Datasets:

findzebra

/

corpus

like 0

## Description Aicardi syndrome is characterized by a triad of callosal agenesis, infantile spasms, and chorioretinal lacunae ('holes'). Flexion spasms in the infant represent the usual mode of clinical presentation (Aicardi, 1999). Clinical Features Aicardi et al. (1969) reported 15 cases, all in females. Dennis and Bower (1972) described a female patient who, in addition to infantile spasms, mental subnormality, specific chorioretinopathy, and 'split brain,' had evidence of heterotopia of the brain by pneumoencephalogram, vertebral anomalies, and characteristic EEG changes. Molina et al. (1989) reported the disorder in 2 sisters, the first observation of affected sibs. The parents were healthy. Germinal mosaicism is a possible explanation. McPherson and Jones (1990) observed cleft lip and palate in Aicardi syndrome and referred to 2 similar previously reported cases. Jones and McPherson (1992) noted that one of the 2 previously reported cases (McPherson and Jones (1990)) had been reported by Robinow et al. (1984). In addition, Robinow had brought to their attention another case of Aicardi syndrome with cleft lip and palate (Sato et al., 1987), bringing the total number of such patients to 4. The patient of Sato et al. (1987) also had holoprosencephaly, another midline defect that may occur occasionally in Aicardi syndrome. In an infant girl with Aicardi syndrome, Tsao et al. (1993) found associated scalp lipomas and a cavernous hemangioma of the leg which became malignant at 11 months, with distant metastases from metastatic angiosarcoma causing death at age 19 months. Trifiletti et al. (1995) reported a 5-year-old girl with choroid plexus papilloma and multiple gastric hyperplastic polyps, and referred to previous cases of Aicardi syndrome associated with brain tumors, especially choroid plexus papilloma. Menezes et al. (1994) described unusually mild Aicardi syndrome in a 10-year-old girl whose symptoms included poorly controlled seizure disorder, typical lacunar retinopathy, partial hypoplasia of the corpus callosum, and developmental delay of 4 to 5 years with marked inattentiveness. King et al. (1998) described an even milder case: a 49-year-old woman who was not severely mentally disabled and whose epilepsy had been well-controlled. She had dysgenesis of the corpus callosum and chorioretinal lacunae, which are typical of Aicardi syndrome. She had previously been diagnosed with cerebral and retinal toxoplasmosis, but there were no intracranial calcifications to support that diagnosis. Sutton et al. (2005) studied 40 girls with Aicardi syndrome and determined that consistent facial features appeared in over half of them, including a prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows. Externally apparent microphthalmia was seen in 10 (25%). Sutton et al. (2005) concluded that Aicardi syndrome has a distinctive facial phenotype. Kamien and Gabbett (2009) reported a girl with features of Aicardi syndrome, including infantile spasms, chorioretinal lacunae, partial agenesis of the corpus callosum, and neuronal migration abnormalities, including nodular heterotopia and polymicrogyria. Dysmorphic features included upslanting palpebral fissures, an upturned nasal tip, deep philtrum, and large ears. In addition, she had a hepatoblastoma and intralobar pulmonary sequestration with congenital cystic adenomatoid malformation. ### Neuroradiologic Findings Hopkins et al. (2008) reported detailed brain MRI findings of 23 patients with Aicardi syndrome, performed at ages 1 day to 7.2 years. There were 22 girls and one 47,XXY male. All patients had polymicrogyria and periventricular heterotopia. Polymicrogyria was mainly in the frontal or perisylvian regions. Widening of the operculum was observed in 13 (72%) of 18 patients. Twenty (95%) patients had intracranial cysts, and 20 (95%) had cerebellar abnormalities, including superior foliar prominence of the vermis, inferior vermian hypoplasia, and dysplastic or hypoplastic cerebellar hemispheres. An enlarged cisterna magna was present in 11 (55%), and 4 (20%) had cerebellar cysts. Ten patients had tectal enlargements. The findings were consistent with a neuronal migration disorder and asymmetric brain development. Cytogenetics Ropers et al. (1982) reported a case of Aicardi syndrome in a girl with presumably balanced X/3 translocation. They postulated that the clinical picture was due to chromosome breakage in the Aicardi locus. The breakpoint was in Xp22, between p22.2 and p22.3. This is the same region as steroid sulfatase, XG (300879), and a gene controlling a serologically defined, male-specific antigen, SDM (Wolf et al., 1980). According to Frezal (1987), Aicardi doubted the validity of the diagnosis in the case of Ropers et al. (1982). Neidich et al. (1988) found 2 new patients with Aicardi syndrome and Xp22 abnormalities. They stated that all patients have been either XX female or 47,XXY Klinefelter syndrome. Nielsen et al. (1991) used 5 DNA markers from the Xp22.3-p21.3 region to study the DNA from a patient with Aicardi syndrome. No evidence for a microdeletion was observed. Ballabio and Andria (1992) analyzed deletions and translocations involving the distal short arm of the X chromosome. Their Figure 2 showed the order of genes in the region Xp22.3-p22.2: short stature (SS; 312865), X-linked recessive chondrodysplasia punctata (CDPX1; 302950), mental retardation (MRX2; 300428), X-linked ichthyosis (XLI; 308100), Kallmann syndrome (KAL; 308700), and, in the most proximal area, Aicardi syndrome and focal dermal hypoplasia (FDH; 305600). The last 2 lyonize, and with deletions males are nullisomic, a presumably lethal state. Females with monosomy show a mosaic pattern. The first 5 loci, which escape lyonization, behave as recessive traits. Schmidt and Du Sart (1992) presented evidence suggesting that in some X/autosomal translocations, the phenotype results from the functional disomy of the region of the X chromosome that is translocated to the autosome. Bursztejn et al. (2009) reported an 8-year-old girl with an initial clinical diagnosis of Aicardi syndrome who was subsequently found to carry a de novo 11.73-Mb terminal deletion of chromosome 1p36 (607872), thus revising the diagnosis. She had onset of infantile spasms at age 3 months, bilateral pupillary coloboma, agenesis of the corpus callosum, and delayed psychomotor development. The report emphasized the phenotypic overlap between the 2 disorders. Inheritance The inheritance of Aicardi syndrome is probably X-linked dominant with lethality in the hemizygous male. All cases would, on this hypothesis, be new mutations (Aicardi et al., 1969; Aicardi, 1999). Hopkins et al. (1979) described the Aicardi syndrome in a 47,XXY male. This is, of course, consistent with the above suggested inheritance. The affected male reported by Curatolo et al. (1980) argues against X-linked dominant inheritance with male lethality. In 18 girls with Aicardi syndrome identified through a survey of neurologists, geneticists, and ophthalmologists, Donnenfeld et al. (1989) found complete agenesis of the corpus callosum in 72% and partial agenesis in 28%. Costovertebral defects including hemivertebrae, scoliosis, and absent or malformed ribs were present in 39%. Chromosomes in all patients and their parents were normal. An unbalanced X;3 translocation involving a breakpoint at Xp22.3 was discovered in a girl with chorioretinal lacunar lesions characteristic of Aicardi syndrome, developmental delay, and infantile seizures. Because the child had a normal-appearing corpus callosum on CT and magnetic resonance scans, she did not meet the criteria for inclusion in the study. Family studies showed a ratio of unaffected male:female sibs of 1:1.7 and a 14% spontaneous abortion rate. The findings were considered consistent with the view that Aicardi syndrome is an X-linked dominant disorder with early embryonic lethality in hemizygous males and that all cases represent new mutations. The finding in the atypical case is consistent with location of the gene in the Xp22.3 area. ### X-Inactivation Studies Neidich et al. (1990) studied X inactivation in peripheral lymphocytes in 7 patients by means of 2 methods: methylation-sensitive restriction analysis and segregation of the active X chromosome in somatic cell hybrids. They found that 3 of the 7 cytogenetically normal girls with Aicardi syndrome had profoundly skewed X inactivation in their lymphocytes, supporting the concept that Aicardi syndrome is X-linked. Three of the 5 girls with the greatest degree of psychomotor retardation and the poorest seizure control had skewed X inactivation. In contrast, the 2 highest functioning children had random X inactivation. No evidence of deletion was found with 8 polymorphic DNA probes from the Xp22 region. Using the highly polymorphic, differentially methylated androgen receptor gene (313700), Hoag et al. (1997) found a random X-inactivation pattern in 10 female patients with Aicardi syndrome. This finding was unexpected because skewed X inactivation had been observed in at least one other condition, incontinentia pigmenti, in which the mode of inheritance has been thought to be X-linked dominant mutation, de novo in females and lethal in males. This would be predicted if there were a selection against cells in which the X chromosome carrying the mutant allele was active. Costa et al. (1997) reported monozygotic twins who were discordant for Aicardi syndrome. Methylation-sensitive RFLP analysis showed a very similar pattern of X inactivation in both twins with no evidence of preferential expression of one particular X chromosome. Costa et al. (1997) concluded that the abnormalities in the affected twin were probably due to a postzygotic event. In informative samples from 33 girls with Aicardi syndrome, Eble et al. (2009) found that 11 (33%) had nonrandom X inactivation, with a greater than 80:20 skewed ratio. Six (18%) of these, had an extremely skewed ratio of greater than 95:5. There was a correlation between X-inactivation patterns and clinical severity, such that nonrandom X inactivation was associated with higher neurologic severity. Conversely, random X inactivation was correlated with vertebral anomalies. Molecular Genetics ### Exclusion Studies Nemos et al. (2009) excluded mutations in the CDKL5 gene (300203) in 10 French patients with Aicardi syndrome. INHERITANCE \- X-linked dominant GROWTH Other \- Postnatal growth retardation HEAD & NECK Head \- Microcephaly Face \- Facial asymmetry Eyes \- Microphthalmia \- Optic nerve coloboma \- Bilateral chorioretinopathy \- Chorioretinal lacunae \- Retinal detachment \- Cataract \- Nystagmus \- Optic atrophy \- Sparse lateral eyebrows Nose \- Upturned nasal tip \- Decreased angle of nasal bridge Mouth \- Prominent premaxilla \- Cleft lip \- Cleft palate RESPIRATORY Lung \- Recurrent pneumonia CHEST Ribs Sternum Clavicles & Scapulae \- Absent ribs \- Extra ribs \- Fused ribs \- Bifid ribs ABDOMEN Gastrointestinal \- Hiatal hernia SKELETAL Spine \- Butterfly vertebrae \- Block vertebrae \- Hemivertebrae \- Spina bifida \- Scoliosis Hands \- Proximally placed thumbs SKIN, NAILS, & HAIR Skin \- Scalp lipoma \- Multiple nevi \- Hypopigmented macules \- Skin tags \- Hemangiomas Hair \- Sparse lateral eyebrows NEUROLOGIC Central Nervous System \- Mental retardation, profound \- Infantile spasms \- Seizures \- Hypotonia \- Dandy-Walker malformation \- Arnola-Chiari malformation \- Cavum septum pellucidum \- Choroid plexus cyst \- Intracranial cysts \- Delayed myelination \- Partial-total agenesis of corpus callosum \- Enlarged lateral and third ventricles \- Cortical heterotopias \- Subependymal heterotopias \- Pachygyria \- Hypoplastic cerebellar vermis \- Dysplasia of the cerebellar hemispheres \- Polymicrogyria, predominantly frontal and perisylvian \- Tectal enlargement \- Widening of the operculum \- Asymmetric brain development ENDOCRINE FEATURES \- Precocious puberty NEOPLASIA \- Hepatoblastoma \- Benign teratoma \- Embryonal carcinoma \- Metastatic angiosarcoma ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

AICARDI SYNDROME

c0175713

omim

https://www.omim.org/entry/304050

{"doid": ["8461"], "mesh": ["D058540"], "omim": ["304050"], "orphanet": ["50"], "synonyms": ["Alternative titles", "CORPUS CALLOSUM, AGENESIS OF, WITH CHORIORETINAL ABNORMALITY"], "genereviews": ["NBK1381"]}

