portal * Medicine portal * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Dermatitis and eczema Atopic dermatitis * Besnier's prurigo Seborrheic dermatitis * Pityriasis simplex capillitii * Cradle cap Contact dermatitis (allergic, irritant) * plants: Urushiol-induced contact dermatitis * African blackwood dermatitis * Tulip fingers * other: Abietic acid dermatitis * Diaper rash * Airbag dermatitis * Baboon syndrome * Contact stomatitis * Protein contact dermatitis Eczema * Autoimmune estrogen dermatitis * Autoimmune progesterone dermatitis * Breast eczema * Ear eczema * Eyelid dermatitis * Topical steroid addiction * Hand eczema * Chronic vesiculobullous hand eczema * Hyperkeratotic hand dermatitis * Autosensitization dermatitis/Id reaction * Candidid * Dermatophytid * Molluscum dermatitis * Circumostomy eczema * Dyshidrosis * Juvenile plantar dermatosis * Nummular eczema * Nutritional deficiency eczema * Sulzberger–Garbe syndrome * Xerotic eczema Pruritus/Itch/ Prurigo * Lichen simplex chronicus/Prurigo nodularis * by location: Pruritus ani * Pruritus scroti * Pruritus vulvae * Scalp pruritus * Drug-induced pruritus * Hydroxyethyl starch-induced pruritus * Senile pruritus * Aquagenic pruritus * Aquadynia * Adult blaschkitis * due to liver disease * Biliary pruritus * Cholestatic pruritus * Prion pruritus * Prurigo pigmentosa * Prurigo simplex * Puncta pruritica * Uremic pruritus Other * substances taken internally: Bromoderma * Fixed drug reaction * Nummular dermatitis * Pityriasis alba * Papuloerythroderma of Ofuji * v * t * e Systemic connective tissue disorders General Systemic lupus erythematosus * Drug-induced SLE * Libman–Sacks endocarditis Inflammatory myopathy * Myositis * Dermatopolymyositis * Dermatomyositis/Juvenile dermatomyositis * Polymyositis* Inclusion body myositis Scleroderma * Systemic scleroderma * Progressive systemic sclerosis * CREST syndrome * Overlap syndrome / Mixed connective tissue disease Other hypersensitivity/autoimmune * Sjögren syndrome Other * Behçet's disease * Polymyalgia rheumatica * Eosinophilic fasciitis * Eosinophilia–myalgia syndrome * fibrillin * Marfan syndrome * Congenital contractural arachnodactyly * v * t * e Hypersensitivity and autoimmune diseases Type I/allergy/atopy (IgE) Foreign * Atopic eczema * Allergic urticaria * Allergic rhinitis (Hay fever) * Allergic asthma * Anaphylaxis * Food allergy * common allergies include: Milk * Egg * Peanut * Tree nut * Seafood * Soy * Wheat * Penicillin allergy Autoimmune * Eosinophilic esophagitis Type II/ADCC * * IgM * IgG Foreign * Hemolytic disease of the newborn Autoimmune Cytotoxic * Autoimmune hemolytic anemia * Immune thrombocytopenic purpura * Bullous pemphigoid * Pemphigus vulgaris * Rheumatic fever * Goodpasture syndrome * Guillain–Barré syndrome "Type V"/receptor * Graves' disease * Myasthenia gravis * Pernicious anemia Type III (Immune complex) Foreign * Henoch–Schönlein purpura * Hypersensitivity vasculitis * Reactive arthritis * Farmer's lung * Post-streptococcal glomerulonephritis * Serum sickness * Arthus reaction Autoimmune * Systemic lupus erythematosus * Subacute bacterial endocarditis * Rheumatoid arthritis Type IV/cell-mediated (T cells) Foreign * Allergic contact dermatitis * Mantoux test Autoimmune * Diabetes mellitus type 1 * Hashimoto's thyroiditis * Multiple sclerosis * Coeliac disease * Giant-cell arteritis * Postorgasmic illness syndrome * Reactive arthritis GVHD * Transfusion-associated graft versus host disease Unknown/ multiple Foreign * Hypersensitivity pneumonitis * Allergic bronchopulmonary aspergillosis * Transplant rejection * Latex allergy (I+IV) Autoimmune * Sjögren syndrome * Autoimmune hepatitis * Autoimmune polyendocrine syndrome * APS1 * APS2 * Autoimmune adrenalitis * Systemic autoimmune disease * v * t * e Lupus nephritis * Class I (Minimal mesangial glomerulonephritis) * Class II (Mesangial proliferative lupus nephritis) * Class III (Focal proliferative nephritis) * Class IV (Diffuse proliferative nephritis) * Class V (Membranous nephritis) * Class VI (Glomerulosclerosis) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Lupus	c0024141	4,331	wikipedia	https://en.wikipedia.org/wiki/Lupus	2021-01-18T19:09:01	{"gard": ["10253"], "mesh": ["D008180"], "umls": ["C0024141"], "orphanet": ["536"], "wikidata": ["Q1485"]}
A number sign (#) is used with this entry because of evidence that familial cold autoinflammatory syndrome-2 (FCAS2) is caused by heterozygous mutation in the NLRP12 gene (609648) on chromosome 19q13. Description Familial cold autoinflammatory syndrome-2 (FCAS2) is an autosomal dominant autoinflammatory disorder characterized by episodic and recurrent rash, urticaria, arthralgia, myalgia, and headache. In most patients, these episodes are accompanied by fever and serologic evidence of inflammation. Most, but not all, patients report exposure to cold as a trigger for the episodes. Additional features may include abdominal pain, thoracic pain, and sensorineural deafness. The age at onset is variable, ranging from the first year of life to middle age, and the severity and clinical manifestations are heterogeneous (summary by Shen et al., 2017). For a phenotypic description and a discussion of genetic heterogeneity of familial cold autoinflammatory syndrome, see FCAS1 (120100). Clinical Features Jeru et al. (2008) reported 2 unrelated families from Guadeloupe with a periodic fever syndrome. Inheritance was autosomal dominant. Affected 10-year-old twin boys in one family had onset in the first days of life of episodic fever, arthralgia, and myalgia. Episodes developed after generalized exposure to cold. Urticaria was observed 2 times in each patient, and both had bilateral sensorineural hearing loss. Headache and lower limb pain occurred during and between episodes. Serum C-reactive protein (CRP; 123260) and IgD were normal. The affected father had attacks lasting 2 to 3 days during childhood, and had episodes of fever and urticaria triggered by mild physical activity as an adult. His audiogram was normal. The proband of the second family was a 9-year-old girl with episodic fever since the first year of life. Episodes were triggered by cold exposure and associated with abdominal pain, vomiting, arthralgia, buccal aphthous ulcers, and lymphadenopathy. Serum CRP was found to be increased during attacks. Her father had attacks from age 5 to 12 years. Borghini et al. (2011) reported an Italian family in which 4 individuals had variable manifestations of FCAS2. The proband was a 32-year-old woman who experienced recurrent episodes of urticarial rash on the face, arms, and trunk associated with fever, arthralgias, myalgia, and headache since age 20 years. The clinical manifestations occurred exclusively during winter; she had complete well-being during the warm season. Fever episodes were associated with elevations in the levels of acute-phase reactants. She had a good response to steroid and antihistamine administration. Her father and paternal aunt had a similar phenotype with onset of features in childhood or infancy, although the father did not have episodes of fever, and the aunt developed optic neuritis. Both the father and aunt were treated with NSAIDs and occasionally steroids. The fourth patient, a 67-year-old paternal uncle of the proband, reported an urticarial-like rash in conjunction with episodes of fever, which he believed were associated with intercurrent viral or bacterial infections. He denied ever having any cold-induced features, and had no musculoskeletal or ocular manifestations. Jeru et al. (2011) reported 2 unrelated patients, from Armenia and Italy, respectively, with FCAS2. Both patients had onset of recurrent and episodic cold-induced myalgia, abdominal pain, and fever in the first years of life. The Italian patient also had associated adenopathy, malar rash, and buccal aphthosis, as well as increased CRP during the episodes, consistent with autoinflammation. Laboratory studies of CRP from the other patient were not available. Notably, neither patient had urticaria. Vitale et al. (2013) reported 6 unrelated Italian probands with FCAS2. The age of symptom onset ranged from 2 to 36 years, and the features included recurrent episodes of fever and cold-induced symptoms. Symptoms were variable, but included rash, urticaria, lymphadenopathy, headache, arthralgia, arthritis, myalgia, and fatigue. One patient had sensorineural hearing loss, and several showed increased acute phase response proteins. The patients showed a response to steroid treatment. Two patients had affected relatives with the mutation, but there were also unaffected mutation carriers in some families, consistent with incomplete penetrance. Xia et al. (2016) reported a 4-generation Chinese family in which 5 individuals had FCAS2. One older patient was deceased. The patients developed cold-associated urticarial rashes on the limbs and trunk in the first year of life. The symptomatic periods in these patients lasted for 12 to 24 hours and appeared a few hours after exposure to cold. The episodes were accompanied by fever and often by joint pain. Hearing loss, mental retardation, and renal disturbance were not observed in any of the affected individuals. Laboratory studies showed increased erythrocyte sedimentation rates and CRP levels in all 4 living patients. Shen et al. (2017) reported 3 unrelated Han Chinese patients with onset of features of FCAS2 in their thirties or forties. They had recurrent fever associated with headache, arthralgia, and myalgia, with skin involvement manifest as erythema nodosa or urticaria. Some patients had lymphadenopathy or splenomegaly. Laboratory studies showed increased ESR, CRP, and leukocytosis during the attacks, all of which normalized between episodes. Only 1 patient reported triggering of the episodes by cold. The episodes occurred every few months and lasted for several weeks. Treatment with prednisone resulted in resolution of symptoms. None had a family history of the disorder and none had sensorineural deafness. Inheritance The transmission pattern of FCAS2 in the family reported by Borghini et al. (2011) was consistent with autosomal dominant inheritance and incomplete penetrance. Molecular Genetics In affected members of 2 unrelated families with FCAS2, Jeru et al. (2008) identified heterozygous mutations in the NLRP12 gene (R284X; 609648.0001 and a splice site mutation 609648.0002). Both mutations were predicted to result in a loss of function. In vitro functional expression studies showed that both mutations reduced inhibitory action against NF-kappa-B (164011) compared to wildtype NLRP12. In 4 affected members of an Italian family with variable manifestations of FCAS2, Borghini et al. (2011) identified a heterozygous missense mutation in the NLRP12 gene (D294E; 609648.0003). The mutation, which was found by direct sequencing of exon 3 of the NLRP12 gene in 50 patients with a similar disorder, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the D294E mutation did not result in decreased inhibitory action against NF-kappa-B, but rather showed similar inhibitory activity as the wildtype protein. Patient-derived monocytes did not show increased quantitative secretion of IL1B (147720) compared to controls when stimulated with pathogen-associated molecular patterns (PAMPs). However, patient cells showed altered kinetics of IL1B secretion, with significant acceleration of IL1B secretion compared to controls in a given time frame. Patient cells also showed increased production of reactive oxygen species and upregulation of antioxidant systems, resulting in rapid exhaustion of the antioxidant systems compared to controls. These changes were most apparent in the more severely affected individual and less apparent in the least affected individual. In 2 unrelated patients with FCAS2, Jeru et al. (2011) identified a heterozygous missense mutation in the NLRP12 gene (R352C; 609648.0004). The mutation, which was found by direct sequencing of the NLRP12 gene, occurred at a CpG dinucleotide and thus could correspond to a hotspot. In vitro functional expression studies in HEK293 cells showed that the mutant protein did not affect the NF-kappa-B inhibitory activity of NRLP12. However, the R352C mutant showed enhanced ability to induce the processing of caspase-1 (CASP1; 147678) compared to wildtype, consistent with a gain-of-function effect. Transfected cells also showed significantly more speck formation compared to controls. Specks represent intracellular aggregates reflecting activation of the caspase 1/IL1B pathway. Although IL1B levels were not ascertained in these patients, the findings suggested that the R352C mutant protein leads to increased CASP1 processing, which would result in increased IL1B secretion and a hyperinflammatory state. Vitale et al. (2013) identified a heterozygous F402L variant in the NLRP12 gene (F402L; 609648.0005) in 5 unrelated Italian probands with FACS2. The variant showed a high frequency (up to 5%) in various databases, as well as incomplete penetrance in some of the family members studied, and Vitale et al. (2013) suggested that it may be a low-penetrance mutation. Functional studies of the variant and studies of patient cells were not performed. Shen et al. (2017) identified a heterozygous F402L mutation in 3 unrelated Han Chinese patients with adult-onset FACS2 and no family history of the disorder. The mutations were found by whole-genome sequencing of periodic fever genes and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Sensorineural deafness (in some patients) Mouth \- Aphthous ulcers, episodic ABDOMEN \- Abdominal pain, episodic Spleen \- Splenomegaly (in some patients) SKELETAL \- Arthralgias, episodic \- Arthritis, episodic SKIN, NAILS, & HAIR Skin \- Rash, episodic \- Urticaria, episodic MUSCLE, SOFT TISSUES \- Myalgias, episodic NEUROLOGIC Central Nervous System \- Headache, episodic METABOLIC FEATURES \- Fever, episodic IMMUNOLOGY \- Lymphadenopathy (in some patients) \- Lymphocytosis, episodic (in some patients) LABORATORY ABNORMALITIES \- Serum C-reactive protein may be increased \- Erythrocyte sedimentation rate may be increased \- Increased acute phase reactants MISCELLANEOUS \- Variable age at onset, range infancy to adult \- Phenotypic variability \- Episodes are triggered by cold exposure \- Episodes can last hours, days, or weeks \- Responsive to steroid treatment \- Incomplete penetrance MOLECULAR BASIS \- Caused by mutations in the NLR family, pyrin-domain containing 12 gene (NLRP12, 609648.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 2	c2673198	4,332	omim	https://www.omim.org/entry/611762	2019-09-22T16:02:52	{"doid": ["0090063"], "mesh": ["C567090"], "omim": ["611762"], "orphanet": ["247868"]}
X-linked juvenile retinoschisis is a condition characterized by impaired vision that begins in childhood and occurs almost exclusively in males. This disorder affects the retina, which is a specialized light-sensitive tissue that lines the back of the eye. Damage to the retina impairs the sharpness of vision (visual acuity) in both eyes. Typically, X-linked juvenile retinoschisis affects cells in the central area of the retina called the macula. The macula is responsible for sharp central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. X-linked juvenile retinoschisis is one type of a broader disorder called macular degeneration, which disrupts the normal functioning of the macula. Occasionally, side (peripheral) vision is affected in people with X-linked juvenile retinoschisis. X-linked juvenile retinoschisis is usually diagnosed when affected boys start school and poor vision and difficulty with reading become apparent. In more severe cases, eye squinting and involuntary movement of the eyes (nystagmus) begin in infancy. Other early features of X-linked juvenile retinoschisis include eyes that do not look in the same direction (strabismus) and farsightedness (hyperopia). Visual acuity often declines in childhood and adolescence but then stabilizes throughout adulthood until a significant decline in visual acuity typically occurs in a man's fifties or sixties. Sometimes, severe complications develop, such as separation of the retinal layers (retinal detachment) or leakage of blood vessels in the retina (vitreous hemorrhage). These eye abnormalities can further impair vision or cause blindness. ## Frequency The prevalence of X-linked juvenile retinoschisis is estimated to be 1 in 5,000 to 25,000 men worldwide. ## Causes Mutations in the RS1 gene cause most cases of X-linked juvenile retinoschisis. The RS1 gene provides instructions for making a protein called retinoschisin, which is found in the retina. Studies suggest that retinoschisin plays a role in the development and maintenance of the retina. The protein is probably involved in the organization of cells in the retina by attaching cells together (cell adhesion). RS1 gene mutations result in a decrease in or complete loss of functional retinoschisin, which disrupts the maintenance and organization of cells in the retina. As a result, tiny splits (schisis) or tears form in the retina. This damage often forms a "spoke-wheel" pattern in the macula, which can be seen during an eye examination. In half of affected individuals, these abnormalities can occur in the area of the macula, affecting visual acuity, in the other half of cases the schisis occurs in the sides of the retina, resulting in impaired peripheral vision. Some individuals with X-linked juvenile retinoschisis do not have a mutation in the RS1 gene. In these individuals, the cause of the disorder is unknown. ### Learn more about the gene associated with X-linked juvenile retinoschisis * RS1 ## Inheritance Pattern This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	X-linked juvenile retinoschisis	c3714753	4,333	medlineplus	https://medlineplus.gov/genetics/condition/x-linked-juvenile-retinoschisis/	2021-01-27T08:25:26	{"gard": ["4690"], "omim": ["312700"], "synonyms": []}
## Summary ### Clinical characteristics. Prothrombin-related thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism. The clinical expression of prothrombin-related thrombophilia is variable; many individuals heterozygous or homozygous for the 20210G>A (G20210A or c.97G>A) allele in F2 never develop thrombosis, and while most heterozygotes who develop thrombotic complications remain asymptomatic until adulthood, some have recurrent thromboembolism before age 30 years. The relative risk for DVT in adults heterozygous for the 20210G>A allele is two- to fivefold increased; in children, the relative risk for thrombosis is three- to fourfold increased. Heterozygosity for 20210G>A has at most a modest effect on recurrence risk after a first episode. Although prothrombin-related thrombophilia may increase the risk for pregnancy loss, its association with preeclampsia and other complications of pregnancy such as intrauterine growth restriction and placental abruption remains controversial. Factors that predispose to thrombosis in prothrombin-related thrombophilia include: the number of 20210G>A alleles; presence of coexisting genetic abnormalities including factor V Leiden; and acquired thrombophilic disorders (e.g., antiphospholipid antibodies). Circumstantial risk factors for thrombosis include pregnancy and oral contraceptive use. Some evidence suggests that the risk for VTE in 20210G>A heterozygotes increases after travel. ### Diagnosis/testing. The diagnosis of prothrombin-related thrombophilia requires molecular genetic testing of F2, the gene encoding prothrombin, to identify the 20210G>A allele (also known as G20210A or c.97G>A). ### Management. Treatment of manifestations: Management depends on the clinical circumstances. The first acute thrombosis is treated according to standard guidelines with a course of low molecular-weight heparin (LMWH) or fondaparinux, and concurrent oral administration of warfarin for at least five days (except in pregnancy). The international-normalized ratio (INR) is used to monitor warfarin anticoagulation. Rivaroxaban, a factor Xa inhibitor, is approved for the treatment of acute VTE and long-term prevention of recurrence. The duration of anticoagulation therapy is determined by assessment of the risks for (1) VTE recurrence and (2) anticoagulant-related bleeding. Individuals with a spontaneous thrombosis with no identifiable provoking factors and those with persistent risk factors are candidates for long-term anticoagulation therapy. Treatment for three months is recommended for individuals with transient (reversible) risk factors such as surgery. Graduated compression stockings should be worn for at least two years following an acute DVT. Agents/circumstances to avoid: Heterozygous and homozygous women with a history of VTE should avoid estrogen-containing contraception and hormone replacement therapy (HRT). Evaluation of relatives at risk: Because there is no clinical evidence that early diagnosis reduces morbidity or mortality, the indications for family testing are unresolved and the decision to test at-risk family members should be made on an individual basis. Pregnancy management: No consensus exists on the optimal management of prothrombin-related thrombophilia during pregnancy; guidelines for treatment of VTE are derived from studies in non-pregnant individuals. ### Genetic counseling. Prothrombin-related thrombophilia is inherited in an autosomal dominant manner: heterozygosity for the 20210G>A allele results in an increased risk for thrombosis; homozygosity for this allele confers a higher risk for thrombosis than heterozygosity. All individuals reported to date with prothrombin-related thrombophilia who are heterozygous for the 20210G>A allele have had an affected parent. Because of the relatively high prevalence of this allele in the general population, occasionally one parent is homozygous or both parents are heterozygous for this allele. If one parent of a heterozygous proband is heterozygous for the 20210G>A allele, the sibs of the proband are at 50% risk of being heterozygous; if one parent is homozygous, the sibs of the proband will be heterozygous. Although technically possible, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are rarely, if ever, performed because the 20210G>A allele only increases the relative risk for thrombophilia and is not predictive of a thrombotic event. ## Diagnosis ### Suggestive Findings No clinical features are specific for prothrombin-related thrombophilia. The diagnosis is suspected in probands with at least one of the more specific features [Chalmers et al 2011, McGlennen & Key 2002, Howard & Hughes 2013, Bates et al 2012, Royal College of Obstetricians and Gynaecologists 2009, Chalmers et al 2011, Royal College of Obstetricians and Gynaecologists 2011a, Tait et al 2012, American College of Obstetricians and Gynecologists 2013b]: * A first unprovoked venous thromboembolism (VTE) before age 50 years * A history of recurrent VTE * Venous thrombosis at certain unusual sites such as the cerebral, mesenteric, portal, or hepatic veins * VTE during pregnancy or the puerperium * VTE associated with the use of estrogen-containing oral contraceptives or hormone replacement therapy (HRT) * An unprovoked VTE at any age in an individual with a first-degree family member with a VTE before age 50 years Prothrombin-related thrombophilia may also be considered in probands who have less specific findings, including the following: * A history of unprovoked VTE considering discontinuation of anticoagulation [National Clinical Guideline Centre 2012] * Selected women with unexplained second trimester fetal loss * A first VTE related to use of tamoxifen or other selective estrogen receptor modulators (SERM) * Age greater than 50 years with a first unprovoked VTE * Neonates and children with non-catheter related idiopathic VTE or stroke ### Testing to Confirm the Diagnosis The diagnosis of prothrombin-related thrombophilia requires molecular genetic analysis of F2, the gene encoding prothrombin, to identify the common pathogenic variant 20210G>A (see Table 1). Note that because the range of plasma concentrations of prothrombin in heterozygotes overlaps with the normal range (see Molecular Genetics, Normal gene product), the plasma prothrombin concentration is not reliable for diagnosis. The decision to test an individual suspected of having prothrombin-related thrombophilia should be based on the likelihood that test results would influence treatment [Baglin et al 2010, Berg et al 2011, De Stefano & Rossi 2013]. Note: (1) Clinical guidelines from the UK and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group stress the uncertain benefit of testing for inherited thrombophilia in several accepted circumstances, including in individuals who have some of the more specific findings [Baglin et al 2010, Berg et al 2011, Tait et al 2012]. See Published Guidelines / Policy Statements. (2) American and British guidelines do not recommend routine testing for thrombophilia in adults or children with VTE [Chalmers et al 2011, Tait et al 2012]. ### Table 1. Molecular Genetic Testing Used in Prothrombin-Related Thrombophilia View in own window Gene 1MethodVariants DetectedProportion of Probands with a Pathogenic Variant Detectable by Method F2Targeted analysis for pathogenic variants 220210G>A (c.97G>A) 3100% 1\. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. 2\. Targeted analysis for the 20210G>A (c.97G>A) pathogenic variant is performed by a variety of comparable methods [Spector et al 2005]. 3\. The official designation of the pathogenic variant is c.97G>A per guidelines at varnomen.hgvs.org. Interpretation of test results. Molecular genetic test results are reliable in individuals on warfarin, heparin, or other antithrombotic agents and are independent of thrombotic episodes. Test results on DNA extracted from peripheral blood leukocytes need to be interpreted with caution in the setting of liver transplantation or hematopoetic stem cell transplantation (HSCT). Diagnosis of prothrombin-related thrombophilia in the setting of liver transplantation requires molecular genetic testing of donor liver, the site of prothrombin synthesis [Mas et al 2003]. * Diagnosis of prothrombin-related thrombophilia in HSCT recipients requires molecular analysis of non-hematopoietic tissue in the recipient (e.g., buccal cells). Note: Testing for the F2 20210G>A allele is not recommended for the following: * General population screening * Routine initial testing prior to the use of estrogen-containing contraceptives, hormone replacement therapy (HRT), or SERMs * Adults with VTE occurring in the setting of major transient risk factors (e.g., surgery, trauma) [Hicks et al 2013] * Routine initial testing in adults with arterial thrombosis * Individuals with unprovoked VTE already receiving long-term anticoagulation treatment * Routine initial testing during pregnancy * Routine testing in women with recurrent fetal loss, placental abruption, fetal growth restriction, or preeclampsia [Baglin et al 2010, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b] * Prenatal or newborn testing * Neonates and children with asymptomatic central venous catheter-related thrombosis * Routine testing in asymptomatic children * Routine testing of unselected children with a first episode of VTE [Chalmers et al 2011] ## Clinical Characteristics ### Clinical Description The clinical expression of prothrombin-related thrombophilia is variable. Many individuals who are heterozygous or homozygous for the F2 20210G>A allele never develop thrombosis. While most individuals with prothrombin-related thrombophilia do not experience a first thrombotic event until adulthood, some have recurrent VTE before age 30 years. #### Venous Thromboembolism (VTE) The primary clinical manifestation of prothrombin-related thrombophilia is venous thromboembolism (VTE). Deep-vein thrombosis (DVT) and pulmonary embolism (PE) are the most common VTE. The most common site for deep-vein thrombosis is the legs, but upper-extremity thrombosis also occurs. Risk for VTE in adults heterozygous for the F2 20210G>A allele The relative risk for VTE is increased two- to fivefold in 20210G>A heterozygotes [Lijfering et al 2009, Rosendaal & Reitsma 2009]. In a large meta-analysis of 79 studies, 20210G>A heterozygosity was associated with a threefold increased risk for VTE [Gohil et al 2009]. Among individuals with DVT, 20210G>A heterozygotes had a significantly higher rate of PE (32%) than those with the factor V Leiden allele (19%) or without thrombophilia (17%). 20210G>A heterozygotes are also at increased risk of developing isolated pulmonary emboli [Martinelli et al 2006] and may develop VTE at a younger age than individuals without the allele [Bank et al 2004, Martinelli et al 2006]. Upper-extremity thrombosis. The available evidence suggests that heterozygosity for 20210G>A is an independent risk factor for upper-extremity thrombosis [Vayá et al 2003, Martinelli et al 2004, Blom et al 2005a, Linnemann et al 2008a]: * The 20210G>A allele was reported in 5%-12% of persons with upper-extremity thrombosis not related to a central venous catheter, suggesting that the allele confers a three- to sixfold increased risk for thrombosis in this location [Vayá et al 2003, Martinelli et al 2004, Blom et al 2005a, Linnemann et al 2008a]. The prevalence of the allele is higher in those with idiopathic (unprovoked) upper-extremity thrombosis than in those with thrombosis related to a central venous catheter [Lechner et al 2008]. * Heterozygosity for 20210G>A was associated with a fivefold increased risk for idiopathic (unprovoked) upper-extremity thrombosis (not related to malignancy or a central venous catheter) [Martinelli et al 2004]. Women heterozygous for 20210G>A who were using oral contraceptives had a nine- to 14-fold increased risk for idiopathic upper-extremity thrombosis [Martinelli et al 2004, Blom et al 2005a]. Cerebral vein thrombosis * 20210G>A heterozygosity is associated with a six- to tenfold increased risk for cerebral vein thrombosis [Martinelli et al 1998, Martinelli et al 2003a, Dentali et al 2006, Lauw et al 2013]. * In two case-control studies, women heterozygous for 20210G>A who used oral contraceptives had an 80-fold and 150-fold increased relative risk for cerebral vein thrombosis, respectively [Martinelli et al 1998, Martinelli et al 2003a]. Hepatic thrombosis and portal vein thrombosis are other reported complications in adult 20210G>A heterozygotes [Janssen et al 2000, Amitrano et al 2004, Primignani et al 2005]. A meta-analysis concluded that 20210G>A heterozygosity was associated with a fourfold increased risk for both idiopathic and liver disease-associated portal vein thrombosis [Dentali et al 2008a]. Thrombosis in unusual locations in adults who are heterozygous for 20210G>A also occurs more frequently than in the general population. However, these events are much less common than DVT or pulmonary emboli, and there is no evidence that identification of a 20210G>A allele should alter management [Tait et al 2012]. * Retinal vein thrombosis and other ocular thrombotic events are reported in 20210G>A heterozygotes [Ben-Ami et al 2002, Glueck & Wang 2009], although the association is much weaker than with DVT and/or PE [Janssen et al 2005, Baglin et al 2010, Tait et al 2012]. * The risk for superficial venous thrombosis was increased nearly fourfold in 20210G>A heterozygotes in one study [Martinelli et al 1999a]. Risk for VTE in family members of probands with the F2 20210G>A allele Whereas the relative risk for a first episode of VTE in asymptomatic family members with a 20210G>A allele is increased two- to fivefold, the absolute risk is low. In several retrospective family studies the absolute incidence of a first VTE was 0.19%/year to 0.41%/year in asymptomatic 20210G>A heterozygotes, compared to 0.05%/year to 0.18%/year in relatives without the allele [Bank et al 2004, Lijfering et al 2009]. * A prospective study of asymptomatic relatives of probands with a 20210G>A allele and arterial or venous thromboembolism found similar annual incidences of a first VTE in relatives with (0.37%/year) and without (0.12%/year) the allele [Coppens et al 2006]. * A large study of family members of probands with thrombophilia found no increased risk of VTE among relatives heterozygous for 20210G>A [Rossi et al 2011]. * The risk for VTE is higher in asymptomatic 20210G>A heterozygotes from families with a strong history of VTE than in unselected individuals identified by population screening [Bank et al 2004, Couturaud et al 2009]. The increased susceptibility to VTE in thrombosis-prone families results from the coinheritance of other unidentified inherited thrombophilic disorders. * In a single large retrospective family study, the annual incidence of a first VTE was 1.10%/year in relatives homozygous for 20210G>A [Bank et al 2004]. In contrast, no VTE events occurred in the small number of homozygous family members included in two other studies [Coppens et al 2006, Lijfering et al 2009]. Relatives heterozygous for 20210G>A in combination with other inherited thrombophilic disorders had an annual incidence of first VTEof 0.45%-0.59%/year [Lijfering et al 2009]. Risk for VTE in children heterozygous for the F2 20210G>A allele A combination of risk factors appears to be necessary to provoke thrombosis in children [Revel-Vilk & Kenet 2006, Raffini 2008, Tuckuviene et al 2011]. VTE in children is usually a complication of one or more medical conditions and/or a central venous catheter. The majority of children reported with VTE had other coexisting inherited and/or circumstantial risk factors [Revel-Vilk et al 2003, Young et al 2008]. An increased prevalence of 20210G>A was found in neonates and children with VTE in some but not all studies. The variation in reported prevalence of the allele likely reflects differences in study design and clinical characteristics of the children included. The available data summarized below suggest that asymptomatic healthy children who are heterozygotes or homozygotes for 20210G>A are at low risk for thrombosis except in the setting of strong circumstantial risk factors [Tuckuviene et al 2011]. Studies that support an association of 20210G>A heterozygosity with VTE in children: * Several retrospective case-control studies found a heterozygous 20210G>A allele in 4%-8% of children with a first VTE compared to 1%-3% of controls, suggesting a three- to fourfold increase in relative risk [Junker et al 1999, Schobess et al 1999]. * In a retrospective review of 38 symptomatic children heterozygous for the 20210G>A allele, additional circumstantial risk factors were present at the time in 92% of VTE events. Central venous catheters and malignancy were among the most common risk factors identified [Young et al 2003, Young et al 2008]. * A meta-analysis found that 20210G>A heterozygosity was associated with a two- to threefold increased risk for a first VTE in children. The risk was increased more than ninefold in children with two or more inherited thrombophilic disorders [Young et al 2008]. Other studies also found a higher risk in children doubly heterozygous for the 20210G>A and factor V Leiden alleles or with the 20210G>A allele in combination with other inherited thrombophilic disorders [Junker et al 1999, Young et al 2003]. Studies that do not support an association of 20210G>A heterozygosity with VTE in children: * Several studies of unselected children with a history of VTE found a low prevalence of 20210G>A heterozygosity, similar to that in controls or in the general population [Revel-Vilk et al 2003, van Ommen et al 2003, Albisetti et al 2007]. * In a prospective study of family members of symptomatic probands, asymptomatic children heterozygous or homozygous for 20210G>A had no thrombotic complications during an average follow-up period of five years [Tormene et al 2002]. Cerebral vein thrombosis in children. Although some evidence suggests that 20210G>A heterozygosity may predispose to central nervous system (CNS) thrombosis in children, the evidence is conflicting. Studies that support an association of 20210G>A heterozygosity with cerebral vein thrombosis in children: * The combination of an inherited or acquired thrombophilic disorder (including 20210G>A heterozygosity) and an underlying medical condition conferred a fourfold increased risk for cerebral vein thrombosis, underscoring the multifactorial etiology of this thrombotic complication [Heller et al 2003]. * A meta-analysis found that a 20210G>A allele was associated with a significant twofold increased risk for the combined outcome of first cerebral vein thrombosis or acute ischemic stroke in children [Kenet et al 2010]. Studies that do not support an association of 20210G>A heterozygosity with cerebral vein thrombosis in children: * In a small case-control study, the prevalence of 20210G>A heterozygosity was similar in children with cerebral vein thrombosis (2.6%) and a group of control children (3.5%) [Kenet et al 2004]. * Data from a large population-based registry suggest a low prevalence of the 20210G>A allele* among children and neonates with cerebral vein thrombosis [deVeber et al 2001]. Note: Throughout this GeneReview, 20210G>A without specification of homo- vs. heterozygosity indicates that the studies described did not specify zygosity. Hepatic, portal, and retinal vein thromboses in children heterozygous for the 20210G>A allele have also been reported. Thrombosis in unusual locations (e.g., cerebral vein and hepatic vein) in children heterozygous for 20210G>A occur less commonly than thrombosis of an extremity or pulmonary embolism. #### Recurrent Thrombosis Risk for recurrent thrombosis in adult 20210G>A heterozygotes Summary. Current evidence suggests that 20210G>A heterozygosity has at most a modest effect on recurrence risk after initial treatment of a first VTE [Kyrle et al 2010]. Although the data are conflicting, the majority of more recent studies found no increase in risk. An evidence review by the EGAPP concluded that 20210G>A heterozygosity is not predictive of VTE recurrence [Berg et al 2011]. The clinical circumstances of the first event (provoked or unprovoked), individual characteristics such as male sex, and global hemostasis tests (e.g. D-dimer) are more important determinants of recurrence. A case-control study found that testing individuals with a first VTE for thrombophilia did not reduce the incidence of recurrence [Coppens et al 2007]. There are no randomized or controlled trials assessing the effect of thrombophilia testing on VTE recurrence risk [Cohn et al 2012]. Studies that support an association of 20210G>A heterozygosity and increased risk for recurrent VTE in adults: In a prospective long-term follow-up study of persons who stopped anticoagulation after treatment for a first VTE, a thrombophilic defect including 20210G>A was associated with a twofold increased recurrence risk [Prandoni et al 2007]. * A meta-analysis and a systematic review both concluded that 20210G>A heterozygosity is associated with a modest but statistically significant increased risk for recurrent VTE after a first event (OR = 1.72, OR=1.74, respectively) [Ho et al 2006, Marchiori et al 2007]. Studies that do not support an association of 20210G>A heterozygosity and increased risk for recurrent VTE in adults: * Multiple retrospective and prospective studies found no significant difference in the rate of recurrent VTE between 20210G>A heterozygotes and individuals without the allele [Eichinger et al 1999, Lindmarker et al 1999, De Stefano et al 2001, González-Porras et al 2006, Christiansen et al 2005]. * In a large family study, the incidence of recurrent VTE in relatives with 20210G>A heterozygosity was 7% after two years, 11% after five years, and 25% after ten years, rates similar to those reported in the general population [Lijfering et al 2009]. * A systematic review pooling data from nine studies found that 20210G>A heterozygosity is not predictive of recurrent VTE [Segal et al 2009]. * 20210G>A heterozygosity is not associated with an increased risk of recurrent cerebral vein thrombosis [Dentali et al 2012, Lauw et al 2013]. * 20210G>A heterozygosity is not associated with a higher risk for recurrent VTE during warfarin therapy [Kearon et al 2008]. Multiple studies showed that the reduction in risk during oral anticoagulation is similar in individuals with and without the allele [Segal et al 2009]. Risk for recurrent thrombosis in 20210G>A homozygotes and in 20210G>A heterozygotes with other risk factors Summary. The risk for recurrent VTE in 20210G>A homozygotes is not well defined, but presumed to be higher than in 20210G>A heterozygotes. Most studies did not include an adequate number of individuals homozygous for the allele to evaluate the effect on recurrence risk [Segal et al 2009, Berg et al 2011]. The available evidence suggests that individuals with multiple thrombophilic defects have a higher risk for recurrent VTE. Studies that support an increased risk for recurrent thrombosis in 20210G>A homozygotes and in 20210G>A heterozygotes with other risk factors: * Individuals who are heterozygous for both the 20210G>A and factor V Leiden alleles (i.e., doubly heterozygous) have a three- to ninefold higher recurrence risk than those with neither allele, and a threefold higher risk than individuals heterozygous for the factor V Leiden allele alone [De Stefano et al 1999, Margaglione et al 1999, Meinardi et al 2002]. * In a prospective study, the annual incidence of recurrent VTE was 12%/year in persons homozygous for the 20210G>A allele or doubly heterozygous for 20210G>A and factor V Leiden, compared to 2.8% in those without either thrombophilia-related allele [González-Porras et al 2006]. * A systematic review found that individuals doubly heterozygous for 20210G>A and factor V Leiden had a nearly fivefold increased risk for recurrent VTE [Segal et al 2009]. Not all studies found an increased risk for recurrent thrombosis in individuals with multiple thrombophilic alleles: * In a family study individuals homozygous for the 20210G>A allele or doubly heterozygous for 20210G>A and factor V Leiden did not have an increased risk for recurrent thrombosis, even when the analysis was restricted to those with a first unprovoked VTE [Lijfering et al 2010]. Risk for recurrent thrombosis in children Summary. The risk for recurrent VTE is likely higher in children with an initial spontaneous (unprovoked) event, a strong family history of thrombosis, and multiple thrombophilic defects [Revel-Vilk & Kenet 2006, Young et al 2008, Young et al 2009]. Data on the risk for recurrent VTE in children who are 20210G>A heterozygotes are limited and conflicting. Multiple studies were not statistically powered because of small sample size. Studies that support an increased risk for recurrent thrombosis in children who are 20210G>A heterozygotes: * In a prospective cohort study, the incidence of recurrent VTE at a median 12 months after the initial event was 58 VTE events/1000 person-years in children with a 20210G>A allele, compared to 11.8/1000 person-years in children without thrombophilia. VTE recurred in 18% of children with 20210G>A compared to 7.6% of controls, suggesting a two- to threefold increase in recurrence risk [Young et al 2009]. * In a meta-analysis of 12 observational studies, 20210G>A was associated with a twofold increased risk for recurrent VTE. The risk was increased four- to fivefold in children with multiple thrombophilic defects [Young et al 2008]. Studies that do not support an increased risk for recurrent thrombosis in children who are 20210G>A heterozygotes: * In a series of Dutch children with VTE, VTE recurred in 11%, none of whom had a 20210G>A allele. The presence of one or more inherited thrombophilic disorders was not an independent risk factor for recurrent VTE [van Ommen et al 2003]. * In another study 20210G>A heterozygosity was not found among children with recurrent thrombosis, all of whom had other acquired risk factors [Revel-Vilk et al 2003]. Risk for recurrent thrombosis in pregnant women Summary. Women with a prior history of VTE have an increased recurrence risk during pregnancy; recurrence rates range from 0% to 15% among published studies. The risk is higher in women with a prior unprovoked episode or an estrogen-related VTE, and in those with coexisting genetic or acquired risk factors. Note: No studies have specifically evaluated the risk for recurrent VTE in pregnant women with a 20210G>A allele. * Analysis of a large in-patient database found that thrombophilia and a prior history of VTE were the strongest risk factors for pregnancy-related VTE, conferring a 52-fold and 25-fold increase in relative risk, respectively [James et al 2006]. * The results of several studies suggest that women with a history of VTE provoked by oral contraceptives or related to pregnancy are at higher risk for recurrent thrombosis during a subsequent pregnancy [De Stefano et al 2006, White et al 2008]. * A prospective study evaluated the safety of withholding anticoagulation during pregnancy in women with a history of a single VTE. In subgroup analysis, women with a previous spontaneous thromboembolic event and thrombophilia had the highest recurrence rate during pregnancy (20%, odds ratio of 10) [Brill-Edwards et al 2000]. Women with either inherited or acquired thrombophilia or with a prior unprovoked VTE (but not both) had recurrence rates of 13% and 7.7%, respectively. #### Pregnancy Complications It is unlikely that 20210G>A heterozygosity is a major factor contributing to pregnancy loss and other adverse pregnancy outcomes. Although multiple retrospective studies have suggested a modest increased risk of fetal loss, most prospective studies have not confirmed an association. The available data suggest that 20210G>A heterozygosity is associated with at most a two- to threefold increased relative risk for pregnancy loss.The association with preeclampsia, fetal growth restriction, and placental abruption is more controversial. A 20210G>A allele is at most one of multiple predisposing factors contributing to these complications. Other genetic and environmental triggers are necessary for the development of pregnancy complications in women heterozygous and homozygous for the 20210G>A allele. Pregnancy loss Summary. Some (though not all) evidence suggests that 20210G>A heterozygosity increases the risk for fetal loss [Kujovich 2004b]. However, despite a modest increase in relative risk, the absolute risk for fetal loss is low and the majority of heterozygous women have normal pregnancies. Studies that show an association between unexplained pregnancy loss and a maternal 20210G>A allele: * 20210G>A heterozygosity was found in 4%-9% of women with recurrent pregnancy loss (the majority in the first trimester), compared with 1%-2% of those with uncomplicated pregnancies, with odds ratios ranging from two to nine [Pihusch et al 2001, Raziel et al 2001, Reznikoff-Etiévan et al 2001]. * Several case-control studies and three meta-analyses found an increased risk for first trimester pregnancy loss in women with a 20210G>A allele [Rey et al 2003, Kovalevsky et al 2004, Robertson et al 2006, Ivanov et al 2009, Yenicesu et al 2010]. * Several meta-analyses concluded that 20210G>A heterozygosity was associated with a two- to threefold increased risk for recurrent first trimester fetal loss and a nearly ninefold increased risk for non-recurrent second trimester loss [Rey et al 2003, Kovalevsky et al 2004, Robertson et al 2006]. Some evidence suggests that women with prothrombin-related thrombophilia have a higher risk for pregnancy loss in the second and third trimesters. Although late fetal loss may reflect thrombosis of placental vessels, the role of thrombophilic disorders including 20210G>A in the complex biologic events predisposing to placental insufficiency is not well defined. * An observational study of women with three consecutive miscarriages before ten weeks’ gestation found that 20210G>A heterozygotes had a rate of recurrent early miscarriage similar to that of women without a thromboplhic disorder. However, heterozygous women had a significantly higher rate of late fetal loss during the next pregnancy (8.8% versus 2.3%) [Bouvier et al 2014]. * Two studies found 20210G>A heterozygosity in 9%-13% of women with a first unexplained third-trimester loss, compared with 2%-3% of controls suggesting a two- to threefold increase in risk [Martinelli et al 2000b, Many et al 2002]. * A meta-analysis found that 20210G>A heterozygosity is associated with a more than threefold higher risk for fetal loss in the second trimester compared to the first trimester. The allele was also associated with a two- to threefold increased risk for third-trimester loss and the risk increased after 24 weeks’ gestation [Robertson et al 2006]. Studies that found no increased risk for pregnancy loss in women with a 20210G>A allele: * Multiple observational and prospective studies found no association between 20210G>A and an increased risk for early or late recurrent pregnancy loss [Bank et al 2004, Kocher et al 2007, Karakantza et al 2008, Pasquier et al 2009, Silver et al 2010]. * A family cohort study suggested that 20210G>A has no effect on the outcome of a subsequent pregnancy after a first fetal loss. The live birth rate in a second pregnancy was high and similar in women with and without the allele (77% and 76%, respectively) [Coppens et al 2007]. * In a meta-analysis of prospective cohort studies, 20210G>A was not associated with an increased risk for a composite outcome of placental mediated complications including pregnancy loss. However, the analysis was not powered to detect small differences in risk due to the small number of studies reviewed [Rodger et al 2010]. Limited available evidence indicates that paternal thrombophilia, including 20210G>A heterozygosity, is not associated with an increased risk for fetal loss [Toth et al 2008, Pasquier et al 2009, Yenicesu et al 2010]. Other obstetric complications Although preeclampsia, fetal growth restriction (FGR), and placental abruption may also involve impaired placental perfusion, their association with inherited thrombophilia is controversial. The conflicting results reported in different studies may reflect the varying diagnostic and selection criteria, different ethnic groups, and small number of cases included [Rodger et al 2008, Funai 2009]. The available evidence does not support an association between 20210G>A heterozygosity and these adverse pregnancy outcomes. Preeclampsia. Preeclampsia is a heterogeneous disorder and it is unlikely that a single thrombophilic variant such as 20210G>A plays a major causal role. The conflicting results of the following studies suggest that 20210G>A heterozygosity does not significantly increase the risk for preeclampsia. Studies showing an increased risk for preeclampsia in women with a 20210G>A allele: * Multiple case-control studies found a significantly higher prevalence of 20210G>A in women with preeclampsia (7%-11%) than in women with normal pregnancies (1%-4%), suggesting a two- to sevenfold increase in risk [Grandone et al 1998, Kupferminc et al 2000a, Benedetto et al 2002, Mello et al 2005]. * A recent prospective study found that a 20210G>A allele was associated with threefold higher risk for recurrent preeclampsia which occurred in 50% of heterozygous women [Facchinetti et al 2009]. * A meta-analysis of eight studies found that 20210G>A heterozygosity was associated with a two- to threefold increased risk for preeclampsia [Robertson et al 2006]. Studies showing no increased risk for preeclampsia in women with a 20210G>A allele: * 20210G>A heterozygosity did not increase the risk for preeclampsia in multiple studies of unselected women screened during pregnancy [Dudding et al 2008, Karakantza et al 2008, Kahn et al 2009, Silver et al 2010]. In one study histopathologic features of placental insufficiency were found in 63% of preeclamptic women, but were not associated with 20210G>A heterozygosity [Kahn et al 2009]. * Two meta-analyses found no significant association between a 20210G>A allele and preeclampsia [Lin & August 2005, Rodger et al 2010]. The absolute risk for preeclampsia was similar in women with and without a 20210G>A allele (3.5% and 3%, respectively) [Rodger et al 2010]. Fetal growth restriction (FGR). The data on the risk for FGR associated with a 20210G>A allele are more limited and also conflicting. There is no consistent association between 20210G>A heterozygosity and FGR. Studies showing an increased risk for FGR in women with a 20210G>A allele: * 20210G>A heterozygosity was found in 7%-15% of women with pregnancies complicated by FGR, compared with 2%-4% of controls, with odds ratios ranging from four to nine [Kupferminc et al 1999, Kupferminc et al 2000b, Martinelli et al 2001, Kupferminc et al 2002]. * Two meta-analyses found that a 20210G>A allele was associated with a two- to threefold increased risk for FGR [Howley et al 2005, Kist et al 2008]. Studies showing no increased risk for FGR in women with a 20210G>A allele: * A large case-control study found no significant association between maternal or fetal thrombophilia and FGR. Women heterozygous for the 20210G>A allele had no increase in risk for a pregnancy complicated by FGR compared with unaffected controls [Infante-Rivard et al 2002]. * In several prospective studies of unselected pregnant women, a 20210G>A allele did not increase the risk for FGR [Karakantza et al 2008, Said et al 2010, Silver et al 2010]. * A large cohort study and a meta-analysis of 11 case-control studies found no association between a maternal or fetal 20210G>A allele (singly or in combination) and FGR [Dudding et al 2008, Facco et al 2009]. Placental abruption. The data on the risk for placental abruption in women with prothrombin-related thrombophilia are limited and conflicting. A large prospective study and a meta-analysis found that 29210G>A heterozygosity conferred a nine- to12-fold increased risk for placental abruption [Robertson et al 2006, Said et al 2010]. In contrast, other prospective studies and a meta-analysis found no association [Karakantza et al 2008, Rodger et al 2010, Silver et al 2010]. There is currently no convincing evidence of an association with placental abruption. ### Factors that Predispose to Thrombosis The clinical expression of prothrombin thrombophilia is influenced by: the number of 20210G>A alleles, coexisting genetic abnormalities, acquired thrombophilic disorders, and circumstantial risk factors. #### Number of 20210G>A Alleles 20210G>A heterozygotes have a relative risk for venous thrombosis that is approximately two- to fivefold increased [Poort et al 1996, Leroyer et al 1998, Middeldorp & van Hylckama Vlieg 2008]. 20210G>A homozygotes are at higher risk, although the magnitude is not well defined. Whereas 20210G>A homozygotes may develop thrombosis more frequently and at a younger age, the risk is much lower than that associated with homozygous protein C deficiency or homozygous protein S deficiency. Numerous reports of asymptomatic 20210G>A homozygotes emphasize the contribution of other genetic and acquired risk factors to thrombosis [Ridker et al 1999, Souto et al 1999]. #### Coexisting Genetic Abnormalities Another inherited thrombophilic disorder is present in 8%-14% of 20210G>A heterozygotes, creating supra-additive effect on overall thrombotic risk. Individuals with multiple thrombophilic disorders develop VTE at a younger age and are at higher risk for recurrent thrombosis than those with a single defect [Ferraresi et al 1997, Makris et al 1997]. Factor V Leiden. Heterozygosity for a factor V Leiden allele occurs in 20%-40% of symptomatic 20210G>A heterozygotes [Poort et al 1996, Emmerich et al 2001]. Individuals doubly heterozygous for 20210G>A and factor V Leiden have an increased relative risk for VTE, although estimates of the magnitude of risk vary. In one analysis, the risk was increased 20-fold in individuals heterozygous for both alleles, suggesting a multiplicative effect on overall thrombotic risk [Ehrenforth et al 1999, Emmerich et al 2001]. A more recent systematic review concluded that double heterozygosity for both thrombophilic alleles confers a more modest sevenfold increase in thrombotic risk [Segal et al 2009]. Doubly heterozygous individuals are at a three- to fourfold higher risk than those with a single thrombophilic allele and are more likely to develop thrombosis in unusual locations (e.g., hepatic, mesenteric, or cerebral veins) [De Stefano et al 1999]. Anticoagulant protein deficiency. In one study of families with thrombophilia, the combination of protein S deficiency and 20210G>A heterozygosity was associated with a nearly 13-fold increased risk for VTE, compared to a fourfold increased risk with 20210G>A heterozygosity alone [Tirado et al 2001]. In contrast, coinheritance of a 20210G>A allele did not increase the risk for thrombosis in a large kindred with protein C deficiency [Bovill et al 2000]. Other genetic factors. An F2 20210G>A allele may also interact with other genetic factors, such as normal sequence variants in the following two genes, which independently may not predispose to thrombosis: * F8, the gene encoding factor XIII. The effect of the F8 Val34Leu variant has been extensively studied with conflicting results [Undas et al 2009, Bereczky & Muszbek 2011]. Two meta-analyses found a slight overall protective effect of an F8 Val34Leu allele against VTE [Wells et al 2006, Gohil et al 2009]. Note: The F8 variant in exon 2 (NM_000132.3:c.157G>T) encodes a normal protein variant officially designated NP_000123.1:p.Val53Leu (commonly known as Val34Leu, which does not count the 19 amino-acid signal sequence) [Kohler et al 1998]. * SERPINE1, the gene encoding PAI1 (plasminogen activator inhibitor type 1). Heterozygosity for the SERPINE1 4G polymorphic allele in combination with 20210G>A heterozygosity was associated with a sixfold increased risk for venous thrombosis. Homozygosity for the SERPINE1 4G polymorphic allele in combination with 20210G>A heterozygosity was associated with a 13-fold increased risk for venous thrombosis [Barcellona et al 2003]. (The risk for 4G/5G was not calculated in this study.) Note: The SERPINE1 polymorphism commonly referred to as 4G/5G is a missense substitution (NG_013213.1: g.4328G>T;rs114094261) that is -675 nucleotides from the transcription start. The missense substitution results in either four or five G nucleotides in a row; hence, the common designation of 4G or 5G alleles. Family history. A family history of thrombosis affecting at least one first-degree relative is a risk factor for VTE even after identification of an inherited thrombophilic disorder (including 20210A heterozygosity) [Bezemer et al 2009]. A positive family history is associated with a three- to fourfold increased risk for VTE among individuals with a 20210G>A or factor V Leiden allele [Noboa et al 2008, Rossi et al 2011]. The risk is higher when multiple members are affected and thrombosis occurs at a young age. #### Acquired Thrombophilic Disorders Hyperhomocysteinemia may increase the thrombotic risk associated with 20210G>A heterozygosity. In one study, the combination of high plasma concentrations of homocysteine (>12 µmol/L) and 20210G>A heterozygosity conferred an estimated 50-fold increase in risk, suggesting a multiplicative effect on overall thrombotic risk [De Stefano et al 2001]. Antiphospholipid antibodies (APLA). The effect of antiphospholipid antibodies on the thrombotic risk associated with a 20210G>A allele is not well defined. One study found that the presence of antiphospholipid antibodies was associated with a fourfold increased risk for thromboembolic events in 20210G>A heterozygotes (OR = 4.4) [DeSancho et al 2010]. Malignancy. Whether inherited thrombophilia increases the risk for VTE in persons with cancer is still controversial [Decousus et al 2007]. Malignancy is associated witha markedly increased risk for VTE, especially during the first few months after diagnosis and in those with distant metastases [Blom et al 2005b]. Because malignancy is such a strong risk factor, it may obscure the effect of mild thrombophilic disorders, including prothrombin thrombophilia. Thrombophilia status was not considered in recent guidelines for prophylaxis and treatment of VTE in patients with cancer [Farge et al 2013]. A few small studies found a similar prevalence of 20210G>A heterozygosity in persons with cancer with and without VTE [Ramacciotti et al 2003, Eroglu et al 2007]. Other evidence suggests that the 20210G>A allele may increase the risk for malignancy-related VTE. * A large population-based case-control study found that persons with cancer and 20210G>A heterozygosity had a 17-fold higher risk for VTE than individuals with neither risk factor, and a fourfold higher risk for VTE than those with cancer and without the 20210G>A allele [Blom et al 2005b]. * Individuals with cancer who are heterozygous for factor V Leiden or 20210G>A have a 20-fold higher risk for developing an upper-extremity thrombosis than individuals with cancer without either thrombophilia-related allele [Blom et al 2005a]. * A meta-analysis found that a 20210G>A allele is associated with a fivefold increased risk for central venous catheter thrombosis in persons with cancer [Dentali et al 2008b]. #### Circumstantial Risk Factors Other predisposing factors include: pregnancy, oral contraceptive use, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), organ transplantation, central venous catheter use, surgery, travel, and minor injury. The 20210G>A allele interacts with these environmental risk factors to increase the risk for VTE. At least 50% of thrombotic episodes in individuals with prothrombin-related thrombophilia are provoked by additional predisposing factors, with pregnancy being the most common [Gerhardt et al 2000]. Circumstantial risk factors play a major role in VTE in children. In several studies 62%-97% of children with VTE had coexisting circumstantial risk factors, with central venous catheters, malignancy, and congenital heart disease among the most frequently reported [Junker et al 1999, Revel-Vilk et al 2003, Young et al 2008, Tuckuviene et al 2011]. Pregnancy. Women with thrombophilia are at higher risk for VTE during pregnancy [Kujovich 2004a, James et al 2006]. * In several studies 20210G>A heterozygotes had a three- to 15-fold higher risk for pregnancy-associated VTE than women without the allele [Gerhardt et al 2000, Martinelli et al 2002, Meglic et al 2003]. * A population based case-control study found that 20210G>A heterozygotes have a 31-fold increased risk of developing VTE during pregnancy or the postpartum period compared with non-pregnant women without the allele [Pomp et al 2008]. * A meta-analysis suggested that 20210G>A heterozygotes have a nearly sevenfold higher risk for pregnancy-related VTE than pregnant women without inherited or acquired thrombophilia [Robertson et al 2006]. Although 20210G>A heterozygosity increases the relative risk for pregnancy-associated VTE, the absolute risk in asymptomatic heterozygotes is low in the absence of other predisposing factors. The highest risk occurs during the first six weeks post partum: * Several retrospective studies estimated the probability of VTE in the range of one in 200 to 300 pregnancies [Gerhardt et al 2000, Gerhardt et al 2003]. A population study estimated that VTE occurs in approximately one in 111 20210G>A heterozygotes during pregnancy [Jacobsen et al 2010]. * In a retrospective family study, no VTE events occurred during pregnancy in asymptomatic 20210G>A heterozygotes. Postpartum VTE complicated 1.5% of pregnancies of 20210G>A heterozygotes compared to 0.4% of those in relatives without thrombophilia [Martinelli et al 2008]. * In two prospective cohort studies of unselected pregnant women, no VTE events occurred during pregnancy or the postpartum period in 20210G>A heterozygotes [Said et al 2010, Silver et al 2010]. Women homozygous for 20210G>A or doubly heterozygous for 20210G>A and factor V Leiden have a higher risk for pregnancy-associated VTE: * The risk for pregnancy-associated VTE was increased 26-fold in 20210G>A homozygotes in one study [Robertson et al 2006]. * The risk for pregnancy-associated VTE was increased 15-fold in 20210G>A heterozygotes, ninefold in those heterozygous for factor V Leiden, and greater than 100-fold in women who were doubly heterozygous for 20210G>A and factor V Leiden [Gerhardt et al 2000]. * VTE complicated 17.8% of pregnancies in women doubly heterozygous for 20210G>A and factor V Leiden, compared to 6.2% of those in women heterozygous for the 20210G>A allele alone, suggesting that the combination confers a nearly threefold greater risk than 20210G>A heterozygosity alone [Samama et al 2003]. The absolute risk for pregnancy-associated VTE in 20210G>A homozygotes and women doubly heterozygous for 20210G>A and factor V Leiden is less well defined: * Women doubly heterozygous for 20210G>A and factor V Leiden have a higher risk for VTE in the range of 1/20 to 1/125 pregnancies [Gerhardt et al 2000, Gerhardt et al 2003, Jacobsen et al 2010]. The estimated absolute risk in 20210G>A homozygotes is approximately 1/40 pregnancies [Robertson et al 2006]. * A family study found a low risk for pregnancy-associated VTE in asymptomatic doubly heterozygous women. No VTE events occurred during pregnancy; postpartum VTE complicated 1.8% of pregnancies [Martinelli et al 2008]. * In a large family cohort of women who were heterozygous, doubly heterozygous or homozygous for factor V Leiden or 20210G>A, the absolute risk for pregnancy associated VTE with women with no, a single, or combined defects was 0.73, 1.97, and 7.65 per 100 pregnancy years, respectively [van Vlijmen et al 2011]. Oral contraceptive use. The use of oral contraceptives substantially increases the risk for VTE in women heterozygous for the F2 20210G>A allele. The risk for thrombosis is much higher during the first year of oral contraceptive use than during subsequent years [Bloemenkamp et al 2000]. * Oral contraceptive use alone and 20210G>A heterozygosity alone are associated with a two- to fourfold and two- to threefold increased risk for VTE, respectively. However, the relative risk for VTE is increased 16- to 59-fold in 20210G>A heterozygotes who use contraceptives, indicating a supra-additive effect [Martinelli et al 1999b, Legnani et al 2002, Wu et al 2005]. * The risk for VTE is also markedly increased in oral contraceptive users who are doubly heterozygous for 20210G>A and factor V Leiden, with reported odds ratios ranging from 17 to 110 [Emmerich et al 2001, Legnani et al 2002, Mohllajee et al 2006]. Although no studies have estimated the thrombotic risk associated with oral contraceptives in 20210G>A homozygotes, the risk is likely to be substantially higher than in women who are heterozygous. Despite the marked increase in relative risk, the absolute incidence of VTE may still be low because of the low baseline risk in young healthy women. * In a recent family study that assessed the risk of a first VTE during OCP use in women heterozygous, doubly heterozygous, or homozygous for factor V Leiden or 20210G>A, the incidence of VTE in women with a single defect or combined defects was 0.35 and 0.94 per 100 person-years, respectively [van Vlijmen et al 2011]. * In another family study the absolute incidence of VTE among women with a 20210G>A allele who used oral contraceptives was 0.2%/years of use [Bank et al 2004]. * A prospective family study found that none of the 84 asymptomatic women with a 20210G>A allele who used oral contraceptives developed VTE during a total of 84 years of use [Coppens et al 2006]. Other contraceptives. The risk for VTE associated with transdermal and vaginal ring contraception is at least as high as the risk for VTE associated with oral contraceptives [Cole et al 2007, Jick et al 2007, Dore et al 2010]. The thrombotic risk of these newer forms of contraception in 20210G>A heterozygotes has not been studied, but is likely to be higher than in women without thrombophilia. Unopposed progestin contraception is associated with a much lower risk for thrombosis than estrogen-containing contraception. A retrospective study found that oral progestin alone did not increase the risk for VTE in high-risk women with a history of thrombosis and/or thrombophilia including a small group of 20210G>A heterozygotes and women doubly heterozygous for 20210G>A and factor V Leiden [Conard et al 2004]. However, no prospective studies confirm the safety of progestin-alone contraception in 20210G>A heterozygotes. Hormone replacement therapy (HRT). Oral HRT is associated with a two- to fourfold increase in relative risk for VTE in healthy postmenopausal users of HRT compared to non-users [Grady et al 2000, Rossouw et al 2002, Canonico et al 2007, Renoux et al 2010]. The risk increases with higher estrogen doses and may differ with the particular estrogen and progestin components [Smith et al 2006, Canonico et al 2010, Renoux et al 2010, Canonico et al 2011]. Limited data suggest that women heterozygous for a 20210G> allele who use HRT have a significantly increased thrombotic risk: * A case-control study found that women with a 20210G>A allele or a factor V Leiden allele who used oral estrogen replacement had a 25-fold increased risk for VTE compared with non-users without either thrombophilic allele [Straczek et al 2005]. * The risk of VTE in postmenopausal HRT users with either a 20210G>A or a factor V Leiden allele was threefold higher than the risk in HRT users without thrombophilia [Roach et al 2013]. * The risk for VTE may differ with the type of hormonal content. In one study, the risk for VTE was fivefold higher with conjugated equine estrogen use than with esterified estrogen use among women with a 20210G>A allele or factor V Leiden allele [Smith et al 2006]. * A meta-analysis found that women with either a 20210G>A allele or a factor V Leiden allele who used oral estrogen had an eightfold increased venous thrombotic risk [Canonico et al 2008]. Transdermal hormone replacement therapy. The available evidence suggests that transdermally administered estrogen has minimal or no effect on thrombotic risk [American College of Obstetricians and Gynecologists 2013a]. * Multiple retrospective studies and a meta-analysis found that current use of low- or high-dose transdermal estrogen replacement with or without a progestin did not increase the risk for VTE. In contrast, oral HRT was associated with a two- to fourfold increase in thrombotic risk [Canonico et al 2007, Canonico et al 2008, Canonico et al 2010, Renoux et al 2010, Laliberté et al 2011]. * There is also evidence that transdermal estrogen is associated with a lower thrombotic risk than oral estrogen in women with inherited thrombophilic disorders such as prothrombin-related thrombophilia [Canonico et al 2007, Canonico et al 2010]. * Women with a 20210G>A allele using transdermal estrogen had a risk similar to that of non-users with the allele. Among women with a 20210G>A allele the use of oral estrogen was associated with a fourfold higher risk for VTE than transdermal estrogen [Straczek et al 2005]. However, no prospective randomized trials have confirmed the safety of transdermal HRT in women with inherited or acquired thrombophilia and/or prior VTE. Selective estrogen receptor modulators (SERMs). Limited data suggest that SERMs such as tamoxifen and raloxifene are associated with a twofold increased risk for VTE, similar to the risk for HRT [Cummings et al 1999, Duggan et al 2003, Abramson et al 2006, Barrett-Connor et al 2006]. The thrombotic risk associated with tamoxifen was higher than raloxifene in trials for primary prevention of breast cancer [Nelson et al 2013]. 20210G>A heterozygosity did not increase the risk for arterial or venous thromboembolism in high-risk healthy women using tamoxifen for breast cancer prevention [Duggan et al 2003, Abramson et al 2006]. However, both studies were limited by the small number of cases included. The risk for VTE in women heterozygous for a 20210G>A allele who use SERMs is uncertain but likely higher than that associated with SERM use alone. Obesity. Obesity (BMI>30 kg/m2) is associated with a two- to threefold increased risk for VTE. Obese women with a 20210 G>A allele have a nearly sevenfold higher risk for VTE than women with neither risk factor. Overweight women (BMI ≥25 and <30 kg/m2) with the allele have a fivefold increased thrombotic risk [Pomp et al 2007]. Organ transplantation. It is unclear whether 20210G>A heterozygosity contributes to thrombotic and other complications after organ transplantation [Pherwani et al 2003, Kujovich 2004c]. * A 20210G>A allele was associated with a trend toward a threefold increased risk for thromboembolic complications after renal transplantation which did not reach statistical significance due to the small number of recipients with the allele [Ghisdal et al 2010]. * 20210G>A heterozygosity was identified in 14% of liver allografts complicated by hepatic artery thrombosis, but not in recipient peripheral blood leukocytes [Mas et al 2003]. However, a recent study found no association with hepatic vascular thrombosis after liver transplantation [Pereboom et al 2011] Central venous catheters. An indwelling central venous catheter is the strongest risk factor for upper-extremity thrombosis, contributing to up to one third of occurrences [Blom et al 2005a]. The data on the contribution of a 20210G>A allele to catheter-related thrombosis are conflicting: * 20210G>A heterozygotes had a two- to threefold increased risk for central venous catheter-related thrombosis [Van Rooden et al 2004]. * Two other studies reported a low prevalence of the allele in persons with catheter-related thrombosis, similar to controls or the general population [Vayá et al 2003, Linnemann et al 2008a]. Surgery. It is still unclear to what extent the F2 20210G>A allele adds to the overall thrombotic risk in individuals undergoing surgery. Any excess risk conferred by 20210G>A heterozygosity is likely small in comparison to the thrombotic risk associated with surgery: * Individuals with a 20210G>A allele or a factor V leiden allele undergoing surgery had a nearly 13-fold increased risk for upper-extremity DVT during a postoperative period of up to three months [Blom et al 2005a]. * In a large prospective trial, a 20210G>A allele was a risk factor for symptomatic VTE after total hip or knee arthroplasty, conferring a tenfold increase in risk. The allele was associated with a sixfold increased risk for symptomatic postoperative pulmonary embolism [Wåhlander et al 2002]. * In contrast, several other studies found no association between a 20210 G>A allele and the risk for VTE after orthopedic surgery [Joseph et al 2005, Ringwald et al 2009]. Travel. Some evidence suggests that 20210G>A heterozygotes are more likely to develop VTE after travel. One study found that air travel was a mild risk factor for a first VTE (OR = 2). However, the combination of air travel and any type of thrombophilia (including 20210G>A heterozygosity) was associated with a 17-fold increase in risk, indicating a multiplicative interaction between the two risk factors [Martinelli et al 2003b]. Minor injury. Minor leg injuries are associated with a fivefold increased risk for VTE. The risk is particularly high after muscle or ligament rupture. Individuals with a 20210G>A allele and a minor leg injury had a nine- to 30-fold higher thrombotic risk than those without these risk factors [van Stralen et al 2008]. ### Thrombosis NOT Convincingly Associated with Prothrombin-Related Thrombophilia Arterial thrombosis in adults. The role of prothrombin-related thrombophilia in arterial disease is controversial, with conflicting results from different studies. The available evidence indicates that the 20210G>A allele is not a major risk factor for arterial thrombosis. The majority of myocardial infarctions (MIs) and strokes occur in the presence of established cardiovascular risk factors including hypertension, hyperlipidemia, diabetes mellitus, and smoking. The contribution of a single thrombophilic allele to these complex diseases is likely small. Most studies of unselected or elderly adult populations found no significant association between the presence of one or two 20210G>A alleles and myocardial infarction or stroke [Ridker et al 1999, Smiles et al 2002, Linnemann et al 2008b]. Other studies also found no increase in the annual incidence of stroke, transient ischemic attack (TIA), or MI associated with a 20210G>A allele [Bank et al 2004, Slooter et al 2005, Bolaman et al 2009]. In a prospective study the annual incidence of a first arterial cardiovascular event was 0.56% in family members with the allele compared to 0.73% in those without the allele [Coppens et al 2006]. The annual incidence of ischemic stroke or TIA was also similar in family members with and without the allele (0.33% and 0.23%, respectively). The results of several meta-analyses suggest at most a weak association with ischemic stroke (pooled OR = 1.4) [Casas et al 2004], and myocardial infarction (per allele relative risk = 1.31) [Ye et al 2006]. The risk for arterial thrombosis in 20210G>A homozygotes is unknown, as very few homozygous individuals have been included in published studies. Myocardial infarction (MI). Although a 20210G>A allele is not a major risk factor for ischemic heart disease, it may contribute to the risk for MI in selected populations. 20210G>A heterozygosity increased the risk for MI 43-fold in women younger than age 50 years with traditional cardiovascular risk factors, particularly smoking [Rosendaal et al 1997]. The risk may also be increased in heterozygous postmenopausal women who use HRT [Psaty et al 2001, Hindorff et al 2006]. Stroke in adults. Although 20210G>A is not a general risk factor for stroke, it may contribute to the risk for stroke in selected populations: In two case-control studies, 20210G>A heterozygosity conferred a fourfold increased risk for ischemic stroke in individuals younger than age 50 years without established cardiovascular risk factors [De Stefano et al 1998, Aznar et al 2004]. Arterial thromboembolism may also occur "paradoxically" through a patent foramen ovale (PFO) in the heart of individuals with venous thrombosis. A meta-analysis concluded that a 20210G>A allele was significantly associated with PFO-related stroke in comparison with controls (OR = 3.85) and persons with non-PFO associated stroke (OR = 2.31) [Pezzini et al 2009]. Stroke in children. Arterial ischemic stroke in children usually occurs in the setting of multiple predisposing factors [Barnes & Deveber 2006]. Data on the association of thrombophilia with ischemic stroke are conflicting and mostly limited to small case series and case-control studies. Stroke accounted for 21% of thrombotic events in a highly selected group of symptomatic children with a 20210G>A allele. Children younger than age two years had a significantly higher rate of arterial thrombosis than older children in whom venous thrombosis was far more common [Young et al 2003]. A meta-analysis of 13 studies found that children with a 20210G>A allele had a twofold increased risk for a first stroke. The risk was increased nearly 19-fold in children with multiple thrombophilic defects [Kenet et al 2010]. However, several other small studies and a smaller meta-analysis found no significant association between 20210G>A heterozygostiy and first ischemic stroke in children [Zenz et al 1998, Kenet et al 2000, Bonduel et al 2003, Haywood et al 2005]. ### Genotype-Phenotype Correlations Homozygotes for the 20210G>A allele have a greater risk for thrombosis than do heterozygotes for the 20210G>A allele, although the magnitude of risk is not well defined. The clinical course of an acute thrombotic episode is not more severe or resistant to anticoagulation in 20210G>A homozygotes than in 20210G>A heterozygotes. ### Prevalence F2 20210G>A heterozygosity is the second most common inherited thrombophilia after factor V Leiden. The prevalence of 20210G>A heterozygosity varies by population. * 20210G>A heterozygosity occurs in 1.7%-3% of the general US and European populations. The highest heterozygosity rate is found in Europe; the allele is extremely rare in Asian, African, and Native American populations. Within Europe the prevalence varies from 3% in southern Europe to 1.7% in northern countries [Rosendaal et al 1998]. * In the US, the prevalence of 20210G>A heterozygosity is 2%-5% in whites, 2.2% in Hispanic whites, and 0%- 0.6% in African Americans, reflecting the world distribution of the allele [Dilley et al 1998, Dowling et al 2003, Chang et al 2009]. * A study of a multiracial American population found 20210G>A heterozygosity in 8.2% of white and 1.1% of African American persons with VTE. The allele was not detected in the African American control population [Dowling et al 2003]. Among adults with VTE, 20210G>A heterozygosity is present in 6%-14% of those with a first VTE, and 18%-21% of those with a personal or family history of recurrent VTE [Poort et al 1996, Margaglione et al 1998, Tosetto et al 1999]. A prospective study identified 20210G>A heterozygosity in 3.7% of children with a first spontaneous VTE [Nowak-Göttl et al 2001]. The prevalence of 20210G>A homozygosity is approximately one in 10,000. 20210G>A homozygosity is found in 1.8%-4.5% of individuals with a history of VTE [Margaglione et al 1999, Barcellona et al 2003]. Double heterozygosity for the 20210G>A and factor V Leiden alleles occurs in approximately one in 1000 individuals in the general population and is found in 1%-5% of persons with VTE [Margaglione et al 1999, Salomon et al 1999, Emmerich et al 2001, Simioni et al 2000]. ## Differential Diagnosis The differential diagnosis of venous thromboembolism (VTE) includes several other inherited and acquired thrombophilic disorders. Because these disorders are not clinically distinguishable, laboratory testing is required for diagnosis in each case. (See also Management, Evaluations Following Initial Diagnosis.) ### Inherited Factor V Leiden refers to the specific G-to-A substitution in F5 that predicts a single amino-acid replacement (Arg506Gln) that destroys a cleavage site for activated protein C. The resulting impaired anticoagulant response to activated protein C results in increased thrombin generation and a prothrombotic state [Kujovich 2011]. Factor V Leiden heterozygosity is found in 3%-8% of the general population and 15%-20% of individuals with a first VTE. Factor V Leiden heterozygosity is identified in 20%-40% of symptomatic 20210G>A heterozygotes with VTE [Poort et al 1996, Emmerich et al 2001]. A specific single nucleotide variant (SNV) (677C>T) in MTHFR, encoding methylenetetrahydrofolate reductase, results in a variant thermolabile enzyme with reduced activity for the remethylation of homocysteine. Homozygosity for 677C>T (also known as C677T) occurs in 10%-20% of the general population and predisposes to mild hyperhomocysteinemia in the setting of suboptimal folate stores. The MTHFR variant does not confer an increased risk for VTE [Bezemer et al 2007]. The official designation for this MTHFR variant is NM_005957.4:c.665C>T, NP_005948.3:p.Ala222Val, or rs1801133. Inherited deficiencies of the natural anticoagulant proteins C, S, and antithrombin are approximately tenfold less common than F2 20210G>A heterozygosity with a combined prevalence of less than 1% of the population. Anticoagulant protein deficiencies are found in 1%-3% of individuals with a first VTE. Elevated levels of lipoprotein(a) are associated with premature atherosclerosis and may also be a risk factor for venous thrombosis. Hereditary dysfibrinogenemias are rare and infrequently cause thrombophilia and thrombosis. See Thrombophilia: OMIM Phenotypic Series, to view genes associated with this phenotype in OMIM. ### Acquired High plasma concentration of homocysteine is present in 10% of individuals with a first VTE. In early studies a high plasma concentration of homocysteine was associated with a twofold increased relative risk for VTE; however, more recent data indicate that a high homocysteine level is a much weaker risk factor for VTE than previously reported [Den Heijer et al 2005]. It was not associated with an increased thrombotic risk in children [Joachim et al 2013]. The plasma concentration of homocysteine reflects genetic as well as environmental factors. Antiphospholipid antibodies comprise a heterogeneous group of autoantibodies directed against proteins bound to phospholipid. Anticardiolipin antibodies and the related anti-beta2 glycoprotein 1 antibodies are detected by solid phase immunoassays. Lupus inhibitors are autoantibodies that interfere with phospholipid-dependent clotting assays. Persistent high titer lupus inhibitors are more strongly associated with arterial and venous thromboembolism than other antiphospholipid antibodies [Galli et al 2003]. Recent evidence indicates that "triple positivity" for all three types of antiphospholipid antibodies confers the highest risk of thrombosis and pregnancy complications [Pengo et al 2010]. An elevated factor VIII level greater than 150% of normal is associated with a four- to fivefold increased risk for a first VTE [Koster et al 1995, Bank et al 2005] and also significantly increases the risk for recurrent thrombosis [Kyrle et al 2000]. Familial clustering of high factor VIII levels occurs although the relative contribution from genetic factors to persistently elevated levels is still unknown. No specific F8 benign variants have been associated with elevaled plasma factor VIII levels [Jenkins et al 2012]. An elevated plasma level of factor IX and factor XI is each associated with a twofold increased risk for VTE [van Hylckama Vlieg et al 2000, Cushman et al 2009]. Elevated plasma levels of both factor VIII and factor IX are associated with an eightfold increased risk for VTE [Meijers et al 2000, van Hylckama Vlieg et al 2000]. An elevated plasma prothrombin level greater than 110% -115% of normal is associated with a twofold increased risk for VTE in the absence of F2 20210G>A [Poort et al 1996, Legnani et al 2003]. The combination of oral contraceptives and high levels of prothrombin and factor V or factor XI had a supra-additive effect on thrombotic risk, with odds ratios ranging from ten to 13 [van Hylckama Vlieg & Rosendaal 2003]. ### Other Although thrombosis has been reported in association with defects or deficiencies of other coagulation and fibrinolytic proteins, including heparin cofactor II, PAI-1, tissue factor pathway inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI), and protein Z, a causal association has not been established [Meltzer et al 2010]. Other genetic risk factors for thrombosis under investigation include a fibrinogen gamma chain variant (10034T), genetic variants in the protein C promoter region, and several single-nucleotide polymorphisms (SNPs) in coagulation proteins [Smith et al 2007, Bezemer et al 2008]. Genome-wide association analysis has also been used to identify novel susceptibility genes for venous thrombosis [Germain et al 2011]. Several global markers of coagulation such as measurement of thrombin generation show promise in identifying individuals at high risk for thrombosis [Eichinger & Kyrle 2009, Kyrle et al 2010]. Testing for these potential risk factors is not routinely recommended and in many cases, assays are not commercially available. ## Management ### Evaluations Following Initial Diagnosis Because of the increased incidence of a second thrombophilic defect among symptomatic individuals with inherited thrombophilia [Emmerich et al 2001], individuals heterozygous or homozygous for the F2 20210G>A allele should be tested for other inherited and acquired thrombophilic disorders in order to evaluate the risk for thrombosis. Testing should include: * An activated protein C resistance or DNA assay for factor V Leiden; * Serologic assays for anticardiolipin antibodies and anti-beta 2 glycoprotein 1 antibodies; * Multiple phospholipid-dependent coagulation assays for a lupus inhibitor. Note: Testing for antiphospholipid antibodies should include assays for all three antibodies (anticardiolipin antibodies, anti-beta2 glycoprotein 1 antibodies, and lupus inhibitors) since only 50% of individuals with the antiphospholipid antibody syndrome have more than one type of antibody. Evaluation of high-risk individuals (i.e., those with a history of recurrent VTE especially at a young age, or those with strong family history of VTE at a young age), should also include assays of: * Protein C activity; * Antithrombin activity; * Protein S activity or free protein S antigen. Note: In an evaluation for thrombophilia: (1) Measurement of plasma concentration of homocysteine is no longer recommended because no data support the use of vitamin supplementation or modification of the duration of anticoagulation in individuals with hyperhomocysteinemia and a history of VTE [den Heijer et al 2007]; (2) there is no clinical rationale for DNA testing for MTHFR variants; and (3) routine measurement of factor VIII and other clotting factor levels is not recommended; however, such testing may be useful in certain instances [Bauer 2010, Jenkins et al 2012] ### Treatment of Manifestations The management of thrombosis in individuals with prothrombin-related thrombophilia depends on the clinical circumstances. The first acute thrombosis should be treated according to standard guidelines with a course of low molecular-weight heparin (LMWH) or fondaparinux (a pentasaccharide) [Kearon et al 2012]. Low molecular-weight heparins and fondaparinux have largely replaced unfractionated heparin because of their many advantages [Garcia et al 2012]. Oral administration of warfarin is started concurrently with LMWH or fondaparinux (except during pregnancy) and monitored with the international-normalized ratio (INR). A target INR of 2.5 (therapeutic range: 2.0-3.0) provides effective anticoagulation, even in F2 20210G>A homozygotes. Rivaroxaban, a direct factor Xa inhibitor, is also approved for the treatment of acute DVT and PE and secondary prevention of recurrent VTE. Note: LMWH and warfarin are both safe in women who are breast-feeding. Rivaroxaban is contraindicated during pregnancy and breast-feeding because animal studies showed reproductive toxicity, and evidence that the drug crosses the placenta and is secreted in milk [Ageno et al 2012]. The duration of oral anticoagulation therapy should be based on an individualized assessment of the risks of VTE recurrence and anticoagulant-related bleeding. Approximately 30% of individuals with VTE experience recurrent thrombosis within the subsequent five years [Prandoni et al 2007]. Recurrence risk is determined by the clinical circumstances of the first event (provoked or unprovoked), adequacy of early treatment, and individual risk factors (see Clinical Description, Recurrent Thrombosis, Risk for recurrent thrombosis in adult 20210G>A heterozygotes. 20210G>A heterozygosity is generally not an indication for long-term anticoagulation in the absence of other risk factors. The presence of a hereditary thrombophilia was not a factor determining the duration of anticoagulation in the 2012 American College of Chest Physicians Guidelines on Antithrombotic Therapy and Prevention of Thrombosis based on evidence that inherited thrombophilic disorders are not major determinants of VTE recurrence risk [Kearon et al 2012] (full text). Other clinical guidelines and expert opinion also conclude that identification of 20210G>A heterozygosity should not affect clinical decision making [Baglin et al 2010, Bauer 2010, Kyrle et al 2010, Heleen van Ommen & Middeldorp 2011, Monagle et al 2012, National Clinical Guideline Centre 2012]. See Published Guidelines / Consensus Statements. Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor [Kearon et al 2012]. Long-term oral anticoagulation is recommended for individuals with a first or recurrent unprovoked (i.e., idiopathic) VTE and no risk factors for bleeding with good anticoagulation monitoring [Kearon et al 2012]. The decision should be based on an assessment of potential risks and benefits regardless of 20210G>A status [Berg et al 2011]. Long-term anticoagulation is considered in selected individuals homozygous for the 20210G>A allele or with multiple inherited or acquired thrombophilic disorders [De Stefano & Rossi 2013]. In these individuals at higher risk for recurrence, the potential benefits of long-term anticoagulation may outweigh the bleeding risks. LMWH, fondaparinux, warfarin, and rivaroxaban are the primary antithrombotic agents used for the acute and long-term treatment of VTE. Several direct thrombin inhibitors (lepirudin, argatroban, and dabigatran), and apixaban, a direct factor Xa inhibitor, are approved for use in specific circumstances [Schulman 2014]. Graduated compression stockings should be worn for at least two years following an acute DVT. Treatment of thrombosis in children. Treatment recommendations for children with VTE are largely adapted from studies in adults. There is no evidence that a 20210G>A allele should influence decisions about the intensity or duration of anticoagulation in children [Monagle et al 2012, Chalmers et al 2011, Heleen van Ommen & Middeldorp 2011, Monagle et al 2012]. British guidelines for antithrombotic therapy in children do not consider inherited thrombophilia as a determinant of either the intensity or duration of therapy. Children with a first VTE should receive initial treatment with either unfractionated heparin (UFH) or LMWH for at least five days. LMWH is favored over warfarin for continued therapy, especially in very young children and those with complex medical problems. Recommendations on the duration of antithrombotic therapy are based on the nature of the thrombotic event (e.g., spontaneous or provoked) [Chalmers et al 2011, Monagle et al 2012, Chalmers et al 2011] (see Published Guidelines / Consensus Statements). Anticoagulation is recommended: * For at least three months after a VTE provoked by a clinical risk factor that has resolved. * Beyond three months until the risk factor has resolved in children with ongoing but potentially reversible risk factors. * For six to 12 months after a first idiopathic (unprovoked) VTE. * Indefinitely for those with recurrent idiopathic VTE Expert opinion emphasizes the importance of a careful risk/benefit assessment in each individual [Raffini & Thornburg 2009, Heleen van Ommen & Middeldorp 2011]. Consensus guidelines are also available for management of stroke in infants and children [Monagle et al 2012] (full text). ### Prevention of Primary Manifestations In the absence of a history of thrombosis, long-term anticoagulation is not recommended for asymptomatic 20210G>A heterozygotes, since the 1%-3% yearly risk for major bleeding from warfarin is greater than the estimated (<1%) yearly risk for thrombosis [Martinelli et al 2000a, Middeldorp & van Hylckama Vlieg 2008, Berg et al 2011]. Prophylactic anticoagulation may be considered in high-risk clinical settings such as surgery, pregnancy, or prolonged immobilization, although currently no evidence confirms the benefit of primary prophylaxis for asymptomatic 20210G>A heterozygotes. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in the 2012 American College of Chest Physicians consensus guidelines [Guyatt et al 2012] (full text). ### Surveillance Individuals receiving long-term anticoagulation require periodic reevaluation to confirm that the benefits of anticoagulation continue to outweigh the bleeding risk. Selected 20210G>A heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. (See Prevention of Primary Manifestations.) ### Agents/Circumstances to Avoid F2 20210G>A heterozygotes: * With a history of VTE should avoid estrogen contraception and HRT; asymptomatic women should be counseled on the risks of estrogen-containing contraception and HRT and should consider alternative forms of contraception and strategies for control of menopausal symptoms. * Who are asymptomatic and elect to use oral contraceptives should avoid formulations with third-generation and other progestins with a higher thrombotic risk; * Who elect short-term hormone replacement therapy for severe menopausal symptoms should use low-dose transdermal preparations, which have a lower thrombotic risk than oral formulations [Straczek et al 2005, Canonico et al 2007, Renoux et al 2010]. F2 20210G>A homozygous women with or without prior VTE should avoid estrogen-containing contraception and HRT. ### Evaluation of Relatives at Risk The genetic status of asymptomatic at-risk family members can be established using molecular genetic testing. However, as there is no clinical evidence that early diagnosis reduces morbidity or mortality, the indications for family testing are unresolved and the decision to test at-risk family members should be made on an individual basis [Segal et al 2009]. Clarification of 20210G>A allele status may be useful in: * Asymptomatic adult family members of probands with one or two known 20210G>A alleles, especially those with a strong family history of VTE at a young age; * Asymptomatic female family members of probands with known prothrombin-related thrombophilia who are pregnant or considering estrogen contraception or pregnancy. There is no clinical evidence to support testing asymptomatic children with a family history of thrombosis and/or inherited thrombophilia. Guidelines suggest delaying testing until children are able to understand the implications of the results and (optimally) can give informed consent for testing [Chalmers et al 2011]. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management No consensus exists on the optimal management of prothrombin thrombophilia during pregnancy; guidelines are derived from studies in non-pregnant individuals [Kujovich 2004a, Royal College of Obstetricians and Gynaecologists 2009, Baglin et al 2010, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]; see Published Guidelines / Consensus Statements. LMWH is the preferred antithrombotic agent for prophylaxis during pregnancy. All women with inherited thrombophilia should undergo individualized risk assessment. Decisions about anticoagulation should be based on the number and type of thrombophilic defects, coexisting risk factors, and personal and family history of thrombosis [Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]. Prophylactic anticoagulation during pregnancy: * Is recommended for all women: * With a history of unprovoked VTE, including those heterozygous for 20210G>A. LMWH should be given during pregnancy followed by six weeks of postpartum anticoagulation [Royal College of Obstetricians and Gynaecologists 2009, Baglin et al 2010, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]. * Heterozygous for the 20210G>A allele with a prior pregnancy or estrogen-related thrombosis who are also at an increased risk for recurrence [Pabinger et al 2005, De Stefano et al 2006, Royal College of Obstetricians and Gynaecologists 2009, Baglin et al 2010, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]. * Should be considered for: * Asymptomatic women doubly heterozygous for 20210G>A and factor V Leiden, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) [Royal College of Obstetricians and Gynaecologists 2009, American College of Obstetricians and Gynecologists 2013b]; * Asymptomatic homozygous women with a family history of thrombosis [Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]. * Is not routinely recommended in asymptomatic heterozygous women with no history of thrombosis or other risk factors. These women should be counseled about potential thrombotic complications during pregnancy and the postpartum period [Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]. * In two large prospective studies, low-risk asymptomatic women with thrombophilia (including 20210G>A heterozygosity) did not receive LMWH during pregnancy in the absence of additional risk factors. All women received a course of postpartum anticoagulation. The low incidence of antepartum VTE in both studies (0% and 0.34%) suggested that anticoagulation may be safely withheld during pregnancy in low-risk 20210G>A heterozygotes who do not have other risk factors [Bauersachs et al 2007, Dargaud et al 2009]. A six-week course of postpartum prophylactic anticoagulation is recommended for: * Heterozygous women with a positive family history of VTE or other additional risk factors; * All asymptomatic homozygous women; * All women with a prior history of VTE [Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]. Prevention of pregnancy loss. It is still unkown if prophylactic antithrombotic therapy improves pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss. The available evidence consists of predominantly uncontrolled trials, observational studies, and a few randomized trials with important methodologic limitations. There are no prospective randomized trials that include an untreated control group that confirms the benefit of LMWH for preventing pregnancy loss in women with inherited thrombophilia. Of note, the ALIFE2 study, a multicenter randomized trial of LMWH versus standard surveillance in women with inherited thrombophilia and a history of recurrent miscarriage, began recruitment in December 2012 (www.trialregister.nl, NTR 3361). Current consensus guidelines and expert opinion recommend against the use of antithrombotic therapy in women with inherited thrombophilia and unexplained recurrent pregnancy loss outside of clinical trials because of the absence of high quality evidence confirming benefit [Baglin et al 2010, Royal College of Obstetricians and Gynaecologists 2011a, Royal College of Obstetricians and Gynaecologists 2011b, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b, Middeldorp 2013]. Studies suggesting that prophylactic anticoagulation improves pregnancy outcome: * The results of several observational studies suggested that prophylactic antithrombotic therapy may improve pregnancy outcome in women with inherited thrombophilia and recurrent pregnancy loss [Brenner et al 2000, Carp et al 2003]. * A recent study of women with a history of unexplained pregnancy loss compared the frequency of obstetric complications in women with factor V Leiden or 20210G>A alleles and women without thrombophilia. Women with a thrombophilic disorder with a prior fetal loss after ten weeks’ gestation who received enoxaparin during their next pregnancy had a significantly lower rate of fetal loss and severe preeclampsia and a higher rate of live births compared to women without a thrombophilic disorder with the same obstetric history who did not receive prophylaxis [Bouvier et al 2014]. * A prospective randomized trial compared prophylactic-dose enoxaparin and low-dose aspirin in women heterozygous for 20210G>A, factor V Leiden, or protein S deficiency, and a history of a single unexplained fetal loss after ten weeks’ gestation. Enoxaparin prophylaxis was associated with a significantly higher live birth rate of 86% compared to 29% with aspirin. However, there were methodologic problems with this study and the results have not been confirmed in other trials. Studies suggesting that prophylactic anticoagulation does not improve pregnancy outcome: * Several studies found no benefit with LMWH on pregnancy outcome in women with inherited thrombophilia [Laskin et al 2009, Warren et al 2009, Visser et al 2011]. * Two recent randomized trials compared the efficacy of LMWH and aspirin to no antithrombotic therapy or placebo in women with unexplained recurrent pregnancy loss. Combined LMWH and low-dose aspirin did not increase the live birth rate in either study [Clark et al 2010, Kaandorp et al 2010]. Because only a small proportion of the study populations had inherited thrombophilia (3.5% and 15.7%), subgroup analyses were insufficiently powered to assess the effect of antithrombotic therapy. * In the recent Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) multinational randomized trial, antepartum prophylactic LMWH did not reduce the incidence of pregnancy loss or placenta-mediated complications in pregnant women with thrombophilia (22% with a 20210G>A allele) who are at high risk for these complications [Rodger et al 2014]. Other pregnancy complications. Data supporting the benefit of antithrombotic therapy in women with inherited thrombophilia and other pregnancy complications are considerably more limited and also conflicting [Gris et al 2011, de Vries et al 2012, Martinelli et al 2012]. There is insufficient evidence that LMWH (with or without aspirin) reduces the risk for preeclampsia, placental abruption, or other obstetric complications in women with or without inherited thrombophilia. Current guidelines recommend against antithrombotic prophylaxis for women with inherited thrombophilia and a history of pregnancy complications [Baglin et al 2010, Bates et al 2012, American College of Obstetricians and Gynecologists 2013b]. ### Therapies Under Investigation Several new oral anticoagulants (which have not been specifically studied in individuals with inherited thrombophilia) are alternatives to warfarin in specific clinical settings. Dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (two new factor Xa inhibitors) are approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation [Weitz et al 2012]. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Prothrombin-Related Thrombophilia	c1867596	4,334	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1148/	2021-01-18T21:01:28	{"mesh": ["C566755"], "synonyms": ["F2-Related Thrombophilia", "Factor II-Related Thrombophilia", "Prothrombin 20210G>A Thrombophilia", "Prothrombin G20210A Thrombophilia", "Prothrombin Thrombophilia"]}
Hepatoid tumor or hepatoid [adeno]carcinoma are terms for a number of uncommon or rare neoplasms in humans, named for a visual resemblance of the cells under the microscope to those of hepatocellular carcinoma, the most common form of liver cancer. They can arise in several parts of the body, and thus form sub-types of diseases such as stomach cancer and pancreatic cancer.[1][2][3] The WHO defines "Hepatoid carcinoma" as "An adenocarcinoma with morphologic characteristics similar to hepatocellular carcinoma, arising from an anatomic site other than the liver".[4] In dogs it may refer to a Perianal gland tumor, based on a similar resemblance to healthy liver cells. ## References[edit] 1. ^ Gálvez-Muñoz, Elisa; Gallego-Plazas, Javier; Gonzalez-Orozco, Verónica; Menarguez-Pina, Francisco; Ruiz-Maciá, José A; Morcillo, Miguel A (2009). "Hepatoid adenocarcinoma of the stomach – a different histology for not so different gastric adenocarcinoma: a case report". International Seminars in Surgical Oncology. 6 (1): 13. doi:10.1186/1477-7800-6-13. PMC 2731104. PMID 19674468. 2. ^ Soofi, Yousef; Kanehira, Kazunori; Abbas, Ali; Aranez, Jose; Bain, Andrew; Ylagan, Lourdes (August 2014). "Pancreatic hepatoid carcinoma: A rare form of pancreatic neoplasm". Diagnostic Cytopathology. 43: 251–256. doi:10.1002/dc.23195. 3. ^ Vlachostergios, Panagiotis J; Voutsadakis, Ioannis A; Barbanis, Sotirios; Karasavvidou, Foteini; Papandreou, Christos N (2009). "AFP-producing hepatoid adenocarcinoma of the stomach: a case report". Cases Journal. 2 (1): 9296. doi:10.1186/1757-1626-2-9296. PMC 2803960. PMID 20062620. 4. ^ "WHO Classification of Tumours, Hepatoid carcinoma". IARC. World Health Organization. Archived from the original on 12 February 2015. Retrieved 2 December 2014. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Hepatoid tumor	c1266090	4,335	wikipedia	https://en.wikipedia.org/wiki/Hepatoid_tumor	2021-01-18T18:41:17	{"umls": ["C1266090"], "wikidata": ["Q23037783"]}
Midline interhemispheric variant of holoprosencephaly (MIH) or syntelencephaly is a form of holoprosencephaly (HPE; see this term) characterized by non-separation of the posterior frontal and parietal lobes, normally-formed callosal genu and splenium, absence of the callosal body, normally-separated hypothalamus and lentiform nucleus, and frequent heterotopic gray matter. ## Epidemiology About 2% to 15% of HPE patients have MIH type. ## Clinical description Patients have rather mild dysmorphic facial features such as ocular hypotelorism, flat or narrow nasal bridge or a relatively normal facial appearance. ## Etiology MIH has mainly been reported in patients with ZIC2 (13q32) mutations. ## Prognosis Prognosis is better than in classical forms of HPE. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Midline interhemispheric variant of holoprosencephaly	c1834877	4,336	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93926	2021-01-23T17:23:52	{"mesh": ["C563579"], "omim": ["157170", "609637", "610829"], "icd-10": ["Q04.2"], "synonyms": ["MIH", "MIH type HPE", "MIHF", "MIHV", "Middle interhemispheric fusion variant", "Middle interhemispheric variant of holoprosencephaly", "Syntelencephaly"]}
Alopecia universalis French actor Tómas Lemarquis with alopecia universalis SpecialtyDermatology Alopecia universalis (AU), also known as alopecia areata universalis, is a medical condition involving the loss of all body hair, including eyebrows, eyelashes, chest hair, armpit hair, and pubic hair. It is the most severe form of alopecia areata.[1] ## Causes[edit] Alopecia universalis can occur at any age, and is currently believed to be an autoimmune disorder, in which a person's immune system attacks the hair follicles. Genetic factors may contribute to AU, as about 20% of those affected have a family member with alopecia.[2] ## Treatment[edit] No standard treatment is used for alopecia universalis. Many treatments have been explored, including immunomodulatory agents such as imiquimod.[3] Tofacitinib citrate may also have benefits. In June 2014, a 25-year-old man with almost no hair on his body was reported to have grown full head of hair, as well as eyebrows, eyelashes, and facial, armpit, and other hair, following eight months of treatment.[4] ### Current treatments[edit] * Contact immunotherapy: Contact immunotherapy involves the use of contact allergens, such as diphencyprone and squaric acid dibutylester, to induce an immune response that is thought to oppose the action of cells causing hair loss.[5][6][7] A review that combined and analyzed the findings of 45 studies comprising 2,227 patients showed any hair regrowth in 54.5% and complete hair regrowth in 24.9% of patients with AT and AU using contact immunotherapy.[8] In addition to its helpful effects in treating AU, it can have side effects that can be very serious, such as severe dermatitis.[5][9] * Corticosteroids: Topical and intralesional corticosteroids, such as clobetasol propionate, have also shown to be an effective treatment for AT and AU patients.[5][6] A controlled study comprising 28 patients found positive terminal hair growth in eight of the patients (28.5%) using a 0.05% clobetasol propionate ointment.[10] This is very similar to the results obtained from immunotherapy treatment trials. Additionally, studies suggest that intralesional applications are much more effective than topical applications of steroids. However, the main side effect is increased risk of cutaneous atrophy at the site of treatment;[6] folliculitis is also an occasional complication.[7] ### Investigational and future treatments[edit] * JAK inhibitors: Janus kinase inhibitors, previously used in the treatment of cancer and other diseases, such as arthritis, have successfully shown to be effective in the initial trials of treatment for alopecia patients.[5][6][11] Multiple cases of treatments have been successful, one of them being of a 22-year-old man with a history of AU and atopic dermatitis (AD). This man was treated with JAK inhibitor tofacitinib, and after 10 months, he experienced hair regrowth on all of his affected body parts and subsequent improvement of his AD.[12][13] Current research and findings suggest that systemic JAK inhibitors eliminate and prevent the development of AA, while topical JAK inhibitors promote hair regrowth and reverse the established disease.[7][14] Many clinical trials are ongoing involving JAK inhibitors such as ruxolitinib and tofacitinib.[5][15] ## See also[edit] * Alopecia areata * Alopecia totalis ## References[edit] 1. ^ "Alopecia universalis \| Disease \| Overview \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2016-03-01. 2. ^ Robins, Douglas N. (September 2007). "Alopecia Universalis: Hair Growth following Initiation of Simvastatin and Ezetimibe Therapy". Journal of Drugs in Dermatology. 6 (9): 946–7. PMID 17941369. Retrieved 31 August 2020. 3. ^ Letada PR, Sparling JD, Norwood C (2007). "Imiquimod in the treatment of alopecia universalis". Cutis; Cutaneous Medicine for the Practitioner. 79 (2): 138–40. PMID 17388216. 4. ^ "Hairless Man Grows Full Head Of Hair In Yale Arthritis Drug Trial". boston.cbslocal.com. 2014-06-19. 5. ^ a b c d e Khan Mohammad Beigi, Pooya (2018), Khan Mohammad Beigi, Pooya (ed.), "Alopecia Totalis/Universalis", Alopecia Areata: A Clinician's Guide, Springer International Publishing, pp. 13–15, doi:10.1007/978-3-319-72134-7_3, ISBN 9783319721347 6. ^ a b c d Darwin, Evan; Hirt, PenelopeA; Fertig, Raymond; Doliner, Brett; Delcanto, Gina; Jimenez, JoaquinJ (2018). "Alopecia areata: Review of epidemiology, clinical features, pathogenesis, and new treatment options". International Journal of Trichology. 10 (2): 51–60. doi:10.4103/ijt.ijt_99_17. ISSN 0974-7753. PMC 5939003. PMID 29769777. 7. ^ a b c Pratt, C. Herbert; King, Lloyd E.; Messenger, Andrew G.; Christiano, Angela M.; Sundberg, John P. (2017-03-16). "Alopecia areata". Nature Reviews Disease Primers. 3: 17011. doi:10.1038/nrdp.2017.11. ISSN 2056-676X. PMC 5573125. PMID 28300084. 8. ^ Lee, Won-Soo; Lee, Young Bin; Kim, Beom Jun; Lee, Solam (2018-10-01). "Hair Regrowth Outcomes of Contact Immunotherapy for Patients With Alopecia Areata: A Systematic Review and Meta-analysis". JAMA Dermatology. 154 (10): 1145–1151. doi:10.1001/jamadermatol.2018.2312. ISSN 2168-6068. PMC 6233743. PMID 30073292. 9. ^ Strazzulla, Lauren C.; Wang, Eddy Hsi Chun; Avila, Lorena; Lo Sicco, Kristen; Brinster, Nooshin; Christiano, Angela M.; Shapiro, Jerry (January 2018). "Alopecia areata: An appraisal of new treatment approaches and overview of current therapies". Journal of the American Academy of Dermatology. 78 (1): 15–24. doi:10.1016/j.jaad.2017.04.1142. ISSN 1097-6787. PMID 29241773. 10. ^ Tosti, Antonella; Piraccini, Bianca Maria; Pazzaglia, Massimiliano; Vincenzi, Colombina (July 2003). "Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis". Journal of the American Academy of Dermatology. 49 (1): 96–98. doi:10.1067/mjd.2003.423. ISSN 0190-9622. PMID 12833016. 11. ^ Clynes, Raphael; Christiano, Angela M.; Vaughan, Roger; Furniss, Megan; Ulerio, Grace; Clark, Charlotte; Cerise, Jane E.; Nguyen, Nhan; Jabbari, Ali (2016-09-22). "Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata". JCI Insight. 1 (15): e89790. doi:10.1172/jci.insight.89790. ISSN 0021-9738. PMC 5033756. PMID 27699253. 12. ^ Morris, Gabriela M.; Nahmias, Zachary P.; Kim, Brian S. (2018-07-01). "Simultaneous improvement of alopecia universalis and atopic dermatitis in a patient treated with a JAK inhibitor". JAAD Case Reports. 4 (6): 515–517. doi:10.1016/j.jdcr.2017.12.016. ISSN 2352-5126. PMC 6047104. PMID 30023415. 13. ^ Navarini, Alexander A.; French, Lars E.; Trüeb, Ralph M.; Kamarachev, Jivko; Maul, Julia-Tatjana; Anzengruber, Florian (2016). "Transient Efficacy of Tofacitinib in Alopecia Areata Universalis". Case Reports in Dermatology. 8 (1): 102–106. doi:10.1159/000445182. ISSN 1662-6567. PMC 4869306. PMID 27194979. 14. ^ Clynes, Raphael; Christiano, Angela M.; Mackay-Wiggan, Julian; Petukhova, Lynn; Singh, Pallavi; Rothman, Lisa; DeStefano, Gina M.; Harel, Sivan; Jong, Annemieke de (September 2014). "Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition". Nature Medicine. 20 (9): 1043–1049. doi:10.1038/nm.3645. ISSN 1546-170X. PMC 4362521. PMID 25129481. 15. ^ Craiglow, Brittany G.; King, Brett A. (December 2014). "Killing Two Birds with One Stone: Oral Tofacitinib Reverses Alopecia Universalis in a Patient with Plaque Psoriasis". Journal of Investigative Dermatology. 134 (12): 2988–2990. doi:10.1038/jid.2014.260. ISSN 0022-202X. PMID 24940651. ## External links[edit] Classification D * ICD-10: L63.1 * 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 * v * t * e Human hair Classification by type * Lanugo * Androgenic * Terminal * Vellus by location * Body * Ear * Nose * Eyebrow * unibrow * Eyelash * Underarm * Chest * Abdominal * Pubic * Leg Head hairstyles (list) * Afro * Afro puffs * Asymmetric cut * Bald * Bangs * Beehive * Big hair * Blowout * Bob cut * Bouffant * Bowl cut * Braid * Brush cut * Bun (odango) * Bunches * Burr * Businessman cut * Butch cut * Buzz cut * Caesar cut * Chignon * Chonmage * Chupryna * Comb over * Conk * Cornrows * Crew cut * Crochet braids * Croydon facelift * Curly hair * Curtained hair * Devilock * Dido flip * Digital perm * Dreadlocks * Duck's ass * Eton crop * Extensions * Feathered hair * Finger wave * Flattop * Fontange * French braid * French twist * Fringe * Frosted tips * Hair crimping * Harvard clip * High and tight * Hime cut * Historical Christian hairstyles * Hi-top fade * Induction cut * Ivy League * Jewfro * Jheri curl * Kiss curl * Layered hair * Liberty spikes * Long hair * Lob cut * Marcelling * Mod cut * Mohawk * Mullet * 1950s * 1980s * Pageboy * Part * Payot * Pigtail * Pixie cut * Polish halfshaven head * Pompadour * Ponytail * Punch perm * Princeton * Professional cut * Queue * Quiff * Rattail * Razor cut * Regular haircut * Ringlets * Shag * Shape-Up * Shimada * Short back and sides * Short brush cut * Short hair * Spiky hair * Straight hair * Standard haircut * Surfer hair * Taper cut * Temple Fade * Tonsure * Updo * Undercut * Waves * Widow's peak * Wings Facial hair (list) * Beard * Chinstrap * Goatee * Shenandoah * Soul patch * Van Dyke * Moustache * Fu Manchu * handlebar * horseshoe * pencil * toothbrush * walrus * Designer stubble * Sideburns Hair loss cosmetic * Removal * waxing * threading * plucking * chemical * electric * laser * IPL * Shaving * head * leg * cream * brush * soap * Razor * electric * safety * straight other * Alopecia * areata * totalis * universalis * Frictional alopecia * Male-pattern hair loss * Hypertrichosis * Management * Trichophilia * Trichotillomania * Pogonophobia Haircare products * Brush * Clay * Clipper * Comb * Conditioner * Dryer * Gel * Hot comb * Iron * Mousse * Pomade * Relaxer * Rollers * Shampoo * Spray * Wax Haircare techniques * Backcombing * Crimping * Curly Girl Method * Hair cutting * Perm * Shampoo and set * Straightening Related topics * Afro-textured hair (kinky hair) * Beard and haircut laws by country * Bearded lady * Barber (pole) * Eponymous hairstyle * Frizz * Good hair * Hairdresser * Hair fetishism (pubic) * Hair follicle * Hair growth * Hypertrichosis * Trichotillomania [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Alopecia universalis	c0263505	4,337	wikipedia	https://en.wikipedia.org/wiki/Alopecia_universalis	2021-01-18T18:30:59	{"gard": ["614"], "mesh": ["C537055"], "icd-10": ["L63.1"], "wikidata": ["Q4734616"]}
## Mapping Tanaka et al. (2009) performed a genomewide association analysis to investigate genetic factors affecting plasma levels of vitamin B6 in the InCHIANTI (1,175 participants) study. The top locus, rs4654748, which is in the NBPF3 (612992) gene and 5-prime of the ALPL gene (171760) in a region of tight linkage disequilibrium on chromosome 1p, was replicated in an independent sample of 687 participants in the Progetto Nutrizione study (p = 8.30 x 10(-18)). The authors suggested that polymorphisms in the ALPL gene influence the plasma levels of vitamin B6 because ALPL is the main enzyme responsible for clearance of vitamin B6. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	VITAMIN B6 PLASMA LEVEL QUANTITATIVE TRAIT LOCUS 1	c2751828	4,338	omim	https://www.omim.org/entry/612957	2019-09-22T16:00:10	{"omim": ["612957"]}
22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a chromosome disorder caused by the loss (deletion) of a small piece of chromosome 22. The deletion occurs near the end of the long arm (or q arm) of the chromosome at a location designated as q13.3. Not everyone with 22q13.3 deletion syndrome will have the same medical, developmental, or behavioral problems (features). Common problems include low muscle tone (hypotonia), intellectual disability, developmental delays especially delayed or absent speech, and tendency to overheat. Children may be tall and thin. Differences in other physical features are usually mild and may include long eyelashes, down slanting eyes, large ears, ears without normal folding, bulb-like tip of nose, pointed chin, large hands, and toenails that flake off as infants and then become hard and brittle as age. Additional medical problems may include gastrointestinal problems such as chronic diarrhea, constipation, or gastroesophageal reflux, seizures, delayed fine motor skills, changes in the way the brain developed, kidney problems especially vesicoureteral reflux (VUR), vision problems such as strabismus, swelling of arms or legs (lymphedema) during teen years, and recurrent infections, especially ear infections. Unusual behaviors may include mouthing or chewing on non-food items, decreased perception of pain, and autistic-like behaviors such as flapping of hands and repetitive motions. Most reported cases of 22q13.3 deletion syndrome are caused by 22q13.3 deletions, which usually includes many genes. The loss or the variation (mutation) of a particular gene on chromosome 22, called the SHANK3 gene, is likely responsible for many of the common features associated with 22q13.3 deletion syndrome, especially intellectual disability, speech problems, low muscle tone, and developmental delay. Additional genes within the deleted area probably contribute to other features of the syndrome. In most cases, a larger deletion increases the number and severity of associated features, especially the severity of low muscle tone, developmental delay, differences in physical features, speech, and autism-like behavior. Smaller deletions located closer to the tip of the 22q seem to be associated with fewer medical, developmental, and behavioral problems. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	22q13.3 deletion syndrome	c1853490	4,339	gard	https://rarediseases.info.nih.gov/diseases/10130/22q133-deletion-syndrome	2021-01-18T18:02:25	{"mesh": ["C536801"], "omim": ["606232"], "umls": ["C1853490"], "orphanet": ["48652"], "synonyms": ["Phelan-McDermid syndrome", "Deletion 22q13.3 syndrome", "Chromosome 22q13.3 deletion syndrome", "Monosomy 22q13", "22q13 deletion", "22q13.3 deletion", "Monosomy 22q13.3"]}