Boucher-Neuhäuser syndrome is a rare disorder that affects movement, vision, and sexual development. It is part of a continuous spectrum of neurological conditions, known as PNPLA6-related disorders, that share a genetic cause and have a combination of overlapping features. Boucher-Neuhäuser syndrome is characterized by three specific features: ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Ataxia describes difficulty with coordination and balance. In Boucher-Neuhäuser syndrome, it arises from a loss of cells (atrophy) in the part of the brain involved in coordinating movements (the cerebellum). Affected individuals have an unsteady walking style (gait) and frequent falls. Another key feature of Boucher-Neuhäuser syndrome is hypogonadotropic hypogonadism, which is a condition affecting the production of hormones that direct sexual development. Affected individuals have a delay in development of the typical signs of puberty, such as the growth of facial hair and deepening of the voice in males, and the start of monthly periods (menstruation) and breast development in females. Other hormone abnormalities lead to short stature in some affected individuals. The third characteristic feature of Boucher-Neuhäuser syndrome is eye abnormalities, most commonly chorioretinal dystrophy. Chorioretinal dystrophy refers to problems with the light-sensitive tissue that lines the back of the eye (the retina) and a nearby tissue layer called the choroid. These eye abnormalities lead to impaired vision. People with Boucher-Neuhäuser syndrome can also have abnormal eye movements, including involuntary side-to-side movements of the eyes (nystagmus). The key features of Boucher-Neuhäuser syndrome can begin anytime from infancy to adulthood, although at least one feature usually occurs by adolescence. Ataxia is often the initial symptom of the disorder, but vision problems or delayed puberty can be the earliest finding. Vision and movement problems worsen slowly throughout life and can result in blindness or the need for a wheelchair for mobility in the most severely affected individuals. People with Boucher-Neuhäuser syndrome can have additional medical problems, including muscle stiffness (spasticity); impaired speech (dysarthria); and difficulty processing, learning, or remembering information (cognitive impairment). ## Frequency Boucher-Neuhäuser syndrome is a rare condition. Its prevalence is unknown. ## Causes Most cases of Boucher-Neuhäuser syndrome are caused by mutations in the PNPLA6 gene. Such mutations are the only known cause of the condition. Researchers speculate that as-yet-unidentified mutations in the PNPLA6 gene or changes in other genes are involved in the remainder of cases. The PNPLA6 gene provides instructions for making a protein called neuropathy target esterase (NTE), which helps regulate the amount of certain fats (lipids) that make up the outer membrane surrounding cells. The correct levels of these lipids are critical to the stability and function of cell membranes. In particular, the NTE protein breaks down (metabolizes) a lipid called lysophosphatidylcholine, which in high amounts can damage cells. NTE is found most abundantly in the nervous system and is thought to help maintain the stability of membranes surrounding nerve cells (neurons). NTE is also thought to play a role in the release of hormones from the pituitary gland, a process that requires particular changes in the cell membrane. The pituitary gland is located at the base of the brain and produces several hormones, including those that help direct sexual development and growth. PNPLA6 gene mutations are thought to impair NTE's function. However, it is unclear how these mutations cause Boucher-Neuhäuser syndrome. Researchers speculate that impairment of lysophosphatidylcholine metabolism alters the balance of lipids in the cell membrane. This imbalance may damage neurons, leading to the movement and vision problems that characterize Boucher-Neuhäuser syndrome. The imbalance may also impair the release of hormones involved in sexual development, accounting for the delayed puberty in affected individuals. Researchers are unsure how mutations in the PNPLA6 gene lead to different combinations of features, resulting in the spectrum of PNPLA6-related disorders. ### Learn more about the gene associated with Boucher-Neuhäuser syndrome * PNPLA6 ## 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

Boucher-Neuhäuser syndrome

c1859093

medlineplus

https://medlineplus.gov/genetics/condition/boucher-neuhauser-syndrome/

{"gard": ["944"], "mesh": ["C565850"], "omim": ["215470"], "synonyms": []}

Ayazi syndrome Other namesChoroideremia-deafness-obesity syndrome This condition is inherited in an X-linked recessive manner Ayazi syndrome (or Chromosome 21 Xq21 deletion syndrome)[1] is a syndrome characterized by choroideremia, congenital deafness and obesity. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] * Mental retardation * Deafness at birth * Obesity * Choroideremia * Impaired vision * Progressive degeneration of the choroid ## Genetics[edit] Ayazi syndrome's inheritance pattern is described as x-linked recessive. Genes known to be deleted are CHM and POU3F4, both located on the Xq21 locus.[1] ## Diagnosis[edit] This section is empty. You can help by adding to it. (August 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (August 2017) ## References[edit] 1. ^ a b "OMIM Entry - # 303110 - CHOROIDEREMIA, DEAFNESS, AND MENTAL RETARDATION". www.omim.org. Retrieved 2015-09-28.[permanent dead link] * Ayazi S (1981). "Choroideremia, obesity, and congenital deafness". Am J Ophthalmol. 92 (1): 63–69. doi:10.1016/s0002-9394(14)75909-4. PMID 7258279. * Merry DE, Lesko JG, Sosnoski DM, Lewis RA, Lubinsky M, Trask B, van den Engh G, Collins FS, Nussbaum RL (1989). "Choroideremia and deafness with stapes fixation: a contiguous gene deletion syndrome in Xq21". Am J Hum Genet. 45 (4): 530–540. PMC 1683514. PMID 2491012. * http://www.wrongdiagnosis.com/a/ayazi_syndrome/symptoms.htm ## External links[edit] Classification D * ICD-10: Q87.8 * OMIM: 303110 * MeSH: C537793 * SNOMED CT: 717761005 External resources * Orphanet: 1435 * Online Mendelian Inheritance in Man (OMIM): 303110 This genetic disorder article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Ayazi syndrome

c3551019

wikipedia

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

{"gard": ["369"], "mesh": ["C537793"], "umls": ["C1844836", "C3551019"], "orphanet": ["1435"], "wikidata": ["Q4831022"]}

Cold autoimmune hemolytic anemia SpecialtyHematology This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Cold autoimmune hemolytic anemia" – news · newspapers · books · scholar · JSTOR (February 2019) Cold autoimmune hemolytic anemia caused by cold-reacting antibodies. Autoantibodies that bind to the erythrocyte membrane leading to premature erythrocyte destruction (hemolysis) characterize autoimmune hemolytic anemia. ## Contents * 1 Presentation * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 4.1 Classification * 5 Treatment * 5.1 Splenectomy * 5.2 Diet and activity * 5.3 Consultations * 6 References ## Presentation[edit] A common complaint among patients with cold agglutinin disease is painful fingers and toes with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the patient is more symptomatic during the colder months. Cold agglutinin mediated acrocyanosis differs from Raynaud phenomenon. In Raynaud phenomena, caused by vasospasm, a triphasic color change occurs, from white to blue to red, based on vasculature response. No evidence of such a response exists in cold agglutinin disease. Other symptoms * Respiratory symptoms: May be present in patients with M pneumoniae infection. * Hemoglobinuria (the passage of dark urine that contains hemoglobin), A rare symptom that results from hemolysis, this may be reported following prolonged exposure to cold, hemoglobinuria is more commonly seen in paroxysmal cold hemoglobinuria. * Chronic fatigue, Due to anemia. ## Causes[edit] Cold agglutinins develop in more than 60% of patients with infectious mononucleosis, but hemolytic anemia is rare. Classic chronic cold agglutinin disease is idiopathic, associated with symptoms and signs in relation to cold exposure. Causes of the monoclonal secondary disease include the following: * B-cell neoplasms - Waldenström macroglobulinemia, lymphoma, chronic lymphoid leukemia, myeloma * Non hematologic neoplasms Causes of polyclonal secondary cold agglutinin disease include the following: * Mycoplasma infections. * Viral infections: Infectious mononucleosis due to Epstein-Barr virus (EBV) or CMV, Mumps, varicella, rubella, adenovirus, HIV, influenza, hepatitis C. * Bacterial infections: Legionnaire disease, syphilis, listeriosis and Escherichia coli. * Parasitic infections: Malaria and trypanosomiasis. * Trisomy and translocation: Cytogenetic studies in patients with cold agglutinin disease have revealed the presence of trisomy 3 and trisomy 12. Translocation (8;22) has also been reported in association with cold agglutinin disease. * Transplantation: Cold agglutinin–mediated hemolytic anemia has been described in patients after living-donor liver transplantation treated with tacrolimus and after bone marrow transplantation with cyclosporine treatments. It is postulated that such calcineurin inhibitors, which selectively affect T-cell function and spare B-lymphocytes, may interfere with the deletion of autoreactive T-cell clones, resulting in autoimmune disease. * Systemic sclerosis: Cold agglutinin disease has been described in patients with sclerodermic features, with the degree of anemia being associated with increasing disease activity of the patient's systemic sclerosis. This may suggest a close association between systemic rheumatic disease and autoimmune hematologic abnormalities. * Hyperreactive malarial splenomegaly: Hyperreactive malarial splenomegaly (HMS) is an immunopathologic complication of recurrent malarial infection. Patients with HMS develop splenomegaly, acquired clinical immunity to malaria, high serum concentrations of anti-Plasmodium antibodies, and high titers of IgM, with a complement-fixing IgM that acts as a cold agglutinin. * DPT vaccination: Diphtheria-pertussis-tetanus (DPT) vaccination has been implicated in the development of autoimmune hemolytic anemia caused by IgM autoantibody with a high thermal range. A total of 6 cases have been reported; 2 followed the initial vaccination and 4 followed the second or third vaccinations. * Other: Equestrian perniosis is a rare cause of persistent elevated titers of cold agglutinins. Also rarely, the first manifestations of cold agglutinin disease can develop when a patient is subjected to hypothermia for cardiopulmonary bypass surgery. ## Pathophysiology[edit] Cold agglutinins, or cold autoantibodies, occur naturally in nearly all individuals. These natural cold autoantibodies occur at low titers, less than 1:64 measured at 4 °C, and have no activity at higher temperatures. Pathologic cold agglutinins occur at titers over 1:1000 and react at 28-31 °C and sometimes at 37 °C. Cold agglutinin disease usually results from the production of a specific IgM antibody directed against the I/i antigens (precursors of the ABH and Lewis blood group substances) on red blood cells (RBCs). Cold agglutinins commonly have variable heavy-chain regions encoded by VH, with a distinct idiotype identified by the 9G4 rat murine monoclonal antibody. ## Diagnosis[edit] ### Classification[edit] AIHA can be classified as warm autoimmune hemolytic anemia or cold autoimmune hemolytic anemia, which includes cold agglutinin disease and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.[1] * * * Autoimmune hemolytic anemia * Warm-antibody type * Primary * Secondary (lymphoproliferative disorders, autoimmune disorders) [2]:259 * Cold-antibody type (anemia) * Primary cold agglutinin disease * Secondary cold agglutinin syndrome * Associated with malignant disease * Acute, transient[2], infection-associated (acute cold antibody mediated AIHA complicating Mycoplasma pneumoniae or viral infections [3]) * Chronic (lymphoproliferative disorders) [2]:259 * Paroxysmal cold hemoglobinuria[2]:259 * Idiopathic * Secondary * Acute, transient (Infections other than syphilis)[2]:259 * Chronic (syphilis)[2]:259 * Mixed cold- and warm-antibody type * Idiopathic * Secondary (lymphoproliferative disorders, autoimmune disorders) [2] * Drug-induced immune hemolytic anemia [2]:259 * Autoimmune type * Drug absorption type * Neoantigen type [4] ## Treatment[edit] Cold agglutinin disease may be managed successfully using protective measures (clothing) alone in most cases. Special protective clothing is sometimes necessary in extreme cases. Therapy is directed at serious symptoms and the underlying disorder, if any is found. Keep in mind that the idiopathic variety of cold agglutinin disease is generally a benign disorder with prolonged survival and spontaneous exacerbations and remissions in the course of the disease. Acute post infectious syndromes usually resolve spontaneously. Anemia is generally mild. Only patients who have serious symptoms related to anemia or have a Raynaud type syndrome that constitutes a threat to life or quality of life require active therapy. The presence of an associated malignancy requires specific therapy. Cold agglutinin disease is so uncommon in children that no specific recommendations for therapy are available. Intravenous immunoglobulin (IVIG) was used successfully in an infant with IgA-associated autoimmune hemolytic anemia. ### Splenectomy[edit] Splenectomy is usually ineffective for the treatment of cold agglutinin disease because the liver is the predominant site of sequestration. However, if the patient has splenomegaly, then the disease may respond to splenectomy. More importantly, a lymphoma localized to the spleen may only be found after splenectomy. ### Diet and activity[edit] Patients with cold agglutinin disease should include good sources of folic acid, such as fresh fruits and vegetables, in their diet. Activities for these individuals should be less strenuous than those for healthy people, particularly for patients with anemia. Jogging in the cold could be very hazardous because of the added windchill factor. ### Consultations[edit] A hematologist-oncologist working in collaboration with a blood banker is helpful in complicated cases of cold agglutinin disease. Careful planning and coordination with multiple personnel are needed if patients are to undergo a procedure during which their body temperature could fall. ## References[edit] 1. ^ Zanella, A.; Barcellini, W. (2014-09-30). "Treatment of autoimmune hemolytic anemias". Haematologica. Ferrata Storti Foundation (Haematologica). 99 (10): 1547–1554. doi:10.3324/haematol.2014.114561. ISSN 0390-6078. PMC 4181250. PMID 25271314. 2. ^ a b c d e f g h Gehrs, B. C.; Friedberg, R. C. (2002). "Concise review: Autoimmune Hemolytic Anemia". American Journal of Hematology. Wiley. 69 (4): 258–271. doi:10.1002/ajh.10062. PMID 11921020. S2CID 22547733. 3. ^ Berentsen, Sigbjørn; Beiske, Klaus; Tjønnfjord, Geir E. (2007-07-21). "Primary chronic cold agglutinin disease: An update on pathogenesis, clinical features and therapy". Hematology (Amsterdam, Netherlands). Informa UK Limited. 12 (5): 361–370. doi:10.1080/10245330701445392. ISSN 1607-8454. PMC 2409172. PMID 17891600. 4. ^ Berentsen, Sigbjørn; Sundic, Tatjana (2015-01-29). "Red Blood Cell Destruction in Autoimmune Hemolytic Anemia: Role of Complement and Potential New Targets for Therapy". BioMed Research International. Hindawi Limited. 2015. 363278-1–363278-11. doi:10.1155/2015/363278. ISSN 2314-6133. PMC 4326213. PMID 25705656. * Emedicine, Harrison's textbook of clinical medicine 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. (December 2015) (Learn how and when to remove this template message) * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Cold autoimmune hemolytic anemia

c0175816

wikipedia

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

{"mesh": ["D000744"], "umls": ["C0175816"], "orphanet": ["228312"], "wikidata": ["Q9615018"]}

A rare genetic disease characterized by benign circumferential skin creases, mainly on the limbs, due to folding of excess skin. The creases often improve spontaneously in childhood. Patients also exhibit variable degrees of intellectual disability, short stature, cleft palate, and facial dysmorphism (including epicanthal folds, microphthalmia, broad nasal bridge, low-set, posteriorly rotated ears, and microstomia, among others). Variable additional features have been reported, such as seizures, infantile hypotonia, hearing impairment, strabismus, and urogenital anomalies. Brain imaging may show hypoplastic corpus callosum or mildly dilated ventricles. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Multiple benign circumferential skin creases on limbs

c0473586

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2505

{"gard": ["3589"], "mesh": ["C537575"], "omim": ["156610", "616734"], "umls": ["C0473586"], "icd-10": ["Q82.8"], "synonyms": ["CCSF", "Circumferential skin creases, Kunze type", "Congenital circumferential skin folds", "Kunze-Riehm syndrome"]}