## Clinical Features Tiemann et al. (2005) reported 3 male newborns from a consanguineous Lebanese family with a rapidly fatal syndrome consisting of fetal akinesia deformation sequence (FADS; see 208150), inguinal hernias, hearing loss, and myopathic changes biochemically characterized by elevated glycogen content, absent branching enzyme (607839), and decreased activity of phosphorylase-a (see PYGM, 608455) in skeletal muscle. Death occurred at 59 days, 18 days, and 39 days of age in the 3 infants. The 3 males were in 2 sibships, the offspring of 2 brothers married to 2 sisters to whom they were related as first cousins. Inheritance Consanguinity and occurrence in sibs suggest autosomal recessive inheritance of this disorder (Tiemann et al., 2005). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	ARTHROGRYPOSIS MULTIPLEX WITH DEAFNESS, INGUINAL HERNIAS, AND EARLY DEATH	c1864939	4,340	omim	https://www.omim.org/entry/610001	2019-09-22T16:05:15	{"mesh": ["C535381"], "omim": ["610001"]}
HIV/AIDS in China can be traced to an initial outbreak of the human immunodeficiency virus (HIV) first recognized in 1989 among injecting drug users along China's southern border.[1][2] Figures from the Chinese Center for Disease Control and Prevention, World Health Organization, and UNAIDS estimate that there were 1.25 million people living with HIV/AIDS in China at the end of 2018, with 135,000 new infections from 2017. The reported incidence of HIV/AIDS in China is relatively low,[3] but the Chinese government anticipates that the number of individuals infected annually will continue to increase.[4] While HIV is a type of sexually transmitted infection,[5] the first years of the epidemic in China were dominated by non-sexual transmission routes, particularly among users of intravenous drugs through practices such as needle sharing.[6] By 2005, 50% of new HIV cases were due to sexual transmission,[7] with heterosexual sex gradually becoming the most common means of new infections in the 2000s.[8] New infections among men who have sex with men (MSMs) grew rapidly thereafter, representing 26% of all new cases in 2014, up from 2.5% in 2006.[9] Another major, non-sexual channel of infection was the Plasma Economy of the 1990s, wherein large numbers of blood donors, primarily in poor, rural areas, were infected with HIV as a result of systematically dangerous practices by state and private blood collection clinics.[10] ## Contents * 1 History * 1.1 Global Background * 1.2 Early stages of the epidemic in China * 1.2.1 Contaminated blood imports * 1.2.2 Southern intravenous drug users * 1.2.3 Bloodhead controversy * 1.2.4 Sex trade * 2 Epidemiology * 2.1 Data collection and reliability * 2.2 Current transmission * 2.3 Mortality rates * 3 Control and prevention * 3.1 Overview: Evolution of policy response * 3.1.1 1985-1988: Protection from foreign infection * 3.1.2 1989-1994: Control of limited epidemic * 3.1.3 1995-2003: Combatting widespread epidemic * 3.1.4 2003-Present: Evidence-based approaches post-SARS * 3.2 International cooperation and funding * 4 Discrimination against people with HIV/AIDS * 5 Traditional Chinese Medicine * 6 Activism * 7 Socioeconomic effect * 8 Media * 8.1 Documentaries * 9 See also * 10 Notes and references * 11 Further reading * 12 External links ## History[edit] ### Global Background[edit] See also: History of HIV/AIDS and Timeline of HIV/AIDS HIV evolved from the simian immunodeficiency virus (SIV), present in numerous species of primates in West Africa and Central Africa, in the early 20th century. SIV jumped from primates to humans several times, although the primary strain of HIV responsible for the global pandemic, HIV-1 group M, is traceable to the region surrounding Kinshasha,[11] likely having initially crossed from chimpanzees around 1920.[12] From there, it spread to the Caribbean around 1967, proceeding to establish itself in New York City and San Francisco circa 1971 and 1976, respectively.[13] The Centers for Disease Control and Prevention (CDC) recognized unusual outbreaks of opportunistic infections among gay men in 1981,[14][15] and the disease was initially referred to as Gay-related immune deficiency (GRID), although it was quickly understood to also infect heterosexuals as well.[16] In 1982, the CDC adopted the name "acquired immune deficiency syndrome" (AIDS).[17] By the end of 1984, 7,699 cases of AIDS and 3,665 deaths had been recorded in America, with an additional cases 762 in Europe. By the end following year, over 20,000 cases were recorded globally, reaching every inhabited region in the world.[12] ### Early stages of the epidemic in China[edit] The first recorded death due to AIDS was a male Argentine-American[18] tourist and California resident who died in Beijing on 6 June 1985.[19] The Chinese government focused initially on preventing foreigners from transmitting the disease to its citizens, viewing it primarily as a consequence of a Western lifestyle.[20] By 1998, HIV/AIDS was present in all 31 provinces and administrative regions of China, and government statistics indicated between 60% and 70% of those infected were drug users.[21] Other major modes of transmission included infected blood spread through blood donation clinics across the country and the sex trade. Before either of these routes of infection were identified, however, a handful of people contracted HIV after receiving transfusions of contaminated hemophilia blood products from the United States.[22] #### Contaminated blood imports[edit] Through the early 1980s, multiple American pharmaceutical firms exported medical blood products contaminated with HIV to East Asia. Bayer Corporation exported plasma knowing the risks of HIV transmission, resulting in over one hundred infections in Taiwan and Hong Kong.[22] Factorate, a Factor VIII product of Armour Pharmaceuticals Company,[18] was imported to China and used in blood transfusions in 19 people in Zhejiang province between 1983 and 1985. Four of the recipients, all hemophiliacs, were infected with HIV, making them at the time the first identified cases of native Chinese infected within the country's borders.[23] Armour had been aware that original sterilization methods for Factorate were inadequate since at least 1985.[24] The Chinese government reacted to the threat of HIV in the blood supply before any confirmed cases of infection had occurred. In September 1984, the Chinese Ministry of Health, in conjunction with the Ministry of Foreign Economic Relations and Trade (now the Ministry of Commerce) and the General Administration of Customs, issued a notice restricting imports on foreign blood products, including a complete ban on blood coagulation factors, specifically to prevent HIV/AIDS from entering the country. The bans were poorly enforced by some local governments, prompting central authorities in August 1985 to issue another notice nationwide, reiterating the ban and ordering all sub-national governments to comply.[25] On 30 January 1986, all blood products, with the sole exception of human serum albumin, were banned from import into China for both organizational and personal use.[26] #### Southern intravenous drug users[edit] Main article: HIV/AIDS in Yunnan In 1989, central authorities became aware of a large outbreak of HIV/AIDS in western Yunnan province, in the border city of Ruili. 146 cases had been identified, mostly in injection drug users (IDUs), and Yunnan soon became the most heavily impacted province in China.[1][27] The outbreak was the first instance of a widespread, native infection in China, and stunned officials previously concerned mainly with preventing infection through sexual contact with foreigners.[20] Yunnan borders the Golden Triangle region of Southeast Asia and has been a major hub for drug trafficking.[28][29] HIV likely crossed into China along heroin trafficking routes from Myanmar.[30] As heroin grew in popularity in Chinese border regions, injections with used needles became more common, greatly accelerating the rate of infection.[31] The disease spread over the next several years, confined mainly to drug using populations of ethnic minorities[32] in poorer, rural areas, reaching other high-risk groups and provinces by 1995.[1][33] Sichuan and Xinjiang first reported HIV outbreaks among injection drug users in 1995, the first two provinces besides Yunnan to do so. The following year, cases were confirmed in Guangdong, Guangxi, Beijing, Shanghai, and Guizhou.[34] Additionally, an independent outbreak of a separate sub-strain of HIV among IDUs began in 1997 in the city of Pingxiang, Guangxi. Drug users crossed the border into northern Vietnam, where heroin was similarly smuggled in from Myanmar, and shared needles with Vietnamese dealers and users to test purchases before returning to China.[35] #### Bloodhead controversy[edit] Main article: Plasma Economy Unique to China was the large-scale transmission of HIV through blood donation centers in the early to mid-1990s. The ban on blood product imports from the preceding decade restricted China's blood supply, making blood donation more lucrative,[36] particularly for inadequately funded rural healthcare systems already weakened by privatization.[37][38] Additionally, medicines containing blood plasma became popular among Chinese consumers, also contributing to demand for blood.[39] By 1990, thousands of public and commercial blood and blood plasma collection centers had been established across China, attracting donors with payments that could equal over a month's worth of income for some farmers.[40] A significant grey market of poorly regulated "bloodheads" (Simplified Chinese: 血头, Traditional: 血頭, xuètóu, coll. xiětóu) concurrently arose.[37] The unsanitary practices in the blood market led to massive propagation of the HIV virus among rural populations. Donation centers frequently recycled needles, mixed blood donations without screening, and failed to adequately sterilize equipment, spreading blood-borne disease to both donors and recipients.[29] For plasma donations, blood was often mixed with other donors' samples and reinjected after plasma extraction.[39][41] Wu, Rou, and Detels (2001) found that 12.5% of plasma donors in eastern China tested positive for HIV, compared to 1.3% of non-donors; infected donors spread the disease to marital and other sexual partners. [42] In 2004, official estimates put the range of people infected via unsafe blood donation practices across the most heavily impacted provinces——Henan, Hebei, Anhui, Shaanxi, and Shanxi——between 200,000 and 300,000. Gansu and Qinghai also reported infections stemming from the commercial blood trade during the same time period. Overall, 24% of all HIV/AIDS cases in China in 2004 had been attributed to blood donation and related activities.[43] The phenomenon was especially prevalent in Henan, where it was promoted by local officials, including Henan Ministry of Health director Liu Quanxi[36] and provincial Communist Party Secretary Li Changchun,[44] to promote economic growth. An internal report compiled in August 2002 by the Henan Ministry of Health, leaked by prominent AIDS activist Wan Yanhai, estimated that 35-45% of blood donors in some areas of the province had been infected due to poor safety precautions in clinics.[39] The Chinese government was slow to admit and respond to the problem after it was identified, and initially repressed efforts to expose it. Shuping Wang and Gao Yaojie, two female doctors from Henan, mounted campaigns to expose the dangerous practices they saw in the early 1990s that put donors at risk for HIV infection.[44] The central government eventually ordered commercial clinics to be shut down in 1995, reopening them in 1997 after stronger regulations on blood donation practices were instituted,[45] although there is evidence that dangerous and unhygienic practices were not completely eliminated.[46] Both Gao and Wang eventually left China for the United States, citing apparent government harassment and intimidation resulting from their advocacy efforts.[47] Even after acknowledging the issue, central and local government bodies sought to suppress discussion or coverage. Wan Yanhai was arrested in 2003 for attempting to screen a movie about the scandal in Beijing.[36] In 2004, while acknowledging some victims had contracted HIV because of inadequate hygiene in blood donation centers and agreeing to provide compensation, authorities still sought to classify such infections as resultant of use of drugs or prostitution in official records.[47] #### Sex trade[edit] While the majority of early infections occurred as a result of intravenous injection transmission or tainted blood supplies, prostitution also played a role spreading HIV/AIDS. China's economy rapidly grew as a result of Reform and Opening Up policies, and patronage of commercial sex workers, many of whom were injecting drug users, grew among both wealthy businessman and migrant worker populations, bringing HIV back to their hometowns and other cities.[29] Overall, however, the commercial sex industry was not as major a vehicle of transmission as drug injection and blood donation were, and HIV infection rates among female sex workers remained relatively low throughout the 2010s.[48] ## Epidemiology[edit] Estimates from the Chinese Center for Disease Control and Prevention, World Health Organization, and UNAIDS calculated approximately 1.25 million people living with HIV/AIDS in China at the end of 2018, with 135,000 new infections over the previous year.[49] It was by far the deadliest notifiable disease of 2018, killing 18,780 individuals, compared to 3,149 for tuberculosis, the second-most deadly.[50] According to the People's Daily in 2018, the official newspaper of the Communist Party of China, the government expects infections to continue to accelerate.[4] Distribution of new infections, 2005 & 2015 25,266 HIV infections were recorded in 2005, with the most (4750) in Yunnan, and only one recorded in Tibet. (Hong Kong and Macau not included.)[51] 81,696 HIV infections were recorded in 2015, with the most (13,457) in Sichuan and the least (148) in Tibet.[51] ### Data collection and reliability[edit] Data on HIV/AIDS up through the early 2000s was very imprecise. Passive disease surveillance methods were established in 1986, with local clinics and medical providers reporting confirmed cases progressively through district, city, and provincial channels, and then ultimately to three separate national agencies under the Ministry of Health.[52][53] The Chinese government did not begin active surveillance and systematic data collection until 1995, when 42 national surveillance sites were established in 23 provincial-level regions with the help of the World Health Organization.[54] By 2006, China had achieved comprehensive HIV/AIDS surveillance nationwide, following expansion of the surveillance network to over 300 sites and reforms of the national reporting systems, although rural areas remained under-covered.[55] By 2010, 1888 surveillance sites had been established.[56] Data from before the development of comprehensive surveillance suffered a number of shortcomings, including minimal coverage of the general population due to focus on high-risk groups, poor data on men who have sex with men (MSM), stovepiping among different government entities, and difficulties obtaining data from private healthcare providers.[57] Through the early 2000s, the Chinese government limited discussion of data and statistics of HIV/AIDS in the country, and media only reported numbers approved by the government.[58][59] Accordingly, estimates from the period of the epidemic often were imprecise, tending to overestimate the overall number of cases. China did not begin to produce regular, systematic estimates of the prevalence of HIV/AIDS until 2003, doing so in conjunction with the United Nations, World Health Organization, and United States Centers for Disease Control.[60] This initial estimate was tentatively 840,000 cases nationwide, but with a potential range of 430,000 to 1.5 million.[61] This was revised down to 650,000 in 2005.[62] Other international estimates tended to greatly overstate the presence and potential growth of HIV in China before more reliable official data was available.[63] For example, in 2002, a report by the United Nations Theme Group on HIV/AIDS in China, entitled "HIV/AIDS: China's Titanic Peril", had estimated up to 1.5 million infected cases, and warned of "[a] potential HIV/AIDS disaster of unimaginable proportion".[64] A 2002 report by the US National Intelligence Council projected 10-15 million cases in China by 2010.[65] Overall, the availability, precision, and coverage of HIV/AIDS data in China improved significantly from 2003 onward.[66] Beginning in 2010, the Chinese government again expanded the scope and number of HIV surveillance sites, increasing coverage of all groups and expanding to cover larger portions of the population and providing more comprehensive information on the disease.[67] Data gathered through the current system has generally been reliable,[68] although issues with standardized protocols across different sites and coordination among different levels of government were identified in independent studies.[67] ### Current transmission[edit] Prevalence of HIV/AIDS in China for the year 2016. HIV in China is primarily transmitted through sexual contact, which accounts for over 90% of new infections.[69][70] Sexual transmission gradually began to overtake the originally predominant routes of transmission, injection drug use and unsafe blood donation practices, throughout the 1990s and into the mid-2000s.[8][71] In 2005, sexual transmission accounted for 50% of all new infections,[7][72] and by 2007, a majority of HIV/AIDS cases overall were related to sexual transmission pathways.[73] Currently, major high-risk groups for HIV infection include intravenous drug users, men who have sex with men (MSM), and sex workers.[74][75] The Chinese government has additionally established data collection and monitoring sites targeting male migrant workers, long-distance truck drivers, male STI clinic patients, antenatal care clinic patients, and college students.[76] MSM in particular have seen a significant increase in transmission rates since epidemiological studies examining them as a group began in 2000.[77][78] MSM represented 26% of new reported cases in 2014, up from 2.5% in 2006.[79] Increased migration from poorer regions with high HIV prevalence to urban areas and somewhat liberalized attitude towards homosexuality in China over the last two decades, resulting in more overall sexual activity, have been hypothesized as factors driving this trend.[80] MSM are also generally at a higher risk for contracting STIs, including syphilis, which may form a coinfection with HIV.[81][82] Drug use contributes little to HIV infection among MSM, with the overwhelming majority of new cases being the result of sexual activity. More than one-fifth of MSM are married to women, which might speed the transmission of HIV to the general population, and outreach to this subgroup in particular can be difficult.[83] ### Mortality rates[edit] The standardized mortality rate of HIV/AIDS rose from .33 per 100,000 people in 1990 to 2.50 per 100,000 in 2016, and the rate is higher in men than in women. Overall rates of mortality continue to grow as more individuals are infected.[84] The provision of antiretroviral therapy (ART) among infected individuals, however, has greatly decreased mortality among patients receiving care since the early 2000s; by 2014 86.9% of eligible patients were receiving some form of ART. [85] ## Control and prevention[edit] ### Overview: Evolution of policy response[edit] The response of the government of China to the HIV/AIDS crisis evolved in tandem with the epidemic itself. Generally, policy moved from preventive and containment measures aimed at keeping the disease from reaching the general population, often with a reliance on enforcement of public morality, to more active, data-driven control measures involving targeted education and harm reduction programs.[86] Early law and policy implementation were often hindered by lack of knowledge among lawmakers on the severity and impact of HIV/AIDS and its potential for growth within China.[87] #### 1985-1988: Protection from foreign infection[edit] The first phase of Chinese HIV/AIDS policy ran from the first recorded in-country death in 1985, of a tourist in Beijing, until 1988/89, when the identified epidemic pattern expanded following the discovery of the outbreak in Yunnan. From 1985 to 1988, only 22 individuals tested positive for HIV in China, 18 of whom were foreigners or Overseas Chinese.[88] HIV/AIDS was commonly viewed as a consequence of a Western lifestyle, and thus government efforts concentrated on protecting China from foreign transmission and promoting moral behavior and traditional values among citizens.[89] "AIDS" was often punned in Chinese as "loving capitalism disease" (simplified Chinese: 爱资病; traditional Chinese: 愛資病; pinyin: Àizībìng), and public health authorities held that because homosexuality and other "abnormal" sexual behaviors were not prevalent in Chinese society, the disease had limited potential to spread.[21][90][91] In December 1985, the Ministry of Health submitted a report to the Central Secretariat of the Communist Party of China and the State Council, outlining the spread of the disease from Africa to Europe and America, emphasizing the predominantly sexual transmission routes, and listing measures the Ministry had taken to prevent its further spread into China.[92] Laws and regulations attempting to eliminate the risk of foreigners infecting native Chinese were promulgated, under the assumption that this could keep the disease out of the country altogether.[93] By 1986, foreigners intending to stay over a year were required to undergo HIV testing, and HIV-positive people were legally barred from entering China.[94][95] The New York Times reported that police in some cities were instructed to prevent foreigners from coming into sexual contact with Chinese people, including in discothèques, dance halls, and brothels.[96] These early policies of containment, which also included wider crackdowns on drug use and sex work, did little to check the spread of the disease, and possibly hindered initial identification of its domestic reservoirs.[97] #### 1989-1994: Control of limited epidemic[edit] The discovery of the outbreak in Yunnan triggered a large increase in the number of reported cases as the disease rapidly spread among high-risk groups. The Yunnan outbreak forced health officials to reconsider aspects of Chinese HIV/AIDS policy,[98] although efforts were still largely focused on policing drug use and prostitution.[99] Social science research on previously taboo topics, including homosexuality, sex work, and drugs, began to proliferate during this period and served to inform policy that did not rely on a view of HIV/AIDS as an inherently Western problem.[100] The Ministry of Health began exploring methods such as the implementation of behavioral interventions and free STI testing among high risk populations.[101] Officials also experimented with less punitive counter-drug policy, such as the establishment of a limited number of methadone clinics in larger, well-equipped medical institutions in 1993.[102] A wide range of officials—including State Council officials and health, security, justice, and education civil servants—were sent on tours to study policy and disease control strategies in places heavily affected by AIDS, such as the United States, Brazil, Australia, and Thailand.[103] #### 1995-2003: Combatting widespread epidemic[edit] In 1995, HIV cases began appearing consistently beyond the borders of Yunnan as the epidemic entered a phase of rapid growth.[104][33] The government grew more concerned with the public health threat HIV/AIDS posed. Previously uncommon harm reduction strategies began to appear in limited capacities, a departure from previous years. Several novel state organizations were established at the national level to strengthen the government response to HIV/AIDS. The compartmentalized nature of the Chinese bureaucracy historically made work on HIV/AIDS difficult because different agencies and departments were responsible for different aspects of data collection, service provision, and healthcare.[105] In 1996, the State Council established STD/AIDS Prevention and Control Coordinating Meeting System (国务院防治艾滋病性病协调会议制度) to coordinate policy at the national level, although this body met infrequently.[106] On 1 July 1998, following nearly two years of planning, the National Center for HIV/AIDS Prevention and Control under the Ministry of Health (卫生部艾滋病预防控制中心) was established. This entity became the National Center for AIDS/STD Control and Prevention of the Chinese Center for Disease Control and Prevention (NCAIDS/STD, 中国疾病控制中心性病艾滋病预防控制中心) in January 2002.[107] A number of substantive policy developments related to HIV/AIDS occurred during this period. In September 1995, the State Council and Ministry of Health release "Recommendations on Strengthening AIDS Prevention and Control" (关于加强和控制艾滋病工作的意见), developing and reviewing laws and regulations related to HIV/AIDS control and improving enforcement mechanisms. HIV/AIDS work was included in the overall national development strategy of China, and the government signaled openness to the support of non-governmental organizations in combatting the epidemic.[108][109] Blood donation centers, closed nationwide in 1995 in response to the Plasma Economy scandal, were reopened in 1997–98 with the passage of the Blood Donation Law (中华人民共和国献血法).[110][111] In 1998, needle exchange programs were implemented in Guangxi, and further expanded in the early 2000s as their efficacy became clear, although some localities and national government departments (such as the Ministry of Public Security) remained opposed to such efforts on the grounds that they encouraged drug use.[112] In November 1998, the State Council released a document entitled "China’s National Medium-and Long-Term Strategic Plan for HIV/AIDS Prevention and Control (1998-2010)" (关于印发中国预防与控制艾滋病中长期规划(1998—2010年)), outlining the Chinese government's goals to be carried out at local, provincial, and national levels, and further monitored through regular assessments. The document included a number of specific objectives and mandates, including: * Ordering local governments to consider HIV/AIDS prevention and treatment as a part of all policy planning and socioeconomic development goals; * Disseminating knowledge about the disease and its prevention (including promotion of condom use) to the general population through publicity campaigns, the school systems, and mass media (a 2001 survey found that 20% of the general population had not even heard of the disease[113]); * Strengthening surveillance and data collection and coordinate standardized testing, training, and screening measures nationally; * Increasing research both on HIV/AIDS treatments and on epidemiological studies of the disease; and * Developing and improving HIV/AIDS-related legislation and regulations nationwide.[114] The State Council further consolidated and expanded work on HIV and AIDS with China's first five-year plan for AIDS/HIV, covering 2001–2005. While still cautious about embracing harm reduction policies for fear of promoting social ills, the plan was a milestone for such policies overall and laid the groundwork for more ambitious efforts in following five-year plans.[101][7] #### 2003-Present: Evidence-based approaches post-SARS[edit] The 2002–04 SARS outbreak, which originated in Foshan, China, led to significant changes to public health policy, including shifts in the state's approach to HIV and AIDS. Funding and political support for HIV/AIDS-related policies began to increase markedly.[115][116] Wu et al. (2007) argue that "SARS showed not only how infectious diseases could threaten economic and social stability but also the effect of China’s policies on international health problems”, resulting in increased expertise and attention devoted to HIV/AIDS overall.[117] The new administration of Hu Jintao and Wen Jiabao, which ascended to power in March 2003, heightened commitment to evidence-based policy to fight HIV/AIDS. Wu Yi was appointed the Minister of Health, and her tenure saw a greater willingness to publicly discuss health crises like HIV/AIDS; Wu even met with activist Gao Yaojie shortly after her appointment.[37][47][118] In September 2003, Vice Minister of Health Gao Qiang outlined five promises of the Chinese government in its fight against AIDS in an address to the United Nations General Assembly's special session on HIV/AIDS. Gao said the Chinese government would commit to free antiretroviral therapy for poor rural and urban citizens, free counseling and treatment services, free treatment for pregnant women and testing for their children, free tuition and fees for children affected by HIV/AIDS, and financial support for any affected families. On World AIDS Day, 1 December 2003, while meeting with an AIDS patient in an effort to decrease stigma surrounding the disease,[21] Premier Wen also formally announced the "Four Frees and One Care" (四免一怀) policy based on the measures outlined by Gao.[116] Funding initially came from a $90 million grant of The Global Fund to Fight AIDS, Tuberculosis and Malaria, focusing on free testing for those in provinces where blood donation had been a major channel of infection.[119] In March 2006, the State Council implemented the "Regulation on the Prevention and Treatment of HIV/AIDS", codifying principles of prevention, treatment, and behavioral interventions into a national framework.[120] It explicitly endorsed methadone treatment and condom education, among other measures, spurring the establishment of over 600 clinics nationwide by 2010.[121] The law also formally proscribed discrimination of people based on their HIV status, and no longer prevented HIV-positive people from entering the country.[citation needed] ### International cooperation and funding[edit] Prior to 2003, the majority of the capital for anti-HIV/AIDS policies and programs in China came from foreign sources, including NGOs like the Red Cross and Bill and Melinda Gates Foundation, foreign government agencies like the US Centers for Disease Control and Prevention, and international multilateral organizations like the UN and WHO.[122] Dedicated funds for HIV/AIDS were first allocated by the Ministry of Finance in 1998.[123] By 2015, 99% of HIV/AIDS response efforts were funded by domestic sources, and total expenditures reached nearly RMB 7 billion (approx. USD 1 billion) for the fiscal year 2017.[124] ## Discrimination against people with HIV/AIDS[edit] Discrimination against HIV-positive individuals is an ongoing issue in China. Various provinces have historically adopted different measures related to people with HIV, most of which restrict their equal access to the public sphere. In some provinces in municipalities in the early 2000s, people with HIV were prohibited from holding certain jobs, HIV mothers could be required to undergo an abortion, and an HIV-positive couple could be legally barred from marriage on medical grounds.[125] The 2006 Regulation on the Prevention and Treatment of HIV/AIDS formally barred legal discrimination against anyone based on the HIV status. While lauding the Regulation as a major step forward, the United Nations Economic and Social Commission for Asia and the Pacific in 2015 reported that local governments often functionally ignored its provisions.[126] A 2016 study in Guangzhou found that large numbers of healthcare providers also discriminated against HIV-positive patients, with over one-third refusing to treat such patients altogether.[127] In January 2013, China saw its first lawsuit awarding damages to a plaintiff on the grounds of HIV/AIDS discrimination. The plaintiff had been rejected for a job as a school teacher by the education bureau of Jinxian County, Jiangxi province specifically due to his HIV status.[128] ## Traditional Chinese Medicine[edit] As of December 2018, the only Traditional Chinese medicine (TCM) therapy approved by the National Medical Products Administration (NMPA) of China was herbal ''tangcao'' tablets (Chinese: 唐草片; pinyin: Tángcǎo piàn). A number of other TCM supplements are under clinical trial reviews, but have not yet met NMPA standards.[129] TCM research efforts are primarily focused on lessening the side affects of highly active antiretroviral therapy (HAART) and protecting against opportunistic infections.[citation needed] Extracts of TCM medicines have served as bases for trials of antiviral therapies, including baicalin[130] and Dantonic.[131] A group of nine HIV/AIDS patients in 2017 were reported to have been functionally cured through TCM treatments,[132] but these trials lacked controlled, regular observations.[133] A 2018 study suggested substantive differences in protein expression and signaling in certain TCM-identified syndromes for those with HIV/AIDS.[134] Controlled studies have yet to demonstrate any effect on long-term survival among HIV/AIDS patients, however, its validity is difficult to discern, and research is lacking on the interactions between Western and Traditional Chinese pharmacological products.[135][136] ## Activism[edit] See also: Censorship in China In China, like elsewhere, HIV/AIDS activists have played an important role in promoting public awareness and education about the disease, helping to prevent discrimination against people living with HIV/AIDS and highlighting factors which may impede efforts to check the spread of the disease. Compared to other social movements, the Chinese government has historically been more tolerant of HIV/AIDS-focused NGOs and civil society organizations, relying on them to reach out to marginalized groups most vulnerable to the disease. The government at all administrative levels has also often sought to suppress or minimize activism perceived as sensitive, obscene, or a threat to stability, including that related to HIV/AIDS.[137] This phenomenon was particularly pronounced in Henan, where the initial blood donation outbreak, in which local authorities were extensively involved, was most severe.[138][139] In 2007, activist Gao Yaojie was placed under house arrest in her home in Zhengzhou in order to prevent her from visiting the United States to receive an award from Vital Voices Global Partnership and meet with Hillary Clinton.[140] ## Socioeconomic effect[edit] The process of the effect of HIV/AIDS can be described as having three key stages: first, the effect experienced at the micro level; second, at the sectoral level; and finally, at the macro level. The effect began to be observed in China at the micro, or household level, and will most certainly be observed in the future at the sectoral level. Individuals and families have been bearing both the economic and social costs of the disease, and the poverty of those affected have increased and will further increase substantially. Expenditures for the health sector will increase, for both treatment and prevention interventions. The macro level has been mostly unaffected . But if without effective preventive action, the HIV spread in the general population at large will affect the macro level as have happened in some countries in sub-Saharan Africa.[141] ## Media[edit] ### Documentaries[edit] Chinese-American director Ruby Yang has recently made a documentary about AIDS in rural China, which premiered on 14 June 2006, entitled The Blood of Yingzhou District.[citation needed] An abridged version of Robert Bilheimer's acclaimed US-made 2003 documentary A Closer Walk was shown on China Central Television (CCTV) on World AIDS Day, December 1 (Friday), 2006, and was rerun Sunday and Monday. It was viewed by around 400 million people. The 75-minute-long documentary, narrated by actors Will Smith and Glenn Close, had premiered in the United States in 2003.[citation needed] ## See also[edit] * The Blood of Yingzhou District * Plasma Economy * Hu Jia (activist) * Gao Yaojie * Wangdu (activist) * Wan Yanhai * HIV/AIDS in Yunnan * Zeng Jinyan ## Notes and references[edit] 1. ^ a b c Xiao et al. 2007, p. 667. 2. ^ He & Detels 2005, pp. 825-826. 3. ^ National Health and Family Planning Commission of the PRC 2015, p. 8. 4. ^ a b "Still a tough battle to win fight against HIV: China Daily editorial". China Daily. November 29, 2018. Retrieved 19 February 2020. 5. ^ Sharp & Hahn 2011, p. 1. 6. ^ Kaufman, Kleinman & Saich 2006, p. 3-5. 7. ^ a b c Wu et al. 2007, p. 682. 8. ^ a b Zhang et al. 2006, p. 2075: "However, our finding of a large number of sexually transmitted CRF01_AE viruses in Yunnan among non-IDUs is new. In particular, the rapid increase of HIV-1 prevalence among non-IDU populations has emerged as an alarming trend. IDU dominance in the late 1980s and throughout the 1990s has now been gradually replaced by those infected through heterosexual contact or other routes.” 9. ^ National Health and Family Planning Commission of the PRC 2015, p. 9-10. 10. ^ He & Detels 2005, p. 827: "At some local government-run blood banks and in many private underground blood banks operated in the early and middle 1990s in central China, blood was often collected from several villagers at the same time, and mixed together in a container or a centrifuge from which the plasma was collected. ... Such procedures, as well as recycling of used needles and inadequately sterilized equipment, allowed HIV to be rapidly transmitted among these donors, generating a large number of HIV-infected farmers and peasants.” 11. ^ Sharp & Hahn 2011, p. 15. 12. ^ a b "History of HIV and AIDS Overview". Avert. 2015-07-20. Archived from the original on 1 March 2020. Retrieved 22 February 2020. 13. ^ Worobey et al. 2016, p. 99. 14. ^ Sharp & Hahn 2011. 15. ^ Curran & Jaffe 2011. 16. ^ Altman, Lawrence K. (June 18, 1982). "CLUE FOUND ON HOMOSEXUALS' PRECANCER SYNDROME". The New York Times. Archived from the original on 22 February 2020. Retrieved 22 February 2020. 17. ^ Marx 1982. 18. ^ a b Yu et al. 1996, p. 1116. 19. ^ "China Bans Import of Blood Products to Keep AIDS Out". Associated Press. 3 September 1985. Archived from the original on 22 February 2020. Retrieved 22 February 2020. 20. ^ a b Xu, Han & Zeng et al. 2013. 21. ^ a b c "The history of AIDS in China". People's Daily. 2009-11-22. Archived from the original on 2014-03-07. Retrieved 2013-06-23. 22. ^ a b Bogdanich, Walt; Koli, Eric (22 May 2003). "2 Paths of Bayer Drug in 80's: Riskier One Steered Overseas". The New York Times. Archived from the original on 11 February 2020. Retrieved 22 February 2020. 23. ^ Pisani & Zhang 2017, p. 3-4. 24. ^ "Drug Maker Turned Aside Alert on AIDS". Associated Press. 6 October 1996. Archived from the original on 22 February 2020. Retrieved 22 February 2020. 25. ^ Ministry of Health of the PRC and General Administration of Customs of the PRC (26 August 1985). 关于禁止ＶＩＩＩ因子制剂等血液制品进口的通知 Archived 2020-02-22 at the Wayback Machine" ["Notice Regarding the Prohibition on Importing Factor VIII and Other Blood Products"] (in Chinese). "防止获得性免疫缺陷（简称AIDS）我国，卫生部已于1984年9月会同经贸部、海关总署以（84）卫药字第22号联合通知，限制进口国外血液制品。通知发出后，有的省、市卫生厅（局）认真执行，严格把关，控制血液制品的进口。但有的省、市卫生厅（局）尚未引起重视，对进口血液制品既不控制，又不认真审查把关，仍在大量进口血液制品，且进口制品经检验不合格的情况也日趋严重。" ["In order to guard against the entry of acquired immunodeficiency syndrome (AIDS) into the country, the Ministry of Health, with the General Administration of Customs and the Ministry of Trade and Foreign Economic Cooperation, disseminated the joint Health Notice (84) No. 22 limiting the import of foreign blood products. Following the notice, some provincial and municipal health bureaux implemented it diligently with strict checks. Some provincial and municipal health bureaux, however, have not attached importance to the notice, not only failing to control the import of foreign blood products, but also not being serious in their examinations and checks. They are still importing large volumes of foreign blood products, and moreover, these products have increasingly come to fail inspections."] 26. ^ Ministry of Health of the PRC (30 January 1986). "关于禁止进口ＶＩＩＩ因子制剂等血液制品的通告" Archived 2020-02-22 at the Wayback Machine ["Announcement Regarding the Prohibition on Importing Factor VIII and Other Blood Products"] (in Chinese). 27. ^ Zhang et al. 2006, p. 2066. 28. ^ Lo 2015. 29. ^ a b c He & Detels 2005, p. 826. 30. ^ Beyrer et al. 2000, p. 79-81. 31. ^ Xiao et al. 2007, p. 669. 32. ^ Beyrer et al. 2000, p. 79. 33. ^ a b Wu, Rou & Cui 2004, p. 9. sfn error: multiple targets (2×): CITEREFWuRouCui2004 (help) 34. ^ Wu, Rou & Cui 2004, pp. 9-10. sfn error: multiple targets (2×): CITEREFWuRouCui2004 (help) 35. ^ Beyrer et al. 2000, p. 80. 36. ^ a b c Kellogg, Tom (23 February 2003). "Whitewashing Criminal Negligence: Health Officials seek to Avoid Responsibility for the Spread of HIV/AIDS in Rural Henan". Human Rights in China. Archived from the original on 29 February 2020. Retrieved 29 February 2020. 37. ^ a b c Hayes 2005, p. 14. 38. ^ Kaufman & Meyers 2006, p. 64. 39. ^ a b c Gittings, John (10 September 2002). "China admits 'blood stations' caused steep rise in Aids". The Guardian. Archived from the original on 29 February 2020. Retrieved 29 February 2020. 40. ^ Wu, Rou & Detels 2001, p. 41-42. 41. ^ Hayes 2005, p. 15. 42. ^ Wu, Rou & Detels 2001, p. 43. 43. ^ Kaufman & Meyers 2006, p. 50. 44. ^ a b Langer, Emily (25 September 2019). "Shuping Wang, whistleblower who exposed China's HIV/AIDS crisis, dies at 59". Washington Post. Archived from the original on 26 September 2019. Retrieved 29 February 2020. 45. ^ Wu, Rou & Detels 2001, p. 44. 46. ^ Hayes 2005, p. 16. 47. ^ a b c Luo, Siling (1 December 2016). "Whistle-Blowing AIDS Doctor Reflects on Roots of Epidemic in China". New York Times. Archived from the original on 30 January 2020. Retrieved 29 February 2020. 48. ^ Pisani & Wu 2007b, pp. 122-124. 49. ^ Feng, Xiaohua. "抗艾渐入核心？药物控制病毒使感染者成为非传染源" [Towards the Core of Fighting AIDS? Medicine Controls Virus, Making Infected Non-Infectious]. Chinese Center for Disease Control and Prevention (in Chinese). Yicai News. Retrieved 18 February 2020. 50. ^ "2018年全国法定传染病疫情概况 [2018 National Legally Designated Infectious Disease Epidemic Summary]" (in Chinese). National Health Commission of the People's Republic of China. Archived from the original on 31 January 2020. Retrieved 1 March 2020. "The top five disease by mortality figures for this report in descending order are: AIDS, tuberculosis, viral hepatitis, rabies, and Japanese encephalitis. (报告死亡数居前5位的病种依次为艾滋病、肺结核、病毒性肝炎、狂犬病和乙型脑炎，占乙类传染病报告死亡总数的99.27%。)" 51. ^ a b "艾滋病数据库". 公共卫生科学数据中心. 中国疾控预防控制中心公共卫生监测与信息服务中心. Archived from the original on 2019-05-08. Retrieved 2019-05-08. 52. ^ Jia et al. 2007, p. 1042: "HIV/AIDS was reportable through three theoretically complementary but practically overlapping components: (1) The HIV/AIDS Reporting System, coordinated by the Division of Epidemiology, National Center for AIDS/STD Prevention and Control (NCAIDS) of the Chinese Academy of Preventive Medicine (CAPM), (2) The Communicable Diseases Reporting System, coordinated by the Division of Epidemiology, Institute of Infectious Disease Control and Prevention, CAPM (includes 35 notifiable infectious diseases), and (3) The National STD Surveillance System, coordinated by the Nanjing STD Center of the Chinese Academy of Medicine (data on eight STDs including HIV); China CDC and US CDC, 2002; China CDC, 2006). Through these three systems, HIV/AIDS case reports flowed from the health facilities or clinics as follows: (1) to the local district, county, or county-level city, (2) to the prefecture or prefecture-level city, (3) to the provincial health departments, and (4) to three separate national agencies." 53. ^ He & Detels 2005, p. 828. 54. ^ Kaufman & Meyers 2006, p. 54. 55. ^ Jia et al. 2007, p. 1043; 1050. 56. ^ Lin et al. 2012, pp. 1-2. 57. ^ Kaufman & Meyers 2006, p. 55-57. 58. ^ M. Wu 2006, p. 266; 269. 59. ^ FIDH 2005, p. 21. 60. ^ Wang et al. 2010, p. ii21. 61. ^ Steinbrook 2004. 62. ^ Wang et al. 2010, p. ii24. 63. ^ Hesketh 2007, p. 622: "[P]redictions of the size of the epidemic were substantially overestimated by several expert bodies. ... The National Intelligence Council claimed that [its] figures were more reliable than previous estimates because they did not rely on official sources, which the National Intelligence Council asserted 'systematically understate the actual figures', but rather incorporated assessments by academics and non-governmental organisations working in the field." 64. ^ UN Theme Group on HIV/AIDS in China 2002, p. 7: The report's estimated range of cases was from 800,000-1,500,000 65. ^ National Intelligence Council 2002. 66. ^ Wang et al. 2010, pp. ii25-ii26: "Repeated rounds of national HIV/AIDS estimate exercises in 2003, 2005, 2007 and 2009 have generated data that more accurately reflect China’s heterogeneous epidemic. Improvements in data quality and data availability have improved the precision of HIV/AIDS estimates, providing information that is critical to public health priority setting and policymaking." 67. ^ a b Lin et al. 2012. 68. ^ Li et al. 2017. 69. ^ Tian, Xiaohang (23 November 2018). "国家卫健委：我国艾滋病全人群感染率约万分之九" [NHC: China's National AIDS Infection Rate Approximately 9 per 10,000]. www.gov.cn (in Chinese). Xinhua News. Archived from the original on 6 May 2019. Retrieved 1 March 2020. "值得注意的是，当前，性传播是我国艾滋病主要传播途径。2017年报告感染者中异性传播占69.6%，男性同性传播占25.5% [It is worth mentioning that at present, sexual transmission is the primary transmission channel of AIDS in China. Of those infected in the 2017 report, 69.6% were from heterosexual transmission, and 25.5% male homosexual.]" 70. ^ "艾滋病检测核心信息 [Core Information on AIDS Testing]" (in Chinese). Chinese Center for Disease Control and Prevention. Archived from the original on 1 March 2020. Retrieved 1 March 2020. "近年来，通过检测并诊断报告的感染者中，每100个就有90个以上是经性途径感染。[In recent years, of those tested, confirmed, and reported as infected, greater than 90 of every 100 were infected through sexual transmission.]" 71. ^ Sun et al. 2010, p. ii10. 72. ^ Wang et al. 2010, p. ii25. 73. ^ Sun et al. 2010, p. ii11. 74. ^ Li et al. 2017, p. 1197. 75. ^ Lin et al. 2012, p. 1. 76. ^ Lin et al. 2012, p. 2. 77. ^ Dong et al. 2019, p. 1. 78. ^ National Health and Family Planning Commission of the PRC 2015. 79. ^ Zheng 2018. 80. ^ Dong et al. 2019, p. 9: "Our study showed an increased tendency in the HIV prevalence among MSM as time progressed (P < 0.001) (Fig. 2). The increasing HIV prevalence may be associated with several factors: 1) the increasing migration for better employment opportunities and living conditions from regions with a high HIV prevalence, such as from southern China or from the countryside, to large cities, which have a relatively open culture and convenient sexual venues (e.g., bars, saunas, parks, and sex clubs.); 2) the gradual changes in attitudes towards sex and increased openness of male homosexuality in China with changes in Chinese society, although homosexuality is still not widely accepted by the general population; and 3) the common occurrence of marriage between MSM and women because MSM might act as a bridge for HIV transmission from other MSM to the general population." 81. ^ Das, Aritra; Jianjun Li; Fei Zhong; Lin Ouyang; Tanmay Mahapatra; Weiming Tang; Gengfeng Fu; Jinkou Zhao; Roger Detels (April 15, 2014). "Factors associated with HIV and syphilis co-infection among men who have sex with men in seven Chinese cities". International Journal of STD & AIDS. 26 (3): 145–155. doi:10.1177/0956462414531560. PMC 4198509. PMID 24737881. 82. ^ Chow, EP; Wilson, DP; Zhang, L (2011). "HIV and syphilis co-infection increasing among men who have sex with men in China: a systematic review and meta-analysis". PLOS One. 6 (8): e22768. Bibcode:2011PLoSO...622768C. doi:10.1371/journal.pone.0022768. PMC 3156129. PMID 21857952. 83. ^ Dong et al. 2019, p. 11. 84. ^ Gao et al. 2019. 85. ^ Pisani & Wu 2007b, pp. 134-136. 86. ^ Sun et al. 2010. 87. ^ Wu, Rou & Cui 2004, p. 11: "Sporadic reports of HIV infection and AIDS cases did generate awareness of AIDS among some lawmakers, but their knowledge of the real implications of the HIV/AIDS epidemic was limited. Therefore, they did not know how to take appropriate action from a legal point of view. ... Lawmakers do not understand the complexity of AIDS issues, and people who have sound knowledge of AIDS have not had the opportunity to be involved in the lawmaking processes." sfn error: multiple targets (2×): CITEREFWuRouCui2004 (help) 88. ^ Yu et al. 1996, p. 1117. 89. ^ Xu, Han & Zeng et al. 2013, §1.1: "这一时期，几乎所有人都认为艾滋病是同西方生活方式相联系的，是从境外进来的，因此，只要守住国门就能杜绝，于是，形成了所谓'御敌于国门之外'的策略。 ... 这一阶段防治特征主要表现为严把国境关：注重监测、严防传入；同时，强调道德宣传，严惩卖淫、嫖娼等行为。此时，对艾滋病综合干预的思想(T推广使用安全套)还未诞生，预防手段显示出明显的意识形态和依靠强硬的行政手段的特点。". 90. ^ FIDH 2005, p. 7: "AIDS was regarded as a disease linked with the ideology of capitalism… In 1987, the Minister of Health, Chen Minzhang, announced that AIDS would not spread in China as it was transmitted by homosexuality and promiscuity, evils which were unknown to China." 91. ^ Gewirtz 2020. 92. ^ Ministry of Health of the People's Republic of China (10 January 1985). "关于加强监测、严防艾滋病传入的报告" [Report on Strengthening Monitoring and Strictly Defending Against Transmission into [China] of AIDS] (in Chinese). Retrieved 7 March 2020. 93. ^ Wu, Rou & Cui 2004, pp. 10-11. sfn error: multiple targets (2×): CITEREFWuRouCui2004 (help) 94. ^ Wu et al. 2007, p. 679-680. 95. ^ Xu, Han & Zeng et al. 2013, §1.1.3. 96. ^ Gargan, Edward A. (22 December 1987). "China Taking Stringent Steps To Prevent the Entry of AIDS". The New York Times. Archived from the original on 22 February 2020. Retrieved 7 March 2020. 97. ^ Wu et al. 2007, p. 680: "In much the same way as other countries, traditional public-health methods of containment and isolation of infectious disease cases proved ineffective. Containment policies occurred in the context of rapid social and economic change, in which there were increases in drug use and changing sexual mixing patterns. These early policies did little to stop transmission of HIV; in fact, they probably promoted concealment of risk activities and made identification of HIV reservoirs more difficult." 98. ^ Xu, Han & Zeng et al. 2013, §1.2.2: "1989年，在云南边境地区的吸毒人群中集中发现146例HIV感染者，引起人们的震惊，开始反思'严防传入'策略的局限性：在日趋开放的社会里，能否通过封闭的方式解决公共卫问题？经过争论与探讨，艾滋病防控策略开始向主动预防转变，对一些干预工作开展探索性的试点。" ["In 1989, the discovery of 146 HIV cases concentrated among drug users in the bborder region of Yunnan shocked many and forced reflection on the limits of the 'protection against [HIV] entering' strategy: as society grew more and more open, could closing [the country] off really solve such a public health problem? After much debate and investigation, AIDS control policy began to turn toward proactive prevention, and pilot schemes exploring the development of intervention work began."] 99. ^ Xue 2005, p. 459. 100. ^ Xue 2005, p. 461. 101. ^ a b Sun et al. 2010, p. ii6. 102. ^ Li et al. 2010, p. 3. 103. ^ Wu et al. 2007, pp. 680-681. 104. ^ Jia et al. 2007, p. 1045: "The surveillance data from 1995 to the present (2006) suggested that the HIV/AIDS epidemic began a Rapid Spread Phase in 1995 (Fig 2). The epidemic expanded rapidly among IDUs in rural border areas of Yunnan Province, where China borders Myanmar, Lao PDR, and Vietnam close to the 'Golden Triangle', soon spreading to IDUs in nearby cities." 105. ^ Kaufman & Meyers 2006, p. 57. 106. ^ FIDH 2005, p. 13. 107. ^ National Center for AIDS/STD Control and Prevention. "Chronology of NCAIDS". ncaids.chinacdc.cn. Archived from the original on 4 October 2018. 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Retrieved 29 February 2020. * Xu, Yinghan; Lai, Maode; Dai, Di; Tang, Deji; Han, Yongjian (1992). "我国首例艾滋病抗体阳性死亡病例的进一步病理研究" [Further Pathological Study on the First Autopsy Involving HIV in China]. 中国法医学杂志 [Chinese Journal of Forensic Medicine] (in Chinese). 1. Retrieved 22 February 2020. * Xue, Bin (2005). "HIV/AIDS policy and policy evolution in China". International Journal of STD & AIDS. 16: 459–464. doi:10.1258/0956462054308477. PMID 16004623. * Yin, Wenyuan; Hao, Yang; Sun, Xinhua; Gong, Xiuli; Li, Fang; Li, Jianhua; Rou, Keming; Sullivan, Sheena G.; Wang, Changhe; Cao, Xiaobin; Luo, Wei; Wu, Zunyou (26 November 2010). "Scaling up the national methadone maintenance treatment program in China: achievements and challenges". International Journal of Epidemiology. 39 (Supplement 2): ii29–ii37. doi:10.1093/ije/dyq210. PMC 2992615. PMID 21113034. * Yu, Elena S. H.; Xie, Qiyi; Zhang, Konglai; Lu, Ping; Chan, Lillian L. (August 1996). "HIV infection and AIDS in China, 1985 through 1994". American Journal of Public Health. 86 (8): 1116–1122. doi:10.2105/ajph.86.8_pt_1.1116. PMC 1380623. PMID 8712271. * Zhang, Yong; Lu, Lin; Ba, Lei; Liu, Li; Yang, Li; Jia, Manhong; Wang, Haibo; Fang, Qing; Shi, Yuhua; Yan, Wenyun; Chang, Guangcai; Zhang, Linqi; Ho, David D.; Chen, Zhiwei (November 14, 2006). "Dominance of HIV-1 Subtype CRF01_AE in Sexually Acquired Cases Leads to a New Epidemic in Yunnan Province of China". PLOS Medicine. 3 (11): 2065–2077. doi:10.1371/journal.pmed.0030443. PMC 1635743. PMID 17105339. * Zheng, Sifan (July 2018). "The growing threat of China's HIV epidemic". The Lancet Public Health. 3 (7): e311. doi:10.1016/S2468-2667(18)30098-7. PMID 29976325. ## Further reading[edit] * Gill B and Okie S. China and HIV — A Window of Opportunity. N Engl J Med 2007; 356(18): 1801–05. * Chen HT, Liang S, Liao Q, Wang S, Schumacher JE, Creger TN, Wilson CM, Dong B, Vermund SH. HIV Voluntary Counseling and Testing among Injection Drug Users in South China: A Study of a Non-Government Organization Based Program. AIDS Behav Mar 9, 2007. * Li, X; Wang, B; Fang, X; Zhao, R; Stanton, B; Hong, Y; Dong, B; Liu, W; Zhou, Y; Liang, S; Yang, H (Oct 2006). "Short-Term Effect of a Cultural Adaptation of Voluntary Counseling and Testing Among Female Sex Workers in China: A Quasi-Experimental Trial". AIDS Educ Prev. 18 (5): 406–19. doi:10.1521/aeap.2006.18.5.406. PMC 1933388. PMID 17067252. * Hong, Y; Stanton, B; Li, X; Yang, H; Lin, D; Fang, X; Wang, J; Mao, R (Jul 2006). "Rural-to-Urban Migrants and the HIV Epidemic in China". AIDS Behav. 10 (4): 421–30. doi:10.1007/s10461-005-9039-5. PMC 1791012. PMID 16421651. * Su, L; Graf, M; Zhang, Y; von Briesen, H; Xing, H; Kostler, J; et al. (2000). "Characterization of a virtually full-length human immunodeficiency virus type 1 genome of a prevalent intersubtype (C/B') recombinant strain in China". J Virol. 74 (23): 11367–11376. doi:10.1128/jvi.74.23.11367-11376.2000. PMC 113242. PMID 11070037. * Zhang, K. AIDS. Beijing: PUMC Publishing House; 2000. pp. 1–4. * Chen J, Zheng Z, Shao Y. Molecular-epidemiological analysis of HIV-1 initial prevalence in Guangxi, China. Zhonghua Liu Xing Bing Xue Za Zhi. 1999; 20: 74–77. (Chinese). * Liao SS. "HIV in China: epidemiology and risk factors. AIDS. 1998; 12 (Suppl B): S19–s25. * Chinese Ministry of Health; UN Theme Group on HIV/AIDS in the People's Republic of China. China responds to AIDS—HIV/AIDS situation and needs assessment report. Beijing: Chinese Ministry of Health; 1997. * Cohen MS, Henderson GE, Aiello P, Zheng H. "Successful eradication of sexually transmitted diseases in the People's Republic of China: implications for the 21st century. J Infect Dis. 1996; 174(S2): S223–s229. ## External links[edit] External links * National Center for STD and AIDS Prevention Control, China CDC * List of HIV/AIDS Research Centers in China—compiled by the Hong Kong AIDS Information Network. * AIDS Concern HK * China HIV/AIDS Information Network * UNICEF China - HIV/AIDS Wikimedia Commons has media related to HIV/AIDS in China. * v * t * e HIV/AIDS topics HIV/AIDS HIV * HIV * Lentivirus * structure and genome * subtypes * CDC classification * disease progression rates * HIV/AIDS * diagnosis * management * pathophysiology * prevention * research * vaccination * PrEP * WHO disease staging system for HIV infection and disease * Children * Teens / Adults * Countries by AIDS prevalence rate Conditions * Signs and symptoms * AIDS-defining clinical condition * Diffuse infiltrative lymphocytosis syndrome * Lipodystrophy * Nephropathy * Neurocognitive disorders * Pruritus * Superinfection * Tuberculosis co-infection * HIV Drug Resistance 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recognition * Abkhazia * Artsakh * Northern Cyprus * Palestine * South Ossetia * Taiwan Dependencies and other territories * British Indian Ocean Territory * Christmas Island * Cocos (Keeling) Islands * Hong Kong * Macau * Book * Category * Asia portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	HIV/AIDS in China	None	4,341	wikipedia	https://en.wikipedia.org/wiki/HIV/AIDS_in_China	2021-01-18T19:08:01	{"wikidata": ["Q871719"]}
A rare, life-threatening mutliple congenital anomalies syndrome characterized by intrauterine growth restriction, postnatal failure to thrive and facial dysmorphism (microcephaly or trigonocephaly, prominent glabellar nevus flammeus (simplex) fading with age, hypotonic facies, low frontal and temporal hairline, hirsutism, synophrys, prominent or proptotic eyes, hypertelorism, upslanting palpebral fissures, depressed and wide nasal bridge, anteverted nares, full cheeks, low-set and posteriorly angulated ears, cleft lip and/or palate, high arched palate, micrognathia and/or retrognathia). A specific posture (BOS posture) is also reported, characterized by external rotation and/or adduction of the shoulders, flexion at the elbows and wrists, ulnar deviation of the wrists and/or the metacarpophalangeal joints. Additional features mainly include severe feeding difficulties, chronic emesis, recurrent infections, hypertrichosis, seizures, truncal hypotonia and hypertonic extremities, as well as cerebral, ocular, cardiac, and other skeletal anomalies, central obesity, severe intellectual disability, sleep disturbance, urinary retention, and an increased risk for renal stones and Wilms tumor. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Bohring-Opitz syndrome	c0796232	4,342	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=97297	2021-01-23T18:43:56	{"gard": ["10140"], "mesh": ["C537419"], "omim": ["605039"], "umls": ["C0796232"], "icd-10": ["Q87.8"], "synonyms": ["BOS syndrome", "Bohring syndrome", "C-like syndrome", "Oberklaid-Danks syndrome", "Opitz trigonocephaly-like syndrome"]}
Phototoxicity Other namesPhotoirritation Effect of the common rue on skin in hot weather. SpecialtyDermatology Phototoxicity, also called photoirritation, is a chemically induced skin irritation, requiring light, that does not involve the immune system.[1] It is a type of photosensitivity.[1][2] The skin response resembles an exaggerated sunburn. The involved chemical may enter into the skin by topical administration or it may reach the skin via systemic circulation following ingestion or parenteral administration. The chemical needs to be "photoactive," which means that when it absorbs light, the absorbed energy produces molecular changes that cause toxicity. Many synthetic compounds, including drug substances like tetracyclines or fluoroquinolones, are known to cause these effects. Surface contact with some such chemicals causes photodermatitis; many plants cause phytophotodermatitis. Light-induced toxicity is a common phenomenon in humans; however, it also occurs in other animals. ## Contents * 1 Scientific background * 2 Photosafety evaluation * 2.1 Physico-chemical properties * 2.2 In vitro test systems * 2.3 During drug development * 3 Phototoxicity in light microscopy * 4 See also * 5 References * 6 External links ## Scientific background[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Phototoxicity" – news · newspapers · books · scholar · JSTOR (December 2018) (Learn how and when to remove this template message) A phototoxic substance is a chemical compound which becomes toxic when exposed to light. * Some medicines: tetracycline antibiotics, sulfonamides, amiodarone, quinolones, psoralen * Many cold pressed citrus essential oils such as bergamot oil[3] * Some plant juices: parsley, lime, and Heracleum mantegazzianum * Porphyrins, a class of natural molecules occurring in the body and accumulating in patients with certain genetic defects in the building chain of the red blood dye heme: porphyria Phototoxicity is a quantum chemical phenomenon. Phototoxins are molecules with a conjugated system, often an aromatic system. They have a low-lying excited state that can be reached by excitation with visible light photons. This state can undergo intersystem crossing with neighboring molecules in tissue, converting them to toxic free radicals. These rapidly attack nearby molecules, killing cells. A typical radical is singlet oxygen, produced from regular triplet oxygen. Because free radicals are highly reactive, the damage is limited to the body part illuminated. ## Photosafety evaluation[edit] ### Physico-chemical properties[edit] ### In vitro test systems[edit] 3T3 Neutral Red Phototoxicity Test – An in vitro toxicological assessment test used to determine the cytotoxic and photo(cyto)toxicity effect of a test article to murine fibroblasts in the presence or absence of UVA light. > "The 3T3 Neutral Red Uptake Phototoxicity Assay (3T3 NRU PT) can be utilized to identify the phototoxic effect of a test substance induced by the combination of test substance and light and is based on the comparison of the cytotoxic effect of a test substance when tested after the exposure and in the absence of exposure to a non-cytotoxic dose of UVA/vis light. Cytotoxicity is expressed as a concentration-dependent reduction of the uptake of the vital dye - Neutral Red. > > Substances that are phototoxic in vivo after systemic application and distribution to the skin, as well as compounds that could act as phototoxicants after topical application to the skin can be identified by the test. The reliability and relevance of the 3T3 NRU PT have been evaluated and has been shown to be predictive when compared with acute phototoxicity effects in vivo in animals and humans." Taken with permission from [1] ### During drug development[edit] Several health authorities have issued related guidance documents, which need to be considered for drug development: * ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) * M3(R2) "Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals"[4] * S9 "Nonclinical Evaluation for Anticancer Pharmaceuticals"[5] * S10 "Photosafety Evaluation"[5] * EMA (European Medicines Agency) * "Note for Guidance on Photosafety Testing" (revision on-hold)[6] * "Question & Answers on the Note for Guidance on Photosafety Testing"[6] * FDA (U.S. Food and Drug Administration) * * MHLW/PMDA (Japanese Ministry of Health, Labour and Welfare / Pharmaceuticals and Medical Devices Agency) * ## Phototoxicity in light microscopy[edit] When performing microscopy on live samples, one needs to be aware that too high light dose can damage or kill the specimens and lead to experimental artefacts. This is particularly important in confocal and superresolution microscopy.[7][8] ## See also[edit] * Photodynamic therapy ## References[edit] 1. ^ a b Anderson, D.M.; Keith, J.; Novac, P.; Elliott, M.A., eds. (1994). Dorland's Illustrated Medical Dictionary (28th ed.). W. B. Saunders Company. ISBN 0721655777. 2. ^ JH Epstein (1999). "Phototoxicity and photoallergy". Seminars in Cutaneous Medicine and Surgery. 18 (4): 274–284. PMID 10604793. 3. ^ "Bergamot oil". Drugs.com. 2018. Retrieved 5 December 2018. 4. ^ "Multidisciplinary Guidelines". ICH. Retrieved 2013-08-06. 5. ^ a b "Safety Guidelines". ICH. Retrieved 2013-08-06. 6. ^ a b "European Medicines Agency - Non-clinical: Toxicology". Ema.europa.eu. 2010-06-24. Retrieved 2013-08-06. 7. ^ Icha, Jaroslav; Weber, Michael; Waters, Jennifer C.; Norden, Caren (2017). "Phototoxicity in live fluorescence microscopy, and how to avoid it". BioEssays. 39 (8): 1700003. doi:10.1002/bies.201700003. hdl:21.11116/0000-0002-8C94-9. ISSN 1521-1878. 8. ^ Laissue, P. Philippe; Alghamdi, Rana A.; Tomancak, Pavel; Reynaud, Emmanuel G.; Shroff, Hari (July 2017). "Assessing phototoxicity in live fluorescence imaging". Nature Methods. 14 (7): 657–661. doi:10.1038/nmeth.4344. hdl:21.11116/0000-0002-8B80-0. ISSN 1548-7105. ## External links[edit] * In Vitro Phototoxicity Test * 3T3 NRU Phototoxicity Test [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Phototoxicity	c1527358	4,343	wikipedia	https://en.wikipedia.org/wiki/Phototoxicity	2021-01-18T18:41:42	{"mesh": ["D017484"], "wikidata": ["Q2088972"]}
A nipple bleb is a blister on the nipple that can be filled with serous or other fluid. It may be pink or light yellow.[1] It is thin-walled and may appear as a small blister, more than 5 mm in diameter. It can also be referred to as a bulla. Some clinicians may also include milk blisters as a type of bleb. In addition, a blocked Montgomery gland may also be called a nipple bleb though its cause is different than a milk or serous-filled bleb on the nipple.[2] In some cases the bleb may be associated with an adjacent blocked sebaceous cyst.[3] It may be caused by a blocked pore that leads to seepage of milk or serous fluid under the epidermis. This causes a white 'bump' that appears opaque and shiny. If the bleb continues to block the flow of milk out of the breast it may develop into a blocked milk duct or even mastitis.[4] A nipple bleb is often treated by the woman herself since a warm saline soak and gentle washing may open the blister and cause it to drain.[3] ## Contents * 1 Symptoms * 2 Treatment * 3 See also * 4 References ## Symptoms[edit] * Shapeless raised, smooth, shiny, pimple-like, tiny bumps formed on breasts or in and around the nipple pore [5] * Raised, water/fluid filled areas on breasts. The colour of the fluid in nipple blebs may vary from white, yellow or transparent * Nipple blebs become flat when pressure is applied on them[6] * Cause discomfort or pain to the lactating mother while breastfeeding * May or may not be painful in general [7] ## Treatment[edit] * Breastfeed more frequently * Learn how to make the baby latch properly * Try wet, warm heating pads before and after each feeding * Massage the area around the duct to help loosen up the blockage * Ice packs can be soothing [6] * Apply gentle pressure to release the bleb[6] * Do not wear tight fitting bra. If the cloth of the bra is rubbing against the nipples, use a nursing pad to ease the friction[6] ## See also[edit] * Areola * Intimate part * Inverted nipple * Lactation * Mammary gland ## References[edit] Wikimedia Commons has media related to Nipples. Look up nipple, teat, or papilla in Wiktionary, the free dictionary. 1. ^ Association, Australian Breastfeeding (4 February 2012). "White spot on the nipple". Retrieved 12 August 2017. 2. ^ "Sore, tender and damaged nipples". New Zealand Ministry of Health. 2015. Retrieved 12 August 2017. 3. ^ a b Walker, p. 534-5. sfn error: no target: CITEREFWalker (help) 4. ^ Walker, Marsha (2011). Breastfeeding management for the clinician : using the evidence. Sudbury, Mass: Jones and Bartlett Publishers. pp. 534–5. ISBN 9780763766511. 5. ^ "Blisters on Nipples - Breastfeeding Support". Breastfeeding Support. 2014-08-18. Retrieved 2018-10-27. 6. ^ a b c d "Information and Tips on How to Treat Nipple Blebs While Breastfeeding". Verywell Family. Retrieved 2018-10-27. 7. ^ "Milk Blister or Bleb: Causes, Treatment, and Prevention". Healthline. Retrieved 2018-10-27. * v * t * e Anatomy of the breast Structure * Nipple * Areola * Areolar gland (gland of Montgomery) * Mammary gland * Lactiferous duct * Terminal end bud * Mammary alveolus * Cooper's ligaments * Tail of Spence * Inframammary fold * Intermammary cleft * Retromammary space Other * Mammary ridge This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e This women's health related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Nipple bleb	None	4,344	wikipedia	https://en.wikipedia.org/wiki/Nipple_bleb	2021-01-18T18:41:43	{"wikidata": ["Q36120397"]}
A rare hemorrhagic disorder due to an acquired platelet anomaly characterized by hemolysis, elevated liver enzymes and thrombocytopenia that affects pregnant or post-partum women, and is frequently associated with severe preeclampsia. Symptoms are variable, typically including right upper quadrant or epigastric abdominal pain, nausea, vomiting, excessive weight gain, generalized edema, hypertension, general malaise, right shoulder pain, backache, and/or headache. Hepatic hemorrhage and rupture, renal failure, and pulmonary edema can result in maternal and/or fetal death. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	HELLP syndrome	c0162739	4,345	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=244242	2021-01-23T18:19:16	{"gard": ["8528"], "mesh": ["D017359"], "umls": ["C0162739"], "icd-10": ["O14.2"], "synonyms": ["Hemolysis, elevated liver enzymes, low platelets in pregnancy", "Hemolysis-elevated liver enzymes-low platelets syndrome"]}