Adult blaschkitis SpecialtyDermatology Adult blaschkitis is a rare inflammatory skin condition presenting as pruritic papules and vesicles along multiple lines of Blaschko.[1][2] ## See also[edit] * Lichen striatus * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 850. ISBN 978-1-4160-2999-1. 2. ^ Grosshans EM (August 1999). "Acquired blaschkolinear dermatoses". Am. J. Med. Genet. 85 (4): 334–7. doi:10.1002/(SICI)1096-8628(19990806)85:4<334::AID-AJMG4>3.0.CO;2-F. PMID 10398254. This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Adult blaschkitis

None

wikipedia

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

{"wikidata": ["Q4685917"]}

## Description Camptodactyly is defined as a permanent flexion contrature of 1 or both fifth fingers at the proximal interphalangeal joints. Additional fingers might be affected, but the little finger is always involved. Usually the condition appears to be sporadic in a family, but clinical examination of relatives reveals that it is an autosomal dominant condition subject to incomplete penetrance and variable expressivity (summary by Malik et al., 2008). Clinical Features In a rural area of western North Carolina, Murphy (1926) described camptodactyly in many members of 5 generations. Eleven of the affected persons also had knee-joint subluxation which was usually easily reduced. Hefner (1929, 1941) reported its occurrence in 4 generations. Camptodactyly, though often occurring as an isolated anomaly, is occasionally a feature of genetically distinct disorders (see craniocarpotarsal dystrophy, 193700). Symptoms include streblodactyly, congenital contracture of fingers, and congenital Dupuytren contracture. Parish et al. (1963) described flexion contractures of the fingers (streblodactyly: streblos = Gr. twisted, crooked) and amino aciduria in 10 females of 3 generations of a family. In 2 females the hands were normal but the same amino aciduria was present. Nine males were normal. Since all females in the direct line were affected by one or both of the traits mentioned, this is by definition hologynic. However, it is not, at least not necessarily, a sex-linked dominant as the authors proposed. In most patients fingers 2 to 5 were affected. This entity may not be different from camptodactyly. Nevin et al. (1966) also found taurinuria in association with camptodactyly. The increased excretion of taurine seemed to be renal in origin. Taurine is not an amino acid but a sulfonated amine which arises as an end product of the metabolism of sulfur-containing amino acids. Several instances of male-to-male transmission were noted in the 4 families they studied. Donofrio and Ayala (1983) reported a family in which 4 females in 2 generations were affected with the disorder reported by Parish et al. (1963) and called streblodactyly. No increase of abortions was noted in these families. The authors suggested sex-limited autosomal dominant inheritance. Streblodactyly is characterized by a permanent flexion contracture of all fingers at the proximal interphalangeal joints. Donofrio and Ayala (1983) suggested that camptodactyly (which often affects only the fifth finger and is clearly an autosomal dominant trait with incomplete penetrance) is distinct from streblodactyly. Malik et al. (2008) studied a large 4-generation German family in which 13 members had camptodactyly segregating in an autosomal dominant fashion. Affected family members exhibited fifth finger camptodactyly associated with knuckle pads on the crooked fifth finger and on fingers 2 and 3. Women were usually more severely affected than men. Mapping In a large German family segregating autosomal dominant camptodactyly associated with knuckle pads, Malik et al. (2008) excluded 5 candidate loci known to be associated with camptodactyly-like phenotypes by microsatellite analysis. A subsequent genomewide scan showed linkage on chromosome 3q11.2-q13.12, with a maximum 2-point lod score of 3.04; recombination events defined a critical 14.94-cM (27.69-Mb) interval between markers D3S2465 and D3S3044. The authors designated the locus CAMPD1. Joints \- Knee-joint subluxation Limbs \- Camptodactyly \- Proximal interphalangeal finger joint contractures Misc \- Fifth finger most frequently affected Lab \- Associated taurinuria Inheritance \- Autosomal dominant ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

CAMPTODACTYLY 1

c1306668

omim

https://www.omim.org/entry/114200

{"omim": ["114200"], "orphanet": ["295016"], "synonyms": ["Alternative titles", "CAMPTODACTYLY AND KNUCKLE PADS"]}

Ureteritis SpecialtyUrology Ureteritis is a medical condition of the ureter that involves inflammation.[1][2] One form is known as "ureteritis cystica".[3] Eosinophilic ureteritis has been observed.[4] Ureteritis is often considered part of a urinary tract infection. ## References[edit] 1. ^ "Ureteritis" at Dorland's Medical Dictionary 2. ^ http://cancerweb.ncl.ac.uk/cgi-bin/omd?ureteritis 3. ^ MD, Edward C. Klatt. "Renal Pathology". library.med.utah.edu. Retrieved 21 April 2018. 4. ^ Yang LB, Wu WX (January 2008). "Eosinophilic ureteritis: case report". Chin. Med. J. 121 (2): 188–9. doi:10.1097/00029330-200801020-00021. PMID 18272052.[permanent dead link] ## External links[edit] Classification D * ICD-10: N28.8 * v * t * e Diseases of the urinary tract Ureter * Ureteritis * Ureterocele * Megaureter Bladder * Cystitis * Interstitial cystitis * Hunner's ulcer * Trigonitis * Hemorrhagic cystitis * Neurogenic bladder dysfunction * Bladder sphincter dyssynergia * Vesicointestinal fistula * Vesicoureteral reflux Urethra * Urethritis * Non-gonococcal urethritis * Urethral syndrome * Urethral stricture * Meatal stenosis * Urethral caruncle Any/all * Obstructive uropathy * Urinary tract infection * Retroperitoneal fibrosis * Urolithiasis * Bladder stone * Kidney stone * Renal colic * Malakoplakia * Urinary incontinence * Stress * Urge * Overflow 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

Ureteritis

c0041959

wikipedia

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

{"umls": ["C0041959"], "icd-10": ["N28.8"], "wikidata": ["Q4115541"]}

Familial atrial fibrillation is an inherited abnormality of the heart's normal rhythm. Atrial fibrillation is characterized by episodes of uncoordinated electrical activity (fibrillation) in the heart's upper chambers (the atria), which cause a fast and irregular heartbeat. If untreated, this abnormal heart rhythm (arrhythmia) can lead to dizziness, chest pain, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, or fainting (syncope). Atrial fibrillation also increases the risk of stroke and sudden death. Complications of atrial fibrillation can occur at any age, although some people with this heart condition never experience any health problems associated with the disorder. ## Frequency Atrial fibrillation is the most common type of recurrent arrhythmia, affecting more than 3 million people in the United States. The risk of developing this irregular heart rhythm increases with age. The incidence of the familial form of atrial fibrillation is unknown; however, recent studies suggest that up to 30 percent of all people who have atrial fibrillation without an identified cause have a history of the condition in their family. ## Causes Changes in some genes can cause atrial fibrillation on their own, while changes in other genes affect a person's risk of developing this condition in combination with a variety of environmental and lifestyle factors. Familial atrial fibrillation often results from rare mutations in single genes. However, these cases represent only a small fraction of all individuals with atrial fibrillation. The first single gene found to be associated with familial atrial fibrillation was KCNQ1, which provides instructions for making a channel that is embedded in the outer membrane of heart (cardiac) muscle cells. This channel transports positively charged atoms (ions) of potassium out of cells. In cardiac muscle, this ion transport plays a critical role in maintaining the heart's normal rhythm. Since that discovery, rare genetic variants in other ion channel genes have been found to cause familial atrial fibrillation. Mutations in ion channel genes lead to the production of altered channels, which may either increase or decrease the flow of ions across the outer cell membrane and alter the way the heart beats. Mutations in other types of genes have also been found to cause familial atrial fibrillation. Some of these genes provide instructions for making cardiac transcription factors, which regulate the activity of certain genes involved in the formation and development of the heart before birth. Other genes provide instructions for making parts of structural elements of cardiac muscle, such as sarcomeres. These structures are necessary for cardiac muscle to contract and produce the heart's pumping action. Mutations in these non-ion channel genes have a variety of effects on the structure and function of cardiac muscle, all of which can lead to an abnormal heartbeat. Most cases of atrial fibrillation are not caused by inherited mutations in single genes. However, relatively common variations (polymorphisms) in more than two dozen genes appear to influence the likelihood of developing the condition. Each of these polymorphisms on its own has a small effect on a person's overall risk, but an individual may have multiple polymorphisms that together have a significant effect. In addition to these common genetic variations, risk factors for atrial fibrillation include high blood pressure (hypertension), diabetes mellitus, a previous stroke, or an accumulation of fatty deposits and scar-like tissue in the lining of the arteries (atherosclerosis). Researchers are working to determine how a combination of genetic changes, environmental influences, and lifestyle factors contribute to a person's risk of developing atrial fibrillation. ### Learn more about the genes associated with Familial atrial fibrillation * ABCC9 * KCNH2 * KCNJ2 * KCNQ1 * LMNA * PRKAG2 * RYR2 * SCN5A Additional Information from NCBI Gene: * GJA5 * KCNA5 * KCNE2 * MYL4 * NKX2-5 * NPPA * NUP155 * SCN1B * SCN2B * SCN3B * SCN4B ## Inheritance Pattern When familial atrial fibrillation is caused by mutations in a single gene (such as KCNQ1), it is inherited in an autosomal dominant pattern. Autosomal dominant inheritance means that one copy of the altered gene in each cell is sufficient to cause the disorder. In these cases, an affected person inherits the mutation from a parent who has the condition. Common genetic variants that increase the risk of atrial fibrillation can also be passed through generations in families. Individuals with these variants may have a family history of atrial fibrillation, but in these cases the condition does not have a clear autosomal dominant inheritance pattern. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Familial atrial fibrillation

c1843687

medlineplus

https://medlineplus.gov/genetics/condition/familial-atrial-fibrillation/

{"gard": ["9740"], "mesh": ["C538261"], "omim": ["608583", "614022", "614049", "614050", "615377", "615378", "615770", "617280", "608988", "607554", "611493", "611494", "612201", "612240", "613055", "613980"], "synonyms": []}

DeWan et al. (2001) reported suggestive, but not statistically significant, results of a genomewide quantitative linkage analysis for creatinine clearance (CRCL), a common measure of renal function. The strongest signals were in regions on chromosomes 1, 3, and 6 in whites and in 2 regions on chromosome 3 in African Americans. The samples studied included every genotyped family from the first half of the HyperGEN study sample (an investigation of hypertension, funded by NHLBI of the NIH), a total of 215 African American sibships and 265 white sibships. DeWan et al. (2002) repeated the analysis when the remaining sibships were genotyped. In the complete sample, they found significant linkage in African Americans between CRCL and chromosome 3p (lod score of 4.66 at 66 cM). To narrow the region, they added 11 linkage markers between 49 cM and 86 cM, and found that the highest multipoint lod score increased from 4.31 at 67 cM to 4.57 at 66 cM in the complete African American sample. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

CREATININE CLEARANCE QUANTITATIVE TRAIT LOCUS

c1846718

omim

https://www.omim.org/entry/607135

{"omim": ["607135"], "synonyms": ["Alternative titles", "CRCL"]}

## Summary ### Clinical characteristics. Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities. ### Diagnosis/testing. The diagnosis of AHDS is established in a male proband with suggestive findings and a hemizygous SLC16A2 pathogenic variant identified by molecular genetic testing, and in a female proband by identification of a heterozygous pathogenic variant in SLC16A2. ### Management. Treatment of manifestations: Multidisciplinary team to provide standard care for hypotonia, poor feeding, DD/ID, spasticity, and extrapyramidal movement disorders. Standard treatment with antiepileptic drugs by an experienced neurologist. Thyroid hormone replacement therapy during childhood has no beneficial effect and could be dangerous by worsening dysthyroidism. Surveillance: In children, assess the following every six months until age four years, then once a year: developmental progress & educational needs; neurologic examination for new manifestations (e.g., seizures, changes in tone, movement disorders); spine for scoliosis and hips for dislocation; mobility and self-help skills. Agents/circumstances to avoid: Administration of L-T4 or L-T3 alone can exacerbate the high serum T3 levels and the resulting hypermetabolism. Therapies under investigation: A T3 analog TRIAC (acide 3,3',5-triiodothyroacetique) has been tested for a maximum of one year in an international multicentric study of 46 individuals with AHDS. The main objective, normalization of the free T3 blood level, was achieved. Other favorable findings were increased body weight; decreased heart rate, systolic blood pressure, and hypertension; and improved development in seven children, two of whom had started TRIAC treatment before age four years and achieved independent sitting and full head control after 12 months of treatment. ### Genetic counseling. AHDS is inherited in an X-linked manner. If the mother of a proband has an SLC16A2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygotes (carriers) and usually will not be clinically affected but may have minor thyroid test abnormalities. Once the SLC16A2 pathogenic variant has been identified in an affected family member, carrier testing of at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible. ## Diagnosis Formal diagnostic criteria for Allan-Herndon-Dudley syndrome have not been established. ### Suggestive Findings Allan-Herndon-Dudley syndrome (AHDS) should be considered in males with the following clinical findings, brain imaging, and thyroid hormone profiles. #### Clinical Findings Neurologic * Onset before age two years often with hypotonia and feeding difficulties * Developmental delay / intellectual disability ranging from mild to profound intellectual disability * Extrapyramidal findings: dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, hypomimia (masked facies) * Pyramidal signs * Late-onset seizures, often with drug resistance Dysthyroidism * Poor weight gain * Reduced muscle mass * Variably present: cold intolerance, sweating, elevated heart rate, irritability Craniofacial. Common facial findings that may be attributed to prenatal and infantile hypotonia include ptosis, open mouth, and a tented upper lip. Ear length is above the 97th centile in about half of adults. Cup-shaped ears, thickening of the nose and ears, upturned earlobes, and a decrease in facial creases and a long face are also reported. #### Laboratory Findings Males with AHDS have pathognomonic thyroid test results (Figure 1) including the following: #### Figure 1. Thyroid profiles of 24 patients with AHDS (black triangles) compared to 25 male patients with other genetically defined intellectual disability (gray circles). Serum levels of: A. TSH * * High serum 3,3',5-triiodothyronine (usually free T3) concentration and low serum 3,3',5'-triiodothyronine (reverse T3, or rT3) concentration Note: All males with SLC16A2 pathogenic variants had high serum T3 concentration and, when obtained, low serum rT3 concentration. This holds true for both total and free hormone concentrations in serum. * Serum tetraiodothyronines (total T4 and free T4) concentration are often reduced, but may be within the low normal range * Free T3/T4 ratio >0.75 (expressed as mmol/mmol) [Remerand et al 2019] * Serum TSH concentrations that are normal or slightly elevated (Figure 1) [Refetoff & Dumitrescu 2007, Dumitrescu & Refetoff 2009, Remerand et al 2019] #### Imaging Brain MRI in children under age five years usually shows severely delayed myelination mimicking hypomyelination, which subsequently improves over time (Figure 2) [Holden et al 2005, Kakinuma et al 2005, Sijens et al 2008, Vaurs-Barrière et al 2009, Gika et al 2010, Tsurusaki et al 2011, Tonduti et al 2013, Remerand et al 2019]. #### Figure 2. (A) T2-weighted sequences of the brain MRI of a child age 12 months with AHDS showing diffusely abnormal white matter; (B) same child at age 7 years showing improved myelination with time Note: Early reports of normal brain MRI findings in this disorder were from older individuals. Cerebral atrophy is also a frequent sign associated with hypomyelination. ### Establishing the Diagnosis Male proband. The diagnosis of AHDS is established in a male proband with suggestive findings and a hemizygous SLC16A2 pathogenic variant identified by molecular genetic testing (see Table 1). Female proband. The diagnosis of AHDS is usually established in a female proband by identification of a heterozygous pathogenic variant in SLC16A2 by molecular genetic testing (see Table 1). Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of AHDS is broad, individuals with the distinctive clinical and laboratory findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of AHDS has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 Single-gene testing. Sequence analysis of SLC16A2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, gene-targeted deletion/duplication analysis is usually performed next to detect intragenic deletions or duplications. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. An intellectual disability, leukodystrophy, or abnormal movement disorder multigene panel that includes SLC16A2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Allan-Herndon-Dudley Syndrome View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method SLC16A2Sequence analysis 3, 4~85 5 Gene-targeted deletion/duplication analysis 6~15% 5, 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. 5\. García-de Teresa et al [2015], Remerand et al [2019] 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. Due to the presence of repetitive elements, deletions of exon 1 with varying breakpoints are frequently observed [García-de Teresa et al 2015]. ## Clinical Characteristics ### Clinical Description Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay [DD] / intellectual disability [ID]) and later-onset pyramidal signs, extrapyramidal findings, and seizures, often with drug resistance. Dysthyroidism can manifest as poor weight gain, reduced muscle mass and variable cold intolerance, sweating, elevated heart rate, irritability, and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities. #### Affected Males To date, information on about 200 individuals with a pathogenic variant in SLC16A2 has been published [Groeneweg et al 2019, Remerand et al 2019]. The following description of the phenotypic features associated with this condition is based on the report by Remerand et al [2019]. ### Table 2. Select Features of Allan-Herndon-Dudley Syndrome in Affected Males View in own window Feature 1% of Persons w/Feature Prenatal/ neonatal findingsWeak fetal movements1.4%-16.6% Fetal arrhythmia0%-1.4% Neonatal hypotonia4.4%-9.4% Premature birth0%-0.7% Neonatal hypotrophy0%-4.2% Congenital microcephaly0%-0.7% Congenital macrocephaly0%-0.7% Hydramnios0%-1.4% Neonatal jaundice0%-20.8% GrowthWeight gain deficiency33.3% Low weight37%-66.6% Short stature12.6%-29.1% Microcephaly10%-33.3% DD/IDID100% 2 Severe-to-profound ID37.5%-83.3% 2 Mild-to-moderate ID16.6%-62.5% 2 Oral language19.9%-69% Walking19.9%-62% NeuromuscularAxial hypotonia74%-100% Amyotrophy34.5%-88% Spasticity/hyperreflexia70.8%-94% Dystonia0%-75% Choreoathetosis0%-50% Paroxysms or kinesigenic dyskinesias0%-9% Ataxia0%-60% Seizures14.8%-29.1% Nystagmus0%-16.6% SkeletalPectus excavatum9.1%-58% Kyphoscoliosis21.1%-53.0% Flat feet with valgus4.3%-77% OtherNarrow/elongated myopathic face31%-75% Cryptorchidism2.8%-33.3% Peripheral dysthyroidism27.9%-66.6% Brain MRISeverely delayed myelination33.1%-79.1% Myelination improvement8.4%-62.4% Brain atrophy17%-41.6% DD = developmental delay; ID = intellectual disability 1\. Features and percentages of persons with feature were evaluated from the cohorts of Schwartz et al [2005], Remerand et al [2019], and the entire literature reporting individuals with AHDS. Variation in percentages can be attributed to either the non-evaluation or lack of systematic evaluation of features in different reports. 2\. Expressed as % of all males with AHDS. All affected individuals had ID ranging from mild to profound. Prenatal/neonatal findings. Infants with AHDS have normal length, weight, and head circumference at birth. Hypotonia, feeding difficulties and early weight gain deficiency can appear in the first weeks or months of life. Prolonged neonatal jaundice has recently been reported. Growth. Weight gain lags behind linear growth; low weight is a frequent feature Linear growth is frequently normal initially, but between 10 and 30% of males with time have short stature; microcephaly becomes apparent with age. Developmental delay / intellectual disability. Most affected males have profound-to-severe intellectual disability with no acquisition of walking; most affected males never speak or may develop only garbled sounds secondary to severely dysarthric speech. Less frequently, affected males have mild-to-moderate intellectual disability, and develop the ability to walk (with or without aid) and use of language allowing academic learning with aid. Neuromuscular. Truncal hypotonia, a main feature of AHDS, persists into adulthood. Adults are described with "limber neck" or poor head control. Progressive hypertonicity of the limbs with brisk reflexes, ankle clonus, and extensor plantar responses (Babinski sign) leads to spastic quadriplegia and joint contractures. Overall muscle mass (particularly proximally) is reduced and associated with generalized muscle weakness. It is common for affected males to experience purposeless movements described as dystonic and/or athetoid and characteristic paroxysms or kinesigenic dyskinesias [Brockmann et al 2005, Fuchs et al 2009]. These can be triggered by somatosensory stimuli, including changing clothes or diaper, or lifting the affected child. During attacks, the body extends and the mouth opens; stretching or flexing of the limbs lasts as long as one to two minutes. Some authors also reported abnormal movements as ataxia [Schwartz et al 2005]. Seizures typically begin during infancy or early childhood. Drug resistance is common [Schwartz & Stevenson 2007, Remerand et al 2019]. Rotary nystagmus and disconjugate eye movements have been reported but are not common [Dumitrescu et al 2004, Remerand et al 2019]. Skeletal. Pectus excavatum and kyphoscoliosis are most likely the result of hypotonia and reduced muscle mass. Behavior. Generally, affected individuals are attentive, friendly, and docile. They are not aggressive or destructive. Other. Peripheral dysthyroidism can be expressed as cold intolerance, sweating, intestinal transit disorders, tachycardia, high blood pressure, and sleep disorders. Life span. Early death has occurred in some individuals, usually caused by recurrent infections and/or aspiration pneumonia. In a few instances survival beyond age 70 years has been reported. #### Affected Heterozygous Females Heterozygous females are generally asymptomatic and have no specific phenotypic findings. About 25% of heterozygous female have an abnormal thyroid profile with elevated T3 levels without any neurologic manifestations [Ramos et al 2011, García-de Teresa et al 2015]. Developmental delay and intellectual disability have been reported in heterozygous females in rare instances, perhaps due to skewed X-chromosome inactivation [Dumitrescu et al 2004, Schwartz et al 2005, Herzovich et al 2007, García-de Teresa et al 2015]. One female had typical features of AHDS with a de novo translocation disrupting SLC16A2 and unfavorable nonrandom X-chromosome inactivation [Frints et al 2008]. One exception of note was the finding in one female of a whole or partial deletion of one X chromosome and a SLC16A2 pathogenic variant on the other X chromosome. However, whether a causative relationship exists between SLC16A2 pathogenic variants and cognitive impairments in heterozygous females has yet to be proven [Schwartz et al 2005]. ### Genotype-Phenotype Correlations It has been repeatedly reported that the severity of the clinical phenotype is related to the residual transport capacity of the mutated MCT8 protein. Large deletions in SLC16A2 are assumed to result in complete inactivation of MCT8 and a consequently severe phenotype. While the most frequent large SLC16A2 deletions are of exon 1, deletions of exons 2-4, exons 2-6, exon 3, exons 3-4, and exon 6 have also been reported [Friesema et al 2004, Jansen et al 2007, Vaurs-Barrière et al 2009, Visser et al 2009, Friesema et al 2010, Gika et al 2010, Zung et al 2011, Yamamoto et al 2013, Anık et al 2014, García-de Teresa et al 2015, Remerand et al 2019]. Several SLC16A2 pathogenic missense variants and an in-frame single amino-acid deletion (Table 7) have been associated with considerable residual MCT8 thyroid hormone transport capacity and a milder clinical phenotype, including some speech development, some reading/writing ability, and/or the ability to walk with or without support [Schwartz et al 2005, Jansen et al 2008, Vaurs-Barrière et al 2009, Visser et al 2009, Visser et al 2013, Philips et al 2014, Novara et al 2017, Masnada et al 2019, Remerand et al 2019]. Independent walking and speech development are unusual in affected males with other pathogenic variants. ### Nomenclature This condition was named MCT8-specific thyroid hormone cell-membrane transporter deficiency following identification of the causative gene, SLC16A2, and the defect in thyroid hormone metabolism. Because of the overlap of clinical findings in individuals with an SLC16A2 pathogenic variant and Allan-Herndon-Dudley syndrome (AHDS), Schwartz et al [2005] analyzed SLC16A2 and identified variants in six families with MCT8-specific thyroid hormone cell-membrane transporter deficiency. Thus, AHDS and MCT8-specific thyroid hormone cell-membrane transporter deficiency are synonyms. ### Prevalence Prevalence of Allan-Herndon-Dudley syndrome (AHDS) is unknown; however, the identification of more than 160 affected individuals in approximately 15 years suggests that the syndrome is more common than previously thought. ## Differential Diagnosis Many disorders demonstrate hypotonia and severe intellectual disability in an X-linked or autosomal recessive inheritance pattern. The main differential diagnoses, described in Table 3, also demonstrate dystonia, spasticity, seizures, or other features that overlap with the neurologic phenotype of Allan-Herndon-Dudley syndrome. More widely, all diseases leading to X-linked intellectual disability, hypomyelinating leukodystrophies or precocious dystonia should be considered as differential diagnoses. ### Table 3. Genes of Interest in the Differential Diagnosis of Allan-Herndon-Dudley Syndrome (AHDS) View in own window Gene 1Differential Diagnosis DisorderMOIClinical Features of Differential Diagnosis Disorder Overlapping w/AHDSDistinguishing from AHDS GJC2Pelizaeus-Merzbacher-like disease 2ARPMD-likeNormal free T3/T4 ratio MECP2MECP2 duplication syndromeXLIn males: infantile hypotonia, severe ID, absent speech, progressive spasticity, & seizures PLP1Pelizaeus-Merzbacher disease (see PLP1 Disorders)XL * Males may present in infancy or early childhood w/nystagmus, hypotonia, & severe DD/ID. * Progresses to severe spasticity & ataxia * MRI shows persistant diffuse hypomyelination. THRANongoitrous congenital hypothyroidism 6 (OMIM 614450)AD * Mild-to-moderate ID * Motor delay, dystonia * Short stature w/delayed bone age * ↑ free T3/T4 ratio * Consider in differential diagnosis of mild forms of AHDS. * Improvement w/L-thyroxine therapy * Normal MRI AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PMD-like = Pelizaeus-Merzbacher–like disease; XL = X-linked 1\. Genes are in alphabetic order 2\. Of note, in one study SLC16A2 pathogenic variants were reported in 11% of 53 families with a severe form of Pelizaeus-Merzbacher-like disease with an unusual improvement in myelination with age [Vaurs-Barrière et al 2009]. ## Management No current published guidelines exist to establish the extent of disease or proper management in an individual diagnosed with Allan-Herndon-Dudley syndrome (AHDS). The following recommendations are based on current literature and the authors' experience. ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Allan-Herndon-Dudley syndrome (AHDS), the evaluations summarized Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Allan-Herndon-Dudley Syndrome View in own window System/ConcernEvaluationComment ConstitutionalMeasure height, weight, BMI, head circumferenceTo be regularly followed NeurologicNeurologic evaluation * To incl brain MRI * Consider EEG if seizures are a concern. DevelopmentDevelopmental assessment * To incl motor, adaptive, cognitive, & speech/language evaluation * Evaluation for early intervention / special education MusculoskeletalOrthopedic, physical medicine & rehabilitation, PT, & OT evaluationTo include assessment of: * Gross motor & fine motor skills * Contractures & kyphoscoliosis * Mobility, activities of daily living, & need for adaptive devices * Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Osteoporosis evaluation in non-ambulatory patients * Osteodensitometry (DEXA) * Phospho-calcic equilibrium Gastrointestinal/ FeedingGastroenterology, nutrition, & feeding team evaluation * To incl evaluation of aspiration risk & nutritional status * Consider evaluation for gastric tube placement in patients w/dysphagia &/or aspiration risk. GastrointestinalAssess for constipationMay be assoc w/weight loss & exacerbation of abnormal movements (dystonia, choreoathetosis) PulmonaryRespiratory function * To incl lung function & respiratory status * Consider evaluation of noninvasive ventilation or antibiotic therapy in patients w/recurrent respiratory infections & hypoventilation. ThyroidFree T3, free T4, total T4, TSH, T3Only if treatment w/T3 analogs Signs of dysthyroidismSigns of dysthyroidism can incl tachycardia, high blood pressure, intestinal troubles, osteoporosis, weight loss. Miscellaneous/ OtherConsultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling Family support/resourcesAssess: * Use of community or online resources such as Parent to Parent; * Need for social work involvement for parental support; * Need for home nursing referral. BMI = body mass index; OT = occupational therapy; PT = physical therapy ### Treatment of Manifestations ### Table 5. Treatment of Manifestations in Individuals with Allan-Herndon-Dudley Syndrome (AHDS) View in own window Manifestation/ ConcernTreatmentConsiderations/Other DD/IDSee DD/ID Management Issues. Poor weight gain / Failure to thrive * Feeding therapy * Nissen fundoplication & gastrostomy tube placement may be required for persistent feeding issues. Low threshold for clinical feeding evaluation &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia Gastrointestinal * Constipation: laxatives, enemas, transanal irrigation * Feeding difficulties: See DD/ID Management Issues. * Symptomatic GERD: antireflux therapy Management may improve weight gain & ↓ abnormal movement DroolingGlycopyrolate or scopolamineConsider the ↑ risk for hyposalivation assoc w/↑ risk for dental caries SpasticityOrthopedics / physical medicine & rehabilitation / PT / OT incl stretching to help avoid contractures & falls * To prevent contractures * Consider need for positioning & mobility devices, disability parking placard. DystoniaMedications such as anticholinergics, L-DOPA, carbamazepine, or lioresalThese therapies have shown no or mild efficacy. DBS has not been evaluated. ChoreoathetosisNo specific medicationDBS has not been evaluated in AHDS. EpilepsyStandardized treatment w/AEDs by experienced neurologist * Many different AEDs may be effective; none has been demonstrated effective specifically for this disorder. * Education of parents/caregivers 1 Musculoskeletal * Hip dislocation &/or kyphoscoliosis: orthopedic surgery * Osteoporosis: calcium & vitamin D supplementation; bisphosphonate therapy as needed Thyroid test abnormalitiesNone * Thyroid hormone replacement therapy during childhood has no beneficial effect & could worsen dysthyroidism. * See Therapies Under Investigation. DysthyroidismTreatment of tachycardia &/or high blood pressure, when evident Sleep disorderFirst consider sleep education; then melatonin or hydroxyzine dichlorhydrate as first medications Family/ Community * Ensure appropriate social work involvement to connect families w/local resources, respite, & support. * Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. * Ongoing assessment of need for palliative care involvement &/or home nursing * Consider involvement in adaptive sports or Special Olympics. AED = antiepileptic drug; DBS = deep brain stimulation; DD = developmental delay; GERD = gastroesophageal reflux disease; ID = intellectual disability; OT = occupational therapy; PT = physical therapy 1\. Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. #### Developmental Disability / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability (DD/ID) in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider: * Individualized education plan (IEP) services: * An IEP provides specially designed instruction and related services to children who qualify. * IEP services will be reviewed annually to determine whether any changes are needed. * As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate. * Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. * PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. * As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. * A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). * Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). * For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures. Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically by an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary. Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases, can improve it. ### Surveillance ### Table 6. Recommended Surveillance for Individuals with Allan-Herndon-Dudley Syndrome View in own window System/ConcernEvaluationFrequency DD/IDMonitor developmental progress & educational needs.Every 6 mos until age 4 yrs, then 1x/yr NeurologicMonitor those w/seizures as clinically indicated.Every 6 mos in those w/epileptic seizures Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).Every 6 mos until age 4 yrs, then 1x/yr Poor weight gain / Failure to thriveMeasurement of growth parameters; evaluation of nutritional status & safety of oral intakeEvery 3 mos in case of poor weight gain, otherwise every 6 mos until age 4 yrs, then 1x/yr MusculoskeletalOrthopedics: monitor for scoliosis, joint problemsEvery 6 mos until age 4 yrs, then 1x/yr or as needed Physical medicine, OT/PT assessment of mobility, self-help skills Osteodensitometry (DEXA); phospho-calcic equilibrium1x/yr in nonambulatory patients Thyroid test abnormalitiesNo specific follow upNone if not being treated w/thyroid analogs Signs of dysthyroidism 1History & physical examination for tachycardia, high blood pressure, intestinal troublesEvery 6 mos until age 4 yrs, then 1x/yr or as needed Family/CommunityAssess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.As requested/needed DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy ### Agents/Circumstances to Avoid Administration of L-T4 or L-T3 alone can exacerbate the high serum T3 levels and the resulting hypermetabolism. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Two unaffected heterozygous pregnant women with unaffected fetuses were treated with L-T4 in the second half of pregnancy [Ramos et al 2011]. It is unclear if this had any effect, either beneficial or detrimental, on the fetus. Of note, many unaffected heterozygous mothers have given birth to normal unaffected children without any prenatal treatment. ### Therapies Under Investigation Recently, an T3 analog TRIAC (acide 3,3',5-triiodothyroacetique) has been tested in an international multicentric study, coordinated by the Erasmus University (Rotterdam, Netherlands) [Groeneweg et al 2019]; 46 persons with AHDS were included and treated with a maximum of one year of TRIAC. The main objective was the normalization of the free T3 blood level; T3 concentration declined significantly (reduction of 61% of baseline). Other findings: a mean increase of body weight of 2.7 kg, a mean decrease of heart rate over 24 hours of five beats per minute, a mean decrease of systolic blood pressure from the 78th centile to the 61st centile, and a mean decrease of hypertension from 34% to 9%. On neurologic examination, of the seven individuals with a completely inactivating SLC16A2 variant who had started TRIAC treatment before age four years, two reached independent sitting and achieved full head control after 12 months of treatment. Seven mild and transient adverse effects related to TRIAC occurred in six individuals: three had increased perspiration and three reported irritability. Beginning in 2017 the European Medicines Agency (EMA) granted TRIAC orphan designation for the treatment of AHDS (EMA/695502/2017). To follow this first clinical study, an international Phase II trial (NCT02396459) to investigate the effects of TRIAC on neurodevelopmental outcomes in children younger than 30 months with AHDS will begin recruiting in early 2020. 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