MOMO syndrome was named for the features associated with the syndrome including macrosomia (being larger than expected from birth), obesity, macrocephaly (having a large head size) and ocular (eye) abnormalities. It has also been proposed that mental (intellectual) disability may be used as an identifying feature of the syndrome instead of macrosomia, as macrosomia has not been reported in all affected individuals. MOMO syndrome is very rare, with only about a dozen reported cases in the scientific literature. The exact cause of MOMO syndrome is unknown. One report has identified that the LINC00237 gene may be the cause of MOMO syndrome. Both autosomal dominant and autosomal recessive inheritance patterns have been suggested. MOMO syndrome is diagnosed when a doctor observes signs consistent with the syndrome. Tests may be completed to rule out other genetic syndromes. Treatment for the syndrome depends on the exact features that each person has. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	MOMO syndrome	c1834759	4,346	gard	https://rarediseases.info.nih.gov/diseases/178/momo-syndrome	2021-01-18T17:59:00	{"mesh": ["C535812"], "omim": ["157980"], "umls": ["C1834759"], "orphanet": ["2563"], "synonyms": ["Macrosomia, obesity, macrocephaly, ocular abnormalities", "Macrocrania, obesity, ocular abnormalities (retinal coloboma and nystagmus)"]}
Absence of ventricular contractions in the context of a lethal heart arrhythmia Asystole Other namesCardiac flatline A rhythm strip showing two beats of normal sinus rhythm followed by an atrial beat and asystole Pronunciation * /əˈsɪstəliː/ SpecialtyCardiology Asystole is the absence of ventricular contractions in the context of a lethal heart arrhythmia (in contrast to an induced asystole on a cooled patient on a heart-lung machine and general anesthesia during surgery necessitating stopping the heart). Asystole is the most serious form of cardiac arrest and is usually irreversible. Also referred to as cardiac flatline, asystole is the state of total cessation of electrical activity from the heart, which means no tissue contraction from the heart muscle and therefore no blood flow to the rest of the body. Asystole should not be confused with very brief pauses in the heart's electrical activity—even those that produce a temporary flatline—that can occur in certain less severe abnormal rhythms. Asystole is different from very fine occurrences of ventricular fibrillation, though both have a poor prognosis, and untreated fine VF will lead to asystole. Faulty wiring, disconnection of electrodes and leads, and power disruptions should be ruled out. Asystolic patients (as opposed to those with a "shockable rhythm" such as ventricular fibrillation or ventricular tachycardia, which can potentially be treated with defibrillation) usually present with a very poor prognosis. Asystole is found initially in only about 28% of cardiac arrest cases in hospitalized patients,[1] but only 15% of these survive, even with the benefit of an intensive care unit, with the rate being lower (6%) for those already prescribed drugs for high blood pressure.[2] Asystole is treated by cardiopulmonary resuscitation (CPR) combined with an intravenous vasopressor such as epinephrine (a.k.a. adrenaline).[3] Sometimes an underlying reversible cause can be detected and treated (the so-called "Hs and Ts", an example of which is hypokalaemia). Several interventions previously recommended—such as defibrillation (known to be ineffective on asystole, but previously performed in case the rhythm was actually very fine ventricular fibrillation) and intravenous atropine—are no longer part of the routine protocols recommended by most major international bodies.[4] Asystole may be treated with 1 mg epinephrine by IV every 3–5 minutes as needed.[citation needed] Survival rates in a cardiac arrest patient with asystole are much lower than a patient with a rhythm amenable to defibrillation; asystole is itself not a "shockable" rhythm. Even in those cases where an individual suffers a cardiac arrest with asystole and it is converted to a less severe shockable rhythm (ventricular fibrillation, or ventricular tachycardia), this does not necessarily improve the person's chances of survival to discharge from the hospital, though if the case was witnessed by a civilian, or better, an EMT, who gave good CPR and cardiac drugs, this is an important confounding factor to be considered in certain select cases.[5] Out-of-hospital survival rates (even with emergency intervention) are less than 2 percent.[6] The term is from 1860, from Modern Latin, from Greek privative a "not, without" + systolē "contraction".[7][8] ## Contents * 1 Cause * 2 See also * 3 References * 4 External links ## Cause[edit] Possible underlying causes, which may be treatable and reversible in certain cases, include the Hs and Ts.[9][10][11] * Hypovolemia * Hypoxia * Hydrogen ions (acidosis) * Hypothermia * Hyperkalemia or Hypokalemia * Hypoglycemia * Tablets or Toxins (drug overdose) * Electric shock * Tachycardia * Cardiac Tamponade * Tension pneumothorax * Thrombosis (myocardial infarction or pulmonary embolism) * Trauma (hypovolemia from blood loss) While the heart is asystolic, there is no blood flow to the brain unless CPR or internal cardiac massage (when the chest is opened and the heart is manually compressed) is performed, and even then it is a small amount. After many emergency treatments have been applied but the heart is still unresponsive, it is time to consider pronouncing the patient dead. Even in the rare case that a rhythm reappears, if asystole has persisted for fifteen minutes or more, the brain will have been deprived of oxygen long enough to cause brain death.[citation needed] * ECG lead showing asystole (flatline) * Asystole * Ventricular Fibrillation ## See also[edit] * Agonal heart rhythm * Ictal asystole ## References[edit] 1. ^ Baldzizhar, Aksana; Manuylova, Ekaterina; Marchenko, Roman; Kryvalap, Yury; Carey, Mary G. (September 2016). "Ventricular Tachycardias". Critical Care Nursing Clinics of North America. 28 (3): 317–329. doi:10.1016/j.cnc.2016.04.004. PMID 27484660. 2. ^ Kutsogiannis, Demetrios J.; Bagshaw, Sean M.; Laing, Bryce; Brindley, Peter G. (4 October 2011). "Predictors of survival after cardiac or respiratory arrest in critical care units". CMAJ : Canadian Medical Association Journal. 183 (14): 1589–1595. doi:10.1503/cmaj.100034. PMC 3185075. PMID 21844108. 3. ^ Kempton, Hannah; Vlok, Ruan; Thang, Christopher; Melhuish, Thomas; White, Leigh (March 2019). "Standard dose epinephrine versus placebo in out of hospital cardiac arrest: A systematic review and meta-analysis". The American Journal of Emergency Medicine. 37 (3): 511–517. doi:10.1016/j.ajem.2018.12.055. PMID 30658877. 4. ^ Neumar, R. W.; Otto, C. W.; Link, M. S.; Kronick, S. L.; Shuster, M.; Callaway, C. W.; Kudenchuk, P. J.; Ornato, J. P.; McNally, B.; Silvers, S. M.; Passman, R. S.; White, R. D.; Hess, E. P.; Tang, W.; Davis, D.; Sinz, E.; Morrison, L. J. (17 October 2010). "Part 8: Adult Advanced Cardiovascular Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care". Circulation. 122 (18_suppl_3): S729–S767. doi:10.1161/CIRCULATIONAHA.110.970988. PMID 20956224. 5. ^ Thomas, Andrew; Newgard, Craig; Fu, Rongwei; Zive, Dana; Daya, Mohamud (2013). "Survival in Out-of-Hospital Cardiac Arrests with Initial Asystole or Pulseless Electrical Activity and Subsequent Shockable Rhythms". Resuscitation. 84 (9): 1261–1266. doi:10.1016/j.resuscitation.2013.02.016. PMC 3947599. PMID 23454257. 6. ^ "Medical Futility in Asystolic Out-of-Hospital Cardiac Arrest". Survey of Anesthesiology. 52 (5): 261–262. October 2008. doi:10.1097/01.SA.0000318635.97636.a6. 7. ^ Harper, Douglas. "asystole". Online Etymology Dictionary. 8. ^ συστολή. Liddell, Henry George; Scott, Robert; A Greek–English Lexicon at the Perseus Project. 9. ^ Mazur G (2004). ACLS: Principles And Practice. Dallas: American Heart Assn. pp. 71–87. ISBN 978-0-87493-341-3. 10. ^ Barnes TG, Cummins RO, Field J, Hazinski MF (2003). ACLS for experienced providers. Dallas: American Heart Assn. pp. 3–5. ISBN 978-0-87493-424-3. 11. ^ ECC Committee, Subcommittees and Task Forces of the American Heart Association (Dec 2005). "2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care - Part 7.2: Management of Cardiac Arrest". Circulation. 112 (24 Suppl): IV1–203 (7.2 IV58–66). doi:10.1161/CIRCULATIONAHA.105.166550. PMID 16314375. ## External links[edit] Classification D * ICD-10: I46.0 * ICD-9-CM: 427.5 Wikimedia Commons has media related to Asystole. * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Asystole	c0018790	4,347	wikipedia	https://en.wikipedia.org/wiki/Asystole	2021-01-18T18:38:13	{"mesh": ["D006323"], "icd-9": ["427.9"], "icd-10": ["I46.0"], "wikidata": ["Q752800"]}
A rare developmental defect during embryogenesis characterized by abnormal retinal development with congenital blindness. Common associated manifestations include sensorineural hearing loss and developmental delay, intellectual disability and/or behavioral disorders. ## Epidemiology To date, more than 400 cases have been described. Affected patients are almost always male. ## Clinical description The ocular findings in affected males are usually bilateral and symmetrical. The iris, anterior chamber and cornea may be normal at birth but greyish-yellow elevated masses (pseudogliomas) are often observed behind the lens along with retinal vascular dysgenesis and leukocoria. Partial or complete retinal detachment develops within the first few weeks or months of life. In infancy and childhood, patients may develop cataracts, nystagmus, anterior/posterior synechiae, band keratopathy and a shallow anterior chamber with increased intraocular pressure. Phthisis bulbi is found later on, along with opacified corneas and sunken orbits. Vision varies from light perception to congenital complete blindness. Most affected males develop progressive asymmetrical sensorineural hearing loss starting in childhood (median age of onset is 12 years). Hearing loss may be severe and bilateral by mid-adulthood. Developmental delay and intellectual disability are found in about 20-30% of patients. Some have cognitive and psychosocial behavioral disorders, including psychosis. Other associated manifestations are highly variable and may include growth failure, microphthalmia, varied chronic seizure disorders, peripheral vascular disease (peripheral ulcers) and erectile dysfunction. Very rare cases of carrier females with retinal findings, such as retinal detachment, abnormal retinal vasculature with associated vision loss or mild sensorineural hearing loss, have been reported. ## Etiology Norrie disease is caused by mutations in the NDP gene (Xp11.4-p11.3), encoding the norrin cystine knot growth factor NDP which is involved in the vascular development of the eye and ear. A large number of disease-causing mutations have been identified. ## Diagnostic methods Diagnosis is based on the characteristic clinical ocular findings and can be confirmed by molecular genetic testing of NDP. No biochemical or functional assays are available. A causative mutation in the NDP gene is recovered in around 85% of male probands. If negative, search for a rearrangement should be conducted. ## Differential diagnosis Differential diagnosis includes retinoblastoma in cases with unilateral pseudoglioma, and other disorders related to NDP mutations such as retinopathy of prematurity, persistent hyperplastic primary vitreous, and familial exudative vitreoretinopathy. ## Antenatal diagnosis Prenatal testing for at-risk pregnancies is possible if the disease-causing mutation has been identified in the family. In rare cases, particularly where there is a family history, ocular abnormalities have been detected on ultrasonography in the third trimester. ## Genetic counseling Norrie disease is inherited in an X-linked manner. Rare de novo mutations have been reported. Genetic counseling should be offered to affected families. Where a female carries the mutation, there will be a 50% risk that male offspring will inherit the disease, and a 50% risk that female offspring will be carriers. Where a male is affected, male offspring are unaffected whereas female offspring are obligate carriers ## Management and treatment Many patients have complete retinal detachment at birth making treatment for preservation of sight difficult. Those that do not have complete retinal detachment may benefit from surgery or laser therapy. Enucleation of the eye may be required in rare cases. Hearing aids should be provided to correct hearing loss and cochlear implantation can be considered. Supportive therapy should be provided for behavioral disorders. ## Prognosis Overall health is generally good in patients with ND. Life expectancy may however be reduced due to general risks associated with the disabling manifestations of the disease. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Norrie disease	c0266526	4,348	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=649	2021-01-23T18:41:18	{"gard": ["7224"], "mesh": ["C537849"], "omim": ["310600"], "umls": ["C0266526"], "icd-10": ["H35.5"], "synonyms": ["Atrophia bulborum hereditaria", "Episkopi blindness", "Norrie-Warburg disease"]}
Angioma serpiginosum SpecialtyDermatology Angioma serpiginosum is characterized by minute, copper-colored to bright red angiomatous puncta that have a tendency to become papular.[1]:592–3[2] ## See also[edit] * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 1622. ISBN 978-1-4160-2999-1. ## External links[edit] Classification D * ICD-10: L81.7 * MeSH: C536366 * v * t * e Pigmentation disorders/Dyschromia Hypo-/ leucism Loss of melanocytes Vitiligo * Quadrichrome vitiligo * Vitiligo ponctué Syndromic * Alezzandrini syndrome * Vogt–Koyanagi–Harada syndrome Melanocyte development * Piebaldism * Waardenburg syndrome * Tietz syndrome Loss of melanin/ amelanism Albinism * Oculocutaneous albinism * Ocular albinism Melanosome transfer * Hermansky–Pudlak syndrome * Chédiak–Higashi syndrome * Griscelli syndrome * Elejalde syndrome * Griscelli syndrome type 2 * Griscelli syndrome type 3 Other * Cross syndrome * ABCD syndrome * Albinism–deafness syndrome * Idiopathic guttate hypomelanosis * Phylloid hypomelanosis * Progressive macular hypomelanosis Leukoderma w/o hypomelanosis * Vasospastic macule * Woronoff's ring * Nevus anemicus Ungrouped * Nevus depigmentosus * Postinflammatory hypopigmentation * Pityriasis alba * Vagabond's leukomelanoderma * Yemenite deaf-blind hypopigmentation syndrome * Wende–Bauckus syndrome Hyper- Melanin/ Melanosis/ Melanism Reticulated * Dermatopathia pigmentosa reticularis * Pigmentatio reticularis faciei et colli * Reticulate acropigmentation of Kitamura * Reticular pigmented anomaly of the flexures * Naegeli–Franceschetti–Jadassohn syndrome * Dyskeratosis congenita * X-linked reticulate pigmentary disorder * Galli–Galli disease * Revesz syndrome Diffuse/ circumscribed * Lentigo/Lentiginosis: Lentigo simplex * Liver spot * Centrofacial lentiginosis * Generalized lentiginosis * Inherited patterned lentiginosis in black persons * Ink spot lentigo * Lentigo maligna * Mucosal lentigines * Partial unilateral lentiginosis * PUVA lentigines * Melasma * Erythema dyschromicum perstans * Lichen planus pigmentosus * Café au lait spot * Poikiloderma (Poikiloderma of Civatte * Poikiloderma vasculare atrophicans) * Riehl melanosis Linear * Incontinentia pigmenti * Scratch dermatitis * Shiitake mushroom dermatitis Other/ ungrouped * Acanthosis nigricans * Freckle * Familial progressive hyperpigmentation * Pallister–Killian syndrome * Periorbital hyperpigmentation * Photoleukomelanodermatitis of Kobori * Postinflammatory hyperpigmentation * Transient neonatal pustular melanosis Other pigments Iron * Hemochromatosis * Iron metallic discoloration * Pigmented purpuric dermatosis * Schamberg disease * Majocchi's disease * Gougerot–Blum syndrome * Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis * Lichen aureus * Angioma serpiginosum * Hemosiderin hyperpigmentation Other metals * Argyria * Chrysiasis * Arsenic poisoning * Lead poisoning * Titanium metallic discoloration Other * Carotenosis * Tar melanosis Dyschromia * Dyschromatosis symmetrica hereditaria * Dyschromatosis universalis hereditaria See also * Skin color * Skin whitening * Tanning * Sunless * Tattoo * removal * Depigmentation This Dermal and subcutaneous growths 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Angioma serpiginosum	c0263637	4,349	wikipedia	https://en.wikipedia.org/wiki/Angioma_serpiginosum	2021-01-18T18:29:30	{"gard": ["10188"], "mesh": ["C536366"], "umls": ["C0263637"], "orphanet": ["95429"], "wikidata": ["Q4763279"]}
A number sign (#) is used with this entry because of evidence that hereditary spastic paraplegia-72 (SPG72) is caused by heterozygous or compound heterozygous mutation in the REEP2 gene (609347) on chromosome 5q31. Autosomal dominant inheritance was reported in one family and autosomal recessive inheritance in another. Description Hereditary spastic paraplegia-72 is a pure form of spastic paraplegia with onset of difficulty walking and stiff legs associated with hyperreflexia and extensor plantar responses in early childhood. The disorder is slowly progressive, and some patients develop the need for assistance in walking. Some patients may have pes cavus or sphincter disturbances. Cognition, speech, and ocular function are normal (summary by Esteves et al., 2014). For a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600), and for autosomal recessive spastic paraplegia, see SPG5A (270800). Clinical Features Esteves et al. (2014) reported a large multigenerational French family in which 10 individuals had a pure form of spastic paraplegia. Patients had onset in childhood (range, infancy to 8 years) of stiff legs or toe walking, which slowly progressed to spastic gait in all patients, as well as spasticity or stiffness at rest in most patients. All patients had hyperreflexia, and all those assessed had extensor plantar responses. Two patients had evidence of upper limb spasticity. The severity was variable: some were able to walk with help or with a cane, whereas others were able to walk independently, but could not run. Three patients had pes cavus, 5 had sphincter disturbances, 2 had slight postural tremor, and 2 had decreased vibration sense at the ankles. Cognition, speech, and ocular function were normal. Esteves et al. (2014) also reported 4 sibs in a Portuguese family with pure spastic paraplegia. One of the sibs had died in adulthood of a nonneurologic disorder. The patients had onset of spasticity with hyperreflexia and extensor plantar responses at age 2. As young adults, 2 walked with help and 2 were unable to run. Additional features were not present. Inheritance The transmission pattern of SPG72 in the French family reported by Esteves et al. (2014) was consistent with autosomal dominant inheritance, whereas the transmission pattern in the Portuguese family reported by Esteves et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In affected members of a large French family with autosomal dominant SPG, Esteves et al. (2014) identified a heterozygous missense mutation in the REEP2 gene (V36E; 609347.0001). Affected members of a Portuguese family with autosomal recessive SPG carried compound heterozygous mutations in the REEP2 gene (c.105+3G-T; 609347.0002 and F72Y; 609347.0003). All 3 mutations were found using a combination of genomewide linkage analysis and exome sequencing. In vitro functional expression studies showed that the V36E mutant protein inhibited the normal binding of wildtype REEP2 to cellular membranes, thus acting in a dominant-negative manner. The F72Y mutant protein had decreased affinity for membranes; together with the splice site mutation, this mutation was expected to cause a complete loss of REEP2 function. INHERITANCE \- Autosomal dominant \- Autosomal recessive GENITOURINARY Bladder \- Sphincter disturbances (in some patients) SKELETAL Feet \- Pes cavus (in some patients) MUSCLE, SOFT TISSUES \- Muscle stiffness NEUROLOGIC Central Nervous System \- Spastic gait \- Tow-walking \- Hyperreflexia \- Extensor plantar responses \- Inability to run (in some patients) Peripheral Nervous System \- Decreased vibratory sense at the ankles (in some patients) MISCELLANEOUS \- Onset in early childhood \- Slowly progressive \- Two unrelated families have been reported, 1 showing autosomal dominant inheritance and 1 showing autosomal recessive inheritance (last curated February 2014) MOLECULAR BASIS \- Caused by mutation in the receptor expression-enhancing protein 2 gene (REEP2, 609347.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	SPASTIC PARAPLEGIA 72, AUTOSOMAL RECESSIVE	c3810160	4,350	omim	https://www.omim.org/entry/615625	2019-09-22T15:51:23	{"doid": ["0110817"], "omim": ["615625"], "orphanet": ["401849"], "synonyms": ["SPG72"]}
A number sign (#) is used with this entry because of evidence that moyamoya disease-5 (MYMY5) is caused by heterozygous mutation in the ACTA2 gene (102620) on chromosome 10q23. See also familial thoracic aortic aneurysm-6 (AAT6; 611788), which is an allelic vascular disorder. Description Moyamoya disease is a cerebrovascular disorder caused by stenotic changes of terminal portions of the internal carotid arteries accompanied by surrounding fine arterial collateral vessels. These vascular networks resemble a 'puff of smoke' (Japanese: moyamoya) in angiographic imaging (summary by Roder et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350). Clinical Features Guo et al. (2009) reported 3 unrelated families segregating both thoracic aneurysms with dissection (TAAD) and moyamoya disease. Onset of stroke in these families ranged from 5 to 46 years. Some patients had isolated moyamoya, some had isolated thoracic aneurysm, and some had both conditions. Inheritance The transmission pattern of moyamoya disease in the families reported by Guo et al. (2009) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of 3 unrelated families with moyamoya disease, Guo et al. (2009) identified 3 different heterozygous mutations in the ACTA2 gene (see, e.g., R258H, 102620.0002 and R258C, 102620.0003). Several members of all families also had TAAD, but isolated moyamoya disease was found in 1 member of each family. Roder et al. (2011) identified a heterozygous mutation in the ACTA2 gene (R179H; 102620.0004) in 1 of 39 unrelated patients of European descent with moyamoya disease and no family history of the disorder. The patient had onset of stroke at age 3 years. No other previously described ACTA2 mutations associated with moyamoya disease (Guo et al., 2009) were found in this cohort. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	MOYAMOYA DISEASE 5	c0026654	4,351	omim	https://www.omim.org/entry/614042	2019-09-22T15:56:42	{"doid": ["13099"], "mesh": ["D009072"], "omim": ["614042"], "orphanet": ["2573"]}
For a discussion of genetic heterogeneity of quantitative trait loci for stature (STQTL), see STQTL1 (606255). Mapping Human height is a classic, highly heritable quantitative trait. To identify genetic variants influencing height, Weedon et al. (2007) examined genomewide association data from 4,921 individuals. Common variants in the HMGA2 (600698) oncogene, exemplified by rs1042725, were associated with height (P = 4 x 10(-8)). HMGA2 was considered a strong biologic candidate for influencing height as homozygous deletion of the orthologous gene in the mouse produces the 'pygmy' phenotype, while mice expressing the truncated gene develop gigantism and lipomatosis; in humans, an individual with a severe overgrowth syndrome carried a chromosomal inversion that truncated the HMGA2 gene product (Ligon et al., 2005). Weedon et al. (2007) confirmed the association in 19,064 adults from 4 further studies. They also observed the association in children and in a tall/short case-control study. They estimated that rs1042725 explains approximately 0.3% of population variation in height (approximately 0.4 cm increased adult height per C allele). The authors stated that this was one of the few examples of a common genetic variant reproducibly associated with a human quantitative trait, and the first consistently replicated association with adult and childhood height. In separate genomewide association studies involving approximately 63,000 individuals, Weedon et al. (2008), Lettre et al. (2008), and Gudbjartsson et al. (2008) confirmed the HMGA2 gene as a locus associated with stature as a quantitative trait. In a study using genomewide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples, Weedon et al. (2008) found association with the SNP rs1042725 (P = 2.5 x 10(-18)). Each of the 20 robustly associated variants identified in the study altered height by between approximately 0.2 and 0.6 centimeters per allele. Lettre et al. (2008) also found association with this SNP (P = 2.7 x 10(-20)) in a metaanalysis of genomewide association study data of height for 15,821 individuals at 2.2 million SNPs, with follow-up of the strongest findings in greater than 10,000 subjects. Gudbjartsson et al. (2008) found significant association with the SNP rs8756 (P = 1.8 x 10(-16)), which was a surrogate for rs1042725 (r(2) = 0.87). Soranzo et al. (2009) performed a genomewide scan in 12,611 participants followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with genomewide significant association with height. All subjects were of European descent, including 1,430 British individuals from the British 1958 Birth Cohort, 2,224 individuals from the TwinsUK Cohort, and 5,746 individuals from a Dutch cohort. Soranzo et al. (2009) confirmed association of the HMGA2 gene with stature as a quantitative trait. The strongest association found in their study was achieved by the SNP rs8756 (combined P = 5.0 x 10(-14)). Hodge et al. (2009) found a significant association between a TC repeat allele of the HMGA2 gene, TC227, corresponding to 27 TC repeats, and height (corrected p = 0.016) in 248 white families with sister-pairs affected with uterine leiomyomata (UL; 150699). The same TC227 repeat was also associated with development of UL. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	STATURE QUANTITATIVE TRAIT LOCUS 9	c1969061	4,352	omim	https://www.omim.org/entry/611547	2019-09-22T16:03:09	{"omim": ["611547"]}
A number sign (#) is used with this entry because of evidence that Singleton-Merten syndrome-2 (SGMRT2) is caused by heterozygous mutation in the DDX58 gene (609631) on chromosome 9p21. Description Singleton-Merten syndrome-2 is characterized by variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies (summary by Jang et al., 2015). For a general phenotypic description and discussion of genetic heterogeneity of Singleton-Merten syndrome, see SGMRT1 (182250). Clinical Features Jang et al. (2015) studied a large 4-generation Korean family with aortic calcification, glaucoma, and skeletal abnormalities. The 56-year-old proband was diagnosed with bilateral glaucoma at 6 years of age and was blind by age 17. In early adulthood, she had arthritis of the hands with metacarpophalangeal contractures; x-rays showed calcific tendinitis and mild calcified ligaments of the interphalangeal and metacarpophalangeal joints, as well as mild erosive changes in the terminal tufts of the distal phalanges. CT scan showed severe calcification of the aorta and coronary arteries as well as mild aortic valve stenosis. The patient also had dry skin with scabbing; skin biopsy showed papillomatosis and hyperkeratosis. Her son was diagnosed with bilateral glaucoma at 3 years of age. He had atopic dermatitis in early childhood that developed into psoriatic skin lesions, and skin biopsy confirmed psoriasiform hyperplasia. At 21 years of age, he was found to have calcification of the aorta, aortic valve, and coronary arteries. One year later, he had acute severe mitral regurgitation due to chordae rupture with subsequent pulmonary edema, and underwent mitral valvuloplasty and aortic valve decalcification. Skeletal survey showed hypoplastic and cone-shaped distal phalanges due to terminal tuft erosion. The proband's 35-year-old niece and her 2 daughters had glaucoma. The niece also had calcification of the proximal ascending aorta and coronary arteries, with mild calcification of the aortic valve, but no stenosis. The proband's 33-year-old nephew did not have glaucoma, but exhibited calcification of the aorta and the subclavian and iliac arteries; his son and daughter both had glaucoma, and x-rays of the hands and feet in all 3 showed erosive changes of the terminal tufts. No one in the family had dental anomalies, dysmorphic facial features, muscle weakness, or hypotonia. Molecular Genetics In a large 4-generation Korean family with glaucoma, aortic calcification, and skeletal anomalies, Jang et al. (2015) performed exome sequencing and identified heterozygosity for a missense mutation in the DDX58 gene (E373A; 609631.0001) that segregated with disease. Analysis of the DDX58 gene in 100 unrelated patients with glaucoma revealed a missense mutation (C268F; 609631.0002) in a 20-year-old Korean woman and her affected mother and maternal grandmother. In this family, features consisted of glaucoma, phalangeal osteoarthropathy with flexion contractures, and acroosteolysis of the distal phalanges. Small aortic calcifications in the arch and abdominal aorta were believed to be age-related in the 61-year-old grandmother; none of the 3 had dental anomalies, facial dysmorphism, muscle weakness, or hypotonia. Jang et al. (2015) designated the phenotype in the 2 families 'atypical Singleton-Merten syndrome' manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities, without dental anomalies. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature (rare) HEAD & NECK Eyes \- Glaucoma \- Blindness secondary to glaucoma Teeth \- Normal dentition CARDIOVASCULAR Heart \- Calcification of aortic valve (in some patients) \- Aortic valve stenosis (in some patients) Vascular \- Calcification of aorta (in some patients) \- Calcification of coronary arteries (in some patients) SKELETAL Hands \- Phalangeal osteoarthropathy \- Metacarpophalangeal contractures \- Distal acroosteolysis Feet \- Distal acroosteolysis SKIN, NAILS, & HAIR Skin \- Psoriasiform rash Skin Histology \- Papillomatosis \- Hyperkeratosis \- Psoriasiform hyperplasia MUSCLE, SOFT TISSUES \- Calcific tendonitis MISCELLANEOUS \- Variable expression of features MOLECULAR BASIS \- Caused by mutation in the DEAD box polypeptide-58 gene (DDX58, 609631.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	SINGLETON-MERTEN SYNDROME 2	c0432254	4,353	omim	https://www.omim.org/entry/616298	2019-09-22T15:49:21	{"mesh": ["C537343"], "omim": ["616298"], "orphanet": ["85191"]}
A total autosomal trisomy that is caused by the presence of a third (partial or total) copy of chromosome 21 and that is characterized by variable intellectual disability, muscular hypotonia, and joint laxity, often associated with a characteristic facial dysmorphism and various anomalies such as cardiac, gastrointestinal, neurosensorial or endocrine defects. ## Epidemiology Prevalence at birth of Down syndrome (DS) in a country depends largely on non-medical factors, i.e. public policies regarding prenatal diagnosis and care for disabled people, and view of the population for DS and for abortion. In brief, it varies from 1/400 to 1/3000 live births. The risk of having a baby with Down syndrome (DS) increases with maternal age, identically in every population. ## Clinical description Clinical features include variable (often mild) intellectual disability, almost constant muscular hypotonia and joint laxity, associated with morphological signs, malformations (half of cases) and increased risks of some medical complications all-life-long. Morphological features (upslanting palpebral fissures, epicanthus, flat neck, round face, small nose, bilateral single palmar crease) can be mild and are not pathognomonic of the condition. The main potential malformations and complications include: short stature, congenital cataract, conductive hearing loss, heart defects (atrio-ventricular canal), digestive malformations (duodenal atresia), Hirschsprung disease, seizures, sleep apnea, sensory deficiencies, leukemia, auto-immune and endocrine pathologies (hypothyroidism, celiac disease, diabetes mellitus type 1, alopecia areata, earlier aging and early-onset Alzheimer disease. ## Etiology In 95% of the cases, trisomy 21 is an additional independent chromosome 21 (47,+21): the extra chromosome is due to an accidental non-disjunction during meiosis. 2-3% of those cases are in a mosaic state. In the remaining 5%, the supernumerary chromosome 21 or portion of chromosome 21 is translocated to another chromosome (Robertsonian translocation in most cases). ## Diagnostic methods The diagnosis is based on karyotyping. ## Differential diagnosis Differential diagnosis includes Zellweger syndrome, 9qter deletion or other chromosomal abnormalities. We can also mention the exceptional Aymé-Gripp syndrome. ## Antenatal diagnosis In 70-75% of fetuses, increased nuchal translucency can be seen on first-trimester ultrasonography. On the second-trimester, malformations (essentially cardiac and digestive) are present in 60% of the cases, and can be associated with minor morphological signs. Prenatal diagnosis can be confirmed by fetal karyotype on amniocentesis or chorionic villous sampling. Non-invasive prenatal screening on maternal blood is now available in several countries in case of an increased risk of DS on prenatal screening. ## Genetic counseling For the parents of a child affected by regular trisomy 21, the recurrence risk is only slightly modified (1% until the age of 40 years, linked to maternal age afterwards). In case of DS caused by translocation, the risk is raised only if one of the parents has a balanced rearrangement. For a person with Down syndrome, the risk of transmitting the disease to the descendants is 1/3 (maybe less for males with DS). ## Management and treatment Early physiotherapy, psychomotor therapy and speech therapy (including alternative non-verbal communication tools, namely sign language and picture exchange, in order to stimulate early communication and induce oral skills) are essential. A person with DS should be involved as soon as possible in decision-making through self-determination. A well-adapted program, including re-education, schooling and social aspects, should be proposed, aiming at obtaining the best possible integration in society (i.e. more than half of people with DS has capabilities to read and write, even partially). Neuropsychological evaluations are important to recognize the specific difficulties and abilities of each person with DS and thus propose cognitive remediation. An adapted medical follow-up is very important in order to detect and treat as soon as possible medical complications. Guidelines have been published. It can be necessary to maintain some support in the adult age, including re-education. Research in medical treatment to improve cognition in people with Down syndrome is active with ongoing clinical trials. ## Prognosis Median life expectancy is now above the age of 60 years in developed countries. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Down syndrome	c0013080	4,354	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=870	2021-01-23T17:53:56	{"mesh": ["D004314"], "omim": ["190685"], "umls": ["C0013080"], "icd-10": ["Q90.0", "Q90.1", "Q90.2", "Q90.9"], "synonyms": ["Trisomy 21"]}
Specific phobia that involves an irrational fear of contracting a disease 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: "Nosophobia" – news · newspapers · books · scholar · JSTOR (June 2020) (Learn how and when to remove this template message) Nosophobia SpecialtyPsychiatry Nosophobia is the irrational fear of contracting a disease, a type of specific phobia. Primary fears of this kind are fear of contracting COVID-19, HIV, pulmonary tuberculosis, venereal diseases, cancer, heart diseases, and catching the cold or flu. Some authors have suggested that the medical students' disease should accurately be referred to as "nosophobia" rather than "hypochondriasis", because the quoted studies show a very low percentage of hypochondriacal character of the condition.[1] The word nosophobia comes from the Greek νόσος nosos for "disease". ## See also[edit] * Hypochondria * Nosocomephobia, the excessive fear of hospitals * List of phobias ## References[edit] 1. ^ Hunter R.C.A, Lohrenz J.G., Schwartzman A.E. "Nosophobia and hypochondriasis in medical students" J Nerv Ment Dis 1964;130:147-52. PMID 14206454 ## External links[edit] Classification D * ICD-10: F45.2 * ICD-9-CM: 300.29 * 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 This psychology-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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Nosophobia	None	4,355	wikipedia	https://en.wikipedia.org/wiki/Nosophobia	2021-01-18T18:32:34	{"icd-9": ["300.29"], "icd-10": ["F45.2"], "wikidata": ["Q3052614"]}
Anti-MAG peripheral neuropathy Other namesNeuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein SpecialtyImmunology, neurology Anti-MAG Peripheral Neuropathy is a specific type of peripheral neuropathy in which the person's own immune system attacks cells that are specific in maintaining a healthy nervous system. As these cells are destroyed by antibodies, the nerve cells in the surrounding region begin to lose function and create many problems in both sensory and motor function. Specifically, antibodies against myelin-associated glycoprotein (MAG) damage Schwann cells. While the disorder occurs in only 10% of those afflicted with peripheral neuropathy, people afflicted have symptoms such as muscle weakness, sensory problems, and other motor deficits usually starting in the form of a tremor of the hands or trouble walking.[1][2] There are, however, multiple treatments that range from simple exercises in order to build strength to targeted drug treatments that have been shown to improve function in people with this type of peripheral neuropathy.[3] ## Contents * 1 Background * 1.1 Myelination by Schwann cells * 1.2 Myelin-associated glycoprotein * 1.3 MAG antibodies * 2 Symptoms * 2.1 Common * 2.2 Severe * 3 Diagnosis * 4 Treatments * 4.1 Immunotherapy and chemotherapy * 4.2 Chlorambucil and prednisone * 4.3 Cyclophosphamide * 4.4 Fludarabine * 4.5 Intravenous immunoglobulin * 4.6 Most promising drug: Rituximab * 5 Current research * 6 References * 7 External links ## Background[edit] ### Myelination by Schwann cells[edit] Myelin is an important part of neuron cells and provides insulation allowing the neuron's action potential to travel faster and more consistently. In order to provide insulation, multiple layers of closely opposing membrane are wrapped around the axon. By acting as an electrical insulator, the conduction ability of the axon is sped up considerably allowing action potentials to travel at a much faster rate, about fifteen times faster in certain cases. This ability allows the nervous system to send messages faster and more accurately. Disruption of the myelin sheath on cells that are normally myelinated allows leakage of action potential much like a faulty wire will allow leakage of electricity in a circuit. This slows the messages being sent along those nerves and disrupts normal function.[4] Schwann cells are the cells in the peripheral nervous system that create and maintain myelin sheaths on neurons. These are the glial cells of the peripheral nervous system and are located around the axons that they serve. Damage to these cells result in degeneration of the myelin sheath and inevitably lead to problems in communication for the nervous system.[4] ### Myelin-associated glycoprotein[edit] Main article: myelin-associated glycoprotein Myelin-associated glycoprotein (MAG) is a glycoprotein that is specific to Schwann cells, which create myelin for nerve cells in the peripheral nervous system. Research through cloning of the rat MAG gene has shown that it is a type I transmembrane protein meaning that it contains domains both inside the cell membrane and outside the cell membrane. Expression of this glycoprotein is very specific to myelin-forming cells and begins very early in the myelination process in order to function in the early development of axons in the central nervous system. The expression continues to be relatively high even in mature animals, however, suggesting that it is associated with not only formation but maintenance as well.[5] Research through knockout mice, or mice with the MAG gene removed, has shown that this glycoprotein serves heavily in the formation of myelin but also show that early development of the peripheral nervous system is relatively normal even without the presence of MAG. The knockout mice generally show many motor deficits, however, as they age caused by the degeneration of the myelinated axons further suggesting the need for these glycoproteins in maintenance of the sheaths.[5] While it is still unclear as to the exact mechanism or pathway by which MAG affects myelination, studies suggest that MAG serves in a receptor role to begin a signaling cascade begun by activation from an external source. MAG has also been shown to bind as a ligand to a receptor on the axonal surface which suggests that the external stimulus activating the creation of myelin comes from the nerve cell or cells that these glycoproteins are bound to.[5] ### MAG antibodies[edit] Antibodies are created by the body that can then attack and disrupt the function of myelin associated glycoproteins. These antibodies have been found to bind to the external domain of the glycoproteins and inhibit any other signaling to occur. As these proteins are important in various signal cascades that eventually lead to the Schwann cells creating myelin, these antibodies basically halt myelin creation leading to the neuropathy. There is still, however, much debate as to the actual cause for these antibodies to be created. There has been some research to suggest that these antibodies are linked to various forms of amyloidosis as patients with amyloidosis experience elevated anti-MAG antibodies usually leading to a form of neuropathy. This does not, however, provide any evidence as to the mechanisms behind the creation of the antibodies.[1][5][6] ## Symptoms[edit] ### Common[edit] People with this disease have shown many sensory and muscular symptoms. Most patients have a sensory ataxia, or sensory loss in various extremities, along with mild to moderate muscle weakness, usually starting in the toes and fingers and moving inward. Most patients also present a mild to moderate tremor in the extremities which increases as the disease progresses.[1] ### Severe[edit] More severe symptoms occur after the disease progresses and there is much more damage to the myelin sheaths in the peripheral nervous system. These can present as debilitating tremors that prevent patients from doing normal tasks, complete sensory loss on limbs, and, in some cases, extensive muscle atrophy.[7] ## Diagnosis[edit] Detection of this type of neuropathy has concentrated mostly on detecting presence of antibodies because the antibodies are the main cause for the disease. Anti-MAG antibodies can be readily detected in a patient's sera using various types of assays, but mainly an ELISA has been shown to be most effective.[1][8] There are also various biological indicators, such as elevated cerebral spinal fluid proteins and elevated IgM monoclonal levels. These can also be tested either by drawing serum from a patient or by drawing spinal fluid from a spinal tap and testing using an assay or blot.[1] ## Treatments[edit] Drug and therapeutic treatments exist in order to battle this disease; however many have proven ineffective. ### Immunotherapy and chemotherapy[edit] While immunotherapy works for some patients in relieving minor symptoms, overall most conventional therapies using steroids, immunosuppressants, chemotherapy, and intravenous immunoglobulin therapies have not helped most patients. This has created a need for newer and more novel therapies to be developed.[1][9] ### Chlorambucil and prednisone[edit] Chlorambucil is a chemotherapy drug normally used to treat leukemia as it is often used as an immunosuppressant drug, and prednisone is a steroid that has also been found to be particularly effective as an immunosuppressant. This combination of drugs has minimal to no benefits in most patients, but a small number do see small improvements such as decreased tremors. This combination has not been very effective in more severe cases, though, and is not considered a long term therapy.[1] ### Cyclophosphamide[edit] Cyclophosphamide is a drug often used in the treatment of lymphomas and works by slowing or stopping cell growth. It also works as an immunosuppressant by decreasing the body's immune response to various diseases and conditions. This drug has been found to make significant improvements in people with anti-MAG neuropathy by relieving sensory loss and helping to improve quality of life in a few short months. There is, however, a risk of cancer because of this treatment and is therefore not used on a regular basis.[1] ### Fludarabine[edit] Fludarabine is a drug normally used to treat hematological malignancies and acts as an immunosuppressant. It has been shown to significantly improve conditions in neuropathy patients, but because of the lack of studies it is not used regularly. There is also a danger of potential toxicity as the treatment takes a year to stabilize the patient.[1] ### Intravenous immunoglobulin[edit] Intravenous immunoglobulin is a blood product administered by IV. It is used to treat various immune deficiencies and autoimmune diseases. While this has been shown to be effective on various types of disorders, there have been no studies that show promise in this technique treating anti-MAG neuropathies. ### Most promising drug: Rituximab[edit] Rituximab is considered to be one of the most promising drugs in the treatment of anti-MAG peripheral neuropathy. This drug is an antibody against a protein which is primarily found on the surface of B cells which, when attached, destroys the B cells. This drug has been used as a treatment in many autoimmune diseases as well as lymphomas and transplant rejection. Because of its ability to suppress the immune system, it has been used to treat anti-MAG neuropathy in the hopes that it will destroy cells that would target necessary glycoproteins on the Schwann cells. Studies in patients has shown that most patients experience marked increase in sensory and motor abilities within the first few months of therapy.[1] There are, however, long term studies that have shown that treatment with rituximab can create many immune problems. As with most immunosuppressant drugs, there is a risk of other infections and diseases that are normally easily fought off by the immune system will be allowed take a foothold. Studies have shown that after long term treatment, patients experience many of these problems as well as a decline in their neuropathy. This has led to further studies being conducted on the drug's safety profile and overall effectiveness as a treatment.[10][11] Unfortunately, more recent studies have concluded that "rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy." [12] ## Current research[edit] Current research has focused mostly on determining treatment options. This has been studied through clinical trials with drugs listed previously or through new therapy techniques that delay loss in function. Most drugs being studied are immunosuppressants that can attack the antibodies or other aspects in the hope of preventing damage to the Schwann cells. This will, ideally, prevent the loss of myelination on peripheral nerve fibers.[13] ## References[edit] 1. ^ a b c d e f g h i j Dalakas, M. C. (2010). "Pathogenesis and Treatment of Anti-MAG Neuropathy". Current Treatment Options in Neurology. 12 (2): 71–83. doi:10.1007/s11940-010-0065-x. PMID 20842571. 2. ^ Launay, M.; Delmont, E.; Benaim, C.; Sacconi, S.; Butori, C.; Desnuelle, C. (2009). "Anti-MAG paraproteinemic demyelinating polyneuropathy: A clinical, biological, electrophysiological and anatomopathological descriptive study of a 13-patients' cohort". Revue Neurologique. 165 (12): 1071–1079. doi:10.1016/j.neurol.2009.04.008. PMID 19487003. 3. ^ Gajos, A.; Kielis, W.; Szadkowska, I.; Chmielowska, E.; Niewodniczy, A.; Bogucki, A. (2007). "Acquired peripheral neuropathies associated with monoclonal gammopathy". Neurologia I Neurochirurgia Polska. 41 (2): 169–175. 4. ^ a b Neuroscience. (2008). Sunderland (Mass.): Sinauer. 5. ^ a b c d Quarles, R. H. (2007). "Myelin-associated glycoprotein (MAG): past, present and beyond". Journal of Neurochemistry. 100 (6): 1431–1448. doi:10.1111/j.1471-4159.2006.04319.x. PMID 17241126. 6. ^ Garces-Sanchez, M.; Dyck, P. J.; Kyle, R. A.; Zeldenrust, S.; Wu, Y.; Ladha, S. S.; et al. (2008). "Antibodies to myelin-associated glycoprotein (anti-MAG) in IgM amyloidosis may influence expression of neuropathy in rare patients". Muscle & Nerve. 37 (4): 490–495. doi:10.1002/mus.20955. PMID 18236455. 7. ^ Kawagashira, Y.; Kondo, N.; Atsuta, N.; Iijima, M.; Koike, H.; Katsuno, M.; et al. (2010). "IgM MGUS Anti-MAG Neuropathy With Predominant Muscle Weakness and Extensive Muscle Atrophy". Muscle & Nerve. 42 (3): 433–435. doi:10.1002/mus.21741. 8. ^ Kuijf, M. L.; Eurelings, M.; Tio-Gillen, A. P.; van Doorn, P. A.; den Berg, L. H.; Hooijkaas, H.; et al. (2009). "Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy". Neurology. 73 (9): 688–695. doi:10.1212/wnl.0b013e3181b59a80. PMID 19720975. 9. ^ Leger, J. M., Chassande, B., Bombelli, F., Viala, K., Musset, L., & Neil, J. (2009). Polyneuropathy associated with monoclonal gammapathy: treatment perspectives. Bulletin De L Academie Nationale De Médecine, 193(5), 1099-1110. 10. ^ Benedetti, L.; Briani, C.; Franciotta, D.; Carpo, M.; Padua, L.; Zara, G.; et al. (2008). "Long-Term Effect of Rituximab in Anti-MAG Polyneuropathy. [Editorial Material]". Neurology. 71 (21): 1742–1744. doi:10.1212/01.wnl.0000335268.70325.33. PMID 19015493. 11. ^ Broglio, L.; Lauria, G. (2005). "Worsening after rituximab treatment in anti-MAG neuropathy. [Letter]". Muscle & Nerve. 32 (3): 378–379. doi:10.1002/mus.20386. PMID 15986418. 12. ^ Léger, JM; Viala, K; Nicolas, G; Créange, A; Vallat, JM; Pouget, J; Clavelou, P; Vial, C; Steck, A; Musset, L; Marin, B (2013). "Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy". Neurology. 80 (24): 2217–25. doi:10.1212/WNL.0b013e318296e92b. PMC 3721095. PMID 23667063. 13. ^ Lunn, M (2008). "What's new in paraproteinemic demyelinating neuropathy in 2007-2008?". Journal of the Peripheral Nervous System. 13 (4): 264–266. doi:10.1111/j.1529-8027.2008.00191.x. PMID 19192065. ## External links[edit] Classification D * ICD-10: G61.8 External resources * Orphanet: 639 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Anti-MAG peripheral neuropathy	c1736154	4,356	wikipedia	https://en.wikipedia.org/wiki/Anti-MAG_peripheral_neuropathy	2021-01-18T18:51:55	{"umls": ["C1736154"], "orphanet": ["639"], "wikidata": ["Q4774221"]}
Osteopetrosis, also known as marble bone disease, is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. ## Epidemiology The overall prevalence and incidence of these conditions is difficult to estimate but autosomal recessive malignant osteopetrosis (ARO; see this term) has an incidence of 1/ 250,000 births, and autosomal dominant osteopetrosis (ADO or Albers-Schönberg osteopetrosis; see this term) has an incidence of 1 in 20,000 births. ## Clinical description Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or ''malignant'' ARO; see this term), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis; see this term). Classic ARO is characterized by fractures, short stature, compressive neuropathies, hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. The presence of primary neurodegeneration, intellectual deficit, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. ## Etiology Osteopetrosis is caused by failure of osteoclast development or function, and mutations in at least ten genes have been identified as causative in humans, accounting for 70% of all cases. ## Diagnostic methods Diagnosis is largely based on clinical and radiographic evaluation and should be confirmed by gene testing where applicable. Once the diagnosis of a primary osteopetrotic condition is made, it is important to distinguish between different subtypes. Correct diagnosis is essential for predicting and understanding the natural history of the disease, providing specific treatments where available, and offering adapted counseling regarding recurrence risks and prenatal diagnosis for severe forms. ## Differential diagnosis Alternative diagnoses include fluorosis; beryllium, lead and bismuth poisoning; myelofibrosis; Paget's disease (sclerosing form); and malignancies (lymphoma, osteoblastic cancer metastases) (see these terms). ## Antenatal diagnosis Antenatal diagnosis is possible if the mutations causing the condition in the family are known. ## Genetic counseling These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. ## Management and treatment Treatment of osteopetrotic conditions is largely symptomatic, although hematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure, and currently offers the best chance of longer-term survival for patients in this group. ## Prognosis The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a consequence of bone marrow suppression. Life expectancy in the adult-onset forms is normal. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Osteopetrosis and related disorders	c0029454	4,357	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2781	2021-01-23T17:52:06	{"gard": ["4155"], "mesh": ["D010022"], "umls": ["C0029454"], "icd-10": ["Q78.2"]}
This lead 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: "Hypervitaminosis" – news · newspapers · books · scholar · JSTOR (February 2017) (Learn how and when to remove this template message) Vitamin overdose SpecialtyToxicology CausesExcessive consumption of vitamins Hypervitaminosis is a condition of abnormally high storage levels of vitamins, which can lead to toxic symptoms. Specific medical names of the different conditions are derived from the vitamin involved: an excess of vitamin A, for example, is called hypervitaminosis A. Hypervitaminoses are primarily caused by fat-soluble vitamins (D and A), as these are stored by the body for longer than the water-soluble vitamins.[1] Generally, toxic levels of vitamins stem from high supplement intake and not from natural food. Toxicities of fat-soluble vitamins can also be caused by a large intake of highly fortified foods, but natural food rarely deliver dangerous levels of fat-soluble vitamins.[2] The Dietary Reference Intake recommendations from the United States Department of Agriculture define a "tolerable upper intake level" for most vitamins. Vitamin overdose can be avoided by not taking more than the normal or recommended amount of multi-vitamin supplement shown on the bottle and not ingesting multiple vitamin-containing supplements concurrently.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Prevention * 4 Epidemiology * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] Organs compromises:[3] * Cloudy urine * Frequent urination * Increased urine amount * Dryness, cracking lips (due to chronic overdose) * Eye irritation * Increased sensitivity of the eyes to light * Irregular heartbeat * Rapid heartbeat * Bone pain * Joint pain * Muscle pain * Muscle weakness * Confusion, mood changes * Convulsions (seizures) * Fainting * Fatigue * Headache * Mental changes * Irritability * Flushing (reddened skin) from niacin (vitamin B3) * Dry, cracking skin * Itching, burning skin, or rash * Yellow-orange areas of skin * Sensitivity to sun (more likely to sunburn) * Hair loss (from long-term overdose) * Intestinal bleeding (from iron) * Appetite loss * Constipation (from iron or calcium) * Diarrhea, possibly bloody * Nausea and vomiting * Stomach pain * Weight loss (from long-term overdose) ## Causes[edit] With few exceptions, like some vitamins from B-complex, hypervitaminosis usually occurs with the fat-soluble vitamins A and D, which are stored, respectively, in the liver and fatty tissues of the body. These vitamins build up and remain for a longer time in the body than water-soluble vitamins.[2] Conditions include: * Hypervitaminosis A * Hypervitaminosis D * Vitamin B3 § Toxicity * Megavitamin-B6 syndrome ## Prevention[edit] Do not take more than the normal or recommended amount of multivitamin supplements.[3] ## Epidemiology[edit] In the United States, overdose exposure to all formulations of "vitamins" (which includes multi-vitamin/mineral products) was reported by 62,562 individuals in 2004 with nearly 80% of these exposures in children under the age of 6, leading to 53 "major" life-threatening outcomes and 3 deaths (2 from vitamins D and E; 1 from polyvitaminic type formula, with iron and no fluoride).[4] This may be compared to the 19,250 people who died of unintentional poisoning of all kinds in the U.S. in the same year (2004).[5] In 2016, overdose exposure to all formulations of vitamins and multi-vitamin/mineral formulations was reported by 63,931 individuals to the American Association of Poison Control Centers with 72% of these exposures in children under the age of five. No deaths were reported.[6] ## See also[edit] * Avitaminosis * Megavitamin therapy * Vitamin C megadosage ## References[edit] 1. ^ "Office of Dietary Supplements - Vitamin A". ods.od.nih.gov. Retrieved 2016-02-03. 2. ^ a b Sizer, Frances Sienkiewicz; Ellie Whitney (2008). Nutrition: Concepts and Controversies (11 ed.). United States of America: Thomson Wadsworth. pp. 221, 235. ISBN 0-495-39065-8. 3. ^ a b c "Multiple vitamin overdose". MedlinePlus Medical Encyclopedia. U.S. National Library of Medicine. 2019-01-28. Retrieved 2019-02-11. This article incorporates text from this source, which is in the public domain. 4. ^ Toxic Exposure Surveillance System (2004). "Annual Report" (PDF). American Association of Poison Control Centers. Archived from the original (pdf) on 2011-01-05. 5. ^ "National Center for Health Statistics". 6. ^ Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W (2017). "2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report" (PDF). Clinical Toxicology. 55 (10): 1072–1254. doi:10.1080/15563650.2017.1388087. PMID 29185815. ## External links[edit] Classification D * ICD-10: E67.0-E67.3 * ICD-9-CM: 278.2, 278.4 External resources * Patient UK: Hypervitaminosis * Dietary reference intakes, official website. * 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 * v * t * e * Poisoning * Toxicity * Overdose History of poison Inorganic Metals Toxic metals * Beryllium * Cadmium * Lead * Mercury * Nickel * Silver * Thallium * Tin Dietary minerals * Chromium * Cobalt * Copper * Iron * Manganese * Zinc Metalloids * Arsenic Nonmetals * Sulfuric acid * Selenium * Chlorine * Fluoride Organic Phosphorus * Pesticides * Aluminium phosphide * Organophosphates Nitrogen * Cyanide * Nicotine * Nitrogen dioxide poisoning CHO * alcohol * Ethanol * Ethylene glycol * Methanol * Carbon monoxide * Oxygen * Toluene Pharmaceutical Drug overdoses Nervous * Anticholinesterase * Aspirin * Barbiturates * Benzodiazepines * Cocaine * Lithium * Opioids * Paracetamol * Tricyclic antidepressants Cardiovascular * Digoxin * Dipyridamole Vitamin poisoning * Vitamin A * Vitamin D * Vitamin E * Megavitamin-B6 syndrome Biological1 Fish / seafood * Ciguatera * Haff disease * Ichthyoallyeinotoxism * Scombroid * Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Hypervitaminosis	c0342951	4,358	wikipedia	https://en.wikipedia.org/wiki/Hypervitaminosis	2021-01-18T18:30:00	{"umls": ["C0342951"], "icd-9": ["278.2", "38.38"], "icd-10": ["E67"], "wikidata": ["Q423927"]}
A number sign (#) is used with this entry because Fanconi anemia of complementation group D2 (FANCD2) is caused by compound heterozygous or homozygous mutation in the FANCD2 gene (613984) on chromosome 3p25. Description Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650. Clinical Features Using complementation assays and immunoblotting, a consortium of American and European groups assigned 29 patients with Fanconi anemia from 23 families and 4 additional unrelated patients to complementation group FA-D2 (Kalb et al., 2007). This amounts to 3 to 6% of FA-affected patients registered in various data sets. Malformations were frequent in FA-D2 patients, and hematologic manifestations appeared earlier and progressed more rapidly when compared with all other patients combined (FA-non-D2) in the International Fanconi Anemia Registry. Biochemical Features Donahue and Campbell (2002) found that fibroblasts from FA patients from complementation groups A, C, D2, and G were hypersensitive to restriction enzyme-induced cell death following electroporation of restriction enzymes. These fibroblasts also showed reduced efficiency in plasmid end-joining activity. Normal sensitivity and activity were restored following retrovirus-mediated expression of the respective FA cDNAs. Molecular Genetics Timmers et al. (2001) identified the D2 complementation group of Fanconi anemia by analysis of cell lines (PD20, VU008, and PD733) from 3 unrelated families with FANCD. Retroviral transduction of the cloned FANCD2 cDNA into FANCD2 cells resulted in functional complementation of mitomycin C sensitivity. The authors found, however, that the gene mutated in the FANCD cell lines HSC62 and VU423 is distinct from FANCD2 and does not map to chromosome 3; they designated this gene FANCD1. Kalb et al. (2007) performed mutation analysis of 33 patients of complementation group FA-D2, which demonstrated the expected number of 66 mutated alleles, 34 of which resulted in aberrant splicing patterns. Many mutations were recurrent and had ethnic associations and shared allelic haplotypes. There were no biallelic null mutations; residual FANCD2 protein of both isotypes was observed in all available patient cell lines. These analyses suggested that, unlike the knockout mouse model, total absence of FANCD2 does not exist in FA-D2 patients, because of constraints on viable combinations of FANCD2 mutations. Although hypomorphic mutations are involved, patients clinically had a relatively severe form of FA. Animal Model Liu et al. (2003) demonstrated that Fancd2-deficient zebrafish embryos developed defects similar to those found in children with FA, including shortened body length, microcephaly, and microphthalmia, which were due to extensive cellular apoptosis. The developmental defects and increased apoptosis could be corrected by injection of human FANCD2 or zebrafish Bcl2 (151430) mRNA, or by knockdown of p53 (191170), indicating that in the absence of Fancd2, developing tissues spontaneously underwent p53-dependent apoptosis. To investigate the in vivo function of the FA pathway, Houghtaling et al. (2003) created mice with a targeted deletion in the distally acting FA gene Fancd2. Similar to human FA patients and other FA mouse models, Fancd2 mutant mice exhibited cellular sensitivity to DNA interstrand crosslinks and germ cell loss. In addition, chromosome mispairing was seen in male meiosis. However, Fancd2 mutant mice also displayed phenotypes not observed in other mice with disruptions of proximal FA genes. These included microphthalmia, perinatal lethality, and epithelial cancers, similar to mice with Brca2/Fancd1 hypomorphic mutations. The phenotypic overlap between Fancd2 null and Brca2/Fancd1 hypomorphic mice was considered consistent with a common function for both proteins in the same pathway, regulating genomic stability. To investigate the role of the FA pathway in repair of DNA double-strand breaks (DSBs), Houghtaling et al. (2005) generated Fancd2-null/Prkdc (600899) (sc/sc) double-mutant mice. Prkdc(sc/sc) mutant mice have a defect in nonhomologous end-joining (NHEJ) and are sensitive to ionizing radiation (IR)-induced DNA damage. Double-mutant animals and primary cells were more sensitive to IR than either single mutant, suggesting that Fancd2 may operate in a DSB repair pathway distinct from NHEJ. Fancd2-null/Prkdc(sc/sc) double-mutant cells were also more sensitive to DSBs generated by a restriction endonuclease. Houghtaling et al. (2005) suggested that the role of Fancd2 in DSB repair may account for the moderate sensitivity of FA cells to irradiation and FA cells sensitivity to interstrand crosslinks that are repaired via a DSB intermediate. INHERITANCE \- Autosomal recessive GROWTH Height \- Small stature Weight \- Low birth weight HEAD & NECK Head \- Microcephaly Ears \- Ear anomaly \- Deafness Eyes \- Strabismus \- Microphthalmia CARDIOVASCULAR Heart \- Congenital heart defect GENITOURINARY External Genitalia (Male) \- Hypergonadotropic hypogonadism \- Cryptorchidism Kidneys \- Absent kidney \- Kidney malformation \- Duplicated kidney \- Duplicated collecting system \- Horseshoe kidney \- Renal ectopia SKELETAL Hands \- Radial aplasia \- Thumb deformity \- Thumb aplasia \- Thumb hypoplasia \- Duplicated thumb SKIN, NAILS, & HAIR Skin \- Anemic pallor \- Bruisability \- Pigmentary changes \- Hyperpigmentation \- Cafe-au-lait spots NEUROLOGIC Central Nervous System \- Mental retardation HEMATOLOGY \- Anemia \- Neutropenia \- Thrombocytopenia \- Reticulocytopenia \- Pancytopenia \- Bleeding NEOPLASIA \- Leukemia LABORATORY ABNORMALITIES \- Multiple chromosomal breaks \- Chromosomal breakage induced by diepoxybutane (DEB), and mitomycin C \- Deficient excision of UV-induced pyrimidine dimers in DNA \- Prolonged G2 phase of cell cycle MOLECULAR BASIS \- Caused by mutation in the Fanconi anemia, complementation group D2 gene (FANCD2, 613984.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	FANCONI ANEMIA, COMPLEMENTATION GROUP D2	c0015625	4,359	omim	https://www.omim.org/entry/227646	2019-09-22T16:27:56	{"doid": ["0111083"], "mesh": ["D005199"], "omim": ["227646"], "orphanet": ["84"], "synonyms": ["Alternative titles", "FAD2", "FANCONI ANEMIA, COMPLEMENTATION GROUP D", "FANCONI PANCYTOPENIA, TYPE 4"], "genereviews": ["NBK1401", "NBK5192"]}
IgG4-related skin disease SpecialtyDermatology IgG4-related skin disease is the recommended name for skin manifestations in IgG4-related disease (IgG4-RD).[1] Multiple different skin manifestations have been described. ## Contents * 1 Classification * 2 See also * 3 References * 4 External links ## Classification[edit] Although a clear understanding of the various skin lesions in IgG4-related disease is a work in progress, skin lesions have been classified into subtypes based on documented cases:[2] * Angiolymphoid hyperplasia with eosinophilia (or lesions that mimic it)[3] and cutaneous pseudolymphoma * Cutaneous plasmacytosis[Note 1] * Eyelid swelling (as part of Mikulicz's disease) * Psoriasis-like eruptions * Unspecified maculopapular or erythematous eruptions * Hypergammaglobulinemic purpura and urticarial vasculitis * Impaired blood supply to fingers or toes, leading to Raynaud's phenomenon or gangrene In addition, Wells syndrome has also been reported in a case of IgG4-related disease.[5] Note: 1. ^ Some do not consider cutaneous plasmacytosis to be a feature of IgG4-related disease for reasons that include: a lack of systemic features, no response to steroid therapy and a different histological pattern.[4] ## See also[edit] * IgG4-related disease ## References[edit] 1. ^ John H. Stone; Arezou Khosroshahi; Vikram Deshpande; John K. C. Chan; J. Godfrey Heathcote; Rob Aalberse; Atsushi Azumi; Donald B. Bloch; William R. Brugge; Mollie N. Carruthers; Wah Cheuk; Lynn Cornell; Carlos Fernandez-Del Castillo; Judith A. Ferry; David Forcione; Günter Klöppe; Daniel L. Hamilos; Terumi Kamisawa; Satomi Kasashima; Shigeyuki Kawa; Mitsuhiro Kawano; Yasufumi Masaki; Kenji Notohara; Kazuichi Okazaki; Ji Kon Ryu; Takako Saeki; Dushyant Sahani; Yasuharu Sato; Thomas Smyrk; James R. Stone; Masayuki Takahira; Hisanori Umehara; George Webster; Motohisa Yamamoto; Eunhee Yi; Tadashi Yoshino; Giuseppe Zamboni; Yoh Zen; Suresh Chari (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. 2. ^ Yoshiki Tokura; Hiroaki Yagi; H. Yanaguchi; Yuta Majima; Akira Kasuya; Taisuke Ito; M Maekawa; Hideo Hashizume (November 2014). "IgG4-related skin disease". British Journal of Dermatology. 171 (5): 959–967. doi:10.1111/bjd.13296. PMID 25065694. 3. ^ Yasuhito Hamaguchi; Manabu Fujimoto; Yukiyo Matsushita; Seiko Kitamura-Sawada; Mitsuhiro Kawano; Kazuhiko Takehara (2011). "IgG4-related skin disease, a mimic of angiolymphoid hyperplasia with eosinophilia". Dermatology. 223 (4): 301–305. doi:10.1159/000335372. PMID 22269779. 4. ^ Angel Fernandez-Flores (2012). "The role of IgG4 in cutaneous pathology" (PDF). Romanian Journal of Morphology and Embryology. 53 (2): 221–231. PMID 22732790. 5. ^ Takashi Karashima; Yoshinori Taniguchi; Tsutomu Shimamoto; Tomoya Nao; Hiroshi Nishikawa; Satoshi Fukata; Masayuki Kamada; Keiji Inoue; Kentaro Oko; Hideki Nakajima; Shigetoshi Sano; Manabu Matsumoto; Naoto Kuroda; Yoshihiro Kamei; Taro Shuin (9 December 2014). "IgG4-related disease of the paratestis in a patient with Wells syndrome: a case report". Diagnostic Pathology. 9: 225. doi:10.1186/s13000-014-0225-5. PMC 4265405. PMID 25487870. ## External links[edit] Classification D [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	IgG4-related skin disease	None	4,360	wikipedia	https://en.wikipedia.org/wiki/IgG4-related_skin_disease	2021-01-18T19:02:17	{"wikidata": ["Q25339485"]}
Non-inflammatory kidney disease Not to be confused with necrosis, nephritis, or nephrotic syndrome. Nephrosis SpecialtyNephrology Nephrosis is any of various forms of kidney disease (nephropathy). In an old and broad sense of the term, it is any nephropathy,[1] but in current usage the term is usually restricted to a narrower sense of nephropathy without inflammation or neoplasia,[2] in which sense it is distinguished from nephritis, which involves inflammation. It is also defined as any purely degenerative disease of the renal tubules.[1] Nephrosis is characterized by a set of signs called the nephrotic syndrome.[2] Nephrosis can be a primary disorder or can be secondary to another disorder.[2] Nephrotic complications of another disorder can coexist with nephritic complications. In other words, nephrosis and nephritis can be pathophysiologically contradistinguished, but that does not mean that they cannot occur simultaneously. Types of nephrosis include amyloid nephrosis and osmotic nephrosis. ## Epidemiology[edit] Disability-adjusted life year for nephritis and nephrosis per 100,000 inhabitants in 2004.[3] no data less than 40 40-120 120-200 200-280 280-360 360-440 440-520 520-600 600-680 680-760 760-840 more than 840 ## References[edit] 1. ^ a b Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier. 2. ^ a b c Nephrosis at the US National Library of Medicine Medical Subject Headings (MeSH) 3. ^ "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved Nov 11, 2009. ## External links[edit] Classification D * MeSH: D009401 * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy This article about a disease of the genitourinary system 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Nephrosis	c0027720	4,361	wikipedia	https://en.wikipedia.org/wiki/Nephrosis	2021-01-18T18:41:03	{"mesh": ["D009401"], "umls": ["C0027720"], "wikidata": ["Q6995207"]}
A number sign (#) is used with this entry because myofibrillar myopathy-5 (MFM5) is caused by heterozygous mutation in the FLNC gene (102565) on chromosome 7q32. For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419). Mutation in the FLNC gene can also cause distal myopathy-4 (MPD4; 614065), which shows a different pattern of muscle involvement and different histologic changes. Clinical Features Vorgerd et al. (2005) reported a German family in which 17 members had adult-onset of slowly progressive skeletal muscle weakness with autosomal dominant inheritance. Although most patients had proximal involvement of the lower limbs with lesser involvement of the upper extremities, 1 patient had distal weakness of the calf muscles only. Initial symptoms included weakness when climbing stairs, waddling gait, and lower back pain. Several patients also had respiratory insufficiency, and 3 patients had evidence of peripheral nerve involvement. Only 1 patient had evidence of cardiac involvement. All patients showed increased serum creatine kinase. Skeletal muscle biopsy showed MFM with amorphous, granular, or hyaline deposits and occasional vacuoles. Other features included internal nuclei, fiber splitting, and necrotic fibers. Oxidative enzymes were decreased. Immunohistochemical analysis showed accumulation of desmin (DES; 125660) and filamin C. Electron microscopy of skeletal muscle biopsy from 1 patient showed Z disc streaming, nemaline rod formation, and intermyofibrillar and subsarcolemmal granulofilamentous protein aggregates. Vorgerd et al. (2005) noted that the features in their family were distinct from those reported by Gamez et al. (2001) (see LGMD1F; 608423). Shatunov et al. (2009) reported a German mother and daughter with adult onset of slowly progressive muscle weakness at ages 60 and 34 years, respectively. Symptoms in the mother began with difficulty climbing stairs and paresis of the pelvic muscles, with proximal upper extremity muscles becoming involved 4 years later. She later had paresis of the neck muscles, muscles surrounding the knees, and distal leg muscles, with hypo- or areflexia. She could not stand or walk on heels or toes, and used a walking frame. The daughter first developed muscle pain increasing with exercise and difficulty climbing stairs. Two years later, she had limb-girdle paresis and hypotrophy of the proximal muscles of the upper limb. Both patients had winging of the scapula and involvement of the paraspinal and abdominal muscles; neither patient had evidence of cardiac or respiratory muscle involvement. Family history indicated that a maternal grandmother, maternal uncle, and a brother had slowly progressive muscle weakness. Skeletal muscle biopsy from the daughter showed marked variation in fiber size and some fibers with internal nuclei. There was type 1 fiber predominance. Several fibers showed polymorphous hyaline and nonhyaline myofibrillary FLNC-positive inclusions with a convoluted, serpentine appearance. Ultrastructural examination showed major myofibrillar abnormalities, with accumulation of Z disc debris, granulofilamentous material, and nemaline rods. There were also mitochondrial aggregates. Chevessier et al. (2015) found that, in addition to protein aggregates, Z-disc lesions similar to those observed in a mouse model of MFM5 (see ANIMAL MODEL) were present in biopsy specimens from patients with different MFM5-associated FLNC mutations. Molecular Genetics In affected members of a German family with autosomal dominant MFM, Vorgerd et al. (2005) identified a heterozygous mutation in the FLNC gene (102565.0001). In a German mother and daughter with adult-onset limb-girdle muscle weakness, Shatunov et al. (2009) identified a heterozygous deletion in the FLNC gene (102565.0002). This family was the only 1 of 127 families with a myopathy examined that was found to have an FLNC mutation, indicating that this subtype of myofibrillar myopathy is rare. Animal Model Chevessier et al. (2015) created knockin mice harboring a W2711X mutation in Flnc corresponding to the W2710X mutation (102565.0001) in human patients with MFM5. Heterozygous knockin mice expressed both wildtype and mutant Flnc alleles at comparable levels. No kyphosis or focal muscle atrophy was observed in mutant mice at any age, but reduced grip strength or muscle weakness was evident beginning at 4 months of age. Histologic analysis of skeletal muscle from sedentary heterozygous knockin mice showed no overt defects up to 8 months of age. However, ultrastructural analysis revealed abnormalities, such as enlarged mitochondria and autophagic vacuoles, in 3-month-old mutant mice. Myofibrillar degeneration in mutant mice started at Z-discs, and myofibrillar lesions were observed. These lesions appeared as electron-dense material between adjacent Z-discs and spanned as little as a single sarcomere or extended across multiple sarcomeres and included several neighboring myofibrils. Similar pathology was also detected in diaphragm and was exacerbated by eccentric exercise. INHERITANCE \- Autosomal dominant RESPIRATORY \- Respiratory insufficiency MUSCLE, SOFT TISSUES \- Muscle weakness, proximal, slowly progressive \- Lower limbs more affected than upper limbs \- Distal muscles may be affected \- Difficulty climbing stairs \- Waddling gait \- Muscle biopsy shows myofibrillar myopathy \- Abnormal muscle fibers with amorphous, granular, or hyaline deposits \- Increased internal nuclei \- Fiber splitting \- Necrotic fibers \- Abnormal aggregates of desmin and filamin C \- Electron microscopy showed Z-disk streaming \- Nemaline rod formation \- Intermyofibrillar and subsarcolemmal granulofilamentous protein aggregates NEUROLOGIC Peripheral Nervous System \- Peripheral nerve involvement may occur LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Adult onset (37 to 57 years) \- Slowly progressive MOLECULAR BASIS \- Caused by mutations in the filamin C gene (FLNC, 102565.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	MYOPATHY, MYOFIBRILLAR, 5	c1836050	4,362	omim	https://www.omim.org/entry/609524	2019-09-22T16:06:00	{"doid": ["0080096"], "mesh": ["C537932"], "omim": ["609524"], "orphanet": ["171445"], "synonyms": ["Alternative titles", "MYOPATHY, MYOFIBRILLAR, FILAMIN C-RELATED", "FILAMINOPATHY, AUTOSOMAL DOMINANT"]}
Pelizaeus-Merzbacher-like disease type 1 is an inherited condition involving the brain and spinal cord (central nervous system). This disease is one of a group of genetic disorders called leukodystrophies. Leukodystrophies are abnormalities of the nervous system's white matter, which consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates nerve fibers and promotes the rapid transmission of nerve impulses. In particular, Pelizaeus-Merzbacher-like disease type 1 involves hypomyelination, which means that the nervous system has a reduced ability to form myelin. The signs and symptoms of this condition are very similar to another leukodystrophy called Pelizaeus-Merzbacher disease, but the two disorders have different genetic causes. Beginning in the first few months of life, infants with Pelizaeus-Merzbacher-like disease type 1 typically experience weak muscle tone (hypotonia), involuntary movements of the eyes (nystagmus), and delayed development of speech and motor skills, such as sitting or grasping objects. As children with Pelizaeus-Merzbacher-like disease type 1 get older, hypotonia changes to muscle stiffness (spasticity). During childhood, individuals with Pelizaeus-Merzbacher-like disease type 1 develop problems with movement and balance (ataxia), difficulty with movements that involve judging distance or scale (dysmetria), tremors that occur mainly during movement (intention tremors), and head and neck tremors (titubation). People with this condition have an inability to perform quick, alternating movements (dysdiadochokinesia), such as quickly tapping different fingers. Some develop involuntary tensing of the muscles (dystonia) and jerking (choreiform) movements. Many people with Pelizaeus-Merzbacher-like disease type 1 develop skeletal issues such as an abnormal curvature of the spine (scoliosis) and require wheelchair assistance from childhood. Muscle abnormalities can lead to difficulty swallowing and problems producing speech (expressive language), but affected individuals can understand speech (receptive language). Most individuals with Pelizaeus-Merzbacher-like disease type 1 have normal intelligence. Rarely, hearing loss, optic atrophy, and recurrent seizures (epilepsy) can occur. ## Frequency The prevalence of Pelizaeus-Merzbacher-like disease type 1 is unknown, but it is thought to be rare. ## Causes Pelizaeus-Merzbacher-like disease type 1 is caused by mutations in the GJC2 gene. This gene provides instructions for making a protein called connexin-47. This protein plays a role in forming channels called gap junctions between cells. Gap junctions made with connexin-47 facilitate communication between nervous system cells called oligodendrocytes or between oligodendrocytes and another type of nervous system cell called astrocytes. Communication between these cells is necessary for the formation of myelin. GJC2 gene mutations that cause Pelizaeus-Merzbacher-like disease type 1 reduce the production of connexin-47, prevent the connexin-47 protein from reaching the cell membrane, or decrease the function of the protein in the gap junction. All of these GJC2 gene mutations disrupt the communication between nerve cells that normally occurs at gap junctions and impair myelin formation. These changes lead to nerve damage in the brain and spinal cord that impairs nervous system function, resulting in the signs and symptoms of Pelizaeus-Merzbacher-like disease type 1. ### Learn more about the gene associated with Pelizaeus-Merzbacher-like disease type 1 * GJC2 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Pelizaeus-Merzbacher-like disease type 1	c1837355	4,363	medlineplus	https://medlineplus.gov/genetics/condition/pelizaeus-merzbacher-like-disease-type-1/	2021-01-27T08:24:50	{"gard": ["12300"], "mesh": ["C563855"], "omim": ["608804"], "synonyms": []}
For other uses, see Tetrasomy (disambiguation). Tetrasomy SpecialtyMedical genetics A tetrasomy is a form of aneuploidy with the presence of four copies, instead of the normal two, of a particular chromosome. ## Contents * 1 Causes * 1.1 Full * 1.2 Autosomal tetrasomies * 1.3 Sex-chromosome tetrasomies * 2 External links ## Causes[edit] ### Full[edit] Full tetrasomy of an individual occurs due to non-disjunction when the cells are dividing (meiosis I or II) to form egg and sperm cells (gametogenesis). This can result in extra chromosomes in a sperm or egg cell. After fertilization, the resulting fetus has 48 chromosomes instead of the typical 46. ### Autosomal tetrasomies[edit] * Cat eye syndrome where partial tetrasomy of chromosome 22 is present * Pallister-Killian syndrome (tetrasomy 12p) * Tetrasomy 9p * Tetrasomy 18p * Tetrasomy 21, a rare form of Down syndrome ### Sex-chromosome tetrasomies[edit] * 48, XXXX syndrome * 48, XXYY syndrome * Klinefelter's syndrome, where XXY tetrasomy is present ## External links[edit] Classification D * ICD-10: Q97 \- Q98 * MeSH: D000782 External resources * Orphanet: 3305 * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Tetrasomy	c2936486	4,364	wikipedia	https://en.wikipedia.org/wiki/Tetrasomy	2021-01-18T18:32:06	{"mesh": ["D058670"], "icd-10": ["Q97", "Q98"], "wikidata": ["Q906664"]}
Actinic elastosis Other namesSolar elastosis Micrograph showing solar elastosis - grey, jumbled spaghetti-like material on bottom of image. H&E stain. SpecialtyDermatology Solar elastosis separates from the epidermis by a narrow band of normal-appearing collagen (grenz zone) with collagen fibers arranged horizontally.[1] Actinic elastosis, also known as solar elastosis, is an accumulation of abnormal elastin (elastic tissue) in the dermis of the skin,[2] or in the conjunctiva of the eye,[3] which occurs as a result of the cumulative effects of prolonged and excessive sun exposure, a process known as photoaging. ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] Actinic elastosis usually appears as thickened, dry, wrinkled skin. Several clinical variants have been recorded. One of the most readily identifiable is the thickened, deeply fissured skin seen on the back of the chronically sun-exposed neck, known as cutis rhomboidalis nuchae.[2] These features are a part of the constellation of changes that are seen in photoaged skin.[2] ## Causes[edit] The origin of the elastotic material in the dermis remains a subject of debate. Theories on the formation of the elastotic material include actinic stimulation of fibroblasts, promoting synthesis of this material, or that the material is a degradation product of collagen, elastin, or both.[2] ## Diagnosis[edit] In the earlier stages of actinic elastosis, elastic fiber proliferation can be seen in the dermis. As the condition becomes more established, the collagen fibers of the papillary dermis and reticular dermis become increasingly replaced by thickened and curled fibers that form tangled masses and appear basophilic under routine haematoxylin and eosin staining. These fibers stain black with the Verhoeff stain.[2] ## Treatment[edit] Numerous treatment options are available for photoaged skin, including dermabrasion, topical application of retinoic acid, carbon dioxide laser resurfacing, hyaluronic acid injection into the dermis, imiquimod, tacrolimus ointment, and topical oestrogen therapy. These treatments have variable efficacy.[2] The most effective prevention strategy for photoaging remains minimization of sun exposure, through use of sunscreen and other sun exposure avoidance measures.[2] ## References[edit] 1. ^ Kim, Miri; Park, Hyun Jeong (2016). "Molecular Mechanisms of Skin Aging and Rejuvenation". Molecular Mechanisms of the Aging Process and Rejuvenation. InTech Open. doi:10.5772/62983. ISBN 978-953-51-2568-6. 2. ^ a b c d e f g Weedon, David (2010). Weedon's Skin Pathology, 3rd Edition. Elsevier. ISBN 978-0-7020-3485-5. 3. ^ Klintworth, G; Cummings, T (2009-08-26). "24; The eye and ocular adnexa". In Stacey, Mills (ed.). Sternberg's Diagnostic Surgical Pathology (5 ed.). ISBN 978-0-7817-7942-5. ## External links[edit] Classification D * ICD-10: L57.8 (ILDS L57.890) * Picture of solar elastosis at DermIS.net * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Dermatitis and eczema Atopic dermatitis * Besnier's prurigo Seborrheic dermatitis * Pityriasis simplex capillitii * Cradle cap Contact dermatitis (allergic, irritant) * plants: Urushiol-induced contact dermatitis * African blackwood dermatitis * Tulip fingers * other: Abietic acid dermatitis * Diaper rash * Airbag dermatitis * Baboon syndrome * Contact stomatitis * Protein contact dermatitis Eczema * Autoimmune estrogen dermatitis * Autoimmune progesterone dermatitis * Breast eczema * Ear eczema * Eyelid dermatitis * Topical steroid addiction * Hand eczema * Chronic vesiculobullous hand eczema * Hyperkeratotic hand dermatitis * Autosensitization dermatitis/Id reaction * Candidid * Dermatophytid * Molluscum dermatitis * Circumostomy eczema * Dyshidrosis * Juvenile plantar dermatosis * Nummular eczema * Nutritional deficiency eczema * Sulzberger–Garbe syndrome * Xerotic eczema Pruritus/Itch/ Prurigo * Lichen simplex chronicus/Prurigo nodularis * by location: Pruritus ani * Pruritus scroti * Pruritus vulvae * Scalp pruritus * Drug-induced pruritus * Hydroxyethyl starch-induced pruritus * Senile pruritus * Aquagenic pruritus * Aquadynia * Adult blaschkitis * due to liver disease * Biliary pruritus * Cholestatic pruritus * Prion pruritus * Prurigo pigmentosa * Prurigo simplex * Puncta pruritica * Uremic pruritus Other * substances taken internally: Bromoderma * Fixed drug reaction * Nummular dermatitis * Pityriasis alba * Papuloerythroderma of Ofuji [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Actinic elastosis	c0263415	4,365	wikipedia	https://en.wikipedia.org/wiki/Actinic_elastosis	2021-01-18T18:59:05	{"icd-10": ["L57.8"], "wikidata": ["Q4676883"]}
Pulmonary alveolar microlithiasis is a disorder in which tiny fragments (microliths) of calcium phosphate gradually accumulate in the small air sacs (alveoli) of the lungs. These deposits eventually cause widespread damage to the alveoli and surrounding lung tissue (interstitial lung disease). People with this disorder may also develop a persistent cough and difficulty breathing (dyspnea), especially during physical exertion. Chest pain that worsens when coughing, sneezing, or taking deep breaths is another common feature. People with pulmonary alveolar microlithiasis may also develop calcium phosphate deposits in other organs and tissue of the body. Though the course of the disease can be variable, many cases slowly progress to lung fibrosis, respiratory failure, or cor pulmonale. The only effective therapy is lung transplantation. In some cases, pulmonary alveolar microlithiasis is caused by mutations in the SLC34A2 gene and inherited in an autosomal recessive manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Pulmonary alveolar microlithiasis	c0155912	4,366	gard	https://rarediseases.info.nih.gov/diseases/11894/pulmonary-alveolar-microlithiasis	2021-01-18T17:58:04	{"mesh": ["C562405"], "omim": ["265100"], "orphanet": ["60025"], "synonyms": []}
A teratogenic embryofetopathy that results from maternal exposition to methimazole (MMI; or the parent compound carbimazole) in the first trimester of pregnancy. MMI is an antithyroid thionamide drug used for the treatment of Graves' disease. In the infant, MMI may result in choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, congenital heart disease (such as ventricular septal defect), renal system malformations and aplasia cutis. Additional features that may be observed include facial dysmorphism (short upslanting palpebral fissures, a broad nasal bridge with a small nose and a broad forehead) and athelia/hypothelia. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Methimazole embryofetopathy	c4510379	4,367	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1923	2021-01-23T17:36:02	{"gard": ["3573"], "icd-10": ["Q86.8"], "synonyms": ["MMI/CMZ embryofetopathy", "MMI/CMZ embryopathy", "Methimazole/carbimazole embryofetopathy", "Methimazole/carbimazole embryopathy"]}
A number sign (#) is used with this entry because of evidence that occipital cortical malformations are caused by homozygous or compound heterozygous mutations in the LAMC3 gene (604349) on chromosome 9q34. Description Occipital cortical malformations (OCCM) is an autosomal recessive condition in which affected individuals develop seizures, sometimes associated with transient visual changes. Brain MRI shows both pachygyria and polymicrogyria restricted to the lateral occipital lobes (summary by Barak et al., 2011). Clinical Features Barak et al. (2011) reported 3 unrelated girls, all born of consanguineous Turkish parents, with seizures associated with occipital cortical malformations. The first girl presented at age 2 years with seizures involving loss of neck tone and consciousness. At age 3, she had decreased visual acuity and mild delayed psychomotor development associated with EEG abnormalities suggestive of absence seizures. Brain MRI showed bilateral occipital pachygyria at the lateral surfaces with smoothing of the cortices, and polymicrogyria with numerous small gyri at the junction of the parietooccipital lobes. There was loss of a clear distinction between the gray and white matter. The second woman presented at age 10 years with staring and blinking spells. She had seizures associated with loss of vision at age 14, and developed generalized tonic-clonic seizures at age 18. At age 33, she had normal visual acuity and normal intelligence. Brain MRI showed bilateral smoothing and thickening of the lateral occipital cortex, consistent with pachygyria, as well as polymicrogyria. Functional MRI showed that the location and function of her primary visual areas were similar to those of controls, although there was some evidence of microstructural changes, perhaps due to fiber disorganization. The third patient was a 16-year-old girl who developed seizures associated with visual loss and deviating eyes at age 11. She was otherwise normal. Imaging studies again showed bilateral occipital pachygyria associated with polymicrogyria. Inheritance Occipital cortical malformations were transmitted as an autosomal recessive trait in the families reported by Barak et al. (2011). Molecular Genetics In a Turkish girl with seizures and occipital cortical malformations on brain imaging, Barak et al. (2011) identified a homozygous deletion in the LAMC3 gene (604349.0001). The mutation was identified by exome sequencing. Two additional girls with a similar phenotype were also found to have biallelic mutations in the LAMC3 gene (604349.0002-604349.0004). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Vision loss, episodic \- Diminished visual acuity (1 patient) \- Strabismus, transient (1 patient) NEUROLOGIC Central Nervous System \- Seizures, absence \- Seizures, tonic-clonic (1 patient) \- Delayed psychomotor development (1 patient) \- Autonomic symptoms \- Pachygyria, occipital \- Polymicrogyria, occipital \- EEG abnormalities MISCELLANEOUS \- Three unrelated girls have been reported (as of July 2011) \- Onset of seizures ranges from 2 to 11 years MOLECULAR BASIS \- Caused by mutation in the laminin, gamma-3 gene (LAMC3, 604349.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	CORTICAL MALFORMATIONS, OCCIPITAL	c3279875	4,368	omim	https://www.omim.org/entry/614115	2019-09-22T15:56:27	{"omim": ["614115"], "orphanet": ["280640"], "synonyms": ["Occipital MCD", "Occipital malformations of cortical development"]}
## Description Hypoglossia-hypodactyly syndrome is characterized by a hypoplastic mandible, absence of the lower incisors, hypoglossia, and a variable degree of absence of the digits and limbs. Intelligence is normal (Hall, 1971). Hall (1971) classified what he termed the 'syndromes of oromandibular and limb hypogenesis,' which comprised a range of disorders with hypoglossia in common. Type I included hypoglossia and aglossia in isolation. Type II included hypoglossia with hypomelia/hypodactylia. Type III included glossopalatine ankylosis with hypoglossia or hypoglossia and hypomelia/hypodactyly. Type IV included intraoral bands with fusion with hypoglossia or hypoglossia and hypomelia/hypodactyly. Type V included several syndromes, such as Hanhart syndrome, Pierre Robin syndrome (261800), Moebius syndrome (157900), and amniotic band syndrome (217100). Hall (1971) noted that complete aglossia or adactylia had not been reported, and suggested that 'hypoglossia-hypodactylia' is a more accurate term. See also hypoglossia and situs inversus (612776). Clinical Features Hanhart (1950) described 3 cases of the same disorder; 2 patients were related and, in the third, the parents were consanguineous. Features included peromelia and micrognathia. In Turkey, Tuncbilek et al. (1977) observed 3 sporadic cases, each with consanguineous parents, and espoused autosomal recessive inheritance. However, general consanguinity rate may be high in the population in question. Epicanthus was a feature in a patient reported by Shokeir (1978). Robinow et al. (1978) observed discordant monozygotic twins; it is noteworthy, although perhaps coincidental, that the parents were second cousins. They also described a case with associated 'apple peel' bowel (243600), which is thought to arise through obliteration of the superior mesenteric artery. This suggested to them that the aglossia-adactylia syndrome might likewise be the result of vascular occlusion, as in the embryopathy experimentally induced by Jost and Poswillo. Opitz (1982) concluded that the disorder is a nonmendelian developmental disturbance. Buttiens and Fryns (1986) described Hanhart syndrome in brother and sister. These persons had retrognathia, microstomia, and symmetric severe limb reduction defects, but normal tongue. Thus, it is arguable whether it should be called Hanhart syndrome. Chandra Sekhar et al. (1987) reported with photographs 2 remarkable cases in which micrognathia was extreme. One patient was a male who died in the neonatal period. Structural abnormalities of the middle ear were described. The second case was a 14-year-old boy with bilateral conductive hearing loss and bilateral absent thumbs. Robertson and Bankier (1999) described an intellectually normal 20-year-old man with severe manifestations of the Hanhart syndrome. He was born to nonconsanguineous parents with no history of exposure to teratogens. Three other sibs were normal. He was 150 cm tall and his head circumference was 53 cm. An extreme degree of micrognathia was present with almost no mandible evident. The tongue was very small with greatly reduced mobility. Upper limb anomalies included right synbrachydactyly of digits 1-2-3 and on the left a terminal transverse defect of the wrist. There was a transverse defect at the level of the left knee for which a prosthesis had been fitted. The right foot had 3 digits. De Smet and Schollen (2001) described 2 newborns with severe limb deformities and hypoglossia, with micro- and retrognathia. One patient had a transverse agenesia just below the knee in both legs and below the elbow of both arms. The second child had less severe deformities. The authors provided a discussion of the classification of these disorders. Camera et al. (2003) described a boy with oromandibular limb hypogenesis and radiologic demonstration of 'angel-shaped phalanx' (105835). Dogan et al. (2010) reported a Turkish infant, born of unrelated and healthy parents, with Hanhart syndrome. He had a small tongue, micrognathia, and bilateral complete absence of the hands and feet. Radiographs showed absence of the carpal and metacarpal bones, mesomelia of the left tibia, absence of the right tibia, and a rudimentary right tarsal bone. The patient died of pneumonia at age 9 months. Dogan et al. (2010) noted that all reported cases had occurred sporadically. INHERITANCE \- Isolated cases HEAD & NECK Face \- Micrognathia \- Retrognathia Eyes \- Epicanthus Mouth \- Hypoglossia \- Microstomia Teeth \- Absence of lower incisors SKELETAL Limbs \- Limb hypoplasia Hands \- Adactylia \- Hypodactyly \- Ectrodactyly Feet \- Adactylia \- Hypodactyly \- Ectrodactyly ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	HYPOGLOSSIA-HYPODACTYLIA	c1863203	4,369	omim	https://www.omim.org/entry/103300	2019-09-22T15:41:23	{"mesh": ["C566308"], "omim": ["103300"], "orphanet": ["989"], "synonyms": ["Alternative titles", "PEROMELIA WITH MICROGNATHISM", "OROMANDIBULAR LIMB HYPOPLASIA", "AGLOSSIA-ADACTYLIA"]}
Prelabor rupture of membranes Other namesPremature rupture of membranes Positive fern test with amniotic fluid as seen under the microscope SpecialtyObstetrics SymptomsPainless gush or a steady leakage of fluid from the vagina[1] ComplicationsBaby: Premature birth, cord compression, infection[2][1] Mother: Placental abruption, postpartum endometritis[2] TypesTerm, preterm[2] Risk factorsInfection of the amniotic fluid, prior PROM, bleeding in the later parts of pregnancy, smoking, a mother who is underweight[2] Diagnostic methodSuspected based on symptoms and examination, supported by testing the fluid or ultrasound[2] Differential diagnosisUrinary incontinence, bacterial vaginosis[3] TreatmentBased on how far along a woman is in pregnancy and whether complications are present[2] Frequency~8% of term pregnancies,[2] ~30% of preterm pregnancies[4] Prelabor rupture of membranes (PROM), previously known as premature rupture of membranes, is breakage of the amniotic sac before the onset of labor.[2] Women usually experience a painless gush or a steady leakage of fluid from the vagina.[1] Complications in the baby may include premature birth, cord compression, and infection.[2][1] Complications in the mother may include placental abruption and postpartum endometritis.[2] Risk factors include infection of the amniotic fluid, prior PROM, bleeding in the later parts of pregnancy, smoking, and a mother who is underweight.[2] Diagnosis is suspected based on symptoms and speculum exam and may be supported by testing the vaginal fluid or by ultrasound.[2] If it occurs before 37 weeks it is known as PPROM (‘preterm’ prelabour rupture of membranes) otherwise it is known as term PROM.[2] Treatment is based on how far along a woman is in pregnancy and whether complications are present.[2] In those at or near term without any complications, induction of labor is generally recommended.[2] Time may also be provided for labor to begin spontaneously.[1][2] In those 24 to 34 weeks of gestation without complications corticosteroids and close observation is recommended.[2] A 2017 Cochrane review found waiting generally resulted in better outcomes in those before 37 weeks.[5] Antibiotics may be given for those at risk of Group B streptococcus.[2] Delivery is generally indicated in those with complications, regardless of how far along in pregnancy.[2] About 8% of term pregnancies are complicated by PROM while about 30% of preterm births are complicated by PROM.[2][4][6] Before 24 weeks PROM occurs in fewer than 1% of pregnancies.[2] Prognosis is primarily determined by complications related to prematurity such as necrotizing enterocolitis, intraventricular hemorrhage, and cerebral palsy.[2][7] ## Contents * 1 Signs and symptoms * 2 Risk factors * 3 Pathophysiology * 3.1 Weak membranes * 3.2 Infection * 3.3 Genetics * 4 Diagnosis * 4.1 Classification * 4.2 Additional tests * 4.3 False positives * 4.4 Differential diagnosis * 5 Prevention * 6 Management * 6.1 Term * 6.2 34 to 37 weeks * 6.3 24 to 34 weeks * 6.3.1 Recommended * 6.3.2 Controversial or not recommended * 6.4 Before 24 weeks * 6.5 Chorioamnionitis * 7 Outcomes * 7.1 Infection (any age) * 7.2 Pre-term birth (before 37 weeks) * 7.3 Fetal development (before 24 weeks) * 7.4 PROM after second-trimester amniocentesis * 8 Epidemiology * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] Most women will experience a painless leakage of fluid out of the vagina. They may notice either a distinct "gush" or a steady flow of small amounts of watery fluid in the absence of steady uterine contractions.[8] Loss of fluid may be associated with the baby becoming easier to feel through the belly (due to the loss of the surrounding fluid), decreased uterine size, or meconium (fetal stool) seen in the fluid.[9] ## Risk factors[edit] A fetus surrounded by the amniotic sac which is enclosed by fetal membranes. In PROM, these membranes rupture before labor starts. The cause of PROM is not clearly understood, but the following are risk factors that increase the chance of it occurring. In many cases, however, no risk factor is identified.[10] * Infections: urinary tract infection, sexually transmitted diseases, lower genital tract infections (e.g. bacterial vaginosis),[8] infections within the amniotic sac membranes (chorioamnionitis)[11] * Tobacco use during pregnancy[10] * Illicit drug use during pregnancy[11] * Having had PROM or preterm delivery in previous pregnancies[8] * Polyhydramnios: too much amniotic fluid [9] * Multiple gestation: being pregnant with two or more fetuses at one time[8] * Having had episodes of bleeding anytime during the pregnancy[8] * Invasive procedures (e.g. amniocentesis)[9] * Nutritional deficits[10] * Cervical insufficiency: having a short or prematurely dilated cervix during pregnancy[9] * Low socioeconomic status[10] * Being underweight[10] ## Pathophysiology[edit] 10-week-old human embryo surrounded by amniotic fluid and fetal membranes ### Weak membranes[edit] Fetal membranes likely break because they become weak and fragile. This weakening is a normal process that typically happens at term as the body prepares for labor and delivery. However, this can be a problem when it occurs before 37 weeks (preterm). The natural weakening of fetal membranes is thought to be due to one or a combination of the following. In PROM, these processes are activated too early:[citation needed] * Cell death: when cells undergo programmed cell death, they release biochemical markers that are detected in higher concentrations in cases of PPROM. * Poor assembly of collagen: collagen is a molecule that gives fetal membranes, as well as other parts of the human body such as the skin, their strength. In cases of PPROM, proteins that bind and cross-link collagen to increase its tensile strength are altered. * Breakdown of collagen: collagen is broken down by enzymes called matrix metalloproteinases (MMPs), which are found at higher levels in PPROM amniotic fluid. This breakdown results in prostaglandin production which stimulates uterine contractions and cervical ripening. MMPs are inhibited by tissue inhibitors of matrix metalloproteinases (TIMPs) which are found at lower levels in PPROM amniotic fluid.[10] ### Infection[edit] Infection and inflammation likely explains why membranes break earlier than they are supposed to. In studies, bacteria have been found in the amniotic fluid from about one-third of cases of PROM. Often, testing of the amniotic fluid is normal, but a subclinical infection (too small to detect) or infection of maternal tissues adjacent to the amniotic fluid, may still be a contributing factor. In response to infection, the resultant infection and release of chemicals (cytokines) subsequently weakens the fetal membranes and put them at risk for rupture.[10] PROM is also a risk factor in the development of neonatal infections.[citation needed] ### Genetics[edit] Many genes play a role in inflammation and collagen production, therefore inherited genes may play a role in predisposing a person to PROM.[10] ## Diagnosis[edit] To confirm if a woman has experienced PROM, a clinician must prove that the fluid leaking from the vagina is amniotic fluid, and that labor has not yet started. To do this, a careful medical history is taken, a gynecological exam is conducted using a sterile speculum, and an ultrasound of the uterus is performed.[9] * History: a person with PROM typically recalls a sudden "gush" of fluid loss from the vagina, or steady loss of small amounts of fluid.[9] * Sterile speculum exam: a clinician will insert a sterile speculum into the vagina in order to see inside and perform the following evaluations. Digital cervical exams, in which gloved fingers are inserted into the vagina to measure the cervix, are avoided until the women is in active labor to reduce the risk of infection.[12] * Pooling test: Pooling is when a collection of amniotic fluid can be seen in the back of the vagina (vaginal fornix). Sometimes leakage of fluid from the cervical opening can be seen when the person coughs or performs a valsalva maneuver.[9] * Nitrazine test: A sterile cotton swab is used to collect fluid from the vagina and place it on nitrazine (phenaphthazine) paper. Amniotic fluid is mildly basic (pH 7.1–7.3) compared to normal vaginal secretions which are acidic (pH 4.5–6).[10] Basic fluid, like amniotic fluid, will turn the nitrazine paper from orange to dark blue.[9] * Fern test: A sterile cotton swab is used to collect fluid from the vagina and place it on a microscope slide. After drying, amniotic fluid will form a crystallization pattern called arborization[11] which resembles leaves of a fern plant when viewed under a microscope.[8] * Fibronectin and alpha-fetoprotein blood tests ### Classification[edit] * Prelabor rupture of membranes (PROM): when the fetal membranes rupture early, at least one hour before labor has started.[8] * Prolonged PROM: a case of prelabor rupture of membranes in which more than 18 hours has passed between the rupture and the onset of labor.[13] * Preterm prelabor rupture of membranes (PPROM): prelabor rupture of membranes that occurs before 37 weeks gestation. * Midtrimester PPROM or pre-viable PPROM: prelabor rupture of membranes that occurs before 24 weeks' gestation. Before this age, the fetus cannot survive outside of the mother's womb.[12] ### Additional tests[edit] The following tests should only be used if the diagnosis is still unclear after the standard tests above. * Ultrasound: Ultrasound can measure the amount of fluid still in the uterus surrounding the fetus. If the fluid levels are low, PROM is more likely.[8] This is helpful in cases when the diagnosis is not certain, but is not, by itself, definitive.[11] * Immune-chromatological tests are helpful, if negative, to rule out PROM, but are not that helpful if positive since the false-positive rate is relatively high (19–30%).[11] * Indigo carmine dye test: a needle is used to inject indigo carmine dye (blue) into the amniotic fluid that remains in the uterus through the abdominal wall. In the case of PROM, blue dye can be seen on a stained tampon or pad after about 15–30 minutes.[9] This method can be used to definitively make a diagnosis, but is rarely done because it is invasive and increases risk of infection. But, can be helpful if the diagnosis is still unclear after the above evaluations have been done.[9] It is unclear if different methods of assessing the fetus in a woman with PPROM affects outcomes.[14] ### False positives[edit] Like amniotic fluid, blood, semen, vaginal secretions in the presence of infection,[9] soap,[10] urine, and cervical mucus[8] also have an alkaline pH and can also turn nitrazine paper blue.[9] Cervical mucus can also make a pattern similar to ferning on a microscope slide, but it is usually patchy[9] and with less branching.[8] ### Differential diagnosis[edit] Other conditions that may present similarly to premature rupture of membranes are the following:[8] * Urinary incontinence: leakage of small amounts of urine is common in the last part of pregnancy * Normal vaginal secretions of pregnancy * Increased sweat or moisture around the perineum * Increased cervical discharge: this can happen when there is a genital tract infection * Semen * Douching * Vesicovaginal fistula: an abnormal connection between the bladder and the vagina * Loss of the mucus plug ## Prevention[edit] Women who have had PROM are more likely to experience it in future pregnancies.[11] There is not enough data to recommend a way to specifically prevent future PROM. However, any woman that has had a history of preterm delivery, because of PROM or not, is recommended to take progesterone supplementation to prevent recurrence.[11][9] ## Management[edit] Summary[11] Fetal age Management Term > 37 weeks * Induction of labor * Antibiotics if needed to prevent group B streptococcus (GBS) transmission Late pre-term 34–36 weeks * Same as for term Preterm 24–33 weeks * * Watchful waiting (expectant management) * Tocolytics to prevent the beginning of labor * Magnesium sulfate infusion for 24–48 hours to allow maximum efficacy of corticosteroids for fetal lungs and also confer benefit to fetal brain and gut before delivery * One time dose of corticosteroids (two separate administrations, 12–24 hours apart) before 34 weeks * Antibiotics if needed to prevent GBS transmission Pre-viable < 24 weeks * Discussion of watchful waiting or induction of labor * No antibiotics, corticosteroids, tocolysis, or magnesium sulfate The management of PROM remains controversial, and depends largely on the gestational age of the fetus and other complicating factors. The risks of quick delivery (induction of labor) vs. watchful waiting in each case is carefully considered before deciding on a course of action.[11] As of 2012, the Royal College of Obstetricians and Gynaecologists advised, based on expert opinion and not clinical evidence, that attempted delivery during maternal instability increases the rates of both fetal death and maternal death, unless the source of instability is an intrauterine infection.[15] In all women with PROM, the age of the fetus, its position in the uterus, and its well being should be evaluated. This can be done with ultrasound, Doppler fetal heart rate monitoring, and uterine activity monitoring. This will also show whether or not uterine contractions are happening which may be a sign that labor is starting. Signs and symptoms of infection should be closely monitored, and, if not already done, a group B streptococcus (GBS) culture should be collected.[citation needed] At any age, if the fetal well-being appears to be compromised, or if intrauterine infection is suspected, the baby should be delivered quickly by induction of labour.[11][12] ### Term[edit] Both expectant management (watchful waiting) and an induction of labor (artificially stimulating labor) are considered in this case. 90% of women start labor on their own within 24 hours, and therefore it is reasonable to wait for 12–24 hours as long as there is no risk of infection.[12] However, if labor does not begin soon after the PROM, an induction of labor is recommended because it reduces rates of infections, decreases the chances that the baby will require a stay in the neonatal intensive care unit (NICU), and does not increase the rate of caesarean sections.[11] If a woman strongly does not want to be induced, watchful waiting is an acceptable option as long as there is no sign of infection, the fetus is not in distress, and she is aware and accepts the risks of PPROM.[11] There is not enough data to show that the use of prophylactic antibiotics (to prevent infection) is beneficial for mothers or babies at or near term because of the potential side effects and development of antibiotic resistance.[16] ### 34 to 37 weeks[edit] When the fetus is 34 to 37 weeks gestation, the risk of being born prematurely must be weighed against the risk of PROM. Previously it was recommended that delivery be carried out as if the baby was term.[11][8] A 2017 Cochrane review however found waiting resulted in better outcomes when pregnancy is before 37 weeks.[5] ### 24 to 34 weeks[edit] Before 34 weeks, the fetus is at a much higher risk of the complications of prematurity. Therefore, as long as the fetus is doing well, and there are no signs of infection or placental abruption, watchful waiting (expectant management) is recommended.[11] The younger the fetus, the longer it takes for labor to start on its own,[9] but most women will deliver within a week.[10] Waiting usually requires a woman to stay in the hospital so that health care providers can watch her carefully for infection, placental abruption, umbilical cord compression, or any other fetal emergency that would require quick delivery by induction of labor.[11] In 2017, a review of watchful waiting vs the early birth strategy was conducted to ascertain which was associated with a lower overall risk. Focusing on the 24–37-week range, the review analysed twelve randomised controlled trials from the "Cochrane Pregnancy and Childbirth's Trials Register", concluding that "In women with PPROM before 37 weeks' gestation with no contraindications to continuing the pregnancy, a policy of expectant management with careful monitoring was associated with better outcomes for the mother and baby."[5] There is believed to be a correlation between volume of amniotic fluid retained and neonatal outcomes before 26 weeks' gestation.[10] Amniotic fluid levels are an important consideration when debating expectant management vs clinical intervention, as low levels, or oligohydramnios, can result in lung and limb abnormalities.[10] Additionally, labor and infection are less likely to occur when there are sufficient levels of amniotic fluid remaining in the uterus.[8] Serial amnioinfusion in pregnancies with PPROM-related oligohydramnios at less than 26 weeks gestation, successfully alleviates oligohydramnios, with perinatal outcomes that are significantly better than the outcome in those with the persistent condition and is comparable with gestations with PPROM in which oligohydramnios never develops.[17] #### Recommended[edit] * Monitoring for infection: signs of infection include a fever in the mother, fetal tachycardia (fast heart rate of the fetus, more than160 beats per minute), or tachycardia in the mother (more than 100 beats per minute). White blood cell (WBC) counts are not helpful in this case because WBC's are normally high in late pregnancy.[11] * Steroids before birth: corticosteroids (betamethasone) given to the mother of a baby at risk of being born prematurely can speed up fetal lung development and reduce the risk of death of the infant, respiratory distress syndrome, brain bleeds, and bowel necrosis.[11] It is recommended that mothers receive one course of corticosteroids between 24 and 34 weeks when there is a risk of preterm delivery. In cases of PPROM these medications do not increase the risk of infection even though steroids are known to suppress the immune system. More than two courses is not recommended because three or more can lead to small birth weight and small head circumference.[11] In pregnancies between 32 and 34 weeks (right around the time that fetal lungs mature) vaginal fluid can be tested to determine fetal lung maturity using chemical markers which can help to decide if corticosteroids should be given.[9] * Magnesium sulfate: Intravenous magnesium sulfate is given to the mother in cases when there is a risk of preterm birth before 32 weeks. This has been shown to protect the fetal brain and reduce the risk of cerebral palsy.[11] * Latency antibiotics: The time from PROM to labor is termed the latency period, and there is an inverse relationship between gestational age and the length of latency, meaning that the earlier the rupture, the longer it will take for labor to begin naturally.[8] As expected, antibiotics given to mothers that experience PPROM serve to protect against infections during this lengthened latency period. Additionally, antibiotics increase the time that babies stay in the womb. Antibiotics don't seem to prevent death or make a difference in the long-term (years after the baby is born). But, because of the short-term benefits, routine use of antibiotics in PPROM is still recommended.[18] The American Congress of Obstetricians and Gynecologists (ACOG) recommends a seven-day course of intravenous ampicillin and erythromycin followed by oral amoxicillin and erythromycin if watchful waiting is attempted before 34 weeks.[11] Amoxicillin/clavulanic acid increases the risk of fetal bowel death (necrotizing enterocolitis) and should be avoided in pregnancy.[11] * Prophylactic antibiotics: If a woman is colonized with GBS, than the typical use of antibiotics during labor is recommended to prevent transmission of this bacteria to the fetus, regardless of earlier treatments.[11] #### Controversial or not recommended[edit] * Preventative tocolysis (medications to prevent contractions): the use of tocolytic medications to prevent labor contractions is controversial. On the one hand, this can delay delivery and allow the fetus more time to develop and benefit from antenatal corticosteroid medication, on the other hand it increases the risk of infection or chorioamnionitis. The use of tocolysis has not shown to benefit mom or baby and currently there is not enough data to recommend or discourage its use in the case of preterm PROM.[11][19] * Therapeutic tocolysis (medications to stop contractions): Once labor has started, using tocolysis to stop labor has not been shown to help, and is not recommended.[11] * Amnioinfusion: This treatment attempts to replace the lost amniotic fluid from the uterus by infusing normal saline fluid into the uterine cavity. This can be done through the vagina and cervix (transcervical amnioinfusion) or by passing a needle through the abdominal wall (transabdominal amnioinfusion). Current data suggests that this treatment prevents infection, lung problems, and fetal death. However, there have not been enough trials to recommend its routine use in all cases of PPROM.[20] * Home care: Typically women with PPROM are managed in the hospital, but, occasionally they opt to go home if watchful waiting is attempted. Since labor usually starts soon after PPROM, and infection, umbilical cord compression, and other fetal emergencies can happen very suddenly, it is recommended that women stay in the hospital in cases of PPROM after 24 weeks.[11] Currently, there is not enough evidence to determine meaningful differences in safety, cost, and women's views between management at home vs. the hospital.[21] * Sealing membranes after rupture: Infection is the major risk associated with PROM and PPROM.[22] By closing the ruptured membranes, it is hoped that there would be a decrease in infection, as well as encouraging the re-accumulation of amniotic fluid in the uterus to protect the fetus and allow for further lung development. Common techniques include placing a sponge over the ruptured membrane and the use of oral autoimmune stimulating drugs to encourage the body's immune system to repair the rupture. There is currently insufficient research to determine whether these or other resealing techniques improve maternal or neonatal outcomes when compared to the current standard of care.[23] ### Before 24 weeks[edit] Before 24 weeks, a fetus is not viable meaning it cannot live outside the mother. In this case, either watchful waiting at home or an induction of labor done.[11] Because the risk of infection is so high, the mother should check her temperature often and return to the hospital if she develops any signs or symptoms of infection, labor, or vaginal bleeding. These women are typically admitted to the hospital once their fetus reaches 24 weeks and then managed the same as women with PPROM before 34 weeks (discussed above). When possible, these deliveries should take place in a hospital that has expertise in the management of the potential maternal and neonatal complications, and has the necessary infrastructure in place to support the care of these patients (i.e. neonatal intensive care unit).[24] Antenatal corticosteroids, latency antibiotics, magnesium sulfate, and tocolytic medications are not recommended until the fetus reaches viability (24 weeks).[11] In cases of pre-viable PPROM, chance of survival of the fetus is between 15–50%, and the risk of chorioamnionitis is about 30%.[9] ### Chorioamnionitis[edit] Chorioamnionitis is a bacterial infection of the fetal membranes, which can be life-threatening to both mother and fetus. Women with PROM at any age are at high risk of infection because the membranes are open and allow bacteria to enter. Women are checked often (usually every 4 hours) for signs of infection: fever (more than 38 °C or 100.5 °F), uterine pain, maternal tachycardia, fetal tachycardia, or foul-smelling amniotic fluid.[10] Elevated white blood cells are not a good way to predict infection because they are normally high in labor.[9] If infection is suspected, artificial induction of labor is started at any gestational age and broad antibiotics are given. Caesarean section should not be automatically done in cases of infection, and should only be reserved for the usual fetal emergencies.[9] ## Outcomes[edit] The consequences of PROM depend on the gestational age of the fetus.[8] When PROM occurs at term (after 36 weeks), it is typically followed soon thereafter by the start of labor and delivery. About half of women will give birth within 5 hours, and 95% will give birth within 28 hours without any intervention.[11] The younger the baby, the longer the latency period (time between membrane rupture and start of labor). Rarely, in cases of preterm PROM, amniotic fluid will stop leaking and the amniotic fluid volume will return to normal.[11] If PROM occurs before 37 weeks, it is called preterm prelabor rupture of membranes (PPROM), and the baby and mother are at greater risk of complications. PPROM causes one-third of all preterm births.[19] PROM provides a path for disease-causing organisms to enter the womb and puts both the mother and baby at risk for infection. Low levels of fluid around the baby also increase the risk of umbilical cord compression and can interfere with lung and body formation of the baby in early pregnancy.[19] ### Infection (any age)[edit] At any gestational age, an opening in the fetal membranes provides a route for bacteria to enter the womb. This can lead to chorioamnionitis (an infection of the fetal membranes and amniotic fluid) which can be life-threatening to both the mother and fetus.[8] The risk of infection increases the longer the membranes remain open and baby undelivered.[11] Women with preterm PROM will develop an intra-amniotic infection 15–25% of the time, and the chances of infection increase at earlier gestational ages.[11] ### Pre-term birth (before 37 weeks)[edit] PROM occurring before 37 weeks (PPROM) is one of the leading causes of preterm birth. Thirty to 35% of all preterm births are caused by PPROM.[10] This puts the fetus at risk for the many complications associated with prematurity such as respiratory distress, brain bleeds, infection, necrotizing enterocolitis (death of the fetal bowels), brain injury, muscle dysfunction, and death.[8] Prematurity from any cause leads to 75% of perinatal mortality and about 50% of all long-term morbidity.[25] PROM is responsible for 20% of all fetal deaths between 24 and 34 weeks' gestation.[10] ### Fetal development (before 24 weeks)[edit] Before 24 weeks the fetus is still developing its organs, and the amniotic fluid is important for protecting the fetus against infection, physical impact, and for preventing the umbilical cord from becoming compressed. It also allows for fetal movement and breathing that is necessary for the development of the lungs, chest, and bones.[8] Low levels of amniotic fluid due to mid-trimester or previable PPROM (before 24 weeks) can result in fetal deformity (e.g. Potter-like facies), limb contractures, pulmonary hypoplasia (underdeveloped lungs),[11] infection (especially if the mother is colonized by group B streptococcus or bacterial vaginosis), prolapsed umbilical cord or compression, and placental abruption.[9] ### PROM after second-trimester amniocentesis[edit] Most cases of PROM occur spontaneously, but the risk of PROM in women undergoing a second trimester amniocentesis for prenatal diagnosis of genetic disorders is 1%. Although, no studies are known to account for all cases of PROM that stem from amniocentesis. This case, the chances of the membranes healing on their own and the amniotic fluid returning to normal levels is much higher than spontaneous PROM. Compared to spontaneous PROM, about 70% of women will have normal amniotic fluid levels within one month, and about 90% of babies will survive.[11] ## Epidemiology[edit] Of term pregnancies (more than 37 weeks) about 8% are complicated by PROM,[10] 20% of these become prolonged PROM.[9] About 30% of all preterm deliveries (before 37 weeks) are complicated by PPROM, and rupture of membranes before viability (before 24 weeks) occurs in less than 1% of all pregnancies.[11] Since there are significantly fewer preterm deliveries than term deliveries, the number of PPROM cases make up only about 5% of all cases of PROM.[9] ## See also[edit] * Placental alpha microglobulin-1 (PAMG-1) * IGFBP1 (Insulin-like growth factor binding protein-1) ## References[edit] 1. ^ a b c d e Norwitz, Errol R.; Arulkumaran, S.; Symonds, I. (2007). Oxford American Handbook of Obstetrics and Gynecology. Oxford University Press, USA. p. 268. ISBN 9780195189384. 2. ^ a b c d e f g h i j k l m n o p q r s t u v Committee on Practice, Bulletins-Obstetrics. (January 2018). "ACOG Practice Bulletin No. 188: Prelabor Rupture of Membranes". Obstetrics and Gynecology. 131 (1): e1–e14. doi:10.1097/AOG.0000000000002455. PMID 29266075. 3. ^ Desai, Shyam V.; Tank, Parikshit (2012). Handbook on Preterm Prelabor Rupture of Membranes in a Low Resource Setting. JP Medical Ltd. p. 22. ISBN 9789350255803. 4. ^ a b Keeling, Jean W. (2013). Fetal and Neonatal Pathology. Springer Science & Business Media. p. 325. ISBN 9781447136828. 5. ^ a b c Bond, DM; Middleton, P; Levett, KM; van der Ham, DP; Crowther, CA; Buchanan, SL; Morris, J (3 March 2017). "Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome". The Cochrane Database of Systematic Reviews. 3: CD004735. doi:10.1002/14651858.CD004735.pub4. PMC 6464692. PMID 28257562. 6. ^ Duff, Patrick (2016). "Management of Premature Rupture of the Membranes in Term Patients". The Global Library of Women's Medicine. doi:10.3843/GLOWM.10119. 7. ^ Mercer, Brian M. (2009). "Preterm Premature Rupture of the Membranes". The Global Library of Women's Medicine. doi:10.3843/GLOWM.10120. 8. ^ a b c d e f g h i j k l m n o p q r Beckmann, Charles (2010). Obstetrics and Gynecology, 6e. Baltimore, MD: Lippincott Williams & Wilkins. pp. Chapter 22: Premature Rupture of Membranes, pg 213–216. ISBN 978-0781788076. 9. ^ a b c d e f g h i j k l m n o p q r s t u v DeCherney, Alan (2013). Current Diagnosis & Treatment : Obstetrics & Gynecology. New York: McGraw-Hill Medical. pp. Chapter 14: Late Pregnancy Complication, section: premature rupture of membranes. ISBN 978-0071638562. 10. ^ a b c d e f g h i j k l m n o p q Cunningham, F (2014). Williams Obstetrics. New York: McGraw-Hill Education. pp. Chapter 23: Abnormal Labor. ISBN 978-0071798938. 11. ^ 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 "Practice Bulletins No. 139". Obstetrics & Gynecology. 122 (4): 918–930. October 2013. doi:10.1097/01.AOG.0000435415.21944.8f. PMID 24084566. 12. ^ a b c d Beckmann, Charles (2014). Obstetrics and Gynecology, 7e. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. Chapter 17: Premature Rupture of Membranes, pg 169–173. ISBN 978-1451144314. 13. ^ Spong, Catherine (2018). Williams Obstetrics. New York: McGraw-Hill Medical. pp. Chapter 22: Normal Labor. ISBN 978-1259644337. 14. ^ Sharp, GC; Stock, SJ; Norman, JE (Oct 3, 2014). "Fetal assessment methods for improving neonatal and maternal outcomes in preterm prelabour rupture of membranes". The Cochrane Database of Systematic Reviews. 10 (10): CD010209. doi:10.1002/14651858.CD010209.pub2. PMID 25279580. 15. ^ "No. 64a: Bacterial Sepsis in Pregnancy" (PDF). Royal College of Obstetricians and Gynaecologists Green–top Guideline. April 2012. 16. ^ Wojcieszek, AM; Stock, OM; Flenady, V (29 October 2014). "Antibiotics for prelabour rupture of membranes at or near term" (PDF). The Cochrane Database of Systematic Reviews. 10 (10): CD001807. doi:10.1002/14651858.CD001807.pub2. PMID 25352443. 17. ^ Vergani, P; Locatelli, A; Verderio, M; Assi, F (2004). "Premature rupture of the membranes at <26 weeks' gestation: role of amnioinfusion in the management of oligohydramnios". Acta Bio-medica : Atenei Parmensis. 75 Suppl 1: 62–6. PMID 15301294. 18. ^ Kenyon, S; Boulvain, M; Neilson, JP (2 December 2013). "Antibiotics for preterm rupture of membranes". The Cochrane Database of Systematic Reviews. 12 (12): CD001058. doi:10.1002/14651858.CD001058.pub3. PMID 24297389. 19. ^ a b c Mackeen, AD; Seibel-Seamon, J; Muhammad, J; Baxter, JK; Berghella, V (27 February 2014). "Tocolytics for preterm premature rupture of membranes". The Cochrane Database of Systematic Reviews. 2 (2): CD007062. doi:10.1002/14651858.CD007062.pub3. PMID 24578236. 20. ^ Hofmeyr, GJ; Eke, AC; Lawrie, TA (30 March 2014). "Amnioinfusion for third trimester preterm premature rupture of membranes". The Cochrane Database of Systematic Reviews. 3 (3): CD000942. doi:10.1002/14651858.CD000942.pub3. PMC 7061243. PMID 24683009. 21. ^ Abou El Senoun, G; Dowswell, T; Mousa, HA (14 April 2014). "Planned home versus hospital care for preterm prelabour rupture of the membranes (PPROM) prior to 37 weeks' gestation". The Cochrane Database of Systematic Reviews. 4 (4): CD008053. doi:10.1002/14651858.CD008053.pub3. PMID 24729384. 22. ^ American College of Obstetricians Gynecologists' Committee on Practice Bulletins—Obstetrics (2016-10-01). "Practice Bulletin No. 172". Obstetrics & Gynecology. 128 (4): e165–e177. doi:10.1097/aog.0000000000001712. ISSN 0029-7844. PMID 27661655. S2CID 46870998. 23. ^ Crowley AE, Grivell RM, Dodd JM (7 July 2016). "Sealing procedures for preterm prelabour rupture of membranes". Cochrane Database of Systematic Reviews. 7: CD010218. doi:10.1002/14651858.CD010218.pub2. PMC 6457929. PMID 27384151. 24. ^ "Obstetric Care Consensus No. 6 Summary: Periviable Birth". Obstetrics and Gynecology. 130 (4): 926–928. October 2017. doi:10.1097/AOG.0000000000002347. ISSN 1873-233X. PMID 28937567. 25. ^ Hösli, Irene (2014). "Tocolysis for preterm labor: expert opinion" (PDF). Arch Gynecol Obstet. 289 (4): 903–9. doi:10.1007/s00404-013-3137-9. PMID 24385286. S2CID 21892232. ## External links[edit] Classification D * ICD-10: O42 * ICD-9-CM: 658.1 * MeSH: D005322 * DiseasesDB: 10600 External resources * MedlinePlus: 000512 * eMedicine: med/3246 * v * t * e Pathology of pregnancy, childbirth and the puerperium Pregnancy Pregnancy with abortive outcome * Abortion * Ectopic pregnancy * Abdominal * Cervical * Interstitial * Ovarian * Heterotopic * Embryo loss * Fetal resorption * Molar pregnancy * Miscarriage * Stillbirth Oedema, proteinuria and hypertensive disorders * Gestational hypertension * Pre-eclampsia * HELLP syndrome * Eclampsia Other, predominantly related to pregnancy Digestive system * Acute fatty liver of pregnancy * Gestational diabetes * Hepatitis E * Hyperemesis gravidarum * Intrahepatic cholestasis of pregnancy Integumentary system / dermatoses of pregnancy * Gestational pemphigoid * Impetigo herpetiformis * Intrahepatic cholestasis of pregnancy * Linea nigra * Prurigo gestationis * Pruritic folliculitis of pregnancy * Pruritic urticarial papules and plaques of pregnancy (PUPPP) * Striae gravidarum Nervous system * Chorea gravidarum Blood * Gestational thrombocytopenia * Pregnancy-induced hypercoagulability Maternal care related to the fetus and amniotic cavity * amniotic fluid * Oligohydramnios * Polyhydramnios * Braxton Hicks contractions * chorion / amnion * Amniotic band syndrome * Chorioamnionitis * Chorionic hematoma * Monoamniotic twins * Premature rupture of membranes * Obstetrical bleeding * Antepartum * placenta * Circumvallate placenta * Monochorionic twins * Placenta accreta * Placenta praevia * Placental abruption * Twin-to-twin transfusion syndrome Labor * Amniotic fluid embolism * Cephalopelvic disproportion * Dystocia * Shoulder dystocia * Fetal distress * Locked twins * Nuchal cord * Obstetrical bleeding * Postpartum * Pain management during childbirth * placenta * Placenta accreta * Preterm birth * Postmature birth * Umbilical cord prolapse * Uterine inversion * Uterine rupture * Vasa praevia Puerperal * Breastfeeding difficulties * Low milk supply * Cracked nipples * Breast engorgement * Childbirth-related posttraumatic stress disorder * Diastasis symphysis pubis * Postpartum bleeding * Peripartum cardiomyopathy * Postpartum depression * Postpartum psychosis * Postpartum thyroiditis * Puerperal fever * Puerperal mastitis Other * Concomitant conditions * Diabetes mellitus * Systemic lupus erythematosus * Thyroid disorders * Maternal death * Sexual activity during pregnancy * Category [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Prelabor rupture of membranes	c0015944	4,370	wikipedia	https://en.wikipedia.org/wiki/Prelabor_rupture_of_membranes	2021-01-18T19:04:40	{"mesh": ["D005322"], "umls": ["C0015944"], "icd-9": ["658.1"], "icd-10": ["O42"], "wikidata": ["Q11703370"]}