Allan-Herndon-Dudley Syndrome

c0795889

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK26373/

{"mesh": ["C537047"], "synonyms": ["MCT8 Deficiency", "MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency"]}

Pantothenate kinase-associated neurodegeneration (formerly called Hallervorden-Spatz syndrome) is a disorder of the nervous system. This condition is characterized by progressive difficulty with movement, typically beginning in childhood. Movement abnormalities include involuntary muscle spasms, rigidity, and trouble with walking that worsens over time. Many people with this condition also develop problems with speech (dysarthria), and some develop vision loss. Additionally, affected individuals may experience a loss of intellectual function (dementia) and psychiatric symptoms such as behavioral problems, personality changes, and depression. Pantothenate kinase-associated neurodegeneration is characterized by an abnormal buildup of iron in certain areas of the brain. A particular change called the eye-of-the-tiger sign, which indicates an accumulation of iron, is typically seen on magnetic resonance imaging (MRI) scans of the brain in people with this disorder. Researchers have described classic and atypical forms of pantothenate kinase-associated neurodegeneration. The classic form usually appears in early childhood, causing severe problems with movement that worsen rapidly. Features of the atypical form appear later in childhood or adolescence and progress more slowly. Signs and symptoms vary, but the atypical form is more likely than the classic form to involve speech defects and psychiatric problems. A condition called HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration), which was historically described as a separate syndrome, is now considered part of pantothenate kinase-associated neurodegeneration. Although HARP is much rarer than classic pantothenate kinase-associated neurodegeneration, both conditions involve problems with movement, dementia, and vision abnormalities. ## Frequency The precise incidence of this condition is unknown. It is estimated to affect 1 to 3 per million people worldwide. ## Causes Mutations in the PANK2 gene cause pantothenate kinase-associated neurodegeneration. The PANK2 gene provides instructions for making an enzyme called pantothenate kinase 2. This enzyme is active in mitochondria, the energy-producing centers within cells, where it plays a critical role in the formation of a molecule called coenzyme A. Found in all living cells, coenzyme A is essential for the body's production of energy from carbohydrates, fats, and some protein building blocks (amino acids). Mutations in the PANK2 gene likely result in the production of an abnormal version of pantothenate kinase 2 or prevent cells from making any of this enzyme. A lack of functional pantothenate kinase 2 disrupts the production of coenzyme A and allows potentially harmful compounds to build up in the brain. This buildup leads to swelling and tissue damage, and allows iron to accumulate abnormally in certain parts of the brain. Researchers have not determined how these changes result in the specific features of pantothenate kinase-associated neurodegeneration. Because pantothenate kinase 2 functions in mitochondria, the signs and symptoms of this condition may be related to impaired energy production. ### Learn more about the gene associated with Pantothenate kinase-associated neurodegeneration * PANK2 ## 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

Pantothenate kinase-associated neurodegeneration

c1846582

medlineplus

https://medlineplus.gov/genetics/condition/pantothenate-kinase-associated-neurodegeneration/

{"gard": ["6564"], "mesh": ["C564603"], "omim": ["607236", "234200"], "synonyms": []}

This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Adenoiditis" – news · newspapers · books · scholar · JSTOR (July 2016) (Learn how and when to remove this template message) Adenoiditis Location of the adenoid SpecialtyPulmonology Adenoiditis is the inflammation of the adenoid tissue usually caused by an infection. Adenoiditis is treated using medication (antibiotics and/or steroids) or surgical intervention. Adenoiditis may produce cold-like symptoms. However, adenoiditis symptoms often persist for ten or more days, and often include pus-like discharge from nose. The infection cause is usually viral. However, if the adenoiditis is caused by a bacterial infection, antibiotics may be prescribed for treatment. A steroidal nasal spray may also be prescribed in order to reduce nasal congestion. Severe or recurring adenoiditis may require surgical removal of the adenoids (adenotonsillectomy). ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Cause * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 Epidemiology * 7 See also * 8 References ## Signs and symptoms[edit] Acute adenoiditis is characterized by fever, runny nose, nasal airway obstruction resulting in predominantly oral breathing, snoring and sleep apnea, Rhinorrhea with serous secretion in viral forms and mucous-purulent secretion in bacterial forms. In cases due to viral infection symptoms usually recede spontaneously after 48 hours, symptoms of bacterial adenoiditis typically persist up to a week. Adenoiditis is sometimes accompanied by tonsillitis. Repeated adenoiditis may lead to enlarged adenoids. ### Complications[edit] Complications of acute adenoiditis can occur due to extension of inflammation to the neighboring organs. ## Cause[edit] Viruses that may cause adenoiditis include adenovirus, rhinovirus and paramyxovirus. Bacterial causes include Streptococcus pyogenes, Streptococcus pneumoniae, Moraxella catarrhalis and various species of Staphylococcus including Staphylococcus aureus. ## Pathophysiology[edit] It is currently believed that bacterial biofilms play an integral role in the harboring of chronic infection by tonsil and adenoid tissue so contributing to recurrent sinusitis and recurrent or persistent ear disease.[1] Also, enlarged adenoids and tonsils may lead to the obstruction of the breathing patterns in children, causing apnea during sleep. The most common bacteria isolated are Haemophilus influenzae, group A beta-hemolytic Streptococcus, Staphylococcus aureus, Moraxella catarrhalis, and Streptococcus pneumoniae. Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are the three most resistant pathogens of otitis and rhinosinisitis in children suffering from these diseases. ## Diagnosis[edit] Optical fiber endoscopy can confirm the diagnosis in case of doubt, directly visualizing the inflamed adenoid.[2] ## Treatment[edit] In cases of viral adenoiditis, treatment with analgesics or antipyretics is often sufficient. Bacterial adenoiditis may be treated with antibiotics, such as amoxicillin - clavulanic acid or a cephalosporin. In case of adenoid hypertrophy, adenoidectomy may be performed to remove the adenoid. ## Epidemiology[edit] Adenoiditis occurs mainly in childhood, often associated with acute tonsillitis. Incidence decreases with age, with adenoiditis being rare in children over 15 years due to physiological atrophy of the adenoid tissue. ## See also[edit] * Tonsilitis ## References[edit] 1. ^ Zautner AE (May 2012). "Adenotonsillar disease". Recent Pat Inflamm Allergy Drug Discov. 6 (2): 121–9. doi:10.2174/187221312800166877. PMID 22452646. 2. ^ Marseglia GL, Caimmi D, Pagella F, Matti E, Labó E, Licari A, Salpietro A, Pelizzo G, Castellazzi AM (October 2011). "Adenoids during childhood: the facts". Int J Immunopathol Pharmacol. 24 (4 Suppl): 1–5. doi:10.1177/03946320110240S401. PMID 22032778. S2CID 10572281. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Adenoiditis