Ectopic aldosterone-producing tumor is an extremely rare aldosterone-producing neoplasm composed of aberrant adrenocortical tissue located outside the adrenal glands (e.g. in retroperitoneum, perirenal or periaortic fatty tissue, thorax, spinal canal, testes, ovaries) typically characterized by symptoms related to increased aldosterone levels (such as sustained, treatment-resistant hypertension and hypokalemia) or symptoms caused by local tumor enlargement. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Ectopic aldosterone-producing tumor	None	4,371	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=231632	2021-01-23T18:57:36	{"icd-10": ["E26.8"], "synonyms": ["Extra-adrenal aldosterone-producing tumor"]}
A rare plasma cell neoplasm characterized by peripheral plasmacytosis, usually with extensive and diffuse infiltration of the bone marrow, and monoclonal paraproteinemia. Neoplastic plasma cells may also be found in extramedullary sites, such as the liver or spleen, among others. Most cases present as primary plasma cell leukemia without previous diagnosis of myeloma. The condition can also represent leukemic transformation of plasma cell myeloma (secondary plasma cell leukemia). Clinical manifestations include lymphadenopathy, organomegaly, renal failure, bone marrow failure, and peripheral neuropathies. High serum levels of lactate dehydrogenase and beta2-microglobulin, as well as hypercalcemia (potentially leading to hypercalcemic crisis) are typically 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Plasma cell leukemia	c0023484	4,372	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=454714	2021-01-23T17:20:06	{"gard": ["9373"], "mesh": ["D007952"], "umls": ["C0023484"], "icd-10": ["C90.1"], "synonyms": ["PCL"]}
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Find sources: "Wheat yellow rust" – news · newspapers · books · scholar · JSTOR (July 2009) (Learn how and when to remove this template message) Wheat yellow rust Yellow rust on the leaves of winter triticale Scientific classification Kingdom: Fungi Division: Basidiomycota Class: Urediniomycetes Subclass: Incertae sedis Order: Uredinales Family: Pucciniastraceae Genus: Puccinia Species: P. striiformis var. tritici Binomial name Puccinia striiformis var. tritici Westend., (1854) Synonyms * Dicaeoma glumarum * Puccinia glumarum * Puccinia rubigo-vera * Puccinia straminis * Puccinia striiformis * Trichobasis glumarum * Uredo glumarum Yellow rust distribution in winter triticale Wheat yellow rust (Puccinia striiformis f.sp. tritici), also known as wheat stripe rust, is one of the three major wheat rust diseases, along with stem rust of wheat (Puccinia graminis f.sp. tritici) and leaf rust (Puccinia triticina f.sp. tritici). ## Contents * 1 History * 2 Symptoms * 3 Worldwide population structure * 4 Disease management * 4.1 Resistance genes * 4.1.1 Lebanon * 5 See also * 6 References * 7 External links ## History[edit] As R.P. Singh, J. Huerta-Espino, and A.P. Roelfs say in their (undated) comprehensive review of literature on the wheat rusts for UN FAO:[1] > Although Gadd first described stripe rust of wheat in 1777, it was not until 1896 that Eriksson and Henning (1896) showed that stripe rust resulted from a separate pathogen, which they named P. glumarum. In 1953, Hylander et al. (1953) revived the name P. striiformis. ## Symptoms[edit] Stripe rust on wheat Yellow rust, or stripe rust, takes its name from the appearance of yellow-colored stripes produced parallel along the venations of each leaf blade. These yellow stripes are actually characteristic of uredinia that produce yellow-colored urediniospores. Primary hosts of yellow rust of wheat are Triticum aestivum (bread wheat), Triticum turgidum (durum wheat), triticale, and a few Hordeum vulgare (barley) cultivars. Other cereal rust fungi have macrocyclic, heteroecious life cycles, involving five spore stages and two phylogenetically unrelated hosts. The alternate host of stripe rust had been unknown until 2009, when a team of scientists at the USDA-ARS Cereal Disease Lab led by Dr. Yue Jin confirmed that barberry (Berberis spp.) is an alternate host.[2] Barberry was known as an alternate host of the closely related stem rust (Puccinia graminis) and for many years, when infection was observed on barberry, it was assumed to be stem rust.[3] Scientists observed rust infection on various barberry species, and inoculated spores onto grass hosts.[2] Kentucky Bluegrass showed infection characteristic of stripe rust. Later, infected wheat plants bearing teliospores were soaked in water and suspended over barberry species.[2] Infection was produced, thus solving a "century-old mystery" of plant pathology.[2] The disease usually occurs early in the growth season, when temperature ranges between 2 and 15 °C (36 and 59 °F); but it may occur to a maximum of 23 °C (73 °F). High humidity and rainfall are favorable conditions for increasing the infection on both leaf blade and leaf sheath, even on spikes when in epidemic form. Symptoms are stunted and weakened plants, shriveled grains, fewer spikes, loss in number of grains per spike and grain weight. Losses can be 50%, but in severe situations 100% is vulnerable. Since yellow rust can occur whenever the wheat plants in green and the environmental condition conducive for the spore infection, yellow rust is a severe problem in the wheat-producing regions worldwide. Temperatures during the time of winter wheat emergence and the coldest period of the year are crucial for epidemic development in winter-habit wheat crops.[4] ## Worldwide population structure[edit] Both the spatial genetic structure and the spatial dissemination of this disease have been investigated.[5] Population genetic analyses indicate a strong regional heterogeneity in levels of recombination, with clear signatures of recombination in the Himalayan and near-Himalayan regions and a predominant clonal population structure in other regions. The existence of a high genotypic diversity, recombinant population structure, high sexual reproduction ability, and the abundance of the alternate host (Berberis spp.) in the Himalayan and neighboring regions suggest the region as a plausible Pst center of origin or at least very close to its centre of origin. However, further exploration may be useful from Central Asia to East Asian regions.[5] ## Disease management[edit] Breeding resistant varieties is the most cost-effective method to control this rust. Fungicides are available but vary in availability depending on their registration restrictions by national or state governments.[6][7] Development of varieties resistant to the disease is always an important objective in wheat breeding programs for crop improvement. This has been done in the past, however as normal, these resistance genes became ineffective due to the acquisition of virulence to that particular resistance gene rendering the variety susceptible - necessitating ongoing variety development.[8] ### Resistance genes[edit] These genes are abbreviated Yr and Yr1, Yr24, etc. #### Lebanon[edit] Although Yr6, Yr7, Yr8, Yr9, Yr10, Yr17, Yr24, Yr25, and Yr27 are no longer effective in Lebanon, Yr1, Yr3, Yr4, Yr5, Yr15 are still effective against yellow rust pathotypes prevalent there.[9] ## See also[edit] * Puccinia striiformis var. striiformis ## References[edit] 1. ^ Singh, R.P.; Huerta-Espino, J.; Roelfs, A.P. "The wheat rusts". www.fao.org. Retrieved 2018-08-25. 2. ^ a b c d Jin, Yue; Szabo, Les J.; Carson, Martin (2010-04-07). "Century-Old Mystery of Puccinia striiformis Life History Solved with the Identification of Berberis as an Alternate Host". Phytopathology. 100 (5): 432–435. doi:10.1094/PHYTO-100-5-0432. ISSN 0031-949X. PMID 20373963. 3. ^ Stakman, E. C. (1918). The black stem rust and the barberry /. Washington, D.C.: Government Printing Office. doi:10.5962/bhl.title.135472. 4. ^ Aslanov, Rufat; Moussa El Jarroudi; Mélanie Gollier; Marine Pallez-Barthel; Marco Beyer (2019-01-04). "Yellow rust does not like cold winters. But how to find out which temperature and time frames could be decisive in vivo?". Journal of Plant Pathology. online first (1): 539–546. doi:10.1007/s42161-018-00233-y. S2CID 91716438. 5. ^ a b Ali, Sajid; Pierre Gladieux; Marc Leconte; Angélique Gautier; Annemarie F. Justesen; Mogens S. Hovmøller; Jérôme Enjalbert; Claude de Vallavieille-Pope (2014-01-23). "Origin, Migration Routes and Worldwide Population Genetic Structure of the Wheat Yellow Rust Pathogen Puccinia striiformis f.sp. tritici". PLOS Pathogens. 10 (1): e1003903. doi:10.1371/journal.ppat.1003903. PMC 3900651. PMID 24465211. 6. ^ "Stripe Rust - Washington State University". wsu.edu. Retrieved 2 August 2018. 7. ^ http://extension.usu.edu/files/publications/factsheet/wheat-stripe-rust08.pdf 8. ^ de Vallavieille-Pope, Claude; Ali, Sajid; Leconte, Marc; Enjalbert, Jérôme; Delos, Marc; Rouzet, Jacques (1 January 2012). "Virulence Dynamics and Regional Structuring of Puccinia striiformis f. sp. tritici in France Between 1984 and 2009". Plant Disease. 96 (1): 131–140. doi:10.1094/pdis-02-11-0078. PMID 30731861. 9. ^ Rola El Amil (Lebanese Agricultural Research Institute, Lebanon) (2020-11-09). (DAY 2) - Phytosanitary Safety for Transboundary pest prevention - Yellow and Black rust population variability. CGIAR Germplasm Health Webinar series. Phytosanitary Awareness Week. International Institute of Tropical Agriculture / CGIAR. Slide at 00:44:37. * Ali S. (2012) Population biology and invasion history of Puccinia striiformis f.sp. tritici at worldwide and local scale, Ph.D. dissertation. Université Paris-Sud 11. * Chen, X. M. 2005. Epidemiology and control of stripe rust [Puccinia striiformis f. sp. tritici] on wheat. Can. J. Plant Pathol. 27:314-337. * Doodson, J.K., Manners, J.G. and Myers, A. (1964). Some effects of yellow rust (Puccinia striiformis) on the growth and yield of spring wheat. Ann. Bot. 28: 459-472. * Eriksson, J. and E. Henning. 1896. Die Getreideroste. Ihre Geschichte und Natur sowie Massregein gegen dieselben. P. A. Norstedt and Soner, Stockholm. 463 pp. * Hogg, W.H., C.E. Hounam, A.K. Malik, and J.C. Zadoks. 1969. Meteorological factors affecting the epidemiology of wheat rusts. WMO Tech Note 99. 143 pp. * Hovmøller, M. S., Sørensen, C. K., Walter, S., Justesen, A. F. (2011) Diversity of Puccinia striiformis on cereals and grasses. Annual Review of Phytopathology 49, 197-217. * Hylander, N., I. Jorstad and J.A. Nannfeldt. 1953. Enumeratio uredionearum Scandinavicarum. Opera Bot. 1:1-102. * Jin, Y., Szabo, L.J., and Carson, M. 2010. Century-old mystery of Puccinia striiformis life history solved with the identification of Berberis as an alternate host. Phytopathology 100:432-435. * Poehlman J.M. and D.A. Sleper. 1995. Breeding Field Crops. 4th Ed. Iowa State Press/Ames, Iowa 50014. * Robbelen, G. and Sharp, E. L., 1978. Mode of inheritance, interaction and application of genes conditioning resistance to yellow rust. Adv. Plant Breeding, 9, 88 pp. * Saari, E. E. and Prescott, J. M., 1985. World distribution in relation to economic losses. Pages 259-298, in: The Cereal Rusts Vol. II: Diseases, distribution, epidemiology and control, A. P. Roelfs and W. R. Bushnell eds., Academic Press, Orlando, Fl. * Stubbs, R. W., 1985. Stripe rust. Pages 61–101 in: The Cereal Rusts Vol. II: Diseases, distribution, epidemiology and control, A. P. Roelfs and W. R. Bushnell eds., Academic Press, Orlando, Fl. Zadoks, J. C. and Bouwman, J. J., 1985. Epidemiology in Europe. Pages 329-369 in: The Cereal Rusts Volume II: Diseases, distribution, epidemiology and control, A. P. Roelfs and W. R. Bushnell eds., Academic Press, Orlando, Fl. ## External links[edit] * http://www.ars.usda.gov/SP2UserFiles/ad_hoc/36400500Publications/CerealRusts/The%20Cereal%20Rusts_VOLUME%20II.pdf * http://www.ars.usda.gov/SP2UserFiles/ad_hoc/36400500Cerealrusts/stripe_rust_control.pdf * http://www.ars.usda.gov/SP2UserFiles/ad_hoc/36400500Cerealrusts/Pst-life-cycle%20Phyto-reprint.pdf * http://www.cimmyt.org * http://www.ars.usda.gov/Main/site_main.htm?modecode=36-40-05-00 * "Norwich Rust Group". Norwich Rust Group. Retrieved 2020-12-18. Taxon identifiers * Wikidata: Q7991848 * NCBI: 168172 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Wheat yellow rust	None	4,373	wikipedia	https://en.wikipedia.org/wiki/Wheat_yellow_rust	2021-01-18T19:02:29	{"wikidata": ["Q7991848"]}
A number sign (#) is used with this entry because Axenfeld-Rieger syndrome type 3 (RIEG3) is caused by heterozygous mutation in the FOXC1 gene (601090) on chromosome 6p25. For a general phenotypic description and a discussion of genetic heterogeneity of Axenfeld-Rieger syndrome, see RIEG1 (180500). See also chromosome 6pter-p24 deletion syndrome (612582), which shows phenotypic overlap with Axenfeld-Rieger syndrome type 3. Clinical Features Gould et al. (1997) examined 13 members of a 4-generation family segregating autosomal dominant Axenfeld-Rieger anomaly and identified 7 affected individuals who had a prominent and anteriorly displaced Schwalbe line, iris stromal hypoplasia, and corectopia (anterior segment dysgenesis); nonocular features of Axenfeld-Rieger syndrome, including jaw, dental, and umbilical anomalies, were not present. However, Mears et al. (1998) later identified affected members of this family who had heart anomalies and hearing loss. Cunningham et al. (1998) described an autosomal dominant syndrome that combined familial Axenfeld-Rieger anomaly with atrial septal defect and sensorineural hearing loss. The 30-year-old proposita was first seen at the age of 6 months with increased intraocular pressures. Her 22-year-old half brother presented with glaucoma at 10 months of age. He was referred for evaluation of murmur and a failure to thrive and was found to have atrial septal defect requiring surgical repair. The proposita's 50-year-old father was also seen in the Wilmer Ophthalmological Institute of the Johns Hopkins Hospital in early infancy with increased intraocular pressures. Failure of both medical and surgical treatment resulted in enucleation of a blind, painful left eye at 10 years of age. Independently, the father was found to have an atrial septal defect at 11 months of age, which eventually required surgical repair. The deceased paternal grandmother of the proposita had been seen in the Wilmer Institute at 38 years of age with end-stage glaucoma and central retinal vein occlusion of the left eye that required enucleation. Thus, 3 generations appeared to have been affected, with 1 instance of male-to-male transmission and an affected child from each of 2 unaffected mothers. The proposita had normal hearing and no evidence of cardiac abnormality. The father was described as having marked bilateral sensorineural hearing loss; his son had moderate sensorineural hearing loss bilaterally. Craniofacial and dental development was normal in all. Baruch and Erickson (2001) described a brother and sister with Axenfeld-Rieger anomaly, hypertelorism, clinodactyly, and cardiac anomalies. The older sib had a sensorineural hearing loss and wore hearing aids; he also underwent surgical correction of a 'very large' patent ductus arteriosus and a diaphragmatic hernia. His sister had a large patent ductus arteriosus that closed spontaneously and a moderate atrial septal defect. The authors noted similarities between the phenotype in these sibs and the disorder described by Cunningham et al. (1998). Grosso et al. (2002) described a family with Axenfeld-Rieger anomaly, cardiac malformations (tricuspid and mitral valve defects), and sensorineural hearing loss. The proband was more severely affected than her father, who was more severely affected than his father. Karyotyping of the proband was normal. A number of other relatives were not available for examination but by report had variable features. No family members had craniofacial anomalies, dental hypoplasia, or involuted periumbilical skin. Weisschuh et al. (2008) studied 5 affected members of a 3-generation family with Axenfeld-Rieger syndrome, all of whom had a displaced Schwalbe line, iridocorneal adhesions, iris hypoplasia, and glaucoma. One individual also had corectopia. The 15-year-old female proband had been diagnosed at birth with Peters anomaly, which was confirmed by ophthalmoscopic examination under anesthesia; gonioscopy, which could only be performed on her right eye, showed aniridia with a 1-mm iris rudiment. Extraocular anomalies were present in all 5 patients: 3 had maxillary hypoplasia, 2 had protuberant umbilical skin, 2 had ureteral stenosis, 1 had hypertelorism, and 1 had atrial septal defect. Cytogenetics In 2 sibs with Axenfeld-Rieger anomaly, hypertelorism, and cardiac anomalies, Baruch and Erickson (2001) found an unbalanced translocation der(6)t(6;8)(p25.1;q24.23), making them monosomic for 6pter-p25.1 and trisomic for 8q24.23-qter. Mapping Gould et al. (1997) performed linkage analysis in a 4-generation family segregating Axenfeld-Rieger anomaly, later found to segregate Axenfeld-Rieger syndrome (Mears et al., 1998), and obtained a maximum lod score of 3.1 (theta = 0) at marker D6S344 on chromosome 6p25. A recombination event defined a 6.4-cM critical interval between D6S1600 and D6S1617. Molecular Genetics In the family originally described by Gould et al. (1997) with Axenfeld-Rieger anomaly, Mears et al. (1998) also reported deafness and heart anomalies and identified a missense mutation in the FOXC1 gene (S82T; 601090.0008). In 9 affected individuals over 3 generations of a family with Axenfeld-Rieger syndrome, Mirzayans et al. (2000) identified heterozygosity for a nonsense mutation (E23X; 601090.0005) in the FOXC1 gene. Affected individuals presented with a variable degree of iris hypoplasia, displaced pupils (corectopia), and a prominent, anteriorly displaced Schwalbe line (posterior embryotoxon) to which peripheral iris strands were attached bridging the iridocorneal angle. Glaucoma was observed in 1 individual. Extraocular features included hypertelorism in 5 patients, microdontia in 4, flat midface in 4, umbilical abnormalities in 2, cardiac defect in 1, and hearing loss in 1. In a mother and son with Axenfeld-Rieger syndrome, Ito et al. (2007) analyzed the FOXC1 gene and identified a missense mutation (601090.0010) that was de novo in the mother. The 2-month-old boy had corectopia and hypertelorism and slight excess of skin at the umbilicus; ophthalmologic examination revealed a posterior embryotoxon and an intraocular pressure of 14 mm Hg, with abnormally high cup-disc ratios (0.85 and 0.80 for left and right eyes, respectively). The 27-year-old mother was subsequently examined and found to have iris hypoplasia, a prominent Schwalbe line, and peripheral anterior synechiae, but no glaucoma; she had no dental or facial abnormalities. The eye findings were bilateral in both patients. In 5 affected members of a 3-generation family with Axenfeld-Rieger syndrome, who displayed a substantial degree of intrafamilial phenotypic variability including Peters anomaly in 1 patient, Weisschuh et al. (2008) identified heterozygosity for a nonsense mutation in the FOXC1 gene (601090.0011). The authors also screened the PITX2 (601542) and CYP1B1 (601771) genes in this family and identified no disease-causing mutations, although they did find that 2 known functional polymorphisms in CYP1B1, V432L and N453S, were carried in heterozygosity by all affected individuals except for the proband, who was homozygous for the common N453 allele, and her brother, who was homozygous for the minor 432L allele. Aldinger et al. (2009) analyzed brain imaging studies in 3 patients from 2 families with missense mutations in FOXC1 resulting in Axenfeld anomaly (601090.0003) and Axenfeld-Rieger syndrome type 3 (601090.0008), respectively, previously reported by Nishimura et al. (1998), Gould et al. (1997), and Mears et al. (1998), and observed mild cerebellar vermis hypoplasia and an abnormal white matter signal corresponding to prominent perivascular spaces; 1 of the patients also showed meningeal defects. Aldinger et al. (2009) concluded that partial loss of FOXC1 function results in cerebellar malformation. Chanda et al. (2008) analyzed the breakpoint architecture in 10 pedigrees with duplications or deletions at chromosome 6p25 and a diagnosis of glaucoma associated with iris hypoplasia or Axenfeld-Rieger syndrome, and found that in contrast to most previous examples, the majority of the segmental duplications and deletions utilized coupled homologous and nonhomologous recombination mechanisms. A junction fragment from a pedigree with Axenfeld-Rieger syndrome and glaucoma, previously studied by Lehmann et al. (2002), exhibited an unprecedented 367-bp insert derived from tandemly arranged breakpoint elements that was unassociated with template switching and occurred in a segmental deletion. Chanda et al. (2008) stated that their results extended the mechanisms involved in structural variant formation and provided strong evidence that a spectrum of recombination, DNA repair, and replication underlie chromosome 6p25 rearrangements. Genotype/Phenotype Correlations Using patient records and clinical questionnaires, Strungaru et al. (2007) reviewed 126 patients diagnosed with Axenfeld-Rieger malformation or syndrome, representing 20 probands, in whom mutations in the PITX2 or FOXC1 genes had been identified. The authors found that 75% of these patients had glaucoma that developed in adolescence or early adulthood, and that patients with PITX2 defects or FOXC1 duplications had a more severe prognosis for glaucoma development than patients with FOXC1 mutations; only 18% of PITX2- or FOXC1-related cases of glaucoma responded to surgical and/or medical therapy. In addition, patients with nonocular findings were more likely to have defects in PITX2 than FOXC1. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Flat midface Ears \- Hearing loss, sensorineural Eyes \- Prominent eyes \- Anteriorly displaced eyes \- Schwalbe line (posterior embryotoxon) \- Iris strands attached to Schwalbe line bridging the iridocorneal angle \- Iris hypoplasia \- Corectopia \- Glaucoma \- Hypertelorism Nose \- Saddle nose Teeth \- Hypodontia \- Small teeth CARDIOVASCULAR Heart \- Atrial septal defect \- Valvular defects Vascular \- Patent ductus arteriosus ABDOMEN External Features \- Umbilical defect (redundant periumbilical skin) NEUROLOGIC Central Nervous System \- Cerebellar vermis hypoplasia MISCELLANEOUS \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the forkhead box C1 gene (FOXC1, 601090.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	AXENFELD-RIEGER SYNDROME, TYPE 3	c0265341	4,374	omim	https://www.omim.org/entry/602482	2019-09-22T16:13:40	{"doid": ["0110122"], "mesh": ["C535679"], "omim": ["602482"], "orphanet": ["782", "98978", "91483"], "synonyms": ["Alternative titles", "AXENFELD-RIEGER ANOMALY WITH CARDIAC DEFECTS AND/OR SENSORINEURAL HEARING LOSS", "ANTERIOR CHAMBER CLEAVAGE SYNDROME", "RIEGER SYNDROME, TYPE 3"]}
A number sign (#) is used with this entry because the autosomal recessive form of thyroid hormone resistance is caused by mutation in the thyroid hormone receptor gene (THRB; 190160). An autosomal dominant form of the disorder (188570) is caused by mutation in the same gene, as is selective pituitary resistance to thyroid hormone (145650). Clinical Features Among 2 of 6 children of a consanguineous marriage, Refetoff et al. (1967) observed congenital deafness, stippled epiphyses, goiter, and abnormally high PBI. They postulated end-organ unresponsiveness to thyroid hormone. A later-born sib was recognized as affected in the neonatal period (Refetoff, 1982). A different type of unresponsiveness to thyroid hormones, presumably genetic, was reported by Lamberg (1973), who described a 25-year-old woman who had had goiter at birth and had undergone thyroidectomy twice for nontoxic goiter during childhood. Concentrations of thyroid hormones and of thyrotropin in the blood were about twice normal and responses to thyrotropin-releasing hormone were normal. The findings were considered compatible with partial resistance to thyroid hormones in peripheral tissues, including the anterior pituitary. A similar patient may have been reported by Bode et al. (1973). These patients may have a defect in the nuclear receptor(s) for thyroid hormone (Charles et al., 1975). Ohzeki et al. (1984) reported a brother and sister, aged 12 and 9, respectively, with large goiters and high levels of thyroid hormones in the face of clinical euthyroidism. The brother showed low birth weight for dates and was also lean and had exophthalmos which prompted the diagnosis of Graves disease. Relevant to this disorder is information on thyroid hormone action at the nuclear level (Oppenheimer, 1985). A stereospecific energy-dependent transport system appears responsible for translocation of triiodothyronine from cytosol to nucleus. The nuclear receptor for T3 is an integral component of a larger chromatin fragment. Refetoff (1982) stated that global resistance to thyroid hormone had been observed in more than 60 persons, most of them in 17 families. Consanguinity was established or suspected in 3 of 17 families and the defect occurred in a set of identical twins and in only 1 of a set of fraternal twins. Some of the families represented autosomal dominant inheritance (see 188570). In no instance had a defect in conversion of T4 and T3 been demonstrated; when measured, serum T3 was found elevated. Molecular Genetics In affected members of the original family reported by Refetoff et al. (1967), in which GRTH segregated as an autosomal recessive, Takeda et al. (1991) identified deletion of the thyroid hormone receptor gene (190160.0003). Heterozygous members of the family were clinically normal. The affected members of the family had severe hyposensitivity to thyroid hormone and exhibited congenital deafness, epiphyseal dysgenesis, and other minor somatic abnormalities; however, the defect was adequately compensated in most tissues by high circulating levels of thyroid hormone. Takeda et al. (1991) concluded that the presence of a single normal allele was sufficient for normal receptor function, and suggested that in autosomal dominant GRTH the presence of an abnormal thyroid hormone receptor interferes with the function of the normal receptor in a dominant-negative fashion. Skel \- Stippled epiphyses Eyes \- Exophthalmos Neck \- Goiter Inheritance \- Autosomal recessive Endocrine \- End-organ unresponsiveness to thyroid hormone \- Thyroid hormone receptor-beta gene (THR1) deletion \- Clinical euthyroidism Misc \- Low birth weight for dates Lab \- Abnormally high PBI \- Elevated blood thyroid hormones \- Elevated thyrotropin \- Normal response to thyrotropin-releasing hormone Ears \- Congenital deafness ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL RECESSIVE	c2940786	4,375	omim	https://www.omim.org/entry/274300	2019-09-22T16:21:42	{"doid": ["11633"], "mesh": ["D018382"], "omim": ["274300"], "orphanet": ["3221"], "synonyms": ["Alternative titles", "GTHR", "THYROID HORMONE UNRESPONSIVENESS", "REFETOFF SYNDROME"]}
Homocystinuria due to CBS deficiency is an inherited disorder in which the body is unable to correctly use the amino acid, homocysteine, one of the building blocks of protein. This form of homocystinuria is caused by a genetic mutation in the CBS gene, which leads to low levels or absence of an enzyme called cystathionine beta-synthase (CBS). When CBS is absent or not working right, homocysteine and other toxic chemicals build up in the blood and urine. Symptoms of this disorder include poor growth and slow weight gain in infancy. Additional symptoms include nearsightedness, dislocation of the lens of the eye, an increased risk of blood clots, and developmental problems. Homocystinuria due to CBS deficiency is inherited in an autosomal recessive pattern. It is diagnosed by newborn screening, or later in life by blood and urine testing. There are two types of homocystinuria due to CBS deficiency. One type responds to treatment with vitamin B6 and the other one does not. Other treatments for this disorder include a protein-restricted diet, betaine treatment, and other supplements. With early treatment, individuals with this condition can have normal growth and development. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Homocystinuria due to CBS deficiency	c0751202	4,376	gard	https://rarediseases.info.nih.gov/diseases/6667/homocystinuria-due-to-cbs-deficiency	2021-01-18T17:59:59	{"mesh": ["D006712"], "omim": ["236200"], "umls": ["C0751202"], "orphanet": ["394"], "synonyms": ["Homocystinuria due to cystathionine beta-synthase deficiency", "Cystathionine beta-synthase deficiency", "CBS deficiency", "Classic homocystinuria"]}
A number sign (#) is used with this entry because myoclonic epilepsy of Lafora, also known as progressive myoclonic epilepsy-2 (EPM2), can be caused by mutation in the laforin (EPM2A; 607566) gene on chromosome 6q24 or the malin gene (NHLRC1; 608072) on chromosome 6p22. Description The Lafora type of progressive myoclonic epilepsy is an autosomal recessive disorder characterized by insidious onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, difficulties in school work, myoclonic jerks, generalized seizures, and often visual hallucination. The myoclonus, seizures, and hallucinations gradually worsen and become intractable. This is accompanied by progressive cognitive decline, resulting in dementia. About 10 years after onset, affected individuals are in near-continuous myoclonus with absence seizures, frequent generalized seizures, and profound dementia or a vegetative state. Histologic studies of multiple tissues, including brain, muscle, liver, and heart show intracellular Lafora bodies, which are dense accumulations of malformed and insoluble glycogen molecules, termed polyglucosans (review by Ramachandran et al., 2009). For a discussion of genetic heterogeneity of progressive myoclonic epilepsy, see EPM1A (254800). Clinical Features Schwarz and Yanoff (1965) described a brother and sister, offspring of a one-and-one-half cousin marriage, with this disease. Seizures began at age 15 in the boy with slowly progressive motor and mental deterioration leading to death at age 23.5 years. The sister's seizures began at age 14 years and progression to dementia and blindness occurred, with death at age 19. Intra- and extracellular Lafora bodies were found in the CNS, retina, axis cylinders of spinal nerves, heart muscle, liver cells, and striated muscle fibers. Norio and Koskiniemi (1979), as well as others, concluded that there are 3 types of what they termed progressive myoclonic epilepsy (PME). The Lafora type shows onset of grand mal seizures and/or myoclonus around the fifteenth year of life, rapid and severe mental deterioration, often with psychotic symptoms, short survival, histologic finding of Lafora bodies, and autosomal recessive inheritance. The Unverricht-Lundborg type, which is frequent in Finland, has onset around the tenth year, variable severity, progressive incapacitation from myoclonus associated with mild mental symptoms, variable survival, 'degenerative' histologic changes, and autosomal recessive inheritance. The Hartung type (159600) is a dominant form of myoclonic epilepsy without inclusion bodies. Canafoglia et al. (2004) found different electrophysiologic profiles representing sensorimotor cortex hyperexcitability in 8 patients with Lafora body disease (age range, 14 to 27 years) and 10 patients with Unverricht-Lundborg disease (ULD) (age range, 25 to 62 years). In general, the ULD patients had a quasistationary disease course, rare seizures, and little or no mental impairment, whereas the Lafora disease patients had recurrent seizures and worsening mental status. Patients with ULD had prominent action myoclonus clearly triggered by voluntary movements. Lafora disease patients experienced spontaneous myoclonic jerks associated with clear EEG paroxysms with only minor action myoclonus. Although both groups had enlarged or giant somatosensory evoked potentials, the pattern in the Lafora disease group was consistent with a distortion of cortical circuitry. Patients with ULD had enhanced long-loop reflexes with extremely brief cortical relay times. The findings were consistent with an aberrant subcortical or cortical loop, possibly short-cutting the somatosensory cortex, that may be involved in generating the prominent action myoclonus that characterizes EPM1. Patients with Lafora disease had varied cortical relay times and delayed and prolonged facilitation as evidenced by sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli. The findings were consistent with an impairment of inhibitory mechanisms in Lafora disease. Gomez-Abad et al. (2005) reported detailed clinical characteristics of 17 patients with Lafora disease caused by mutations in the NHLRC1 gene. Age at onset ranged from 12 to 15 years, with the exception of 7 and 22 years in 2 patients. Seizures were the most common presentation, including generalized tonic-clonic seizures (50%); simple partial occipital seizures (18.7%); partial seizures with secondary generalization (12.4%); absence seizures (6.3%); and myoclonic seizures (6.3%). One patient presented with hepatic failure and did not develop neurologic symptoms. Other variable features included cognitive decline, inability to attend school, gait disturbance, inability to walk alone, and complete deterioration of mental status. Diagnosis Sarlin et al. (1960) claimed that electroencephalographic abnormalities distinguished heterozygotes from homozygous normals. Schwarz and Yanoff (1965) proposed diagnosis by liver or muscle biopsy. Busard et al. (1986, 1987) demonstrated that the diagnosis can be made reliably on axillary skin biopsy; all patients show typical periodic acid-Schiff (PAS)-positive inclusions in the myoepithelial cells of the secretory acini of the apocrine glands and/or in the cells of the eccrine duct. However, the method had no value for carrier detection. In patients with Lafora disease, Lafora bodies are found in myoepithelial cells surrounding axillary apocrine (odoriferous) glands, whereas outside the axilla, Lafora bodies are found in the cells composing the ducts of the eccrine (perspiration) glands. In 2 unrelated patients with Lafora disease, 1 with mutation in the EPM2A gene and the other with mutation in the NHLRC1 gene, Andrade et al. (2003) reported that the diagnosis had been made by Lafora bodies present in the myoepithelial cells of the axillary apocrine glands. In 2 other unrelated patients, each with mutations in the 2 different genes, the diagnosis of Lafora disease was made by Lafora bodies in the eccrine duct cells of forearm biopsies. The authors noted that patients with either genetic form of the disease have Lafora bodies in both apocrine myoepithelial cells and eccrine duct cells. Andrade et al. (2003) reported a patient who had originally been diagnosed with an atypical form of Lafora disease (de Quadros et al., 2000) based on an axillary biopsy showing PAS-positive material in the cells lining the gland lumen, but not in myoepithelial cells or in eccrine glands. Mutation analysis showed that the patient actually had Unverricht-Lundborg disease. Andrade et al. (2003) noted the difficulty in diagnosing Lafora disease by axillary biopsy, and favored biopsy of skin outside the axilla. Pathogenesis Harriman and Millar (1955) noted that the Lafora material has the properties of an acid mucopolysaccharide, and suggested that the Lafora bodies in the brain may be amyloid. Yokoi et al. (1968) arrived at a preliminary conclusion that the Lafora body is polyglucosan in nature. They pictured the existence of an enzyme defect which leads to deposition of polyglucosans near their site of synthesis in the agranular endoplasmic reticulum. In cultured fibroblasts, Fluharty et al. (1970) described bodies which may be the equivalent of the Lafora body observed histologically. Lafora bodies are dense aggregates of abnormally branched glycogen molecules called polyglucosans (Andrade et al., 2003). Gentry et al. (2005) found that malin directly bound and interacted with the laforin protein in HEK293T cells in vivo. Laforin is polyubiquitinated in a malin-dependent manner, which leads to laforin degradation. Mutations in the NHLRC1 gene abolished both laforin polyubiquitination and degradation. Gentry et al. (2005) concluded that malin regulates laforin protein concentrations and that mutations in the NHLRC1 gene resulting in loss of the E3 ligase activity of malin underlie the onset of Lafora disease in patients with these mutations. Mapping By linkage studies in 3 Italian families with Lafora disease, Lehesjoki et al. (1992) demonstrated that the gene is located at a locus other than that for the Unverricht-Lundborg type on chromosome 21q22.3. Serratosa et al. (1995) studied linkage in 9 families in which Lafora disease had been proven by biopsy in at least 1 member. Using microsatellite markers spaced an average of 13 cM apart, they used linkage analysis in all 9 families and homozygosity mapping in 4 consanguineous families to assign the gene for Lafora disease to 6q23-q25. An extended pedigree with 5 affected members independently proved linkage. The multipoint 1-lod unit support interval covered a 2.5-cM region surrounding D6S403. Homozygosity mapping defined a 17-cM region in 6q23-q25 flanked by D6S292 and D6S420. The 9 families with a total of 19 patients affected with Lafora disease originated from the United States, Spain, Palestine, and Iran. Maddox et al. (1997) studied a 2-generation family in which a recombination event reduced the Lafora critical region to a 4-cM interval flanked by markers D6S308 and D6S311. Sainz et al. (1997) narrowed the assignment of the MELF locus within 6q24 by study of recombinants and homozygosities. ### Genetic Heterogeneity Serratosa et al. (1999) commented that in spite of the homogeneity of the Lafora disease phenotype, with the presence of Lafora bodies in all affected individuals, there are approximately 20% of families with Lafora disease in which the phenotype does not segregate with the 6q23-q25 critical region. The simplest explanation for this genetic heterogeneity is that another gene or genes in the same metabolic pathway are altered in the Lafora disease families not linked to 6q23-q25. Chan et al. (2003) performed genomewide linkage analysis on 4 consanguineous French-Canadian families with classic Lafora disease. A 2-point maximum lod score of 5.2 was obtained for a 2.2-Mb region on chromosome 6p22. All families shared the same 9 marker disease haplotype. The authors termed the locus EPM2B. Molecular Genetics Ganesh et al. (2006) and Singh and Ganesh (2009) provided detailed reviews of the molecular basis of Lafora disease, with specific review of the mutational spectrum of EPM2A and NHLRC1 genes. ### EPM2A In 10 families with myoclonic epilepsy of Lafora, Minassian et al. (1998) identified 6 distinct DNA sequence variations in the EPM2A gene and 1 homozygous microdeletion, each segregating with the disorder (see, e.g., 607566.0001-607566.0003). These mutations were predicted to cause deleterious effects in the laforin protein, resulting in the disorder. ### EPM2B In 34 probands with Lafora disease, Chan et al. (2003) identified 17 different mutations in the NHLRC1 gene in 26 families, including 8 deletions, 1 insertion, 7 missense changes, and 1 nonsense change (see, e.g., C26S; 608072.0001). Eighteen families were homozygous and 8 were compound heterozygous for the mutations. Gomez-Abad et al. (2005) identified 18 mutations, including 12 novel mutations, in the malin gene (see, e.g., 608072.0005-608072.0007) in 23 of 25 patients with Lafora disease who did not have mutations in the laforin gene. P69A (608072.0002) was the predominant mutation, identified in 14 chromosomes from 9 unrelated patients; haplotype analysis suggested a founder effect for only 2 of these families. Singh et al. (2005) identified 6 different mutations in the NHLRC1 gene in 5 of 8 Japanese families with Lafora disease. Another Japanese family had a mutation in the EPM2A gene, and 2 Japanese families did not have mutations in either gene. Singh et al. (2005) concluded that mutations in the NHLRC1 gene are a common cause of Lafora disease in Japan. Singh et al. (2006) identified 7 different mutations, including 2 novel mutations, in the NHLRC1 gene in affected members of 8 families with Lafora disease. The authors stated that 39 different mutations had been identified in the NHLRC1 gene. Population Genetics Chan et al. (2003) identified a homozygous C26S mutation in the NHLRC1 gene in affected members of 4 French Canadian families with Lafora disease. Haplotype analysis indicated a founder effect. Singh et al. (2006) identified an additional French Canadian family with the C26S mutation, and they devised a DNA-based diagnostic test to screen for the C26S mutation for use in the French Canadian population. Genotype/Phenotype Correlations Ganesh et al. (2002) related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified 2 subsyndromes: (1) classic Lafora disease with adolescent-onset stimulus-sensitive grand mal, absence, and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (P = 0.0007); (2) atypical Lafora disease with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (P = 0.0015). The authors further investigated the effect of 5 missense mutations in the carbohydrate-binding domain (CBD4; coded by exon 1) and 3 missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in transfected HeLa cells. Expression of 3 mutant proteins in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the 3 CBD4 mutants showed cytoplasmic clumping. However, 2 of the CBD4 mutants targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. In a clinical analysis of patients with Lafora disease, Gomez-Abad et al. (2005) found that 21 patients with NHLRC1 mutations had a slightly longer disease course and later age at death compared to 70 patients from 54 families with EPM2A mutations. Two patients with NHLRC1 mutations reached the fourth decade of life. Among a total of 77 families with Lafora disease, 70.1% of probands had EPM2A mutations and 27.3% of probands had NHLRC1 mutations. No mutations in either gene were identified in 2 (2.6%) unrelated probands. Singh et al. (2006) compared the clinical course of 13 patients with NHLRC1 mutations to 22 patients with EPM2A mutations. Although age at onset was similar in the 2 groups (approximately 12 years), patients with NHLRC1 mutations had a slower rate of disease progression and thus appeared to live longer. For example, respiratory assistance was required in patients with NHLRC1 and EPM2A mutations at a mean of 20 years and 6.5 years after disease onset, respectively. Cognitive decline, ataxia, and spasticity appeared 2 to 4 years after disease onset in both groups. Singh et al. (2006) postulated that malin, encoded by the NHLRC1 gene, may act upstream of laforin, encoded by the EPM2A gene, in a cellular cascade. History This disorder was first described by Lafora and Glueck (1911). Ortiz-Hidalgo (1986) gave an account of the man for whom myoclonic epilepsy and the intraneuronal bodies observed microscopically are named. Gonzalo Rodriguez-Lafora (1886-1971) was born and died in Madrid and worked there under Ramon y Cajal except for a few years of study in Germany and France and 3 years in Washington, D.C., where he was neuropathologist for the National Psychiatric Institute. The Lafora sign, i.e., picking of the nose in the early stages of cerebrospinal meningitis, is hardly pathognomonic of that disease. Animal Model Ganesh et al. (2002) disrupted the Epm2a gene in mice. At 2 months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibited swelling in the endoplasmic reticulum, Golgi networks, and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies became more prominent at 4 to 12 months, organelles and nuclei were disrupted. The Lafora bodies, present both in neuronal and nonneural tissues, were positive for ubiquitin and advanced glycation end products only in neurons, suggesting a different pathologic consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predated the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures, and EEG epileptiform activity. The authors hypothesized that Lafora disease is a primary neurodegenerative disorder that may utilize a nonapoptotic mechanism of cell death. More than 5% of purebred miniature wirehaired dachshunds (MWHDs) in the United Kingdom suffer an autosomal recessive progressive myoclonic epilepsy (PME), which Lohi et al. (2005) showed to be Lafora disease. Using homozygosity and linkage analysis, they mapped the MWHD disease locus to canine chromosome 35, which is syntenic in its entirety to human 6p25-p21. They then cloned canine Epm2b (NHLRC1; 608072). PCR identified a repeat region in affected dogs and revealed biallelic expansion of the dodecamer repeat with 19 to 26 copies of the D sequence. Comparing the amount of Epm2b mRNA in skeletal muscle from 3 affected dogs and 2 controls with quantitative RT-PCR showed that affected mRNA levels were more than 900 times reduced. To determine whether the extra D sequence is specific to MWHDs, Lohi et al. (2005) sequenced Epm2b from 2 normal unrelated dogs from each of 128 breeds. Sixty percent of their chromosomes had 3 repeats (2 Ds and 1 T) and 40%, 2 repeats (1 D and 1 T). Almost all breeds had examples of both variants in homozygous or heterozygous state. They tested the next non-MWHD PME case to present to the clinic, a basset hound, and found a homozygous 14-copy expansion of the repeat. Lohi et al. (2005) described a canine epilepsy mutation that represents a tandem repeat expansion outside humans and devised a test to detect and counteract it through controlled breeding. Valles-Ortega et al. (2011) found that malin-knockout mice developed Lafora disease at around 11 months of age. Mutant animals showed neurodegeneration and seizures associated with Lafora bodies in several brain regions, including the hippocampus and cerebellum. Lafora bodies contained poorly branched glycogen and muscle glycogen synthase (GYS1; 138570), particularly in the insoluble fraction. Lafora bodies were present in neurons, astrocytes, and interneurons. Malin-null mice showed increased susceptibility to kainate-induced epilepsy. Duran et al. (2014) generated a double-transgenic mouse model in which malin was deleted in all tissues and Gys1 was specifically deleted in the brain. Glycogen content in the brain was significantly decreased in Gys1 heterozygous mice and was absent in Gys1 homozygous-null malin-knockout mice. Double-knockout mice did not show the increase in markers of neurodegeneration, the impairments in electrophysiologic properties of hippocampal synapses, or the susceptibility to kainate-induced epilepsy seen in the malin-knockout model, consistent with rescue from neurodegeneration. These mice also did not show impaired autophagy, as observed in malin-knockout mice. Additional mouse models with overaccumulation of glycogen showed impaired autophagy, suggesting that the accumulation of glycogen itself can cause autophagy impairment. The findings indicated that glycogen accumulation accounts for the neurodegeneration and functional consequences seen in the malin-knockout model, as well as the impaired autophagy. Duran et al. (2014) suggested that regulation of glycogen synthesis may be a key target for the treatment of Lafora disease. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Loss of vision \- Photosensitivity ABDOMEN Liver \- Hepatic failure (less common) NEUROLOGIC Central Nervous System \- Myoclonic epilepsy, progressive \- Generalized tonic-clonic seizures \- Absence seizures \- Simple partial occipital seizures \- Simple partial seizures with secondary generalization \- Myoclonus \- Mental deterioration \- Dementia \- Apraxia \- Visual hallucinations \- Gait disturbances \- Neurologic deterioration \- Disorganized EEG \- Intracellular PAS-positive polyglucosan inclusion bodies ('Lafora' bodies) Behavioral Psychiatric Manifestations \- Psychosis LABORATORY ABNORMALITIES \- Intracellular PAS-positive polyglucosan inclusion bodies ('Lafora' bodies) can be found in various tissues (brain, liver, muscle, heart, skin) MISCELLANEOUS \- Onset in late childhood/adolescence (approximately 15 years) \- Short survival (less than 10 years after onset) \- Rapidly progressive disorder \- Genetic heterogeneity \- Patients with mutation in the NHLRC1 gene have slightly longer survival MOLECULAR BASIS \- Caused by mutation in the laforin gene (EPM2A, 607566.0001 ) \- Caused by mutation in the malin gene (NHLRC1, 608072.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	MYOCLONIC EPILEPSY OF LAFORA	c0751783	4,377	omim	https://www.omim.org/entry/254780	2019-09-22T16:24:39	{"doid": ["3534"], "mesh": ["D020192"], "omim": ["254780"], "orphanet": ["501"], "synonyms": ["Alternative titles", "MELF", "LAFORA DISEASE", "LAFORA BODY DISEASE", "EPILEPSY, PROGRESSIVE MYOCLONIC, 2A", "EPM2"], "genereviews": ["NBK1389"]}
A number sign (#) is used with this entry because of evidence that Ehlers-Danlos syndrome spondylodysplastic type 3 (EDSSPD3) is caused by homozygous mutation in the zinc transporter gene SLC39A13 (608735) on chromosome 11p11. Description Ehlers-Danlos syndrome spondylodysplastic type 3 is characterized by short stature, hyperelastic skin and hypermobile joints, protuberant eyes with bluish sclerae, finely wrinkled palms, and characteristic radiologic features (Giunta et al., 2008). For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see 130070. Clinical Features Giunta et al. (2008) described a 'spondylocheiro dysplastic form of Ehlers-Danlos syndrome' in 6 patients from 2 consanguineous families. Clinical features included postnatal growth retardation, moderate short stature, protuberant eyes with bluish sclerae, hands with finely wrinkled palms, atrophy of the thenar muscles, and tapering fingers. Patients had thin, hyperelastic skin and hypermobile small joints consistent with an Ehlers-Danlos-like phenotype. Radiologic features included mild to moderate platyspondyly, mild to moderate osteopenia of the spine, small ileum, flat proximal femoral epiphyses, short, wide femoral necks, and broad metaphyses (elbows, knees, wrists, and interphalangeal joints). Biochemical Features Giunta et al. (2008) found that all 6 patients with a spondylocheirodysplastic form of EDS had an increased lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP) ratio indicating underhydroxylation of collagen. The ratio in patients (mean 0.89 +/- 0.18) was lower than that in individuals with EDS VI (225400; mean 5.97 +/- 0.99) but markedly higher than that in controls (mean 0.19 +/- 0.02). Mass-spectral analysis of the alpha-1 (120150) and alpha-2 (120160) chains of type I collagen revealed underhydroxylation of lysyl and prolyl residues. In vitro activities of lysyl hydroxylase (153454) and prolyl 4-hydroxylase (176710) were normal. Mapping By a genomewide SNP scan and linkage analysis, Giunta et al. (2008) defined a 16.9-Mb critical region for SCD-EDS on chromosome 11 between markers D11S1779 and D11S4191 (combined maximum lod score of 5.3). Molecular Genetics In all 6 affected members of 2 families with spondylocheirodysplastic EDS, Giunta et al. (2008) identified homozygosity for a 9-bp in-frame deletion in exon 4 of the membrane-bound zinc transporter SLC39A13 (608735.0001). Fukada et al. (2008) identified a homozygous loss-of-function mutation in the SLC39A13 gene (G74D; 608735.0002) in 2 sibs with an Ehlers-Danlos syndrome-like phenotype similar to that reported by Giunta et al. (2008). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature, moderate Weight \- Birthweight at or below 3rd centile Other \- Growth retardation, postnatal HEAD & NECK Eyes \- Protuberant eyes \- Blue sclerae \- Downslanting palpebral fissures \- Corneal diameter, normal Mouth \- High palate \- Bifid uvula Teeth \- Delayed eruption of teeth \- Malocclusion \- Hypodontia SKELETAL Spine \- Platyspondyly \- Osteopenia \- Irregular endplates Pelvis \- Small ilia \- Short, wide femoral neck \- Mildly flattened proximal femoral epiphyses Limbs \- Joint laxity (elbow) \- Widened metaphyses (elbows and knees) Hands \- Small joint laxity \- Finger contractures \- Slender, tapered fingers \- Finely wrinkled palms \- Thenar muscle atrophy \- Hypothenar muscle atrophy \- Inability to adduct thumbs \- Short metacarpals \- Short phalanges \- Widened metaphyses (metacarpal and phalanges) \- Flattened epiphyses (metacarpal and phalanges) Feet \- Pes planus SKIN, NAILS, & HAIR Skin \- Velvety, smooth skin \- Hyperelastic skin \- Thin skin \- Easy bruisability \- Finely wrinkled palms \- Prominent veins \- Cigarette-paper scars \- Delayed wound healing MUSCLE, SOFT TISSUES \- Thenar muscle atrophy \- Hypothenar muscle atrophy LABORATORY ABNORMALITIES \- Lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP) ratio approximately 1 \- Normal lysyl hydroxylase activity \- Normal prolyl 4-hydroxylase activity MISCELLANEOUS \- Waddling gait MOLECULAR BASIS \- Caused by mutation in the solute carrier family 39 (zinc transporter), member 13 gene (SLC39A13, 608735.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	EHLERS-DANLOS SYNDROME, SPONDYLODYSPLASTIC TYPE, 3	c2676510	4,378	omim	https://www.omim.org/entry/612350	2019-09-22T16:01:47	{"mesh": ["C567340"], "omim": ["612350"], "orphanet": ["157965"], "synonyms": ["Alternative titles", "SPONDYLOCHEIRODYSPLASIA, EHLERS-DANLOS SYNDROME-LIKE"]}
Myelomeningocele is the most severe form of spina bifida. It happens when parts of the spinal cord and nerves come through the open part of the spine. It causes nerve damage and other disabilities. Seventy to ninety percent of children with this condition also have too much fluid on their brains (hydrocephalus). This happens because fluid that protects the brain and spinal cord is unable to drain like it should. The fluid builds up, causing pressure and swelling. Without treatment, a person’s head grows too big, and they may have brain damage. Other disorders of the spinal cord may be seen, including syringomyelia and hip dislocation. The cause of myelomeningocele is unknown. However, low levels of folic acid in a woman's body before and during early pregnancy is thought to play a part in this type of birth defect. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Myelomeningocele	c0025312	4,379	gard	https://rarediseases.info.nih.gov/diseases/3475/myelomeningocele	2021-01-18T17:58:50	{"mesh": ["D008591"], "umls": ["C0025312"], "synonyms": ["Meningomyelocele"]}