c0396023

wikipedia

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

{"umls": ["C0396023"], "wikidata": ["Q1640292"]}

## Summary ### Clinical characteristics. Adenine phosphoribosyltransferase (APRT) deficiency is characterized by excessive production and renal excretion of 2,8-dihydroxyadenine (DHA), which leads to kidney stone formation and crystal-induced kidney damage (i.e., DHA crystal nephropathy) causing acute kidney injury episodes and progressive chronic kidney disease (CKD). Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age; in at least 50% of affected persons symptoms do not occur until adulthood. If adequate treatment is not provided, approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD), usually in adult life. ### Diagnosis/testing. The diagnosis of APRT deficiency is established in a proband by absence of APRT enzyme activity in red cell lysates or identification of biallelic pathogenic variants in APRT. The detection of the characteristic round, brown DHA crystals by urine microscopy is highly suggestive of the disorder. ### Management. Treatment of manifestations: Treatment with the xanthine oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase) allopurinol or febuxostat can improve kidney function, even in individuals with advanced CKD. The prescribed dose of allopurinol and febuxostat should not routinely be reduced in affected individuals who have impaired kidney function. Ample fluid intake is advised. Surgical management of DHA nephrolithiasis is the same as for other types of kidney stones. ESRD is treated with dialysis and kidney transplantation. Even after kidney transplantation, treatment with an XOR is recommended. Surveillance: Measurement of eGFR and urinary DHA excretion (or urine microscopy for assessment of DHA crystalluria) every 6-12 months; routine follow up to facilitate adherence to pharmacologic treatment at least annually; periodic renal ultrasound examination should be considered to evaluate for new asymptomatic kidney stones. Agents/circumstances to avoid: Azathioprine and mercaptopurine should not be given to individuals taking either allopurinol or febuxostat. Evaluation of relatives at risk: It is recommended that sibs of an affected individual undergo APRT enzyme activity measurement or molecular genetic testing (if the pathogenic variants in a family have been identified) to allow early diagnosis and treatment and improve long-term outcome. Pregnancy management: The safety of allopurinol and febuxostat in human pregnancy has not been systematically studied. Some post-transplantation immunosuppressive therapies can have adverse effects on the developing fetus. Ideally a thorough discussion of the risks and benefits of maternal medication use during pregnancy should take place with an appropriate health care provider prior to conception. ### Genetic counseling. APRT deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being normal. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified. ## Diagnosis ### Suggestive Findings Adenine phosphoribosyltransferase (APRT) deficiency (also known as 2,8-dihydroxyadeninuria) should be suspected in individuals with the following clinical, radiographic, laboratory, and pathology findings [Balasubramaniam et al 2016, Runolfsdottir et al 2016, Garigali et al 2019, Runolfsdottir et al 2019a]. Clinical manifestations * Kidney stone disease and renal colic * Chronic kidney disease (CKD) * Crystal nephropathy (confirmed by kidney biopsy; see Pathology) * Reddish-brown diaper stain in infants and young children * Allograft dysfunction following kidney transplantation Radiographic findings * Radiolucent kidney stones, detected by ultrasound or computed tomography (CT). Stones are not seen on a plain abdominal x-ray. * Ultrasound examination frequently demonstrates increased echogenicity of the kidneys. Laboratory findings * Urine microscopy. The round and brown DHA crystals can usually be detected by urine microscopy (Figure 1A). Small and medium-sized DHA crystals display a central Maltese cross pattern when viewed by polarized light microscopy (Figure 1B), while larger crystal aggregates do not as they are impermeable to light. Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced DHA clearance by the kidney [Bollée et al 2010, Edvardsson et al 2013]. (2) High urine pH in individuals with radiolucent stones provides an additional clue to the diagnosis of APRT deficiency because uric acid stones develop in acidic urine [Edvardsson et al 2013] (see Differential Diagnosis). * Kidney stone analysis. Analysis of DHA crystals and kidney stone material using infrared or ultraviolet spectrophotometry (at both acidic and alkaline pH) and/or x-ray crystallography differentiates DHA from uric acid and xanthine, which also form radiolucent stones. Although stones in persons with APRT deficiency are predominantly composed of DHA, they may contain trace amounts of other minerals. * Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see Establishing the Diagnosis). * Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. #### Figure 1. Urinary 2,8-dihydroxyadenine (DHA) crystals from an individual with adenine phosphoribosyltransferase deficiency. These crystals have a characteristic appearance and polarization pattern. A. Conventional light microscopy shows the typical brown DHA crystals. (more...) Pathology. Renal histopathologic findings in persons with APRT deficiency and CKD or acute allograft dysfunction are characterized by diffuse tubulointerstitial DHA crystal deposits accompanied by inflammation and fibrosis (see Figure 2), which may be observed even in individuals without a history of kidney stones [Nasr et al 2010, Zaidan et al 2014, Agrawal et al 2015, Lusco et al 2017]. #### Figure 2. Kidney biopsy findings from an individual with adenine phosphoribosyltransferase deficiency and kidney failure due to 2,8- dihydroxyadenine crystal nephropathy A. 2,8-dihydroxyadenine crystals are seen within tubular lumens (arrows). Significant tubular (more...) Note: It is important not to confuse the histopathologic manifestations of DHA crystal nephropathy with those of other crystal nephropathies, particularly those caused by oxalate (particularly primary hyperoxaluria) and uric acid deposits [Nasr et al 2010]. ### Establishing the Diagnosis The diagnosis of APRT deficiency is established in a proband with absent APRT enzyme activity in red cell lysates or biallelic pathogenic variants in APRT identified by molecular genetic testing (see Table 1). See Figure 3 for a diagnostic algorithm [Edvardsson et al 2013]. #### Figure 3. Algorithm for diagnostic evaluation of adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadeninuria From Edvardsson et al [2013]. Used with permission. Note: Kidney stone analysis suggesting APRT deficiency is not reliable enough to establish the diagnosis. #### APRT Enzyme Activity APRT activity measured in red cell lysates ranges from 16 to 32 nmol/hr per mg hemoglobin in healthy individuals. In almost all individuals with APRT deficiency, APRT enzyme activity measured in red cell lysates (or other cell extracts) is absent; however, exceptions do occur. For example, two enzyme isoforms resulting from the following APRT pathogenic variants have substantial activity in red cell lysates: * p.Val150Phe [Deng et al 2001] (present in some individuals of northern European heritage) * p.Met136Thr [Ikeda et al 2016] (present in >70% of Japanese, who are homozygous for this pathogenic variant) Thus, in individuals with these two pathogenic variants, in vivo assays (e.g., uptake of adenine by intact erythrocytes or leukocytes) are required to verify APRT deficiency. Note: (1) If enzyme activity is within normal limits or in the heterozygote range in an individual who has recently received a red cell transfusion, enzyme activity measurement should be repeated after three months. (2) Heterozygotes for an APRT pathogenic variant cannot be reliably identified by enzyme assay in cell extracts as the enzyme activity range in these individuals overlaps with that of controls. #### Molecular Genetic Testing Approaches can include single-gene testing and use of a multigene panel. * Single-gene testing. Sequence analysis of APRT is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. * A multigene panel that includes APRT and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. ### Table 1. Molecular Genetic Testing Used in Adenine Phosphoribosyltransferase Deficiency View in own window Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method APRTSequence analysis 3, 4~87% 5 Gene-targeted deletion/duplication analysis 6Rare 7 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 4\. Approximately 50 pathogenic variants have been identified in the coding region of APRT in >400 affected individuals from >25 countries, including at least 200 individuals from Japan (see Molecular Genetics). 5\. DNA sequence analysis of the APRT coding region and intron/exon junctions from 31 affected individuals (62 chromosomes) with complete APRT deficiency failed to identify 13% of the mutated alleles [Bollée et al 2010]. It remains to be determined whether pathogenic variants occur outside of the sequenced regions or are due to epigenetic changes. 6\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 7\. Rare deletions of both APRT and GALNS, as well as a complex 254-bp deletion with 8-bp insertion, have been described (see Molecular Genetics). Note that enzyme activity measurements in cell extracts alone may not be sufficient to determine the functional significance of novel variants (see APRT Enzyme Activity). ## Clinical Characteristics ### Clinical Description More than 400 individuals with adenine phosphoribosyltransferase (APRT) deficiency have been reported in the medical literature [Bollée et al 2010, Bollée et al 2012, Harambat et al 2012, Balasubramaniam et al 2014, Zaidan et al 2014, Runolfsdottir et al 2016, Huq et al 2018, Runolfsdottir et al 2019a, Runolfsdottir et al 2019b]. ### Table 2. Presenting Renal Manifestations in APRT Deficiency View in own window Presenting Renal ManifestationApproximate Frequency Kidney stone disease 160%-90% Chronic kidney disease 2, 3>50% Acute kidney injury 430% 5 End-stage renal disease15% 1\. In both children and adults 2\. In adult life 3\. Due to DHA crystal nephropathy 4\. Due to urinary tract obstruction 5\. Runolfsdottir et al [2016] Age at presentation. APRT deficiency may present at any age; there is no typical age of clinical onset. However, in at least 50% of affected individuals, symptoms do not occur until adulthood. * The age at diagnosis among individuals in the APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC) ranged from six months to 72 years (median age: 37 years) [Runolfsdottir et al 2016]. * Approximately 35% of persons with APRT deficiency are diagnosed before age 18 years. * In a significant number of asymptomatic individuals, a diagnosis of APRT deficiency has been suggested by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals and subsequently confirmed by enzyme activity or genetic testing. Of note, abdominal ultrasound and CT examinations performed for other reasons may identify kidney stones in individuals with APRT deficiency who may be otherwise asymptomatic [Huq et al 2018]. Kidney stone disease. Between 60% and 90% of affected individuals have already developed kidney stones at diagnosis. In the absence of pharmacotherapy (see Management, Table 4), the majority of those untreated symptomatic persons experience stone recurrence [Runolfsdottir et al 2019a], abdominal pain, and/or lower urinary tract symptoms (e.g., straining, hesitancy, dribbling, incomplete bladder emptying). Chronic kidney disease (CKD) secondary to DHA crystal nephropathy is present in more than 50% of individuals at diagnosis [Runolfsdottir et al 2016]. As many as 15% of affected individuals have progressed to end-stage renal disease (ESRD) at the time of diagnosis of APRT deficiency [Harambat et al 2012, Runolfsdottir et al 2016]. * In some of these individuals, the diagnosis was not made until after kidney transplantation had been performed. * The relatively frequent occurrence of advanced CKD and even ESRD at the time of diagnosis is concerning and suggests a lack of familiarity with this easily treatable condition [Runolfsdottir et al 2019a]. ESRD. Approximately 20%-25% of affected individuals develop ESRD, usually in adult life, if adequate treatment is not provided. * Importantly, individuals with APRT deficiency who are diagnosed and treated early with allopurinol or febuxostat have a much more favorable renal outcome [Runolfsdottir et al 2019a] (see Management, Table 4). * Timely diagnosis and institution of pharmacologic therapy appears to reduce stone burden and retard or possibly prevent CKD progression to ESRD, even in severely affected individuals. APRT deficiency is not known to affect organs other than the kidney; however, the authors and other investigators have encountered occasional individuals with APRT deficiency complaining of eye discomfort [Neetens et al 1986; Author, personal observation], which merits further study. ### Genotype-Phenotype Correlations No genotype-phenotype correlations have been established; clinical features are known to vary greatly among individuals with the same pathogenic variants [Bollée et al 2010, Runolfsdottir et al 2016]. ### Nomenclature Originally, two types of APRT deficiency with identical clinical manifestations were described, based on the level of residual APRT activity in cell extracts (erythrocyte lysates) [Sahota et al 2001]. However, this distinction is of historic interest only, as APRT enzyme activity in intact cells has been shown to be less than 1% in both types [Kamatani et al 1985] (see APRT Enzyme Activity). ### Prevalence The estimated heterozygote frequency in different populations ranges from 0.4% to 1.2% [Hidaka et al 1987, Sahota et al 2001], suggesting that the prevalence of a homozygous state is at least 1:50,000 to 1:100,000. If this holds true, at least 70,000-80,000 individuals should be affected worldwide, of whom 40,000 would be expected to be in Asia, 9,000 in Europe, and 8,000 in the Americas, including at least 3,000 affected individuals in the US alone. Most of these individuals are currently unrecognized, and thus not benefitting from medical therapy. Evidence suggests that APRT deficiency may be a seriously underrecognized cause of kidney stones and crystal nephropathy, progressing over time to ESRD in a significant proportion of untreated individuals [Zaidan et al 2014]. ## Differential Diagnosis Differential diagnosis of APRT deficiency includes other known causes of radiolucent kidney stones such as uric acid nephrolithiasis (OMIM 605990) and xanthinuria (OMIM PS278300). The diagnosis of APRT deficiency should be considered in all individuals with chronic kidney disease or kidney failure, particularly in those with renal histopathologic features of crystal nephropathy, even in the absence of a history of nephrolithiasis. Pathologists and physicians must be aware that kidney biopsy findings in persons with APRT deficiency may have a similar appearance to and be confused with those of primary hyperoxaluria type 1, type 2, and type 3 [Bollée et al 2010, Runolfsdottir et al 2016]. ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with adenine phosphoribosyltransferase (APRT) deficiency, the evaluations in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended. ### Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with APRT Deficiency View in own window System/ConcernEvaluationComment RenalMeasurement of serum creatinine (&/or cystatin C) concentration Urine screening for DHA crystalluria & albuminuria or proteinuria Ultrasound or CT exam of kidneysTo assess kidney stone burden Consider kidney biopsy.In individuals w/↓ renal function &/or proteinuria EyesConsider ophthalmologic consultation.In those w/ocular or vision symptoms Miscellaneous/ OtherConsultation w/clinical geneticist &/or genetic counselor DHA = 2,8-dihydroxyadenine ### Treatment of Manifestations ### Table 4. Targeted Treatment for Prevention/Reduction of Kidney Stones in Individuals with APRT Deficiency View in own window GoalTreatmentDosageConsiderationsOther Reduction of renal DHA excretion 1Allopurinol 2, 3, 45-10 mg/kg/day (max dose: 800 mg/day) either 1x/day or in 2 divided dosesAllopurinol dose should not routinely be reduced in those w/impaired kidney function. * Lifelong therapy w/allopurinol or febuxostat needed for all affected individuals, even after kidney transplantation * Allopurinol or febuxostat can improve kidney function, even in individuals w/advanced CKD. Febuxostat 280 mg/day 5 * May be more efficacious than allopurinol 6 * Febuxostat dose should not routinely be reduced in those w/impaired kidney function. Reduction of urine DHA supersaturation & crystallizationAmple fluid intakeNAMay provide an adjunctive benefit to pharmacologic therapy CKD = chronic kidney disease; DHA = 2,8-dihydroxyadenine; NA = not applicable 1\. There are no data to support dietary purine restriction as a treatment of this condition, particularly when treatment with allopurinol or febuxostat is used and urine DHA excretion is already very low. 2\. Both allopurinol and febuxostat are oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase). 3\. Generally effective and well tolerated 4\. Minimizes urinary DHA excretion and crystalluria, stone formation, crystal deposition in the kidney, and development of kidney failure [Bollée et al 2010, Edvardsson et al 2018, Runolfsdottir et al 2019a] 5\. No data are available on appropriate dosing for pediatric age groups. 6\. A comparison between allopurinol (400 mg/day) and febuxostat (80 mg/day) on urinary DHA excretion found that febuxostat was significantly more efficacious [Edvardsson et al 2018]. ### Table 5. Treatment of Manifestations in Individuals with APRT Deficiency View in own window Manifestation/ ConcernTreatmentConsideration/Other DHA kidney stones 1Standard surgical managementIncl extracorporeal shock wave lithotripsy CKD 2Aggressive management of hypertensionConsider ACE inhibitors or angiotensin-receptor blockers in those w/proteinuria. Standard reduction of cardiovascular risk factors ESRD 3DialysisIt is not known if affected individuals on dialysis benefit from allopurinol &/or febuxostat therapy, unless a kidney transplant is planned. Kidney transplant * In all individuals: treatment w/allopurinol or febuxostat for ≥6 wks prior to transplantation, if possible 4 * Lifelong therapy w/allopurinol or febuxostat post transplantation required to prevent recurrent DHA crystal nephropathy in transplanted organ ACE = angiotensin-converting enzyme; CKD = chronic kidney disease; DHA = 2,8-dihydroxyadenine; ESRD = end-stage renal disease 1\. For prevention of new kidney stone formation, see Table 4. 2\. Including measures to relieve symptoms, control complications, and slow the progression of the disease (see the KDIGO CKD guideline) 3\. Management of APRT deficiency in those with ESRD 4\. Author, unpublished observation ### Prevention of Primary Manifestations Adequate treatment of APRT deficiency with allopurinol or febuxostat prevents kidney stone formation and the development of CKD in most, if not all, individuals with the disorder [Edvardsson et al 2001, Bollée et al 2010, Harambat et al 2012] (see Table 4). ### Surveillance No consensus surveillance guidelines have been established. ### Table 6. Recommended Surveillance for Individuals with APRT Deficiency View in own window System/ConcernEvaluationFrequency RenalMeasurement of eGFR derived from serum creatinine &/or serum cystatin CEvery 6-12 mos or as clinically indicated Urine microscopy for assessment of DHA crystalluria 1, 2, 3 if direct DHA measurements not available 4 Renal ultrasound 5Periodically OtherAssess medication compliance.At least annually eGFR = estimated glomerular filtration rate 1\. Using first morning void urine specimen, if possible 2\. In those receiving pharmacotherapy 3\. Although not optimal, the absence of DHA crystals on urine microscopy can be considered indicative of adequate treatment. A highly significant correlation between 24-hour urinary DHA excretion and DHA crystalluria has been observed [Runolfsdottir et al 2019b]. 4\. See Therapies and Assays Under Investigation for information about the UPLC-MS/MS assay for therapeutic monitoring [Thorsteinsdottir et al 2016, Edvardsson et al 2018]. 5\. To evaluate for new, asymptomatic kidney stones ### Agents/Circumstances to Avoid Azathioprine and mercaptopurine should be avoided by individuals taking XOR inhibitors (allopurinol or febuxostat). Inhibition of xanthine oxidase may cause increased plasma concentrations of azathioprine or mercaptopurine, leading to toxicity. ### Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Approximately 15% of individuals with APRT deficiency may be asymptomatic [Bollée et al 2010, Runolfsdottir et al 2016]; these individuals are usually identified during family screening. Evaluations can include the following: * Molecular genetic testing if the pathogenic variants in the family are known. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic pathogenic variants. * APRT enzyme activity measurements, particularly if the pathogenic variants in the family are not known See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management The safety of allopurinol and febuxostat in human pregnancy has not been systematically studied. Animal studies using high doses of allopurinol have revealed evidence of adverse fetal effects in mice but not in rabbits or rats; it is not clear if these effects are a result of direct fetal toxicity or maternal toxicity. Thus, allopurinol should only be prescribed during pregnancy when the benefit of treatment is believed to outweigh the risk. Treatment with allopurinol during pregnancy should be considered in women with APRT deficiency who have CKD with reduced glomerular filtration rate (GFR) or who have undergone kidney transplantation. Animal studies using high doses of febuxostat in rats and rabbits have not supported a teratogenic effect. However, very high doses in pregnant rats have been associated with neonatal loss and low pup birthweight. Some post-transplantation immunosuppressive therapies can also have adverse effects on the developing fetus. A thorough discussion of the risks and benefits of maternal medication use during pregnancy should ideally take place with an appropriate health care provider prior to conception. See MotherToBaby for further information on medication use during pregnancy. ### Therapies and Assays Under Investigation Urinary DHA measurements. The authors' group has recently developed a urinary DHA assay using ultra-high-performance liquid chromatography – tandem mass spectrometry (UPLC-MS/MS) [Thorsteinsdottir et al 2016], which is expected to facilitate both the clinical diagnosis and monitoring of pharmacotherapy of individuals with APRT deficiency [Edvardsson et al 2018]. Further clinical studies to examine the sensitivity and specificity of the assay are currently under way. 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