## Description Yellow nail syndrome (YNS) is classically considered to comprise a clinical triad of yellow nails, lymphedema, and respiratory tract involvement. Two of these symptoms are required for the diagnosis, since the complete triad is only observed in about one-third of patients. Onset is usually after puberty (Hoque et al., 2007). Clinical Features Samman and White (1964) delineated the yellow nail syndrome, reporting 13 cases. The nails are typically slow growing and excessively curved, with a yellowish discoloration, and frequently show ridging due to interrupted growth. Onycholysis can occur in one or more nails. There is associated leg edema. Wells (1966) described a family with 8 cases in 4 sibships of 2 generations. In the proband, who had yellow nails, lymphedema began in the legs at the age of 51. At times edema also affected the genitalia, hands, face, and vocal cords. Lymphangiograms were interpreted as showing primary hypoplasia of lymphatics. Zerfas and Wallace (1966) described a sporadic case with onset of lymphedema at age 10. Recurrent pleural effusion occurred in some cases. Govaert et al. (1992) reported a girl who was born at 33 weeks' gestation with nonimmune hydrops and a recurrent left chylothorax to a mother with the yellow nail syndrome. The nonimmune hydrops in this case was diagnosed on a 29-week ultrasound examination. Slee et al. (2000) reported a case of a newborn infant who, at 23 weeks' gestation, was found to have hydrops on antenatal ultrasonography; bilateral chylothorax was found at delivery. The mother had the yellow nail syndrome, with typical nail changes, and bronchiectasis. The infant had a recurrent cough, possibly preceding early onset of bronchiectasis. Although lymphedema is the most consistent association with yellow nails, other associations include bronchiectasis, sinusitis, chronic cough, and pleural effusions. Nail changes include slow growth, yellow-green discoloration, transverse and longitudinal overcurvature, onycholysis, shedding, cross-ridging, and loss of lunulae and cuticles (Hoque et al., 2007). In a retrospective study of 11 patients with a diagnosis of YNS, Hoque et al. (2007) found only 1 with a relevant family history that included bronchiectasis and sinusitis, but not yellow nails. Age at onset in the majority of the patients was after 50 years. Four of the 11 patients had complete recovery of their nails over a mean period of 4 to 5 years. A literature review revealed that most of the reported cases have been sporadic. Hoque et al. (2007) concluded that yellow nail syndrome is a sporadic acquired condition rather than a dominantly inherited condition, as currently classified. Molecular Genetics Finegold et al. (2001) identified a mutation in the FOXC2 gene (602402.0007) in affected members of a family with lymphedema-distichiasis syndrome (153400). None of these patients were reported as having yellow nails. However, the same mutation was found in 7 affected members of another family with lymphedema-distichiasis syndrome, 3 of whom also had yellow nails. Finegold et al. (2001) concluded that there is phenotypic overlap between lymphedema-distichiasis syndrome and lymphedema-yellow nail syndrome. The authors stated that the phenotypic classification of autosomal dominant lymphedema does not appear to reflect the underlying genetic causation of these disorders, as they may be allelic. Rezaie et al. (2008) suggested that lymphedema with yellow nails is not a distinct disorder but rather in the spectrum of lymphedema-distichiasis syndrome. They noted that 6 of the 7 patients in the family of Finegold et al. (2001) reported as having yellow-nail syndrome also had distichiasis, which is characteristic of the lymphedema-distichiasis syndrome. In addition, Rezaie et al. (2008) noted that Finegold et al. (2001) found no FOXC2 mutations in 4 additional families with lymphedema and yellow nails. Rezaie et al. (2008) stated that yellow discoloration of the nails is not uncommon with lymphedema, but does not necessarily indicate a diagnosis of so-called 'yellow nail syndrome,' in which the nail changes are very specific. In yellow nail syndrome, the nail plate is yellow and overcurved, but remains translucent and smooth. By contrast, yellow nails in lymphedema syndromes become thickened, rough, and opaque. Associated features such as chronic sinusitis, bronchiectasis or pleural effusion are often essential for a diagnosis of yellow nail syndrome. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Nails \- Yellow nails \- Slow-growing nails \- Excessively curved nails MUSCLE, SOFT TISSUES \- Lymphedema, predominantly in the lower limbs \- Onset of lymphedema around puberty \- Lymphography shows hypoplasia of the lymphatic vessels MISCELLANEOUS \- Yellow nails have been observed in some patients with a mutation in the forkhead box C2 gene (FOXC2, 602402.0007 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	YELLOW NAIL SYNDROME	c0221348	4,380	omim	https://www.omim.org/entry/153300	2019-09-22T16:38:44	{"doid": ["0050468"], "mesh": ["D056684"], "omim": ["153300"], "icd-10": ["L60.5"], "orphanet": ["662"], "synonyms": ["Alternative titles", "YNS", "LYMPHEDEMA AND YELLOW NAILS"]}
## Clinical Features Smith et al. (2008) reported 3 sibs, 2 boys and a girl, with a similar syndrome comprising hypotonia, seizures, and dysmorphic features. Two of the children had precocious puberty. At birth, all had severe hypotonia and abnormal facial features including brachycephaly, plagiocephaly, and prominent eyes. Other features included transverse palmar creases, folded toes, severe developmental delay, and onset of myoclonic and generalized seizures within the first 2 years of life. Variable features included preauricular tags and inverted nipples. One of the boys died unexpectedly at age 9 years. The other boy and the girl developed signs of precocious puberty at ages 7 and 5, respectively. Laboratory studies showed increased serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Smith et al. (2008) noted that some of the features were similar to that of Prader-Willi syndrome (176270), but none of the children had feeding problems or obesity. Extensive cytogenetic and metabolic studies did not show any abnormalities. Autosomal recessive inheritance was postulated. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	HYPOTONIA, SEIZURES, AND PRECOCIOUS PUBERTY	c2748586	4,381	omim	https://www.omim.org/entry/612777	2019-09-22T16:00:39	{"mesh": ["C567566"], "omim": ["612777"]}
Woodhouse-Sakati syndrome is a disorder that primarily affects the body's network of hormone-producing glands (the endocrine system) and the nervous system. The signs and symptoms of this condition, which gradually get worse, vary widely among affected individuals, even within the same family. People with Woodhouse-Sakati syndrome produce abnormally low amounts of hormones that direct sexual development (hypogonadism), which typically becomes apparent during adolescence. Without hormone replacement therapy, affected individuals do not develop secondary sexual characteristics such as pubic hair, breast growth in females, or a deepening voice in males. Females with Woodhouse-Sakati syndrome do not have functional ovaries and may instead have undeveloped clumps of tissue called streak gonads. The uterus may also be small or absent in affected females. Males with this disorder have testes that produce little to no sperm. As a result, people with Woodhouse-Sakati syndrome usually have an inability to conceive children (infertility). By their mid-twenties, almost all affected individuals develop diabetes mellitus, and they may also have reduced production of thyroid hormones (hypothyroidism). People with Woodhouse-Sakati syndrome also experience hair loss beginning in childhood that gradually gets worse, often resulting in the loss of all scalp hair (alopecia totalis) during adulthood. Eyelashes and eyebrows are sparse or absent, and affected men have little or no facial hair. Some affected individuals have additional characteristic facial features including a long, triangular face; widely spaced eyes (hypertelorism); and a prominent bridge of the nose. More than half of people with Woodhouse-Sakati syndrome have neurological problems. A group of movement abnormalities called dystonias are common in affected individuals, generally beginning in adolescence or young adulthood. These movement abnormalities can include involuntary tensing of the muscles (muscle contractions) or twisting of specific body parts such as an arm or a leg. Other neurological features can include difficulty with speech (dysarthria) or swallowing (dysphagia), mild intellectual disability, and hearing loss caused by changes in the inner ears (sensorineural hearing loss). The hearing problems develop after the individual has acquired spoken language (post-lingual), usually in adolescence. In some affected individuals, abnormal deposits of iron in the brain have been detected with medical imaging. For this reason, Woodhouse-Sakati syndrome is sometimes classified as part of a group of disorders called neurodegeneration with brain iron accumulation (NBIA). ## Frequency Woodhouse-Sakati syndrome is a rare disorder; its prevalence is unknown. Only a few dozen affected families, mostly in the Middle East, have been described in the medical literature. ## Causes Woodhouse-Sakati syndrome is caused by mutations in the DCAF17 gene. This gene provides instructions for making a protein whose function is unknown. The protein is found in several organs and tissues in the body, including the brain, skin, and liver. Most of the DCAF17 gene mutations that have been identified in people with Woodhouse-Sakati syndrome result in a protein that is abnormally short and breaks down quickly or whose usual function is impaired. Loss of DCAF17 protein function likely accounts for the features of Woodhouse-Sakati syndrome, although it is unclear how a shortage of this protein leads to hormone abnormalities and the other signs and symptoms. Researchers suggest that the variation in features of the disorder even within a single family may be caused by the effects of variations in other genes called modifiers; however, these genes have not been identified. ### Learn more about the gene associated with Woodhouse-Sakati syndrome * DCAF17 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Woodhouse-Sakati syndrome	c0342286	4,382	medlineplus	https://medlineplus.gov/genetics/condition/woodhouse-sakati-syndrome/	2021-01-27T08:25:36	{"gard": ["5592"], "mesh": ["C536742"], "omim": ["241080"], "synonyms": []}
This article may be in need of reorganization to comply with Wikipedia's layout guidelines. Please help by editing the article to make improvements to the overall structure. (July 2012) (Learn how and when to remove this template message) Duct ectasia of breast One of the symptoms of mammary duct ectasia is inverted nipples. SpecialtyBreast surgery Symptomsnipple retraction, inversion, pain, green-brown discharge Complicationsnipple discharge, breast discomfort, infection, concern about breast cancer[1] CausesAging, smoking, inverted nipples Diagnostic methodduct widening Differential diagnosismammary duct ectasia, plasma cell mastitis Duct ectasia of the breast, mammary duct ectasia or plasma cell mastitis is a condition in which occurs when a milk duct beneath the nipple widens, the duct walls thicken and the duct fills with fluid. This is the most common cause of greenish discharge.[1] Mammary duct ectasia can mimic breast cancer. It is a disorder of peri- or post-menopausal age.[2] Duct ectasia syndrome is a synonym for nonpuerperal mastitis, but the term has also been occasionally used to describe special cases of fibrocystic diseases or mastalgia or as a wastebasket definition of benign breast disease. Correlation of duct widening with the "classical" symptoms of duct ectasia syndrome is unclear. However, duct widening was recently very strongly correlated with noncyclic breast pain.[3] Duct diameter is naturally variable, subject to hormonal interactions. Duct ectasia syndrome in the classical meaning is associated with additional histological changes.[citation needed] ## Contents * 1 Symptoms * 2 Causes * 3 Pathogenesis * 4 Diagnosis * 5 Duct Ectasia Syndrome * 6 Prognosis * 7 Terminology * 8 References * 9 External links ## Symptoms[edit] Signs of duct ectasia can include nipple retraction, inversion, pain,[4] and classic green-brown discharge. ## Causes[edit] Breasts are made up of fibrous connective tissues, which are made up of cells, fibers and a gel-like substance.[5] ## Pathogenesis[edit] The duct widening is commonly believed to be a result of secretory stasis, including stagnant colostrum, which also causes periductal inflammation and fibrosis. However, because nonspecific duct widening is common it might be also coincidental finding in many processes. Smokers seem more often affected by duct ectasia syndrome although the reported results are not entirely consistent. The correlation with smoking status appears weaker than for subareolar abscess. Correlation with the actual duct widening is not known. Both duct widening and duct ectasia syndrome are frequently bilateral, hence systemic causes are likely involved. ## Diagnosis[edit] Detail of a mammography showing liponecrosis (round/oval calcifications) and plasma cell mastitis with typical rod-like calcifications Noninvasive methods to determine duct diameter in live patients are available only recently and it is not clear how the results should be compared with older results from biopsies. Histologically, dilation of the large duct is prominent. Duct widening with associated periductal fibrosis is frequently included in the wastebasket definition of fibrocystic disease. In plasma cell rich lesions diagnosed on core biopsies, steroid-responsive IgG4-related mastitis can be identified by IgG/IgG4 immunostaining.[6] ## Duct Ectasia Syndrome[edit] The term duct ectasia syndrome has been used to describe symptoms of nonpuerperal mastitis, possibly associated with nipple inversion and nipple discharge. In some contexts, it was used to describe a particular form of nonpuerperal mastitis coincident with fibrocystic disease, frequently involving pasty (coloured) nipple discharge, nipple retraction, retroareolar abscess and blue dome cysts. Abscessation is not very frequent but by some definitions recurrent subareolar abscess is merely a variant of duct ectasia syndrome - abscessation would be obviously more frequent with this definition. Duct ectasia syndrome has been associated with histopathological findings that are distinct from a simple duct widening. In addition to nonspecific duct widening the myoepithelial cell layer is atrophic, missing or replaced by fibrous tissue. The original cuboidal epithelial layer may be also severely impaired or missing. Characteristic calcifications are often visible on mammographic images. Periductal mastitis, comedo mastitis, secretory disease of the breast, plasma cell mastitis and mastitis obliterans are sometimes considered special cases or synonyms of duct ectasia syndrome. ## Prognosis[edit] The condition is usually self-limiting, and thus not indicated for surgery. ## Terminology[edit] The term has several meanings on histological and symptomatic levels and on both levels usage overlaps with mastalgia, fibrocystic disease and specific sub- or superclasses of nonpuerperal mastitis. While this is not ideal for a definition it results from actual usage in international literature. Because research literature regarding duct ectasia is anything but abundant it is probably easiest to determine the exact meaning(s) intended by the respective authors on a case by case basis and this section can offer only a few hints. Typical usage in North America is a synonym of nonpuerperal mastitis, including the special cases of granulomatous mastitis, comedo mastitis, subareolar abscess with or without squamous metaplasia of lactiferous ducts and fistulation.[7] Simple duct widening should be carefully distinguished from more complex histological changes. ## References[edit] 1. ^ a b "Mammary duct ectasia - MayoClinic.com". 2. ^ "Nipple Problems and Discharge". The Johns Hopkins University. Retrieved 22 April 2014. 3. ^ Peters F, Diemer P, Mecks O, Behnken LLJ (2003). "Severity of mastalgia in relation to milk duct dilatation". Obstet Gynecol. 101 (1): 54–60. doi:10.1016/S0029-7844(02)02386-4. PMID 12517645. 4. ^ Browning J, Bigrigg A, Taylor I (December 1986). "Symptomatic and incidental mammary duct ectasia". J R Soc Med. 79 (12): 715–6. PMC 1290571. PMID 3806542. 5. ^ "NCI Dictionary of Cancer Terms". National Cancer Institute. 2011-02-02. Retrieved 2020-03-19. 6. ^ Chougule A, Bal A, Das A, Singh G (January 2015). "IgG4 related sclerosing mastitis: expanding the morphological spectrum of IgG4 related diseases". Pathology. 47 (1): 27–33. doi:10.1097/PAT.0000000000000187. PMID 25474510. 7. ^ "Mammary Duct Ectasia: Stanford University criteria". May 27, 2006. ## External links[edit] Classification D * ICD-10: N60.4 * ICD-9-CM: 610.4 * DiseasesDB: 3994 * v * t * e Breast disease Inflammation * Mastitis * Nonpuerperal mastitis * Subareolar abscess * Granulomatous mastitis Physiological changes and conditions * Benign mammary dysplasia * Duct ectasia of breast * Chronic cystic mastitis * Mammoplasia * Gynecomastia * Adipomastia (lipomastia, pseudogynecomastia) * Breast hypertrophy * Breast atrophy * Micromastia * Amastia * Anisomastia * Breast engorgement Nipple * Nipple discharge * Galactorrhea * Inverted nipple * Cracked nipples * Nipple pigmentation Masses * Galactocele * Breast cyst * Breast hematoma * Breast lump * Pseudoangiomatous stromal hyperplasia Other * Pain * Tension * Ptosis * Fat necrosis * Amazia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Duct ectasia of breast	c0152442	4,383	wikipedia	https://en.wikipedia.org/wiki/Duct_ectasia_of_breast	2021-01-18T18:58:30	{"umls": ["C0152442"], "icd-9": ["610.4"], "icd-10": ["N60.4"], "wikidata": ["Q3718771"]}
## Summary ### Clinical characteristics. X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of PRPS1-related disorders, is characterized by peripheral neuropathy, early-onset (prelingual) bilateral profound sensorineural hearing loss, and optic neuropathy. The onset of peripheral neuropathy is between ages five and 12 years. The lower extremities are affected earlier and more severely than upper extremities. Initial manifestations often include foot drop or gait disturbance. Onset of visual impairment is between ages seven and 20 years. Intellect and life span are normal. Carrier females do not have findings of CMTX5. ### Diagnosis/testing. Diagnosis is based on clinical findings, family history consistent with X-linked inheritance, and identification of a pathogenic variant in PRPS1, the only gene in which pathogenic variants are known to cause CMTX5. ### Management. Treatment of manifestations: Peripheral neuropathy, hearing loss, and visual impairment are managed in a routine manner. Surveillance: Regular neurologic and ophthalmologic evaluations to monitor symptom development and disease progression. Agents/circumstances to avoid: Medications known to cause acquired peripheral neuropathy. Evaluation of relatives at risk: It is appropriate to evaluate at-risk males at birth with detailed audiometry to assure early diagnosis and treatment of hearing loss. ### Genetic counseling. CMTX5 is inherited in an X-linked manner. Carrier women have a 50% chance of transmitting the PRPS1 pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and typically will not be affected. Males pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in the family. ## Diagnosis ### Clinical Diagnosis X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), part of the spectrum of PRPS1-related disorders, is characterized by the following: Peripheral neuropathy * Motor nerve conduction velocities (NCVs) of affected males reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy. * Compound motor/sensory action potentials are not induced. * Needle electromyography (EMG) reveals polyphasic potentials with a prolonged duration and reduced recruitment pattern. Early-onset sensorineural hearing loss * Pure tone audiograms demonstrate bilateral profound sensorineural hearing loss. * Auditory brain stem response waveforms may not be obtained. * Temporal bone computed tomography reveals no abnormal findings. Optic neuropathy * Fundoscopic examination shows bilateral optic disc pallor, indicating optic atrophy. * Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. * Electroretinogram is normal. ### Testing Phosphoribosylpyrophosphate synthetase (PRS) enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes [Torres et al 1996]. PRS enzyme activity in three individuals with CMTX5 was decreased compared to controls [Kim et al 2007]. Note: Because it is difficult to assay PRS1 enzyme activity separately from that of the other two isoforms (PRS2 and PRS3), decrease in PRS enzyme activity is assumed to reflect decreased activity of PRS1, not PRS2 or PRS3. Serum uric acid concentrations measured in three individuals with CMTX5 of Korean descent and two of European descent (originally reported as having Rosenberg-Chutorian syndrome) were within the normal range [Kim et al 2007]. #### Molecular Genetic Testing Gene. PRPS1, encoding phosphoribosyl pyrophosphate synthetase I, is the only gene in which pathogenic variants are known to cause CMTX5. ### Table 1. Molecular Genetic Testing Used in CMTX5 View in own window Gene 1MethodVariants Detected 2Variant Detection Frequency by Method 3 PRPS1Sequence analysis 4Sequence variants100% 5, 6, 7 Deletion/duplication analysis 8Exon/whole-gene deletions or duplicationsUnknown 9 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants. 3\. The ability of the test method used to detect a pathogenic variant that is present in the indicated 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\. Two families reported to date [Kim et al 2007] 6\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. 7\. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female. 8\. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 9\. No deletions or duplications of PRPS1 have been reported to cause Charcot-Marie-Tooth neuropathy X type 5. ### Testing Strategy To confirm/establish the diagnosis in a proband, identification of a pathogenic variant in PRPS1 is necessary. Carrier testing for at-risk relatives requires prior identification of the pathogenic variant in the family. Note: (1) Carriers are heterozygotes for this X-linked disorder and are not known to be at risk of developing clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the pathogenic variant in an affected male relative or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis and then, if no pathogenic variant is identified, by deletion/duplication analysis. Prenatal diagnosis and preimplantation genetic testing for at-risk pregnancies require prior identification of the pathogenic variant in the family. ## Clinical Characteristics ### Clinical Description The symptom triad of CMTX5 is peripheral neuropathy, sensorineural hearing loss, and optic neuropathy. The age at onset of symptoms of peripheral neuropathy ranges from five to 12 years. The initial manifestation is often foot drop or gait disturbance. Deep tendon reflexes are usually absent. Motor signs predominate, but impairment of sensory function may accompany motor dysfunction or develop during disease progression. Lower extremities are affected earlier and more severely than upper extremities. Typically, boys with CMTX5 have early-onset (prelingual) sensorineural hearing loss. The age at onset of visual impairment ranged from seven to 20 years. Affected individuals have normal intellect. Both peripheral neuropathy and optic neuropathy progress with time. With advancing disease, affected individuals may become dependent on crutches or a wheelchair. There is no evidence that life span is shortened in individuals with CMTX5 [Rosenberg & Chutorian 1967, Kim et al 2007]. Carrier females do not have findings of CMTX5. Sural nerve biopsy demonstrates demyelination and axonal loss. Electron microscopic examination reveals onion bulb formation [Kim et al 2007]. ### Genotype-Phenotype Correlations Across the four disease phenotypes included as PRPS1-related disorders, only pathogenic missense variants have been reported to date. No correlation between specific PRPS1 pathogenic missense variants and phenotype is known. ### Penetrance Penetrance is complete for CMTX5. ### Prevalence Prevalence has not been estimated. Two families with CMTX5 have been identified worldwide [Rosenberg & Chutorian 1967, Kim et al 2007]. CMTX5 appears to be very rare; however, it may be underdiagnosed as a result of under-recognition by physicians. ## Differential Diagnosis Peripheral neuropathy. See Charcot-Marie-Tooth Hereditary Neuropathy Overview. X-linked Charcot-Marie-Tooth disease (CMTX). CMTX5 is clearly distinguishable from the five other forms of X-linked Charcot-Marie-Tooth disease [Kim et al 2005] (see Charcot-Marie-Tooth Neuropathy X Type 1): * CMTX type 1 is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families. The gene in which mutation is causative is GJB1 (Cx32). * CMTX2 with intellectual disability maps to Xp22.2 [Ionasescu et al 1991, Ionasescu et al 1992]. * CMTX3 with spasticity and pyramidal tract signs maps to Xq26 [Ionasescu et al 1991, Ionasescu et al 1992, Huttner et al 2006]. * CMTX4 (Cowchock syndrome) with deafness and intellectual disability resulting from mutation in AIFM1 [Cowchock et al 1985, Priest et al 1995, Rinaldi et al 2012]. * CMTX6, resulting from mutation in PDK3. Males have childhood onset of a slowly progressive motor and sensory neuropathy that is largely axonal (variable mild conduction slowing) with steppage gait and absent tendon reflexes. Carrier females may have a mild sensory motor axonal neuropathy [Kennerson et al 2013]. Sensorineural hearing loss. It is important to suspect CMTX5 when boys with early-onset sensorineural hearing loss develop gait disturbance and visual disturbance. See Deafness and Hereditary Hearing Loss Overview. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CMTX5, the following evaluations are recommended: * Neurologic examination * Pure tone audiograms, auditory brain stem response test * Evaluation of visual acuity, fundoscopic examination * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Peripheral neuropathy. See Charcot-Marie-Tooth Hereditary Neuropathy Overview, Management. Sensorineural hearing loss. See Deafness and Hereditary Hearing Loss Overview, Management. Optic atrophy. Use of routine low-vision aids as needed is appropriate. ### Prevention of Secondary Complications Daily heel cord stretching exercises are desirable to prevent Achilles’ tendon shortening from peripheral neuropathy, which can occur in individuals with CMTX5. ### Surveillance Individuals should be evaluated regularly by a team comprising otologists, ophthalmologists, neurologists, physiatrists, and physical and occupational therapists to determine neurologic status and functional disability. While profound hearing loss begins during infancy, optic neuropathy and peripheral neuropathy in CMTX5 vary in age of onset of manifestations and progression. Thus, regular ophthalmologic and neurologic exams are warranted to monitor symptom development and progression. ### Agents/Circumstances to Avoid Obesity makes walking more difficult. Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. ### Evaluation of Relatives at Risk It is appropriate to evaluate at-risk males at birth with detailed audiometry to assure early diagnosis and treatment of hearing loss. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Dietary S-adenosylmethionine (SAM) supplementation could theoretically alleviate some of the symptoms of Arts syndrome by providing an oral source of purine nucleotide precursor that is not PRPP dependent. Furthermore, SAM is known to cross the blood-brain barrier. An adult with HPRT deficiency is reported to have benefitted neurologically from SAM administration without untoward side effects [Glick 2006]. An open-label clinical trial of SAM in two Australian brothers (ages 14 and 13 in 2010) with Arts syndrome is continuing [J Christodoulou et al, unpublished data; approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia]. Oral SAM supplementation is presently set at 30 mg/kg/day. The boys appear to have had significant benefit from this therapy based on decreased number of hospitalizations and stabilization of nocturnal BIPAP requirements; however, slight deterioration in their vision has been noted. Mildly affected carrier females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested. Whether treatment with SAM supplementation would benefit individuals with allelic disorders (PRS superactivity, Charcot-Marie-Tooth neuropathy X type 5) remains to be investigated. 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Charcot-Marie-Tooth Neuropathy X Type 5	c1839566	4,384	gene_reviews	https://www.ncbi.nlm.nih.gov/books/NBK1876/	2021-01-18T21:35:18	{"mesh": ["C537129"], "synonyms": ["CMTX5", "Rosenberg-Chutorian Syndrome"]}
Werner syndrome (WS) is a rare inherited syndrome characterized by premature aging with onset in the third decade of life and with cardinal clinical features including bilateral cataracts, short stature, graying and thinning of scalp hair, characteristic skin disorders and premature onset of additional age-related disorders. ## Epidemiology The prevalence among Japanese and Sardinian populations is estimated to be 1/50,000 due to the presence of founder mutations. Prevalence in other populations is unknown, but may be around 1/200,000. ## Clinical description WS patients are normal at birth and during childhood, apart from the absence of a pubertal growth spurt. WS presents between the ages of 20 and 30 with major symptoms of early onset bilateral cataracts, thinning and graying of the hair, short stature and skin changes (ankle ulceration, hyperkeratosis, tight skin, age spots, ''bird-like'' facies and subcutaneous atrophy). In most cases, additional age-related disorders are seen and include osteoporosis, diabetes mellitus, mesenchymal neoplasms and atherosclerosis. Voice changes are frequent and flat feet are sometimes present. Patients with WS have a high risk of developing cancer, in particular sarcomas of mesenchymal origin and melanomas that are not due to sun exposure. Death is usually due to malignancies or myocardial infarction caused by extensive atherosclerosis. ## Etiology WS is caused by a mutation in the WRN gene, located on chromosome 8p11-12. WRN codes for one of the five RecQ helicases in humans. Nonsense mutations, insertions and/or deletions or substitutions in the WRN gene all lead to genome instability. Mutations in the WRN gene are found in approximately 90% of clinically diagnosed WS cases. The other 10% are operationally categorized as atypical Werner syndrome (see this term) and are due to other causes (such as a mutation in the LMNA gene). ## Diagnostic methods A clinical diagnosis is based on the presence of all major symptoms (cataracts, skin changes, premature graying/thinning of hair and short stature) and two additional signs (such as osteoporosis or voice change) presenting after adolescence. Molecular analysis can identify most of the mutations in the WRN gene by standard exon sequencing and sequencing of RT-PCR products, in combination with Western blot analysis showing the absence of normal WRN protein. ## Differential diagnosis Differential diagnoses include mandibuloacral dysplasia (MAD), partial lipodystrophy, Rothmund-Thomson syndrome (RTS) and Hutchinson-Gilford progeria syndrome (HGPS; see these terms). Type 2 diabetes mellitus can also share similarities with WS. ## Genetic counseling WS is inherited in an autosomal recessive manner. Once a patient is diagnosed with WS, the patient and family should receive genetic counseling in order to identify those that could develop the disease and those who are carriers. Offspring of a patient with WS are obligate carriers, but unlikely to be affected, given the low likelihood of marrying a carrier unless there is consanguinity. ## Management and treatment There is no cure for WS and treatment involves a multidisciplinary team. Cataracts can be treated with surgery. Regular physical examinations are needed to check for skin ulcers, diabetes, malignancies or cardiovascular disease. Any malignancies should be treated with surgery, chemotherapy and/or radiation. Smoking should be avoided and a healthy lifestyle, including regular exercise and a diet low in fat, should be followed. Psychological counseling may also be beneficial in supporting patients and family members affected by WS. ## Prognosis Patients with WS have a shortened life expectancy but prognosis depends on the age-related diseases present and their severity. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Werner syndrome	c0043119	4,385	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=902	2021-01-23T18:11:28	{"gard": ["7885"], "mesh": ["D014898"], "omim": ["277700"], "umls": ["C0043119"], "icd-10": ["E34.8"], "synonyms": ["Adult progeria", "WS"]}
Lichen planopilaris (LPP) affects the scalp and hair. It is a form of lichen planus, an inflammatory condition affecting the skin and mucous membranes. Symptoms may include scaly skin and redness around hair follicles, bald patches, and pain, burning, or itching on the scalp. Tiny, red bumps (papules) may appear around hair clusters. LLP can cause scarring which leads to permanent hair loss (cicatricial alopecia). There are 3 forms of LPP which differ by the pattern and location of symptoms: classic LPP, frontal fibrosing alopecia, and Lassueur Graham-Little Piccardi syndrome. The cause of LPP is unknown. It is thought to be an auto-immune disorder of the hair follicles. A diagnosis of LPP is made based on a clinical exam and microscopic examination of a piece of tissue from the affected area. Treatment options may include different oral and topical medications and light therapy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Lichen planopilaris	c0023645	4,386	gard	https://rarediseases.info.nih.gov/diseases/3247/lichen-planopilaris	2021-01-18T17:59:25	{"mesh": ["C535892"], "umls": ["C0023645"], "orphanet": ["525"], "synonyms": ["Follicular lichen planus", "Frontal fibrosing alopecia (subtype)", "Kossard disease", "Lichen planopilaris classic type", "LPP", "Lichen planus follicularis", "Lichen follicularis"]}
CLPB deficiency is a rare disorder characterized by neurological problems and a shortage of infection-fighting white blood cells (neutropenia). Signs and symptoms of the condition develop by early childhood, and their severity varies widely among affected individuals. In the most severely affected individuals, features of CLPB deficiency are apparent in infancy and sometimes at birth. Affected babies have serious neurological problems, which can include an exaggerated startle reaction (hyperekplexia) to unexpected stimuli such as loud noises, reduced movement, muscle tone that is either decreased (hypotonia) or increased (hypertonia), swallowing problems, difficulty breathing, and recurrent seizures (epilepsy). These babies may also have movement abnormalities, such as difficulty coordinating movements (ataxia), involuntary tensing of the muscles (dystonia), or uncontrolled movements of the body (dyskinesia). In addition, these babies have recurrent, life-threatening infections due to severe neutropenia. Affected individuals are at risk of developing a blood cell disorder called myelodysplastic syndrome or a form of blood cancer called leukemia. Because of their severe health problems, affected infants usually live only a few weeks or months. Moderately affected individuals have neurological problems similar to those described above, although they are less severe. They include hypotonia, muscle stiffness (spasticity), and movement abnormalities. Other features of moderate CLPB deficiency include epilepsy and mild to severe intellectual disability. Neutropenia in these individuals can lead to recurrent infections, although they are not life-threatening. Mildly affected individuals have no neurological problems, and although they have neutropenia, it does not increase the risk of infections. Some people with mild CLPB deficiency develop deposits of calcium in the kidneys (nephrocalcinosis) or kidney (renal) cysts. Many people with mild, moderate, or severe CLPB deficiency have clouding of the lenses of the eyes (cataracts) from birth (congenital) or beginning in infancy. CLPB deficiency is associated with increased levels of a substance called 3-methylglutaconic acid in the urine (3-methylglutaconic aciduria). This abnormality, which provides a clue to the diagnosis, does not appear to cause any health problems. ## Frequency CLPB deficiency is a rare disorder; the prevalence is not known. At least 26 cases have been reported in the medical literature. ## Causes CLPB deficiency is caused by mutations in the CLPB gene, which provides instructions for making a protein whose function is unknown. Based on its similarity to a protein in other organisms, the CLPB protein is thought to help unfold misfolded proteins so they can be refolded correctly. If not fixed, misfolded proteins cannot function properly and may be damaging to cells. CLPB gene mutations likely reduce or eliminate the amount of functional CLPB protein. The severity of the condition is thought to be related to the amount of functional protein remaining: severe CLPB deficiency is likely caused by a complete absence of CLPB protein, while moderate and mild CLPB deficiency result when some functional CLPB protein is produced. Researchers are unsure how reduction or absence of this protein leads to the signs and symptoms of CLPB deficiency. ### Learn more about the gene associated with CLPB deficiency * CLPB ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	CLPB deficiency	c4225393	4,387	medlineplus	https://medlineplus.gov/genetics/condition/clpb-deficiency/	2021-01-27T08:25:30	{"omim": ["616271"], "synonyms": []}
Infantile pyruvate carboxylase (PC) deficiency (Type A) is a rare, severe form of PC deficiency characterized by infantile-onset, mild to moderate lactic acidemia, and a generally severe course. ## Epidemiology The specific prevalence of type A pyruvate carboxylase deficiency is not known but it has been reported most often in Native Americans from North American Algonquian-speaking groups including the Mi'kmaq, Cree, and Ojibwa tribes. In these groups, the carrier frequency may be as high as 1/10. ## Clinical description Patients with Type A PC deficiency usually first present with symptoms at the age of two to five months, often after normal early development. Clinical manifestations include mild to moderate metabolic acidosis with acute vomiting and tachypnea, failure to thrive, apathy, delayed intellectual and motor development, hypotonia, pyramidal dysfunction, ataxia, nystagmus and seizures. Renal tubular acidosis has also been reported. ## Etiology PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5). ## Diagnostic methods Biochemical testing shows hypoglycemia and ketosis, increased alanine and proline levels, but normal citrulline and lysine levels, along with a normal lactate-to-pyruvate ratio despite acidemia, and normal hydroxybutyrate/acetoacetate (H/A) ratio in plasma. Blood lactic acid levels are usually between 2 and 10 mmol/l. PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing. ## Genetic counseling PC deficiency is inherited in an autosomal recessive manner. ## Prognosis Most affected patients die in infancy or in early childhood. Surviving children require special care and schooling. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Pyruvate carboxylase deficiency, infantile type	c0034341	4,388	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353308	2021-01-23T16:52:44	{"mesh": ["D015324"], "omim": ["266150"], "icd-10": ["E74.4"], "synonyms": ["Pyruvate carboxylase deficiency type A"]}
A number sign (#) is used with this entry because of evidence that platelet-type bleeding disorder-19 (BDPLT19) is caused by homozygous mutation in the PRKACG gene (176893) on chromosome 9q21. One such family has been reported. Clinical Features Manchev et al. (2014) reported a brother and sister, born of consanguineous parents of West Indian origin, with a bleeding disorder. Both sibs had onset in early childhood of recurrent bleeding episodes, including epistaxis and spontaneous hematomas; the sister also had menorrhagia and ovarian cyst ruptures. Laboratory studies showed severe thrombocytopenia with 90% of the platelets being macrocytic. Bone marrow biopsy of the proposita showed abnormal megakaryocytic clusters with no apparent defect in differentiation or ploidization. Inheritance The transmission pattern of BDPLT19 in the family reported by Manchev et al. (2014) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 sibs, born of consanguineous parents of West Indian descent, with platelet-type bleeding disorder-19, Manchev et al. (2014) identified a homozygous missense mutation in the PRKACG gene (I74M; 176893.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Studies of patient platelets suggested that the mutation caused a loss of function, resulting in defective platelet activation, impaired cytoskeleton reorganization, and impaired megakaryocyte proplatelet formation. INHERITANCE \- Autosomal recessive HEAD & NECK Nose \- Epistaxis GENITOURINARY Internal Genitalia (Female) \- Menorrhagia SKIN, NAILS, & HAIR Skin \- Spontaneous hematomas HEMATOLOGY \- Bleeding tendency \- Anemia \- Macrothrombocytopenia \- Platelets show defective activation MISCELLANEOUS \- Onset in early childhood \- One consanguineous family of Indian descent has been reported (last curated January 2015) MOLECULAR BASIS \- Caused by mutation in the cAMP-dependent protein kinase, catalytic, gamma gene (PRKACG, 176893.0001 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	BLEEDING DISORDER, PLATELET-TYPE, 19	c4015405	4,389	omim	https://www.omim.org/entry/616176	2019-09-22T15:49:44	{"doid": ["0111048"], "omim": ["616176"], "orphanet": ["438207"], "synonyms": []}
Acute myeloblastic leukemia with maturation Myeloblast SpecialtyHematology, oncology Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).[1] Acute myeloid leukemia (AML) is a type of cancer affecting blood cells that eventually develop into non-lymphocyte white blood cells. The disease originates from the bone marrow, the soft inner portion of select bones where blood stem cells develop into either lymphocyte or in this particular condition, myeloid cells. This acute disease prevents bone marrow cells from properly maturing, thus causing an accumulation of immature myeloblast cells in the bone marrow. Acute myeloid leukemia is more lethal than chronic myeloid leukemia, a disease that affects the same myeloid cells, but at a different pace. Many of the immature blast cells in acute myeloid leukemia have a higher loss of function and thus, a higher inability to carry out normal functions than those more developed immature myeloblast cells in chronic myeloid leukemia (O’Donnell et al. 2012). Acute in acute myeloid leukemia means that the amounts of blast cells are increasing at a very high rate. Myeloid refers to the type of white blood cells that are affected by the condition. Acute myeloid leukemia is the most common acute leukemia that is affecting the adult population. The 5-year survival rate for the cancer stands at around 26% (ACS, 2016). M2 acute myeloblastic leukemia with maturation refers to the subtype of acute myeloid leukemia characterized by the maturation stages of the myeloid cell development and the location of the AML1 gene. One of the hallmarks of M2 subtype acute myeloid leukemia is the formation of a fusion protein, AML1-ETO or RUNX1-RUNX1T1, due to a translocation of chromosome 8 to chromosome 21 or t(8;21) (Miyoshi et al., 1991, Andrieu et al., 1996). This cytogenetic abnormality has been found in 90% of M2 acute myeloblastic leukemia; while the other 10% constitutes a mix of M1 and M4 acute myeloid leukemia (GFHC, 1990). Another translocation between chromosome 6p23 and chromosome 9q34 is also associated with the M2 subtype. The t(6;9) causes the formation of a fusion oncogene made of DEK (6p23) and CAN/NUP214 (9q34). This rare translocation has a poor prognosis compared to the t(8;21) because 70% of t(6;9) acute myeloid leukemia patients have the FLT3-ITD mutation (Schwartz et al., 1983, Kottaridis, 2001). The FLT-ITD mutation is one of the most lethal mutations in acute myeloid leukemia (Chi et al., 2008). M2 acute myeloblastic leukemia with maturation, as classified by the FAB system, constitutes 25% of adult AML. ## Contents * 1 Cause * 1.1 Genetics * 1.2 Molecular mechanism * 1.3 Autophagy in M2 AML * 2 Diagnosis * 3 Treatments * 4 References * 5 External links ## Cause[edit] This subtype is characterized by a translocation of a part of chromosome 8 to chromosome 21, written as t(8;21).[2] On both sides of the splice the DNA coded for different proteins, RUNX1 and ETO, These two sequences are then transcribed and translated into a single large protein, "M2 AML" which allows the cell to divide unchecked, leading to cancer. ### Genetics[edit] Acute myeloid leukemia is a very heterogeneous disease, composed of a variety of translocations and mutations. However, one tenth of all acute myeloid leukemia cases diagnosed have the AML1-ETO fusion oncoprotein due to the t(8;21) translocation. AML1 or RUNX1 is a DNA-binding transcription factor located at the 21q22. ETO is a protein with transcriptional repressing abilities located at the 8q22. Less than 1% of acute myeloid leukemia patients have the t(6;9) mutation. The rare translocation causes the formation of fusion oncoprotein DEK-NUP214 (Huret, 2005). DEK functions as a transcriptional repressor by interfering with histone acetyl transferases, regulator for a number of stem cells, and activates gene expression in myeloid cells (Koleva et al., 2012). The NUP214 protein is involved in mRNA export as well as nuclear membrane localization and nuclear pore complex (Koser et al., 2011). ### Molecular mechanism[edit] Figure 1. Overview of major interaction with tumor suppressor p14ARF and downstream effects of fusion protein AML1-ETO in M2 acute myeloid leukemia. Elimination of the tumor suppressor ARF gene is often seen in cancer cells. In adult M2 acute myeloblastic leukemia with maturation, ARF expression is suppressed via chromosome translocations that fuse AML1 or Runx1 to an ETO gene. The AML1 or Runx1 gene is in charge of activating transcription of the ARF gene while the ETO protein is involved in transcriptional repression. The AML1-ETO fusion protein ultimately causes transcriptional repression of the p14ARF gene, which deregulates the expression levels of Mdm2 and p53. The down regulation of ARF, increases Mdm2 levels due to the lack of regulation by the ARF gene. Unregulated, overexpressed Mdm2 will suppress p53 levels. The suppression of p53 levels is an anti-apoptotic mechanism for cancer cells to survive (Elagib, 2006, Weinberg, 2014). The fusion oncoprotein involves the gene AML1 (now known as RUNX1) and ETO (now known as RUNX1T1). AML1, located at the 21q22, normally has the ability to activate transcription of the ARF gene and ETO, located at the 8q22, normally has the ability to repress transcription. The fusion protein AML1-ETO is commonly found in acute myeloid leukemia patients. p14ARF is a well known tumor suppressor that serves as the safety net when p53 tumor suppressor's functions are inhibited. Many cancers recognize the potential of the p14ARF tumor suppressor to block cell growth so it is commonly mutated or inhibited in cancer cells. The AML1-ETO is incapable of p14ARF transcription as the fusion protein took on AML1's involvement with ARF gene expression and ETO's transcription repression. The Akt/PKB signaling is a pathway that is pro-survival and growth. By activating Mdm2, the signal transduction pathway will trigger the anti-apoptotic downstream effects of Mdm2. With no p14ARF to regulate and inhibit Mdm2, there will be an increased level of suppression of p53. Mdm2 is a proto-oncogene that directly antagonizes p53 to ubiquitination (Figure 1). The p53 protein is known as the “guardian of the genome” due to its ability to induce DNA repair enzymes and regulate cell cycle advancements. The down regulation of p53 by Mdm2 would lead to unchecked proliferative growth. The direct consequence of having the fusion protein, AML1-ETO, is the lack of p53 regulation in pre-leukemic cells. Therefore, there are an increased number of immature cells that are unable to carry out normal function, which is essentially cancer (Faderi et al., 2000, Song et al. 2005, Weinberg, 2014). ### Autophagy in M2 AML[edit] Autophagy is an innate pathway used for degradation of cellular components (Kobayashi, 2015). In recent studies, scientists recognize the significance of autophagy both as a potential anti-apoptotic response to cancer treatments as well as a potential mechanism for getting rid of undesirable fusion proteins such as AML1-ETO. In a 2013 study, scientists demonstrated that the degradation of fusion oncoprotein AML1-ETO is not mediated by autophagy through a set of drug dosage trials testing the levels of AML1-ETO protein expression. The acute myeloid leukemia Kasumi-1 cell line was selected for the experiment due to its AML1-ETO positive characteristics. These cells were treated with increasing concentrations of each histone deacetylase inhibitors – valproic acid (VPA) (epileptic and bipolar drug) or vorinostat (cutaneous T cell lymphoma drug), which are known to induce autophagy associated with loss of the fusion protein. The two inhibitors were added to the cell line in doses of 0, 0.38 uM, 0.74 uM, and 1.5 uM. The cell lysates were then treated with autophagy inhibitors Baf or CQ, or control. Through immunoblotting, there is no reduction of AML1-ETO observed across the different concentrations of VPA or vorinostat. The results indicate that AML1-ETO degradation is not mediated by autophagy, but there is an observed pro-survival autophagy in the leukemic cells (Torgersen et al., 2013). Thus, an inhibition of autophagy would be a viable treatment method for subtype M2 acute myeloid leukemia. ## Diagnosis[edit] The first red flag that indicates M2 acute myeloblastic leukemia with maturation is the skewed ratio of white blood cells to red blood cells. Leukemia is initially diagnosed by a peripheral blood smear, a procedure used to check for cell count and cell shapes. Then a bone marrow aspiration and biopsy would be conducted to collect and view the bone, bone marrow, and blood under a microscope. Cytogenetic assays, such as fluorescence in situ hybridization (FISH) would help evaluate the structure and function of the cell's chromosomes. The criteria for an acute myeloid leukemia case to fall under the M2 subtype is the following: 20%+ nonerythroid cells in peripheral blood or bone marrow are myeloblasts; monocytic precursors are < 20% in bone marrow and granulocytes are 10%+ of cells (Mihova, 2013). ## Treatments[edit] Generally, acute myeloid leukemia is treated using chemotherapy consisting of an induction phase and consolidation phase (Dohner et al., 2009). Patients may also consider hematopoietic stem cell transplantation as a second mode of tackling the cancer. The most novel research is being done in tyrosine kinase inhibitors; however M2 acute myeloid leukemia treatment research involves molecules that inhibit the fusion oncoprotein AML1-ETO. Therefore, in terms of M2 subtype acute myeloid leukemia, the most prominent target is the abnormal AML1-ETO fusion protein. Similarly, chronic myeloid leukemia (CML) is comparable to acute myeloid leukemia M2 because it also forms a fusion oncoprotein – BCR-Abl. The developed tyrosine kinase inhibitor, imatinib mesylate, has had a tremendous effect on stopping cancer progression in the majority of chronic myeloid leukemia patients. BCR-Abl is constitutively active due chromosome translocation; therefore it over-phosphorylates the tyrosine kinase. Imatinib mesylate works to block BCR-Abl's activity by blocking the active kinase domain (Fava et al., 2011). Celastrol is a compound extracted from Tripterygium wilfordii that has anti-cancer properties. It was found to inhibit cell proliferation through the down regulation of AML1-ETO fusion oncoprotein. Celastrol inhibits the fusion oncoprotein by inducing mitochondrial instability and initiating caspase activity The decrease of AML1-ETO also results in lower levels of C-KIT kinases, Akt/PKB, STAT3, and Erk1/2 – all of which are involved in cell signaling and gene transcription.[3] Histone deacetylase inhibitors such as valproic acid (VPA), vorinostat, and all-trans retinoic acid (ATRA) are effective in targeting acute myeloid leukemia with the AML1-ETO fusion protein. The HDAC inhibitors are known to induce apoptosis through accumulation of DNA damage, inhibition of DNA repair, and activation of caspases. These inhibitors are extra sensitive to the fusion proteins. Vorinostat has been proven to cause a greater accumulation of DNA damage in fusion protein expressing cells and is directly correlated with the reduction of DNA repair enzymes (Garcia et al., 2008). Romidepsin, a drug in phase two clinical trials, has demonstrated higher efficacy in patients with AML1-ETO fusion protein leukemia (Odenike et al., 2008). Although many clinical evaluations have proven HDAC inhibitors have a promising effect on M2 subtype acute myeloid leukemia, it has not been approved as an official treatment. In t(6;9) acute myeloid leukemia, FLT3-ITD and the DEK-NUP214 protein are potential targets for treatment. Sorafenib is a kinase inhibitor used as a treatment for kidney and liver cancer. The kinase inhibitor blocks serine-threonine kinase RAF-1 as well as FLT-ITD (Kindler, 2010). The drug has been proven to be effective in reducing FLT3-ITD overexpression (Metzelder et al., 2009). In patients with DEK-NUP214, it was found that the fusion oncoprotein caused an upregulation of mTORC1 (Sanden et al., 2013). Thus, a mTORC inhibitor could be a potential treatment. ## References[edit] 1. ^ "Acute Myeloid Leukemia - Signs and Symptoms". 2. ^ Taj AS, Ross FM, Vickers M, et al. (1995). "t(8;21) myelodysplasia, an early presentation of M2 AML". Br. J. Haematol. 89 (4): 890–2. doi:10.1111/j.1365-2141.1995.tb08429.x. PMID 7772527. S2CID 35020709. 3. ^ Yu, Xianjun; Ruan, Xuzhi; Zhang, Jingxuan; Zhao, Qun (30 April 2016). "Celastrol Induces Cell Apoptosis and Inhibits the Expression of the AML1-ETO/C-KIT Oncoprotein in t(8;21) Leukemia". Molecules. 21 (5): 574. doi:10.3390/molecules21050574. PMC 6274014. PMID 27144550. * American Cancer Society (ACS) (2016). Cancer Facts and Figures. * Andrieu V, Radford-Weiss I, Troussard X, Chane C, Valensi F, Guesnu M, et al. (1996). "Molecular detection of t(8;21)/AML1-ETO in AML M1/M2: correlation with cytogenetics, morphology and immunophenotype". British Journal of Haematology. 92 (4): 855–865. doi:10.1046/j.1365-2141.1996.415954.x. PMID 8616078. S2CID 40227895. * Bennett, J.H. (1852). Leucocythemia or White Cell Blood, pp 7–82. Edinburgh. * Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1976). "Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group". Br J Haematol. 33 (4): 451–8. doi:10.1111/j.1365-2141.1976.tb03563.x. PMID 188440. S2CID 9985915. * Chi Y, Lindgren V, Quigley S, Gaitonde S (2008). "Acute Myelogenous Leukemia With t(6;9)(p23;q34) and Marrow Basophilia: An Overview". Arch Pathol Lab Med. 132 (11): 1835–7. doi:10.1043/1543-2165-132.11.1835 (inactive 2021-01-14). PMID 18976025.CS1 maint: DOI inactive as of January 2021 (link) * Cullen P (1811). "Case of splenitis acutus in which the serum of the blood drawn from the arm had the appearance of milk". Edinburgh Medical Journal: 169–171. * Dohner H, Estey E, Amadori S, Appelbaum F, Buchner T, Burnett A, et al. (2009). "Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet". Blood. 115 (3): 453–474. doi:10.1182/blood-2009-07-235358. PMID 19880497. * Elagib K, Goldfarb A (2006). "Oncogenic pathways of AML1-ETO in acute myeloid leukemia: multifaceted manipulation of marrow maturation". Cancer Lett. 251 (2): 179–186. doi:10.1016/j.canlet.2006.10.010. PMC 1931834. PMID 17125917. * Faderl S, Kantarjian HM, Estey E, Manshouri T, Chan CY, Rahman Elsaied A, et al. (2000). "The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM-2 protein expression in adult acute myelogenous leukemia". Cancer. 89 (9): 1976–1982. doi:10.1002/1097-0142(20001101)89:9<1976::aid-cncr14>3.3.co;2-e. PMID 11064355. * Falini B, Tiacci E, Martelli MP, Ascani S, Pileri SA (2010). "New classification of acute myeloid leukemia and precursor-related neoplasms: changes and unsolved issues". Discov Med. 10 (53): 281–92. PMID 21034669. * Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E, D'Emilio A, Stagno F, Coutre P, Hurtado-Monroy R, Santini V, Martino B, Pane F, Piccin A, Giraldo P, Assouline S, Durosinmi MA, Leeksma O, Pogliani EM, Puttini M, Jang E, Reiffers J, Valsecchi MG, Kim DW (2011). "Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib". Journal of the National Cancer Institute. 103 (7): 553–561. doi:10.1093/jnci/djr060. PMID 21422402. * Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, et al. (2008). "Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes". Blood. 111 (3): 1060–6. doi:10.1182/blood-2007-06-098061. PMID 17962510. S2CID 15029739. * Gilliland D, Griffin J (2000). "The roles of FLT3 in hematopoiesis and leukemia". Blood. 100 (5): 1532–42. doi:10.1182/blood-2002-02-0492. PMID 12176867. S2CID 2362311. * Francais Groupe, de Cytogenetique Hematoplogique (1990). "Acute myelogenous leukemia with an 8;21 translocation: a report on 148 cases from the Groupe Francais de Cytogenetique Hematologique". Cancer Genetics and Cytogenetics. 44 (2): 169–179. doi:10.1016/0165-4608(90)90043-A. * Huret, J. t(6;9)(p23;q34). (2005). Atlas Genet Cytogenet Oncol Haematol. * Kindler T, Lipka DB, Fischer T (2010). "FLT3 as a therapeutic target in AML: still challenging after all these years". Blood. 116 (24): 5089–5102. doi:10.1182/blood-2010-04-261867. PMID 20705759. S2CID 18080783. * Kobayashi S (2015). "Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy". Biological & Pharmaceutical Bulletin. 38 (8): 1098–103. doi:10.1248/bpb.b15-00096. PMID 26235572. * Koleva RI, Ficarro SB, Radomska HS, Carrasco-Alfonso MJ, Alberta JA, Webber JT, Luckey CJ, Marcucci G, Tenen DG, Marto JA (2012). "C/EBPa and DEF coordinately regulation myeloid differentiation". Blood. 119 (21): 4878–88. doi:10.1182/blood-2011-10-383083. PMC 3367892. PMID 22474248. * Köser J, Maco B, Aebi U, Fahrenkrog B (2011). "The nuclear pore complex becomes alive: new insights into its dynamics and involvement in different cellular processes". Atlas of Genetics and Cytogenetics in Oncology and Haematology (2). doi:10.4267/2042/38203. * Kottaridis P (2001). "The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials" (PDF). Blood. 98 (6): 1752–1759. doi:10.1182/blood.v98.6.1752. PMID 11535508. * Levy JM, Thorburn A (2011). "Targeting autophagy during cancer therapy to improve clinical outcomes". Pharmacol Ther. 131 (1): 130–141. doi:10.1016/j.pharmthera.2011.03.009. PMC 3539744. PMID 21440002. * Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, et al. (2009). "Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation". Blood. 113 (26): 6567–6571. doi:10.1182/blood-2009-03-208298. PMID 19389879. S2CID 206878993. * Mihova, D. (2013). Leukemia - Acute - Acute myeloid leukemia with maturation (FAB AML M2). Pathologyoutlines.com. Retrieved 5 May 2016, from http://www.pathologyoutlines.com/topic/leukemiaM2.html * Miyoshi H.; et al. (1991). "t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1". Proc. Natl. Acad. Sci. USA. 88 (23): 10431–10434. Bibcode:1991PNAS...8810431M. doi:10.1073/pnas.88.23.10431. PMC 52942. PMID 1720541. * O'Donnell M, Abboud C, Altman J, Appelbaum F, Arber D, Attar E, et al. (2012). "Acute Myeloid Leukemia". 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J Cell Mol Med. 9 (1): 59–71. doi:10.1111/j.1582-4934.2005.tb00337.x. PMC 6741304. PMID 15784165. * Torgersen M, Engedal N, Boe S, Hokland P, Simonsen A (2013). "Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells". Blood. 122 (14): 2467–2476. doi:10.1182/blood-2013-05-500629. PMID 23970379. * Velpeau A (1827). "Sur la resorptiendu pus et sur l'alteration du sang dans les malades". Revue Medicine. 2: 216–218. * Virchow R (1845). "Weisses Blut". Froriep's Notizen. 36: 151–156. * Weber J, Taylor L, Roussel M, Sherr C, Bar-Sagi D (1999). "Nucleolar Arf sequesters Mdm2 and activates p53". Nature Cell Biology. 1 (1): 20–26. doi:10.1038/8991. PMID 10559859. S2CID 25132981. * Weinberg, R. (2014). The Biology of Cancer (2nd ed.). New York: Garland Science. * Yu X, Ruan X, Zhang J, Zhao Q (2016). "Celastrol Induces Cell Apoptosis and Inhibits the Expression of the AML1-ETO/C-KIT Oncoprotein in t(8;21) Leukemia". Molecules. 21 (5): 574. doi:10.3390/molecules21050574. PMC 6274014. PMID 27144550. ## External links[edit] Classification D * ICD-O: M9874/3 * MeSH: D015470 * v * t * e Myeloid-related hematological malignancy CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: * Acute myeloblastic leukemia * M0 * M1 * M2 * APL/M3 MP * Chronic neutrophilic leukemia Monocyte AML * AMoL/M5 * Myeloid dendritic cell leukemia CML * Philadelphia chromosome * Accelerated phase chronic myelogenous leukemia Myelomonocyte AML * M4 MD-MP * Juvenile myelomonocytic leukemia * Chronic myelomonocytic leukemia Other * Histiocytosis CFU-Baso AML * Acute basophilic CFU-Eos AML * Acute eosinophilic MP * Chronic eosinophilic leukemia/Hypereosinophilic syndrome MEP CFU-Meg MP * Essential thrombocytosis * Acute megakaryoblastic leukemia CFU-E AML * Erythroleukemia/M6 MP * Polycythemia vera MD * Refractory anemia * Refractory anemia with excess of blasts * Chromosome 5q deletion syndrome * Sideroblastic anemia * Paroxysmal nocturnal hemoglobinuria * Refractory cytopenia with multilineage dysplasia CFU-Mast Mastocytoma * Mast cell leukemia * Mast cell sarcoma * Systemic mastocytosis Mastocytosis: * Diffuse cutaneous mastocytosis * Erythrodermic mastocytosis * Adult type of generalized eruption of cutaneous mastocytosis * Urticaria pigmentosa * Mast cell sarcoma * Solitary mastocytoma Systemic mastocytosis * Xanthelasmoidal mastocytosis Multiple/unknown AML * Acute panmyelosis with myelofibrosis * Myeloid sarcoma MP * Myelofibrosis * Acute biphenotypic leukaemia * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Acute myeloblastic leukemia with maturation	c1879321	4,390	wikipedia	https://en.wikipedia.org/wiki/Acute_myeloblastic_leukemia_with_maturation	2021-01-18T18:32:27	{"gard": ["527"], "mesh": ["D015470"], "umls": ["C1879321"], "orphanet": ["98834"], "wikidata": ["Q4677940"]}