Adenine Phosphoribosyltransferase Deficiency

c0268120

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK100238/

{"mesh": ["C538228"], "synonyms": ["2,8-Dihydroxyadeninuria; APRT Deficiency"]}

A number sign (#) is used with this entry because C4B deficiency is caused by mutation in the C4B gene (120820). Clinical Features Partial deficiency of C4 was found in 3 persons during a screening of 42,000 healthy Japanese (Torisu et al., 1970). Of 26 patients with autoimmune chronic active hepatitis beginning in childhood, Vergani et al. (1985) found low C4 in 18 (69%) and low C3 serum levels in 5 (19%). Associated characteristics indicated a defect in synthesis of C4 and a genetic basis thereof was indicated by the fact that C4 phenotyping in 20 patients and in 26 parents showed that 90% and 81%, respectively, had null allotypes at either the C4A or C4B locus compared with 59% in controls. Homozygous deficiency of C4A (614380) is associated with systemic lupus erythematosus (152700) and with type I diabetes mellitus; homozygous deficiency of C4B is associated with susceptibility to bacterial meningitis (Winkelstein, 1987). In 3 African-American patients with systemic lupus erythematosus (SLE; 152700), Wilson and Perez (1988) found complete deficiency of plasma C4B. Lhotta et al. (1990) stated that only 17 cases of complete deficiency of C4 had been described. They described a patient with complete deficiency and renal disease, first presenting as severe Henoch-Schonlein purpura with renal involvement at the age of 17. Six years later, he developed hypertension and nephrotic syndrome, requiring hemodialysis followed by cadaveric kidney graft. After 2 years of uncomplicated course, the patient suffered a recurrence of his primary disease in the grafted kidney. Molecular Genetics Awdeh et al. (1981) analyzed C4 types in relatives of a C4-deficient proband and provided evidence that the deficiency results from homozygosity for a rare, double-null haplotype. The family contained persons with 1, 2, 3, or 4 expressed C4 genes, and the mean serum C4 levels roughly reflected the number of structural genes present. To evaluate the molecular basis of the C4-null phenotypes, Partanen et al. (1988) used Southern blotting techniques to analyze genomic DNA from 23 patients with systemic lupus erythematosus (SLE; 152700) and from healthy controls. They confirmed the earlier findings of high frequencies of C4-null phenotypes and of HLA-B8,DR3 antigens. In addition, they found that among the patients most of both the C4A (120810)- and C4B-null phenotypes resulted from gene deletions. Among the controls, only the C4A-null phenotypes were predominantly the result of gene deletions. In all SLE cases, the C4 gene deletions extended also to a closely linked pseudogene, CYP21A (613815). Altogether, 52% of the patients and 26% of the controls carried a C4/CYP21A deletion. Partanen et al. (1989) found that deletions in 6p involving the C4 and CYP21 loci fell within the range of 30 to 38 kb, as determined by pulsed-field gel electrophoresis. Because the deletion sizes in most other gene clusters were more heterogeneous, the results suggested to Partanen et al. (1989) the involvement of a specific mechanism in the generation of C4/CYP21 deletions. In a 9-year-old girl with SLE and complete C4 deficiency, Welch et al. (1990) found uniparental isodisomy 6. The girl had 2 identical chromosome 6 haplotypes from the father and none from the mother. Fasano et al. (1992) studied a 7-year-old patient with recurrent sinopulmonary infections in whom the rare C4A*Q0,B*Q0 double-null haplotype was shown to be due to a recombination event within the C4B locus in the mother, who possessed a C4A*Q0,B*1 haplotype and a C4A*3,B*1 haplotype. By segregation analysis, they mapped the recombination to a region 3-prime to the unique 6.4-kb TaqI restriction fragment of the maternal C4B locus. Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients from the UK and 537 from Spain, and 1,179 controls for gene copy number (GCN) of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0; 120810.0001) resulting in a null allele. The loss-of-function SNP in C4A was not associated with SLE in either population. Boteva et al. (2012) used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. Overall, the findings indicated that partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease. Population Genetics Ranford et al. (1987) found an extraordinarily high frequency of C4 deficiency in the Australian aboriginal population of Darwin: 29% as compared with 12% in aborigines in Alice Springs and 17% in Canberra blood donors. Partial C4B deficiency was also higher in Darwin aborigines than in the other populations. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

COMPLEMENT COMPONENT 4B DEFICIENCY

c3280641

omim

https://www.omim.org/entry/614379

{"doid": ["0060298"], "omim": ["614379"], "orphanet": ["169147"], "synonyms": ["Immunodeficiency due to C1, C4, or C2 component complement deficiency", "Alternative titles", "C4B DEFICIENCY", "Immunodeficiency due to an early component of complement deficiency"]}

A number sign (#) is used with this entry because multiple epiphyseal dysplasia-5 (EDM5) is caused by heterozygous mutation in the matrilin-3 gene (MATN3; 602109) on chromosome 2p24. Clinical Features Mortier et al. (2001) reported a 3-generation Belgian family with an autosomal dominant form of multiple epiphyseal dysplasia (MED) characterized by easy fatigue and joint pain, mainly in the knees and hips, starting in early childhood; normal stature; and osteoarthrosis in early adulthood. Linkage analysis with microsatellite markers, which were either intragenic or closely linked, excluded linkage of the MED phenotype to previously identified autosomal dominant MED loci. In the family studied by Chapman et al. (2001), originally described by Mortier et al. (2001), all affected individuals had normal birth length and adult height around the third percentile (150 to 165 cm). Most had complained of knee and hip pain after exercise from early childhood, and some of the affected individuals had had hip replacements or undergone knee surgery for deformities and early-onset osteoarthritis. Radiographs at or after the age of puberty showed a normal spine but persisting epiphyseal dysplasia, mainly of hips and knees. An affected individual carrying the arg121-to-trp mutation (602109.0002) presented at the age of 10 years with knee pain after exercise, genu valgum, and normal stature. Radiographs of the skeleton revealed normal spine and hands but predominant involvement of the epiphyses of the hips, knees, and ankles. On follow-up, the genu valgum had resolved spontaneously. Complaints of joint pain became less frequent and, surprisingly, knee and hip radiographs normalized by the age of 24 years. His affected father also experienced joint pain as a teenager with spontaneous improvement after puberty. Elsbach (1959) described a 4-generation Delft family with what they called bilateral microepiphyseal dysplasia. Mostert et al. (2003) provided follow-up on this family. The index case had died before reevaluation but his affected younger brother was available for study. He had onset of hip and knee pain at age 4 years. He had hip replacement on the left side at age 28 and on the right side at age 37. He had a right knee replacement at age 43. Although he was the smallest in height among his peers in primary school, he eventually reached a height of 1.71 m (less than 15th centile for Dutch reference population). Clinical features of affected members included bilateral simultaneous onset of pain in hip and knee joints, short stature, waddling gait, and decreased range of motion of the hip. Radiographic findings included coxa valga, flattened femoral head, an unusual teardrop configuration of the medial acetabular wall, small epiphyses of the proximal and distal femur, and small epiphyses of the proximal tibia with or without flattened condyles of the knees. Makitie et al. (2004) reviewed the clinical and radiographic features in 12 affected members from 7 families with autosomal dominant multiple epiphyseal dysplasia due to mutation in the MATN3 gene. They found a uniform pattern of skeletal anomalies in all patients with considerable degree of variability in severity, both between and within families. The characteristic clinical findings were onset of symptoms in early childhood with predominance of knee- and hip-related complaints, normal stature, and early-onset osteoarthritis. Radiographs showed small and irregular epiphyses and mild metaphyseal irregularities and striations, especially at the knees and hips, and mild spinal changes. Molecular Genetics In the family originally described by Mortier et al. (2001) with MED, Chapman et al. (2001) identified mutations in the MATN3 gene (602109.0001-602109.0002). The mutations occurred within the single von Willebrand factor A (vWFA) domain. In affected members of 7 families with MED, Jackson et al. (2004) identified 4 novel mutations (see 602109.0004) and 1 recurrent mutation (R121W; 602109.0002) in the MATN3 gene. All of the disease-causing mutations were located within the beta sheet of the vWFA domain. In all available affected members of the family with MED described by Elsbach (1959), Mostert et al. (2003) identified heterozygosity for a missense mutation (602109.0007) within the vWFA domain of the MATN3 gene. Maeda et al. (2005) noted that previous reports regarding more than 18 families with MED indicated that MATN3 mutations in EDM5 are confined to exon 2, which encodes the vWFA domain. Maeda et al. (2005) reported a novel MATN3 mutation outside the vWFA domain (602109.0006) in a 38-year-old patient with MED. The man presented with bilateral hip pain at age 32 years. His height was 155 cm. Radiographic changes were found in the hips and hands. His mother and an elder sister had acetabular dysplasia. INHERITANCE \- Autosomal dominant GROWTH Height \- Normal stature SKELETAL \- Early onset osteoarthritis \- Multiple epiphyseal dysplasia Pelvis \- Arthralgia (hip) \- Small proximal femoral epiphyses \- Broad, short femoral neck \- Coxa vara \- High greater trochanter Limbs \- Small, irregular epiphyses (distal femoral, proximal tibiae, distal radii, distal ulnae) \- Mild metaphyseal irregularities (distal femoral, proximal tibiae, proximal humeri, distal radii, distal ulnae) \- Genua valga \- Arthralgias (knees) \- Submetaphyseal vertical striations Hands \- Small, irregular epiphyses (first metacarpal) \- Delayed carpal ossification Feet \- Delayed tarsal ossification MISCELLANEOUS \- Genetic heterogeneity (see EDM1 132400 , EDM2 600204 , EDM3 600969 , EDM4 226900 ) \- Allelic to spondyloepimetaphyseal dysplasia, MATN-3 related ( 608728 ) \- Allelic to hand osteoarthritis ( 607850 ) MOLECULAR BASIS \- Caused by mutation in the matrilin 3 gene (MATN3, 602109.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