Vasculitis Other namesVasculitides[1] Petechia and purpura on the lower limb due to medication-induced vasculitis. Pronunciation * /væskjʊˈlaɪtɪs/ SpecialtyRheumatology SymptomsWeight loss, fever, myalgia, purpura ComplicationsGangrene, Myocardial infarction Vasculitis is a group of disorders that destroy blood vessels by inflammation.[2] Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis.[3] Vasculitis is primarily caused by leukocyte migration and resultant damage. Although both occur in vasculitis, inflammation of veins (phlebitis) or arteries (arteritis) on their own are separate entities. ## Contents * 1 Signs and symptoms * 2 Cause * 2.1 Classification * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] Possible signs and symptoms include:[4] * General symptoms: Fever, unintentional weight loss * Skin: Palpable purpura, livedo reticularis * Muscles and joints: Muscle pain or inflammation, joint pain or joint swelling * Nervous system: Mononeuritis multiplex, headache, stroke, tinnitus, reduced visual acuity, acute visual loss * Heart and arteries: Heart attack, high blood pressure, gangrene * Respiratory tract: Nose bleeds, bloody cough, lung infiltrates * GI tract: Abdominal pain, bloody stool, perforations (hole in the GI tract) * Kidneys: Inflammation of the kidney's filtration units (glomeruli) ## Cause[edit] ### Classification[edit] Vasculitis can be classified by the cause, the location, the type of vessel or the size of vessel. * Underlying cause. For example, the cause of syphilitic aortitis is infectious (aortitis simply refers to inflammation of the aorta, which is an artery.) However, the causes of many forms of vasculitis are poorly understood. There is usually an immune component, but the trigger is often not identified. In these cases, the antibody found is sometimes used in classification, as in ANCA-associated vasculitides. * Location of the affected vessels. For example, ICD-10 classifies "vasculitis limited to skin" with skin conditions (under "L"), and "necrotizing vasculopathies" (corresponding to systemic vasculitis) with musculoskeletal system and connective tissue conditions (under "M"). Arteritis/phlebitis on their own are classified with circulatory conditions (under "I"). * Type or size of the blood vessels that they predominantly affect.[5] Apart from the arteritis/phlebitis distinction mentioned above, vasculitis is often classified by the caliber of the vessel affected. However, there can be some variation in the size of the vessels affected. A small number have been shown to have a genetic basis. These include adenosine deaminase 2 deficiency and haploinsufficiency of A20. According to the size of the vessel affected, vasculitis can be classified into:[6][7] * Large vessel: Takayasu's arteritis, Temporal arteritis * Medium vessel: Buerger's disease, Kawasaki disease, Polyarteritis nodosa * Small vessel: Behçet's syndrome, Eosinophilic granulomatosis with polyangiitis, Cutaneous vasculitis, granulomatosis with polyangiitis, Henoch–Schönlein purpura, and microscopic polyangiitis. Condition of some disorders have vasculitis as their main feature. The major types are given in the table below: Comparison of major types of vasculitis Vasculitis Affected organs Histopathology Cutaneous small-vessel vasculitis Skin, kidneys Neutrophils, fibrinoid necrosis Granulomatosis with polyangiitis Nose, lungs, kidneys Neutrophils, giant cells Eosinophilic granulomatosis with polyangiitis Lungs, kidneys, heart, skin Histiocytes, eosinophils Behçet's disease Commonly sinuses, brain, eyes and skin; can affect other organs such as lungs, kidneys, joints Lymphocytes, macrophages, neutrophils Kawasaki disease Skin, heart, mouth, eyes Lymphocytes, endothelial necrosis Buerger's disease Leg arteries and veins (gangrene) Neutrophils, granulomas "Limited" granulomatosis with polyangiitis vasculitis Commonly sinuses, brain, and skin; can affect other organs such as lungs, kidneys, joints; Takayasu's arteritis, polyarteritis nodosa and giant cell arteritis mainly involve arteries and are thus sometimes classed specifically under arteritis. Furthermore, there are many conditions that have vasculitis as an accompanying or atypical feature, including: * Rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and dermatomyositis * Cancer, such as lymphomas * Infections, such as hepatitis C * Exposure to chemicals and drugs, such as amphetamines, cocaine, and anthrax vaccines which contain the Anthrax Protective Antigen as the primary ingredient. In pediatric patients varicella inflammation may be followed by vasculitis of intracranial vessels. This condition is called post varicella angiopathy and this may be responsible for arterial ischaemic strokes in children.[8] Several of these vasculitides are associated with antineutrophil cytoplasmic antibodies.[9] These are: * Granulomatosis with polyangiitis * Eosinophilic granulomatosis with polyangiitis * Microscopic polyangiitis ## Diagnosis[edit] Micrograph showing a vasculitis (Eosinophilic granulomatosis with polyangiitis). H&E stain. Severe vasculitis of the major vessels, displayed on FDG-PET/CT * Laboratory tests of blood or body fluids are performed for patients with active vasculitis. Their results will generally show signs of inflammation in the body, such as increased erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP), anemia, increased white blood cell count and eosinophilia. Other possible findings are elevated antineutrophil cytoplasmic antibody (ANCA) levels and hematuria. * Other organ functional tests may be abnormal. Specific abnormalities depend on the degree of various organs involvement. A Brain SPECT can show decreased blood flow to the brain and brain damage. * The definite diagnosis of vasculitis is established after a biopsy of involved organ or tissue, such as skin, sinuses, lung, nerve, brain, and kidney. The biopsy elucidates the pattern of blood vessel inflammation. * Some types of vasculitis display leukocytoclasis, which is vascular damage caused by nuclear debris from infiltrating neutrophils.[10] It typically presents as palpable purpura.[10] Conditions with leucocytoclasis mainly include hypersensitivity vasculitis (also called leukocytoclastic vasculitis) and cutaneous small-vessel vasculitis (also called cutaneous leukocytoclastic angiitis). * An alternative to biopsy can be an angiogram (x-ray test of the blood vessels). It can demonstrate characteristic patterns of inflammation in affected blood vessels. * 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT)has become a widely used imaging tool in patients with suspected Large Vessel Vasculitis, due to the enhanced glucose metabolism of inflamed vessel walls.[11] The combined evaluation of the intensity and the extension of FDG vessel uptake at diagnosis can predict the clinical course of the disease, separating patients with favourable or complicated progress.[12] * Acute onset of vasculitis-like symptoms in small children or babies may instead be the life-threatening purpura fulminans, usually associated with severe infection. Laboratory Investigation of Vasculitic Syndromes[13] Disease Serologic test Antigen Associated laboratory features Systemic lupus erythematosus ANA including antibodies to dsDNA and ENA [including SM, Ro (SSA), La (SSB), and RNP] Nuclear antigens Leukopenia, thrombocytopenia, Coombs' test, complement activation: low serum concentrations of C3 and C4, positive immunofluorescence using Crithidia luciliae as substrate, antiphospholipid antibodies (i.e. anticardiolipin, lupus anticoagulant, false-positive VDRL) Goodpasture's disease Anti-glomerular basement membrane antibody Epitope on noncollagen domain of type IV collagen Small vessel vasculitis Microscopic polyangiitis Perinuclear antineutrophil cytoplasmic antibody Myeloperoxidase Elevated CRP Granulomatosis with polyangiiitis Cytoplasmic antineutrophil cytoplasmic antibody Proteinase 3 (PR3) Elevated CRP Eosinophilic granulomatosis with polyangiitis perinuclear antineutrophil cytoplasmic antibody in some cases Myeloperoxidase Elevated CRP and eosinophilia IgA vasculitis (Henoch-Schönlein purpura) None Cryoglobulinemia Cryoglobulins, rheumatoid factor, complement components, hepatitis C Medium vessel vasculitis Classical polyarteritis nodosa None Elevated CRP and eosinophilia Kawasaki's Disease None Elevated CRP and ESR In this table: ANA = Antinuclear antibodies, CRP = C-reactive protein, ESR = Erythrocyte Sedimentation Rate, dsDNA = double-stranded DNA, ENA = extractable nuclear antigens, RNP = ribonucleoproteins; VDRL = Venereal Disease Research Laboratory ## Treatment[edit] Treatments are generally directed toward stopping the inflammation and suppressing the immune system. Typically, corticosteroids such as prednisone are used. Additionally, other immune suppression medications, such as cyclophosphamide and others, are considered. In case of an infection, antimicrobial agents including cephalexin may be prescribed. Affected organs (such as the heart or lungs) may require specific medical treatment intended to improve their function during the active phase of the disease. ## References[edit] 1. ^ "Vasculitis - Definition from the Merriam-Webster Online Dictionary". Archived from the original on 1 July 2016. Retrieved 8 January 2009. 2. ^ "Glossary of dermatopathological terms. DermNet NZ". Archived from the original on 20 December 2008. Retrieved 8 January 2009. 3. ^ "Vasculitis" at Dorland's Medical Dictionary 4. ^ "The Johns Hopkins Vasculitis Center - Symptoms of Vasculitis". Archived from the original on 27 February 2009. Retrieved 7 May 2009. 5. ^ Jennette JC, Falk RJ, Andrassy K, et al. (1994). "Nomenclature of systemic vasculitides. Proposal of an international consensus conference". Arthritis Rheum. 37 (2): 187–92. doi:10.1002/art.1780370206. PMID 8129773. 6. ^ "Overview of Vasculitis". Archived from the original on 3 April 2015. Retrieved 5 October 2016. 7. ^ Gündüz, Özgür (18 October 2011). "Histopathological Evaluation of Behçet's Disease and Identification of New Skin Lesions". Pathology Research International. 2012: 209316. doi:10.1155/2012/209316. ISSN 2090-8091. PMC 3199096. PMID 22028988. 8. ^ Nita R Sutay, Md Ashfaque Tinmaswala, Shilpa Hegde . "International Journal of Medical Research and Health Sciences \| 404 Page". Archived from the original on 17 November 2015. Retrieved 19 August 2015. 9. ^ Millet A, Pederzoli-Ribeil M, Guillevin L, Witko-Sarsat V, Mouthon L (2013) Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group? Ann Rheum Dis 10. ^ a b A Brooke W Eastham, Ruth Ann Vleugels and Jeffrey P Callen. "Leukocytoclastic Vasculitis". Medscape. Updated: Oct 25, 2018 11. ^ Maffioli L, Mazzone A (2014). "Giant-Cell Arteritis and Polymyalgia Rheumatica". NEJM. 371 (17): 1652–1653. doi:10.1056/NEJMc1409206. PMC 4277693. PMID 25337761. 12. ^ Dellavedova L, Carletto M, Faggioli P, Sciascera A, Del Sole A, Mazzone A, Maffioli LS (2015). "The prognostic value of baseline 18F-FDG PET/CT in steroid-naïve large-vessel vasculitis: introduction of volume-based parameters". European Journal of Nuclear Medicine and Molecular Imaging. 55 (2): 340–8. doi:10.1007/s00259-015-3148-9. PMID 26250689. S2CID 21446786. 13. ^ Burtis CA, Ashwood ER, Bruns DE (2012). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th edition. Elsevier Saunders. p. 1568. ISBN 978-1-4160-6164-9. ## External links[edit] Classification D * ICD-10: I77.6, I80, L95, M30-M31 * ICD-9-CM: 446, 447.6 * MeSH: D014657 * DiseasesDB: 13750 External resources * Patient UK: Vasculitis * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension * v * t * e Cutaneous vasculitis and other vascular-related cutaneous conditions Cutaneous vasculitis * Erythema elevatum diutinum * Capillaritis * Urticarial vasculitis * Nodular vasculitis Microvascular occlusion * Calciphylaxis * Cryoglobulinemic purpura/Cryoglobulinemic vasculitis * vascular coagulopathy: Livedoid vasculitis * Livedoid dermatitis * Perinatal gangrene of the buttock * Malignant atrophic papulosis * Sneddon's syndrome Purpura * Nonthrombocytopenic purpura: Cryofibrinogenemic purpura * Drug-induced purpura * Food-induced purpura * IgA vasculitis * Obstructive purpura * Orthostatic purpura * Purpura fulminans * Purpura secondary to clotting disorders * Purpuric agave dermatitis * Pigmentary purpuric eruptions * Solar purpura * Traumatic purpura * Waldenström hyperglobulinemic purpura * Painful bruising syndrome * ungrouped: Paroxysmal hand hematoma * Postcardiotomy syndrome * Deep vein thrombosis * Superficial thrombophlebitis * Mondor's disease * Blueberry muffin baby * Fibrinolysis syndrome Systemic vasculitis * see Template:Systemic vasculitis Vascular malformations * Arteriovenous malformation * Bonnet–Dechaume–Blanc syndrome * Cobb syndrome * Parkes Weber syndrome * Sinusoidal hemangioma * lymphatic malformation * Hennekam syndrome * Aagenaes syndrome * telangiectasia: Generalized essential telangiectasia * Hereditary hemorrhagic telangiectasia * Unilateral nevoid telangiectasia Ulcer * Venous ulcer * Arterial insufficiency ulcer * Hematopoietic ulcer * Neuropathic ulcer * Acroangiodermatitis Lymphedema * see Template:Lymphatic vessel disease Ungrouped vascular-related cutaneous conditions * Raynaud's phenomenon * Thromboangiitis obliterans * Erythromelalgia * Septic thrombophlebitis * Arteriosclerosis obliterans * Bier spots/Marshall–White syndrome * Cholesterol embolus * Reactive angioendotheliomatosis * Trousseau's syndrome * v * t * e Systemic connective tissue disorders General Systemic lupus erythematosus * Drug-induced SLE * Libman–Sacks endocarditis Inflammatory myopathy * Myositis * Dermatopolymyositis * Dermatomyositis/Juvenile dermatomyositis * Polymyositis* Inclusion body myositis Scleroderma * Systemic scleroderma * Progressive systemic sclerosis * CREST syndrome * Overlap syndrome / Mixed connective tissue disease Other hypersensitivity/autoimmune * Sjögren syndrome Other * Behçet's disease * Polymyalgia rheumatica * Eosinophilic fasciitis * Eosinophilia–myalgia syndrome * fibrillin * Marfan syndrome * Congenital contractural arachnodactyly [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Vasculitis	c0042384	4,391	wikipedia	https://en.wikipedia.org/wiki/Vasculitis	2021-01-18T18:44:44	{"gard": ["9565"], "mesh": ["D014657"], "umls": ["C0042384"], "icd-9": ["447.6", "446"], "icd-10": ["M31", "I80", "L95", "I77.6", "M30"], "orphanet": ["52759"], "wikidata": ["Q644318"]}
Difficulty controlling the mouth or throat for swallowing Oropharyngeal dysphagia SpecialtyGastroenterology, ENT surgery Oropharyngeal dysphagia arises from abnormalities of muscles, nerves or structures of the oral cavity, pharynx, and upper esophageal sphincter. ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Differential diagnosis * 3 Diagnosis * 4 Treatment * 4.1 Surgery * 5 References * 6 External links ## Signs and symptoms[edit] Some signs and symptoms of swallowing difficulties include difficulty controlling food in the mouth, inability to control food or saliva in the mouth, difficulty initiating a swallow, coughing, choking, frequent pneumonia, unexplained weight loss, gurgly or wet voice after swallowing, nasal regurgitation, and dysphagia (patient complaint of swallowing difficulty).[1] Other symptoms include drooling, dysarthria, dysphonia, aspiration pneumonia, depression, or nasopharyngeal regurgitation as associated symptoms.[2][3] When asked where the food is getting stuck patients will often point to the cervical (neck) region as the site of the obstruction. ### Complications[edit] If left untreated, swallowing disorders can potentially cause aspiration pneumonia, malnutrition, or dehydration.[1] ## Differential diagnosis[edit] * A stroke can cause pharyngeal dysfunction with a high occurrence of aspiration. The function of normal swallowing may or may not return completely following an acute phase lasting approximately 6 weeks.[4] * Parkinson's disease can cause "multiple prepharyngeal, pharyngeal, and esophageal abnormalities". The severity of the disease most often correlates with the severity of the swallowing disorder.[4] * Neurologic disorders such as stroke, Parkinson's disease, amyotrophic lateral sclerosis, Bell's palsy, or myasthenia gravis can cause weakness of facial and lip muscles that are involved in coordinated mastication as well as weakness of other important muscles of mastication and swallowing. * Oculopharyngeal muscular dystrophy is a genetic disease with palpebral ptosis, oropharyngeal dysphagia, and proximal limb weakness. * Decrease in salivary flow, which can lead to dry mouth or xerostomia, can be due to Sjögren syndrome, anticholinergics, antihistamines, or certain antihypertensives and can lead to incomplete processing of food bolus. * Xerostomia can reduce the volume and increase the viscosity of oral secretions making bolus formation difficult as well as reducing the ability to initiate and swallow the bolus[4] * Dental problems can lead to inadequate chewing. * Abnormality in oral mucosa such as from mucositis, aphthous ulcers, or herpetic lesions can interfere with bolus processing. * Mechanical obstruction in the oropharynx may be due to malignancies, cervical rings or webs, crico-phyringeus muscle dysfunction, or cervical osteophytes. * Increased upper esophageal sphincter tone can be due to Parkinson's disease which leads to incomplete opening of the UES. This may lead to formation of a Zenker's diverticulum. * Pharyngeal pouches typically cause difficulty in swallowing after the first mouthful of food, with regurgitation of the pouch contents. These pouches may be accompanied by malodorous breath due to decomposing foods residing in the pouches. (See Zenker's diverticulum) * Dysphagia is often a side effect of surgical procedures like anterior cervical spine surgery, carotid endarterectomy, head and neck resection, oral surgeries like removal of the tongue, and partial laryngectomies[4] * Radiotherapy, used to treat head and neck cancer, can cause tissue fibrosis in the irradiated areas. Fibrosis of tongue and larynx lead to reduced tongue base retraction and laryngeal elevation during swallowing[4] * Infection may cause pharyngitis which can prevent swallowing due to pain. * Medications can cause central nervous system effects that can result in swallowing disorders and oropharyngeal dysphagia. Examples: sedatives, hypnotic agents, anticonvulsants, antihistamines, neuroleptics, barbiturates, and antiseizure medication. Medications can also cause peripheral nervous system effects resulting in an oropharyngeal dysphagia. Examples: corticosteroids, L-tryptophan, and anticholinergics[4] ## Diagnosis[edit] Oropharyngeal dysphagia is going to be suspected if the patient answers yes to one of the following questions: Do you cough or choke when trying to eat? After you swallow, does the food ever come back out through your nose?[3] A patient will most likely receive a Modified Barium swallow (MBS). Different consistencies of liquid and food mixed with barium sulfate are fed to the patient by spoon, cup or syringe, and x-rayed using videofluoroscopy. A patient's swallowing then can be evaluated and described. Some clinicians might choose to describe each phase of the swallow in detail, making mention of any delays or deviations from the norm. Others might choose to use a rating scale such as the Penetration Aspiration Scale. The scale was developed to describe the disordered physiology of a person's swallow using the numbers 1-8.[5][3] Other scales also exist for this purpose. A patient can also be assessed using videoendoscopy, also known as flexible fiberoptic endoscopic examination of swallowing (FFEES). The instrument is placed into the nose until the clinician can view the pharynx and then he or she examines the pharynx and larynx before and after swallowing. During the actual swallow, the camera is blocked from viewing the anatomical structures. A rigid scope, placed into the oral cavity to view the structures of the pharynx and larynx, can also be used, though this prevents the patient from swallowing.[1] Other less frequently used assessments of swallowing are imaging studies, ultrasound and scintigraphy and nonimaging studies, electromyography (EMG), electroglottography (EGG)(records vocal fold movement), cervical auscultation, and pharyngeal manometry.[1] ## Treatment[edit] Thickening agents Food thickeners can be used to improve swallowing in pediatric populations.[6] Postural techniques.[1] * Head back (extension) – used when movement of the bolus from the front of the mouth to the back is inefficient; this allows gravity to help move the food. * Chin down (flexion) – used when there is a delay in initiating the swallow; this allows the valleculae to widen, the airway to narrow, and the epiglottis to be pushed towards the back of the throat to better protect the airway from food. * Chin down (flexion) – used when the back of the tongue is too weak to push the food towards the pharynx; this causes the back of the tongue to be closer to the pharyngeal wall. * Head rotation (turning head to look over shoulder) to damaged or weaker side with chin down – used when the airway is not protected adequately causing food to be aspirated; this causes the epiglottis to be put in a more protective position, it narrows the entrance of the airway, and it increases vocal fold closure. * Lying down on one side – used when there is reduced contraction of the pharynx causing excess residue in the pharynx; this eliminates the pull of gravity that may cause the residue to be aspirated when the patient resumes breathing. * Head rotation to damaged or weaker side – used when there is paralysis or paresis on one side of the pharyngeal wall; this causes the bolus to go down the stronger side. * Head tilt (ear to shoulder) to stronger side – used when there is weakness on one side of the oral cavity and pharyngeal wall; this causes the bolus to go down the stronger side. Swallowing maneuvers.[1] * Supraglottic swallow - The patient is asked to take a deep breath and hold their breath. While still holding their breath they are to swallow and then immediately cough after swallowing. This technique can be used when there is reduced or late vocal fold closure or there is a delayed pharyngeal swallow. * Super-supraglottic swallow - The patient is asked to take a breath, hold their breath tightly while bearing down, swallow while still holding the breath hold, and then coughing immediately after the swallow. This technique can be used when there is reduced closure of the airway. * Effortful swallow - The patient is instructed to squeeze their muscles tightly while swallowing. This may be used when there is reduced posterior movement of the tongue base. * Mendelsohn maneuver - The patient is taught how to hold their adam's apple up during a swallow. This technique may be used when there is reduced laryngeal movement or a discoordinated swallow.[7] Medical device In order to strengthen muscles in the mouth and throat areas, researchers at the University of Wisconsin–Madison, led by Dr. JoAnne Robbins, developed a device in which patients perform isometric exercises with the tongue.[8] Diet modifications Diet modification may be warranted. Some patients require a soft diet that is easily chewed, and some require liquids of a thinned or thickened consistency. The effectiveness of modifying food and fluid in preventing aspiration pneumonia has been questioned and these can be associated with poorer nutrition, hydration and quality of life.[9] There has been considerable variability in national approaches to describing different degrees of thickened fluids and food textures. However, the International Dysphagia Diet Standardisation Initiative (IDDSI) group produced an agreed IDDSI framework consisting of a continuum of 8 levels (0-7), where drinks are measured from Levels 0 – 4, while foods are measured from Levels 3 – 7.[10] Environmental modifications Environmental modification can be suggested to assist and reduce risk factors for aspiration. For example, removing distractions like too many people in the room or turning off the TV during feeding, etc. Oral sensory awareness techniques Oral sensory awareness techniques can be used with patients who have a swallow apraxia, tactile agnosia for food, delayed onset of the oral swallow, reduced oral sensation, or delayed onset of the pharyngeal swallow.[1] * pressure of a spoon against tongue * using a sour bolus * using a cold bolus * using a bolus that requires chewing * using a bolus larger than 3mL * thermal-tactile stimulation (controversial) Prosthetics * Palatal lift or Palatal obturator * Maxillary denture ### Surgery[edit] These are usually only recommended as a last resort. * Tracheotomy * Tracheostomy * Vocal fold augmentation/injection * Thryoplasty medialization * Arytenoid adduction * Partial or total laryngectomy * Laryngotracheal separation * Supralaryngectomy * Palatoplasty * Cricopharyngeal myotomy * Zenker's diverticulectomy * Percutaneous endoscopic gastrostomy * Feeding tube ## References[edit] 1. ^ a b c d e f g Logemann, Jeri A. (1998). Evaluation and treatment of swallowing disorders. Austin, Tex: Pro-Ed. ISBN 978-0-89079-728-0. 2. ^ Bartlett RS, Thibeault SL (2018). "Insights into Oropharyngeal Dysphagia from Administrative Data and Clinical Registries: A Literature Review". American Journal of Speech-Language Pathology. 27 (2): 868–883. doi:10.1044/2018_AJSLP-17-0158. PMC 6105122. PMID 29710238.CS1 maint: uses authors parameter (link) 3. ^ a b c Kim JP, Kahrilas PJ (January 2019). "How I Approach Dysphagia". Current Gastroenterology Reports. 21 (10): 49. doi:10.1007/s11894-019-0718-1. PMID 31432250. S2CID 201064709.CS1 maint: uses authors parameter (link) 4. ^ a b c d e f Murray, J. (1999). Manual of Dysphagia Assessment in Adults. San Diego: Singular Publishing. 5. ^ Rosenbek JC, Robbins JA, Roecker EB, Coyle JL, Wood JL (1996). "A penetration-aspiration scale". Dysphagia. 11 (2): 93–8. doi:10.1007/BF00417897. PMID 8721066. S2CID 23867541. 6. ^ Duncan DR, Larson K, Rosen RL (January 2019). "Clinical Aspects of Thickeners for Pediatric Gastroesophageal Reflux and Oropharyngeal Dysphagia". Curr Gastroenterol Rep. 21 (7): 30. doi:10.1007/s11894-019-0697-2. PMID 31098722. S2CID 157056723.CS1 maint: uses authors parameter (link) 7. ^ "The Remediation of Dysphagia at California State University, Chico". Retrieved 2008-02-23. 8. ^ "Advances in Swallowing Disorders Therapy". Swallowing Disorder Foundation. June 1, 2013. Retrieved July 28, 2014. 9. ^ O'Keeffe ST (July 2018). "Use of modified diets to prevent aspiration in oropharyngeal dysphagia: is current practice justified?". BMC Geriatrics. 18 (1): 167. doi:10.1186/s12877-018-0839-7. PMC 6053717. PMID 30029632. 10. ^ Cichero JA, Lam P, Steele CM, Hanson B, Chen J, Dantas RO, Duivestein J, Kayashita J, Lecko C, Murray J, Pillay M, Riquelme L, Stanschus S (April 2017). "Development of International Terminology and Definitions for Texture-Modified Foods and Thickened Fluids Used in Dysphagia Management: The IDDSI Framework". Dysphagia. 32 (2): 293–314. doi:10.1007/s00455-016-9758-y. PMC 5380696. PMID 27913916. ## External links[edit] Classification D * ICD-10: R13 * ICD-9-CM: 787.22 * MeSH: D003680 * DiseasesDB: 17942 External resources * MedlinePlus: 003115 * eMedicine: pmr/194 * Swallowing and Feeding * v * t * e Symptoms and signs relating to the human digestive system or abdomen Gastrointestinal tract * Nausea * Vomiting * Heartburn * Aerophagia * Pagophagia * Dysphagia * oropharyngeal * esophageal * Odynophagia * Bad breath * Xerostomia * Hypersalivation * Burping * Wet burp * Goodsall's rule * Chilaiditi syndrome * Dance's sign * Aaron's sign * Arapov's sign * Markle sign * McBurney's point * Sherren's triangle * Radiologic signs: Hampton's line * Klemm's sign Accessory * liver: Councilman body * Mallory body * biliary: Boas' sign * Courvoisier's law * Charcot's cholangitis triad/Reynolds' pentad * cholecystitis (Murphy's sign * Lépine's sign * Mirizzi's syndrome) * Nardi test Defecation * Flatulence * Fecal incontinence * Encopresis * Fecal occult blood * Rectal tenesmus * Constipation * Obstructed defecation * Diarrhea * Rectal discharge * Psoas sign * Obturator sign * Rovsing's sign * Hamburger sign * Heel tap sign * Aure-Rozanova's sign * Dunphy sign * Alder's sign * Lockwood's sign * Rosenstein's sign Abdomen Pain * Abdominal pain * Acute abdomen * Colic * Baby colic * Abdominal guarding * Blumberg sign Distension * Abdominal distension * Bloating * Ascites * Tympanites * Shifting dullness * Ascites * Fluid wave test Masses * Abdominal mass * Hepatosplenomegaly * Hepatomegaly * Splenomegaly Other * Jaundice * Mallet-Guy sign * Puddle sign * Ballance's sign * Aortic insufficiency * Castell's sign * Kehr's sign * Cullen's sign * Grey Turner's sign Hernia * Howship–Romberg sign * Hannington-Kiff sign Other * Cupola sign * Fothergill's sign * Carnett's sign * Sister Mary Joseph nodule [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Oropharyngeal dysphagia	c0267071	4,392	wikipedia	https://en.wikipedia.org/wiki/Oropharyngeal_dysphagia	2021-01-18T18:56:29	{"mesh": ["D003680"], "icd-9": ["787.22"], "icd-10": ["R13"], "wikidata": ["Q3533214"]}
Prominent inferior labial artery is characterized by the appearance of a pulsating papule in the lower vermilion, a centimeter of two from the oral comissure, formed by an especially tortuous segment of the inferior labial artery.[1] ## See also[edit] * Skin lesion ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. Page 586. ISBN 0-7216-2921-0. This Dermal and subcutaneous growths 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Prominent inferior labial artery	c4073264	4,393	wikipedia	https://en.wikipedia.org/wiki/Prominent_inferior_labial_artery	2021-01-18T18:30:22	{"umls": ["C4073264"], "wikidata": ["Q7249750"]}
## Clinical Features Smith (1939) described a sibship of 8 children, 4 of whom had total deafness in one or the other ear. The tympanic membranes were normal. Labyrinthine testing was normal. There was no history of consanguinity, mumps, or syphilis. The mother, her father, and her sister also had unilateral deafness while another sister became deaf and lost speech after measles. This latter sister married a deaf and dumb man. One of their 3 children, a girl, had unilateral deafness. She had 2 children, one of whom has unilateral deafness. Thus there were 9 persons with total unilateral deafness in 4 generations. Four were deaf in the right ear and 4 in the left, while the side was unknown in 1 case. Everberg (1960) studied 122 children with total unilateral deafness and normal hearing in the other ear. More than 1 case of unilateral deafness in the same family was found in 12 of the 122 families of these children. Inheritance \- Autosomal dominant Ears \- Unilateral hearing loss ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	DEAFNESS, UNILATERAL	c2607947	4,394	omim	https://www.omim.org/entry/125000	2019-09-22T16:42:33	{"mesh": ["D046088"], "omim": ["125000"]}
Micrograph showing lymphovascular invasion (top of image) in a case of laryngeal cancer. H&E stain. Lymphovascular invasion (LVI or lymphovascular space invasion) is the invasion of a cancer to the blood vessels and/or lymphatics. ## Contents * 1 Terminology * 2 Pathology * 3 Prognostic significance * 3.1 Breast cancer * 3.2 Urothelial carcinoma * 3.3 Colorectal cancer * 4 See also * 5 References ## Terminology[edit] Lymph: A clear or white fluid that travels through vessels, moves within tissues and work to keep all the parts of the body clean. Vascular: The body's network of blood vessels. When cancer spreads to lymph and vascular system, it is thus termed as Lymphovascular Invasion. ## Pathology[edit] Lymphovascular invasion, especially in carcinomas, usually precedes spread to the lymph nodes that drain the tissue in which the tumour arose. Conversely, cancers with lymph node spread (known as a lymph node metastases), usually have lymphovascular invasion. Lymph node metastases usually precede secondary tumours, i.e. distant metastases. The absence of LVI in the context of proven lymph node metastasis is usually thought to be due to sampling error.[1] ## Prognostic significance[edit] The predictive value and prevalence of lymphovascular invasion is strongly dependent on the type of cancer. In other words, LVI in one type of cancer may be much less important than LVI in another type of cancer. Generally speaking, it is associated with lymph node metastases[2][3] which themselves are predictive of a poorer prognosis.[4] In the context of (histologically) proven lymph node metastases, LVI may have less prognostic significance or no prognostic significance. ### Breast cancer[edit] Main article: Breast cancer Whether LVI is a significant prognostic factor in breast cancer is widely debated, and there is no clear consensus.[5][6] ### Urothelial carcinoma[edit] Main article: Urothelial carcinoma In urothelial carcinoma, LVI is an independent predictor of a poorer prognosis that has more predictive power than tumour stage.[7] ### Colorectal cancer[edit] Main article: Colorectal cancer In sporadic colorectal carcinoma, LVI of a poorer prognosis.[8] ## See also[edit] * Perineural invasion * Malignancy ## References[edit] 1. ^ Han JS, Molberg KH, Sarode V (2011). "Predictors of invasion and axillary lymph node metastasis in patients with a core biopsy diagnosis of ductal carcinoma in situ: an analysis of 255 cases". Breast J. 17 (3): 223–9. doi:10.1111/j.1524-4741.2011.01069.x. PMID 21545433. 2. ^ Schoppmann SF, Bayer G, Aumayr K, Taucher S, Geleff S, Rudas M, et al. (August 2004). "Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer". Ann. Surg. 240 (2): 306–12. doi:10.1097/01.sla.0000133355.48672.22. PMC 1356408. PMID 15273556. 3. ^ Fang WL, Chang SC, Lin JK, Wang HS, Yang SH, Jiang JK, Chen WC, Lin TC (2005). "Metastatic potential in T1 and T2 colorectal cancer". Hepatogastroenterology. 52 (66): 1688–91. PMID 16334758. 4. ^ Moreira LF, Kenmotsu M, Gochi A, Tanaka N, Orita K (1999). "Lymphovascular and neural invasion in low-lying rectal carcinoma". Cancer Detect. Prev. 23 (2): 123–8. doi:10.1046/j.1525-1500.1999.09908.x. PMID 10101593. 5. ^ Ejlertsen B, Jensen MB, Rank F, Rasmussen BB, Christiansen P, Kroman N, et al. (May 2009). "Population-based study of peritumoral lymphovascular invasion and outcome among patients with operable breast cancer". J. Natl. Cancer Inst. 101 (10): 729–35. doi:10.1093/jnci/djp090. PMID 19436035. 6. ^ Song YJ, Shin SH, Cho JS, Park MH, Yoon JH, Jegal YJ (September 2011). "The role of lymphovascular invasion as a prognostic factor in patients with lymph node-positive operable invasive breast cancer". J Breast Cancer. 14 (3): 198–203. doi:10.4048/jbc.2011.14.3.198. PMC 3200515. PMID 22031801. 7. ^ Cheng, L.; Montironi, R.; Davidson, DD.; Lopez-Beltran, A. (Jun 2009). "Staging and reporting of urothelial carcinoma of the urinary bladder". Mod Pathol. 22 Suppl 2: S70–95. doi:10.1038/modpathol.2009.1. PMID 19494855. 8. ^ Lim, SB.; Yu, CS.; Jang, SJ.; Kim, TW.; Kim, JH.; Kim, JC. (Apr 2010). "Prognostic significance of lymphovascular invasion in sporadic colorectal cancer". Dis Colon Rectum. 53 (4): 377–84. doi:10.1007/DCR.0b013e3181cf8ae5. PMID 20305435. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Lymphovascular invasion	c1708790	4,395	wikipedia	https://en.wikipedia.org/wiki/Lymphovascular_invasion	2021-01-18T18:53:44	{"umls": ["C1708790"], "wikidata": ["Q6708283"]}
## Description Childhood absence epilepsy (CAE, ECA), a subtype of idiopathic generalized epilepsy (EIG; 600669), is characterized by a sudden and brief impairment of consciousness that is accompanied by a generalized, synchronous, bilateral, 2.5- to 4-Hz spike and slow-wave discharge (SWD) on EEG. Seizure onset occurs between 3 and 8 years of age and seizures generally occur multiple times per day. About 70% of patients experience spontaneous remission of seizures, often around adolescence. There are no structural neuropathologic findings in patients with ECA (Crunelli and Leresche, 2002). ### Genetic Heterogeneity of Susceptibility to Childhood Absence Epilepsy The ECA1 locus has been mapped to chromosome 8q24; see also EIG1 (see 600669), which also maps to 8q24. Susceptibility to the development of childhood absence epilepsy may be conferred by variation in several genes: ECA2 (see 607681), conferred by variation in the GABRG2 gene (137164) on chromosome 5q31.1; ECA4 (611136), conferred by variation in the GABRA1 gene (137160) on chromosome 5q34; ECA5 (612269), conferred by variation in the GABRB3 gene (137192) on chromosome 15q12; and ECA6 (see 611942), conferred by variation in the CACNA1H gene (607904) on chromosome 16p13. See EIG11 (607628) for discussion of a locus previously designated ECA3 on chromosome 3q26. Clinical Features Childhood absence epilepsy accounts for 5 to 15% of childhood epilepsies (Fong et al., 1998). Manifestations begin at age 6 to 7 years, in contrast to juvenile absence epilepsy (JAE; 607631), which begins around puberty. The main features are frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Generalized tonic-clonic seizures (GTCS) often develop during adolescence. Otherwise, absence seizures may either remit or persist into adulthood (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Fong et al. (1998) defined 3 subsyndromes of ECA. The first subsyndrome, which accounts for approximately 40 to 60% of ECA patients, is characterized by absence seizures as the sole phenotype and remits spontaneously during adolescence. The second subsyndrome, which accounts for another 40% of ECA patients, persists into adolescence and adulthood, during which patients develop tonic-clonic seizures. The third subsyndrome accounts for a smaller percentage (possibly 10 to 12%) of ECA patients and is characterized by the development of tonic-clonic and myoclonic seizures during adolescence, after the onset of absences in childhood. Wallace et al. (2001) stated that febrile seizures (121210) occur in about 3% of children and that 10 to 15% of persons with childhood absence epilepsy have febrile seizures before the onset of epilepsy. Febrile convulsions are a common seizure type in relatives of childhood absence epilepsy probands (Italian League Against Epilepsy Genetic Collaborative Group, 1993). Inheritance Winawer et al. (2003) studied 84 persons from 31 families with myoclonic or absence seizures and found that 65% (20 families) were concordant for seizure type (myoclonic, absence, or both). In 2 families, all affected members had myoclonic seizures; in 12 families, all affected members had absence seizures; in 2 families, all affected members had myoclonic and absence seizures. The number of families concordant for juvenile myoclonic epilepsy (JME; 606904) was greater when compared to JAE and CAE, but not when JAE was compared to CAE. Winawer et al. (2003) concluded that there are distinct genetic effects on absence and myoclonic seizures, and suggested that examining seizure types as opposed to syndromes may be more useful in linkage studies. Population Genetics Overall, the annual incidence of childhood absence epilepsy is 2 to 8 per 100,000 children under the age of 15 to 16 years, with a prevalence of 2 to 10% among children with any type of epilepsy (Crunelli and Leresche, 2002). Mapping Fong et al. (1998) studied clinical and electroencephalographic traits of 78 members of a 5-generation family in Bombay, India, with childhood absence epilepsy. The model-free affected-pedigree member method was used during initial screening, and only individuals with absence seizures and/or EEG 3-4-Hz spike- and multispike-slow wave complexes were considered to be affected. Significant P values were obtained for several markers on 8q. Two-point linkage analysis assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum lod score of 3.6 for D8S502. For 5 smaller multiplex families, the summed maximum lod score was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all 5 smaller families. Recombinations positioned the ECA1 locus to a 3.2-cM interval. Using YACs and BACs, Sugimoto et al. (2000) constructed a physical map of the ECA1 region on 8q24. By accurate ordering of STS markers within the physical map, they narrowed the locus to 1.5 Mb flanked by D8S554 and D8S502, which was confirmed by pairwise linkage analysis in 6 families (lod score of 4.1 at theta = 0 for D8S534). Molecular Genetics ### Exclusion Studies In 2 families with childhood absence epilepsy mapping to chromosome 8q24 (ECA1), Morita et al. (1999) did not identify mutations in the JRK gene (603210). ### Associations Pending Confirmation See 608146 for discussion of a possible association of childhood absence epilepsy with variation in the NIPA2 gene on chromosome 15q11. Animal Model The activation of peri- or extrasynaptic GABA receptors by ambient GABA causes a persistently active, or tonic, inhibitory current. Extrasynaptic GABA-A receptors in thalamocortical neurons contain the delta subunit (GABRD; 137163). In an established rat model of absence epilepsy with spontaneous spike-wave discharges called GAERS (genetic absence epilepsy rats from Strasbourg), Cope et al. (2009) found increased tonic current amplitude at thalamocortical GABA-A receptors beginning at postnatal day 17 compared to controls. Similarly increased tonic GABA-A receptor activation was observed in other mouse strains of absence epilepsy, including stargazer and lethargic, but not in tottering mice. In addition, pharmacologic spike-wave discharge-inducing agents were found to enhance the tonic GABA-A receptor current in thalamocortical neurons. Increased tonic inhibition was due to compromised GABA uptake by the GABA transporter GAT1 (SLC6A1; 137165) in the thalamus. Blockade or knockout of GAT1 in normal animals induced absence-like seizures. Finally, mice without thalamic GABA-A receptors were resistant to pharmacologically induced seizures. Overall, these results showed that enhanced extrasynaptic GABA-A receptor activation in the thalamus may underlie absence seizures. INHERITANCE \- Autosomal dominant NEUROLOGIC Central Nervous System \- Absence seizures \- Generalized tonic-clonic seizures (often develop in adolescence) \- Febrile seizures may occur \- EEG shows 3-4-Hz spike and multispike slow wave complexes MISCELLANEOUS \- Onset in childhood (6-7 years) \- High frequency of absence seizures (several per day) \- Seizures may remit in adolescence \- Seizures may persist into adulthood \- Accounts for 5-15% of childhood epilepsies \- Genetic heterogeneity (see ECA2, 607681 and ECA3, 607682 ) ▲ 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 inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	EPILEPSY, CHILDHOOD ABSENCE, SUSCEPTIBILITY TO, 1	c1838604	4,396	omim	https://www.omim.org/entry/600131	2019-09-22T16:16:34	{"omim": ["600131"], "orphanet": ["64280"], "synonyms": ["Pyknolepsy"]}
Post-vacation blues Other namesPost-holiday blues SymptomsTiredness, loss of appetite, nostalgia, depression CausesReturning home or to a normal routine from a long vacation TreatmentTime Frequency57% of travellers Post-vacation blues (Canada and US), post-holiday blues (UK, Ireland and some Commonwealth countries), vacation/holiday blues or post-travel depression (PTD) is a type of mood that persons returning home from a long trip (usually a vacation) may experience.[1] ## Contents * 1 Background * 2 Treatment * 3 Similar moods * 4 See also * 5 References ## Background[edit] A person may suffer from post vacation blues after returning home or to a normal routine from a long vacation, especially if it was a pleasurable one.[2][3] The longer a trip lasts, the more intense the post vacation blues may be. This is because after the person returns home, they realize how boring and unsatisfactory their normal lifestyle routine is when compared to the activities they did while on their holiday/vacation. It is easier to overcome/adjust to a normal routine the shorter the trip was. Post vacation blues may result in tiredness, loss of appetite, strong feelings of nostalgia, and in some cases, depression. Jet lag may intensify the post vacation blues.[4] According to an article in The Mirror, 57% of British travellers reported experiencing post-holiday blues.[5] ## Treatment[edit] In general, post vacation blues will wear off over time.[1] It usually takes a few days, but in extreme cases the mood can last for several weeks before wearing off. Faster ways of treating post vacation blues are for the person to share their experiences with family and friends, or to look at photos and souvenirs[citation needed]. Some may find comfort in re-living their holiday/vacation experiences; for example, if one really enjoyed jet-skiing during their holiday, they may purchase their very own jet-ski for personal use.[citation needed] Another well known method of curing post vacation blues is to plan or book the next vacation, this offers a distraction and also provides the person something to look forward to.[citation needed] ## Similar moods[edit] * Post-Christmas blues * Monday blues – may be experienced by persons after weekends. * Post-party blues – may be experienced by persons after an enjoyable party or nightlife experience, not to be confused with a hangover, which can have similar psychological effects due to high alcohol intake. * New employee apathy/Freshman apathy * Spring fever * In Japan, a phenomenon known as gogatsu-byou (五月病, literally "May sickness") leaves some people feeling depressed a month after they started a new school year or new job, as their expectations were not met.[6] ## See also[edit] * Human factors * Human reliability * Seasonal affective disorder * Homesickness * Nostalgia ## References[edit] 1. ^ a b "After Vacation: Tips to Bounce Back Fast". WebMD. 2. ^ "HuffPost is now part of Oath". HuffPost is now part of Oath. Retrieved 5 March 2019. 3. ^ Dana McMahan. "Do well-needed vacations actually bum us out?". NBC News. 4. ^ Dillner, Luisa (19 May 2013). "How do you recover from jet lag?". the Guardian. Retrieved 5 March 2019. 5. ^ Lillywhite, Octavia (3 September 2017). "5 ways to beat post-holiday blues, according to an expert". The Mirror. Retrieved 5 March 2019. 6. ^ Abe, Namiko. "Gogatsu byou – May Sickness". ThoughtCo. Retrieved August 31, 2017. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Post-vacation blues	None	4,397	wikipedia	https://en.wikipedia.org/wiki/Post-vacation_blues	2021-01-18T18:47:55	{"wikidata": ["Q5488618"]}
Ischemic monomelic neuropathy is a rare, immediate, limb-threatening complication of hemodialysis access surgery.[1][2] Symptoms are acute hand pain and forearm muscle weakness. The major risk factors are the presence of diabetes mellitus, and the creation of a brachial artery-to-cephalic vein fistula as the vascular access. The treatment is prompt sacrifice of the access by surgical ligation.[citation needed] ## References[edit] 1. ^ Wodicka, R; Isaacs, J (May 2010). "Ischemic monomelic neuropathy". The Journal of Hand Surgery. 35 (5): 842–3. doi:10.1016/j.jhsa.2009.08.014. PMID 19942360. 2. ^ Thermann, F; Kornhuber, M (2011). "Ischemic monomelic neuropathy: a rare but important complication after hemodialysis access placement--a review". The Journal of Vascular Access. 12 (2): 113–9. doi:10.5301/JVA.2011.6365. PMID 21360465. This article about a medical condition affecting the circulatory system is a stub. You can help Wikipedia by expanding it. * v * t * e This article needs additional or more specific categories. Please help out by adding categories to it so that it can be listed with similar articles. (November 2019) [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Ischemic monomelic neuropathy	None	4,398	wikipedia	https://en.wikipedia.org/wiki/Ischemic_monomelic_neuropathy	2021-01-18T19:04:30	{"wikidata": ["Q85770088"]}
Viral encephalitis SpecialtyInfectious disease Viral encephalitis is inflammation of the brain parenchyma, called encephalitis, by a virus. The different forms of viral encephalitis are called viral encephalitides. It is the most common type of encephalitis and often occurs with viral meningitis. Encephalitic viruses first cause infection and replicate outside of the central nervous system (CNS), most reaching the CNS through the circulatory system and a minority from nerve endings toward the CNS. Once in the brain, the virus and the host's inflammatory response disrupt neural function, leading to illness and complications, many of which frequently are neurological in nature, such as impaired motor skills and altered behavior. Viral encephalitis can be diagnosed based on the individual's symptoms, personal history, such as travel history, and different clinical tests such as histology, medical imaging, and lumbar punctures. A differential diagnosis can also be done to rule out other causes of the encephalitis. Many encephalitic viruses often have characteristic symptoms of infection, helping to aid diagnosis. Treatment is usually supportive in nature while also providing antiviral drug therapy. The primary exception to this is herpes simplex encephalitis, which is treatable with acyclovir. Prognosis is good for most individuals who are infected by an encephalitic virus but is poor among those who develop severe symptoms, including viral encephalitis. Long-term complications of viral encephalitis typically relate to neurological damage, such as experiencing seizures, memory loss, and intellectual impairment. Encephalitic viruses are typically transmitted either from person-to-person or are arthropod-borne viruses, called arboviruses. The young and the elderly are at the highest risk of viral encephalitis. Many cases of viral encephalitis are not identified either because of lack of testing or mild illness, and serological surveys indicate that asymptomatic infections are common. Various ways of preventing viral encephalitis exist, such as vaccines that are either in standard vaccination programs or which are recommended when living in or visiting certain regions, and various measures aimed at preventing mosquito, sandfly, and tick bites in order to prevent arbovirus infection. ## Contents * 1 Etiology * 1.1 Transmission * 2 Pathogenesis * 3 Diagnosis * 3.1 Examination * 3.2 Histology * 3.3 Clinical evaluation * 3.4 Differential diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 Prevention * 8 See also * 9 References * 10 External links ## Etiology[edit] Many viruses are capable of causing encephalitis during infection, including:[1] * California encephalitis virus[2] * Chandipura virus[3] * Chikungunya virus[4] * Cytomegalovirus * Dengue virus * Eastern equine encephalitis virus * Enteroviruses * Epstein-Barr virus * Herpes simplex virus * HIV[5] * Human herpesvirus 6 * Human herpesvirus 7 * Influenza viruses[4][6] * Inkoo virus[7] * Jamestown Canyon virus[8] * Japanese encephalitis virus * La Crosse virus * Lymphocytic choriomeningitis mammarenavirus[9] * Measles virus * Mumps virus * Murray Valley encephalitis virus[10] * Nipah virus * Powassan virus[8] * Rabies virus * Rubella virus * SARS-CoV-2[11] * Snowshoe hare virus[7] * St. Louis virus * Tahyna virus[7] * Tick-borne encephalitis virus * Varicella-zoster virus, which causes both chickenpox and shingles * Venezuelan equine encephalitis virus * West Nile virus * Western equine encephalitis virus * Zika virus ### Transmission[edit] Encephalitic viruses vary in their manner of transmission. Some are transmitted from person-to-person, whereas others are transmitted by animals, especially bites from arthropods such as mosquitos, sandflies, and ticks, such viruses being called arboviruses.[12] An example of person-to-person transmission is the herpes simplex virus, which is transmitted by means of intimate physical contact.[13] An example of arboviral transmission is the West Nile virus, which usually is incidentally transmitted to people from the bites of Culex mosquitos, especially Culex pipiens.[14] ## Pathogenesis[edit] Viruses that cause viral encephalitis first infect the body and replicate outside of the central nervous system (CNS). Thereafter, most reach the spinal cord and brain via the circulatory system. Exceptions to this include herpesviruses and the rabies virus, which travel from nerve endings to the CNS. Once in the brain, the virus and the host's inflammatory response disrupt neural cell function, including causing fluid buildup in the brain, vascular congestion, and bleeding. Widespread presence of white blood cells and microglia in the CNS is common as a response to CNS infection. For some forms of viral encephalitis, such as Eastern equine encephalitis and Japanese encephalitis, there may be a significant amount of necrosis of nerve cells. Following encephalitis caused by arboviruses, calcification may occur in the CNS, especially among children. Herpes simplex encephalitis tends to produce necrotic lesions in the CNS.[1] ## Diagnosis[edit] ### Examination[edit] If viral encephalitis is suspected, then questions can be asked about the individual's history and physical examination can be performed. Important aspects of one's history include immune status, exposure to animals, including insects, travel history, vaccination history, geography, and time of year. Symptoms usually occur acutely,[4] and the most common symptoms of infection are fever, headache, altered mental status, sensitivity to light, stiff neck and back, vomiting, confusion, and, in severe cases, seizures, paralysis, and coma. Neuropsychiatric features such as behavioral changes, hallucinations, or cognitive decline are frequent. Severe symptoms are most common among infants and the elderly. Most infections are asymptomatic, lacking symptoms, whereas most symptomatic cases are mild illnesses.[1][12] Virus-specific symptoms may also exist or tests may indicate one virus. Specific examples include:[1] * Enterovirus 71 may cause tremors, twitching, impaired balance and coordination, fluid accumulation in the lungs, and cranial nerve palsies. * Epstein-Barr virus encephalitis is usually accompanied by enlargement of the lymph nodes and enlargement of the spleen * Herpes zoster encephalitis may be accompanied by rash and skin vesicles, and because it involves the frontal lobe and temporal lobe, is often characterized by psychiatric features, memory deficits, and loss of language faculties. * Many arboviral encephalitides, such as Japanese encephalitis, primarily affect the basal ganglia, sometimes causing motor symptoms such as involuntary movements and movements similar to those observed in Parkinson's disease. * Nipah virus may produce brainstem and cerebellar signs, hypertension, and segmental myoclonus, or twitching of a group of connected muscles. * Zika virus characteristically may cause microcephaly among newborn children if a pregnant woman is infected. ### Histology[edit] The brain histology of viral encephalitis shows dead neurons with nuclear dissolution and elevated eosinophil count, called hypereosinophilia, within cells' cytoplasm when viewed with an optical microscope. Because encephalitis is an inflammatory response, inflammatory cells situated near blood vessels, such as microglia, macrophages, and lymphocytes, are visible. Virions within neurons are visible via electron microscopes.[1] ### Clinical evaluation[edit] Preferred diagnostic test according to suspected etiology.[4] Virus Preferred diagnostic test Cytomegalovirus CSF PCR or CSF-specific IgM Dengue/Chikungunya/Zika CSF PCR or CSF-specific IgM Enterovirus Stool and throat PCR are preferred over CSF PCR Epstein-Barr virus Serum EBV capsid antigen IgG and IgM (VCA) and EBV nuclear antigen IgG (EBNA) Herpes simplex virus CSF PCR, can be repeated within 2 to 7 days of disease onset if negative with high clinical suspicion; or CSF for HSV-IgG after 10–14 days of disease onset HHV-6 CSF PCR paired with serum PCR to exclude viral integration into host DNA that causes false positives Influenza Culture, antigen test, PCR of respiratory secretions Measles CSF-specific IgG Varicella-zoster virus CSF-specific IgG Neuroimaging and lumbar puncture (LP) are both essential methods of diagnosing viral encephalitis. Computed tomography (CT) or magnetic resonance imaging (MRI) help identify increased intracranial pressure and the risk of uncal herniation before performing an LP. Cerebrospinal fluid (CSF), if analyzed, should be analyzed for opening pressure, cell counts, glucose, protein, and IgG and IgM antibodies. CSF testing should also include polymerase chain reaction (PCR) testing for herpes simplex viruses 1 and 2 and enteroviruses. About 10% of patients have normal CSF results. Additional testing, such as serology for various arboviruses and HIV testing, may also be performed based on the individual's history and symptoms. Brain biopsy and body fluid specimen cultures and PCR may also be useful in some cases. Electroencephalography (EEG) is abnormal in more than 80% of viral encephalitis cases, including those who are experiencing seizures, and may need to be monitored continuously to identify non-convulsive status. Lack of testing resources may prevent accurate diagnosis.[1][4] Test results specific to certain viruses include:[1] * For herpes simplex virus encephalitis, a CT scan may show low-density lesions in the temporal lobe. These lesions usually appear 3 to 5 days after the start of the infection. * Japanese encephalitis often has distinct EEG patterns, including diffuse delta activity with spikes, diffuse continuous delta activity, and alpha coma activity. ### Differential diagnosis[edit] A broad differential diagnosis can be performed that looks at many potential causes of the encephalitis, infectious and noninfectious. Potential alternatives to viral encephalitis include malignancy, autoimmune or paraneoplastic diseases such as anti-NMDA receptor encephalitis, a brain abscess, tuberculosis or drug-induced delirium, exposure to certain drugs or toxins, neurosyphilis, vascular disease, metabolic disease, or encephalitis from infection caused by a bacterium, fungus, protozoan, or parasitic worm.[1][6][13] In children, differential diagnosis may not be able to distinguish between viral encephalitis and immune-mediated inflammatory CNS diseases, such as acute disseminated encephalomyelitis, as well as immune-mediated encephalitis, so other diagnostic methods may need to be used.[4] ## Treatment[edit] Treatment of viral encephalitis is primarily supportive with intravenous antiviral therapy due to there being no specific medical therapy for most viral infections involving the central nervous system. Individuals may require intensive care for frequent neurological exams or respiratory support, and treatment for electrolyte disturbance, autonomic disregulation, and renal and hepatic dysfunction, as well as for seizures and non-compulsive status epilepticus.[1][4] A very specific exception is herpes simplex virus (HSV) encephalitis, which can be treated with acyclovir for 2 to 3 weeks if it is provided early enough. Acyclovir significant decreases morbidity and mortality of HSV encephalitis and limits the long-term behavioral and cognitive impairments that occur with illness. As such, and because HSV is the most common cause of viral encephalitis, acyclovir is often administered as soon as possible to all patients suspected of having viral encephalitis even if the exact viral origin is not yet known. Viral resistance to acyclovir rarely occurs, primarily among the immunocompromised, in which case foscarnet should be used. Although not as effective, nucleoside analogs are used for other herpesviruses as well, such as acyclovir, with possible adjunctive corticosteroids for immunocompetent individuals, for varicella-zoster virus encephalitis and a combination of ganciclovir and foscarnet for cytomegalovirus encephalitis.[1][13] Serial intracranial pressure (ICP) is important to monitor as elevated ICP is associated with poor prognosis. Elevated ICP can be relieved with steroids and mannitol, though there is limited data of the efficacy of such treatment with regards to viral encephalitis. Seizures can be managed with valproic acid or phenytoin. Status epilepticus may required benzodiazepines. Antipsychotic drugs may be needed for a short time period if behavior alternations are present. Given the possibility of complications developing from viral encephalitis, an interdisciplinary team consisting of the clinicians, therapists, rehabilitation specialists, and speech therapists is important in order to help patients.[1] ## Prognosis[edit] If treated, most individuals recover from viral encephalitis without long-term problems related to the illness. Mortality rates vary for those who do not receive treatment, for example being about 70% for herpes encephalitis[13] but low for the La Crosse virus. Individuals who remain symptomatic after initial infection may have difficulty concentrating, behavior or speech disorders, or memory loss. Rarely, individuals may remain in a persistent vegetative state. The most common long-term complication of viral encephalitis is seizures that may occur in 10% to 20% of patients over several decades. These seizures are resistant to medical therapy. However, individuals who have unilateral mesial temporal lobe seizures after viral encephalitis have good results following neurosurgery. Prognoses related to specific viruses include:[1] * For Eastern equine encephalitis, some children may experience seizures, severe mental retardation, and various forms of paralysis. * For Japanese encephalitis, extrapyramidal symptoms relating to motor function may remain. * For St. Louis encephalitis, low blood sodium level and excess, unsuppressable release of antidiuretic hormone * For Western equine encephalitis, some children may experience seizures and behavioral changes. * For pregnant women infected with Zika virus, the newborn child may have microcephaly. Other potential complications following viral encephalitis include:[1] * Encephalopathy * Flaccid paralysis * Impaired intelligence * Low blood sodium level * Mononeuropathy * Mood and behavioral changes * Residual neurological deficits ## Epidemiology[edit] While the etiology of many cases of encephalitis is unknown, viruses account for about 70% of confirmed encephalitis cases, with the herpes simplex virus being the most common cause at about 50% of encephalitis cases.[13] The incidence of viral encephalitis is about 3.5 to 7.5 per 100,000 people, with the highest incidence among the young and the elderly. Viral encephalitis caused by some viruses, such as the measles virus and the mumps virus, has become less common due to widespread vaccination. For others, such as Epstein-Barr virus and cytomegalovirus, incidence has increased due to the increased prevalence of AIDS, organ transplantation, and chemotherapy, which have increased the number of immunocompromised people who have weakened immune systems or who are susceptible to opportunistic infections. Time of the year, geography, and animal, including insect, exposure are also important. For example, arbovirus infections are seasonal and cause viral encephalitis at the highest rate during the summer and early fall when mosquitos are most active. Similarly, those who live in warm, humid climates where there are more mosquitos are more likely to experience viral encephalitis.[1][6] ## Prevention[edit] As many encephalitic viruses are transmitted by mosquitos, many prevention efforts revolve around preventing mosquito bites. In areas where such arboviruses are widespread, people should use protective clothing and should sleep under a mosquito net. Removing containers of stagnant water and spraying insecticides can be beneficial. Activities that increase the likelihood of tick bites should be avoided. Vaccines against some arboviruses that cause viral encephalitis exist, such as those against Eastern equine encephalitis, Western equine encephalitis, and Venezuelan equine encephalitis. Although these vaccines are not perfectly effective, they are recommended for people who live in or travel to high-risk areas.[1][6] Some vaccines that are included in standard vaccination programs, such as the MMR vaccine, which prevents measles, mumps, and rubella, are also capable of preventing viral encephalitis.[15] ## See also[edit] * List of central nervous system infections ## References[edit] 1. ^ a b c d e f g h i j k l m n o Said, S.; Kang, M. (16 December 2019). Viral encephalitis. StatPearls Publishing LLC. PMID 29262035. Retrieved 28 March 2020. 2. ^ Hammon, W. M.; Reeves, W. C. (1952). "California encephalitis virus, a newly described agent". Calif Med. 77 (5): 303–309. PMC 1521486. PMID 13009479. 3. ^ Ghosh, S.; Basu, A. (January–February 2017). "Neuropathogenesis by Chandipura virus: An acute encephalitis syndrome in India". Natl Med J India. 30 (1): 21–25. PMID 28731002. 4. ^ a b c d e f g Costa, B. K. D.; Sato, D. K. (2020). "Viral encephalitis: a practical review on diagnostic approach and treatment". Jornal de Pediatria. 96 (Suppl. 1): 12–19. doi:10.1016/j.jped.2019.07.006. PMID 31513761. Retrieved 27 March 2020. 5. ^ Chen, Z.; Zhong, D.; Li, G (2019). "The role of microglia in viral encephalitis: a review". J Neuroinflammation. 16 (1): 76. doi:10.1186/s12974-019-1443-2. PMC 6454758. PMID 30967139. 6. ^ a b c d "Understanding encephalitis -- the basics". WebMD. WebMD. 26 March 2019. Retrieved 27 March 2020. 7. ^ a b c Evans, A. B.; Winkler, C. W.; Peterson, K. E. (2019). "Differences in Neuropathogenesis of Encephalitic California Serogroup Viruses". Emerg Infect Dis. 25 (4): 728–738. doi:10.3201/eid2504.181016. PMC 6433036. PMID 30882310. 8. ^ a b Pastula, D. M.; Smith, D. E.; Beckham, J. D.; Tyler, K. L. (2016). "Four emerging arboviral diseases in North America: Jamestown Canyon, Powassan, chikungunya, and Zika virus diseases". J Neurovirol. 22 (3): 257–260. doi:10.1007/s13365-016-0428-5. PMC 5087598. PMID 26903031. 9. ^ Lavergne, A.; de Thoisy, B.; Tirera, S.; Donato, D.; Bouchier, C.; Catzeflies, F.; Lacoste, V. (2016). "Identification of lymphocytic choriomeningitis mammarenavirus in house mouse (Mus musculus, Rodentia) in French Guiana". Infect Genet Evol. 37: 225–230. doi:10.1016/j.meegid.2015.11.023. PMID 26631809. Retrieved 27 March 2020. 10. ^ Mackenzie, J. S.; Lindsay, M. D. A.; Smith, D. W.; Imrie, A (2017). "The ecology and epidemiology of Ross River and Murray Valley encephalitis viruses in Western Australia: examples of One Health in Action". Trans R Soc Trop Med Hyg. 111 (6): 248–254. doi:10.1093/trstmh/trx045. PMC 5914307. PMID 29044370. 11. ^ Carod-Artal, F. J. (1 May 2020). "Neurological Complications of Coronavirus and COVID-19". Revista de Neurología. 70 (9): 311–322. doi:10.33588/rn.7009.2020179. PMID 32329044. 12. ^ a b "Encephalitis, Viral". World Health Organization. World Health Organization. Retrieved 27 March 2020. 13. ^ a b c d e Bradshaw, M. J.; Venkatesan, A. (2016). "Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management". Neurotherapeutics. 13 (3): 493–508. doi:10.1007/s13311-016-0433-7. PMC 4965403. PMID 27106239. 14. ^ "West Nile Virus". World Health Organization. World Health Organization. 3 October 2017. Retrieved 27 March 2020. 15. ^ "Understanding encephalitis -- prevention". WebMD. WebMD. 26 March 2019. Retrieved 27 March 2020. ## External links[edit] Classification D * ICD-10: A83-A86 * ICD-9-CM: 062-064 * MeSH: D018792 * 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 Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors [MSNs]: medium spiny neurons [CREB]: cAMP response element-binding protein [NC]: neurogenic claudication [LSS]: lumbar spinal stenosis [DDD]: degenerative disc disease [CI]: confidence interval [E2]: estradiol [CEEs]: conjugated estrogens	Viral encephalitis	c0014055	4,399	wikipedia	https://en.wikipedia.org/wiki/Viral_encephalitis	2021-01-18T19:02:44	{"mesh": ["D018792", "D004671"], "umls": ["C0014055"], "icd-9": ["062", "064"], "wikidata": ["Q3053951"]}

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