EPIPHYSEAL DYSPLASIA, MULTIPLE, 5

c1846843

omim

https://www.omim.org/entry/607078

{"doid": ["0070299"], "mesh": ["C535505"], "omim": ["607078"], "orphanet": ["93311"], "synonyms": ["Alternative titles", "MULTIPLE EPIPHYSEAL DYSPLASIA, MATN3-RELATED", "MICROEPIPHYSEAL DYSPLASIA, BILATERAL HEREDITARY"], "genereviews": ["NBK1123"]}

Partington syndrome is a form of syndromic X-linked mental retardation (S-XLMR) characterised by the association of mild to moderate intellectual deficit, dysarthria and dystonic hand movements. So far, less than 20 cases have been described in the literature. The syndrome is caused by mutations in the Aristaless-related homeobox (ARX) gene (Xp22.13). Transmission is X-linked recessive. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Partington syndrome

c0796250

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=94083

{"gard": ["4235"], "mesh": ["C536300"], "omim": ["309510"], "synonyms": ["Partington-Mulley syndrome", "X-linked intellectual disability-dystonia-dysarthria syndrome"]}

A number sign (#) is used with this entry because of the association between late-onset Alzheimer disease-2 (AD2) and the apolipoprotein E (107741) E4 allele. For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300. Clinical Features Using positron emission tomography (PET), Reiman et al. (1996) found that 11 cognitively normal subjects aged 50 to 65 years who were homozygous for the APOE4 allele had reduced glucose metabolism in the same regions of the brain as patients with probable Alzheimer disease. The affected areas included temporal, parietal, posterior cingulate, and prefrontal regions. These findings provided preclinical evidence that the presence of the APOE4 allele is a risk factor for Alzheimer disease. Reiman et al. (1996) suggested that PET may offer a relatively rapid way of testing treatments to prevent Alzheimer disease in the future. Reiman et al. (2001) found that 10 cognitively normal apoE4 heterozygotes aged 50 to 63 years also had abnormally low measurements of the cerebral metabolic rate for glucose in the same regions as AD patients. Over a period of 2 years, the E4 heterozygotes had declines in several regions, including temporal, posterior cingulate, prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus. These declines were significantly greater than those of 15 non-E4 carriers. Using PET scans, Reiman et al. (2004) found that 12 young adult volunteers, ranging in age from 20 to 39 years, who were heterozygous for the apoE4 allele had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Reiman et al. (2004) concluded that carriers of the E4 allele have brain abnormalities in young adulthood, several decades before the possible onset of dementia. Rippon et al. (2006) examined potential modifying risk factors for familial AD in a Latino population comprising 778 AD patients from 350 families. The population was primarily from the Dominican Republic and Puerto Rico and had been previously studied by Romas et al. (2002). The APOE E4 allele was associated with a nearly 2-fold increased risk of AD, a history of stroke (601367) was associated with a 4-fold increase, and a statistical interaction between APOE E4 and stroke was observed. Women with the E4 allele who were on estrogen replacement therapy did not have an increased risk of AD, but in women with a history of stroke, estrogen therapy was a deleterious effect modifier. Among risk factors, diabetes mellitus, myocardial infarction, head injury, hypertension, and smoking were not associated with AD. Among 100 patients with AD, van der Flier et al. (2006) found an association between presence of the E4 allele and the typical amnestic phenotype, characterized by initial presentation of forgetfulness and difficulties with memory. Those with the memory phenotype were 3 times more likely to carry an E4 allele compared to AD patients who displayed a nonmemory phenotype, with initial complaints including problems with calculation, agnosia, and apraxia. The memory phenotype was almost exclusively observed in homozygous E4 carriers. Borroni et al. (2007) also reported an association between the memory phenotype of AD and presence of the E4 allele. Among 319 late-onset AD patients, 77.6% of E4 allele carriers presented with the memory phenotype compared to 64.6% of noncarriers. Wolk et al. (2010) compared the phenotypes of 67 AD patients carrying at least 1 APOE E4 allele to 24 AD patients without an E4 allele. Both groups of patients had a cerebrospinal fluid profile consistent with AD. E4 carriers had significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. E4 carriers also had greater atrophy of the medial temporal lobe and smaller hippocampal volumes on neuroimaging, whereas noncarriers had greater frontoparietal atrophy. The findings suggested that APOE genotype may influence selective regional brain pathology, which in turns reflects phenotypic variation in the specific cognitive symptoms of AD. Kunz et al. (2015) found that young adults at genetic risk for AD (APOE-E4 carriers) exhibit reduced grid cell-like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid cell-like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE-E4 carriers. Kunz et al. (2015) concluded that their results provided evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset. Mapping Pericak-Vance et al. (1988) excluded linkage to the AD1 locus on chromosome 21 (104300) in 13 families with FAD. Pericak-Vance et al. (1989, 1990) presented evidence for linkage to 2 markers on chromosome 19. When analysis was limited to the affecteds only, a lod score of 2.5 at theta = 0 was obtained for linkage with BCL3 (109560). Pericak-Vance et al. (1991) found evidence of linkage to chromosome 19 in their late-onset FAD families, and to chromosome 21 in their early-onset FAD families. When only affected persons were used in the analysis, a high lod score was obtained also with ATP1A3 (182350), which maps to 19q12-q13.2. In a study of 48 kindreds with multiple cases of Alzheimer disease in 2 or more generations and with family age-at-onset means ranging from 41 to 83 years, Schellenberg et al. (1991) found negative lod scores for those families with onset after age 60, those families with onset before age 60, and for Volga German families with mean age of onset of 56. The early-onset non-Volga German families with onset before age 60 had low positive lod scores. Schellenberg et al. (1991) concluded that the AD gene on chromosome 21 is not responsible for late-onset FAD nor for the early-onset FAD represented by the Volga German kindreds. Of 23 families with FAD, Schellenberg et al. (1992) excluded linkage to 19q in early-onset families, but small positive lod scores were obtained for late-onset families. Specific linkage to the APOC2 locus (608083) was excluded in all families. Sillen et al. (2006) conducted a genomewide linkage study on 188 individuals with AD from 71 Swedish families, using 365 markers (average intermarker distance 8.97 cM). They performed nonparametric linkage analyses in the total family material as well as stratified the families with respect to the presence or absence of APOE4. The results suggested that the disorder in these families was tightly linked to the APOE region (19q13). The next highest lod score was to chromosome 5q35, and no linkage was found to chromosomes 9, 10, and 12. Harold et al. (2009) undertook a 2-stage genomewide association study of Alzheimer disease involving 16,000 individuals, which they stated was the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), they replicated the established association with the APOE locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)). Molecular Genetics Corder et al. (1993) found that the risk for late-onset AD increased from 20 to 90% and mean age of onset decreased from 84 to 68 years with increasing number of APOE*E4 alleles (107741.0016) in 42 families with late-onset AD. Onset was early in 4 other families tested; 2 had chromosome 21 APP (104760) mutations and 2 showed linkage to chromosome 14, thus representing AD1 (104300) and AD3 (607822), respectively. The frequency of APOE*E4 was not elevated in these families or in 12 other early-onset families. Homozygosity for APOE*E4 was virtually sufficient alone to cause AD by age 80. Bray et al. (2004) applied highly quantitative measures of allele discrimination to cortical RNA from individuals heterozygous for the APOE E2, E3, and E4 alleles. A small, but significant, increase in the expression of E4 allele was observed relative to that of the E3 and E2 alleles (P less than 0.0001). Similar differences were observed in brain tissue from confirmed late-onset Alzheimer disease subjects, and between cortical regions BA10 (frontopolar) and BA20 (inferior temporal). Stratification of E4/E3 allelic expression ratios according to heterozygosity for the -219G-T promoter polymorphism (107741.0030) revealed significantly lower relative expression of haplotypes containing the -219T allele (P = 0.02). Bray et al. (2004) concluded that, in human brain, most of the cis-acting variance in APOE expression may be accounted for by the E4 haplotype, but there are additional small cis-acting influences associated with the promoter genotype. Population Genetics Romas et al. (2002) found that both early-onset and late-onset familial AD occurs in Caribbean Hispanics. In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics was strongly associated with APOE4. Misc \- Late onset Neuro \- Presenile and senile dementia \- Parkinsonism \- Long tract signs Lab \- Neurofibrillary tangles composed of disordered microtubules in neurons Inheritance \- Autosomal dominant allele (19q) with additional multifactorial component in late-onset cases ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

ALZHEIMER DISEASE 2

c0276496

omim

https://www.omim.org/entry/104310

{"doid": ["0110035"], "mesh": ["D000544"], "omim": ["104310"], "orphanet": ["1020"], "synonyms": ["Alternative titles", "ALZHEIMER DISEASE 2, LATE-ONSET", "ALZHEIMER DISEASE ASSOCIATED WITH APOE4"]}

For a general phenotypic description and a discussion of genetic heterogeneity of susceptibility to thyrotoxic periodic paralysis, see 188580. Mapping Cheung et al. (2012) conducted a genomewide association study and a replication study with a total of 123 southern Chinese with thyrotoxic periodic paralysis (TTPP) (cases) and 1,170 healthy controls and identified a susceptibility locus on chromosome 17q24.3 near KCNJ2 (600681) (rs312691; odds ratio = 3.3; p metaanalysis = 1.8 x 10(-14)). All subjects with TTPP also had Graves disease (275000), and subsequent TTPP versus Graves disease comparison confirmed that the association at 17q24.3 was specific to TTPP. The area under the curve of rs312691 genotype for risk prediction of TTPP in subjects with Graves disease was 0.73. Expression quantitative trait locus analysis identified SNPs in the region flanking rs312691 (+/- 10 kb) that could potentially affect KCNJ2 expression (p = 0.0001). The SNP rs312691 is located in a gene-poor region and is approximately 150 kb downstream of KCNJ2 and approximately 195 kb downstream of KCNJ16 (605722). Cheung et al. (2012) considered the KCNJ2 the more biologically plausible candidate gene for TTPP, as KCNJ16 is not expressed in skeletal muscle and KCNJ16 knockout mice have no behavioral or physical abnormalities. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

THYROTOXIC PERIODIC PARALYSIS, SUSCEPTIBILITY TO, 3

c0268446

omim

https://www.omim.org/entry/614834

{"omim": ["614834"], "orphanet": ["79102"]}

A number sign (#) is used with this entry because alpha-fetoprotein deficiency (AFPD) is caused by homozygous mutation in the AFP gene (104150) on chromosome 4q13. Description Alpha-fetoprotein deficiency appears to be a benign genetic trait (Greenberg et al., 1992; Sharony et al., 2004). Clinical Features Faucett et al. (1989) and Greenberg et al. (1992) documented AFP deficiency in 2 infants. One was found in the case of a 36-year-old woman who had amniocentesis for genetic indications; amniotic fluid AFP levels were undetectable and chromosome analysis showed a 46,XX pattern. The maternal serum AFP level was likewise undetectable. A healthy, term female infant was delivered. In the cord blood, AFP level was undetectable. The second mother had an amniocentesis because of low maternal serum AFP levels. Amniotic fluid AFP level was undetectable. Chromosome analysis showed a 46,XY pattern; a normal, term male infant was delivered. This appears to be a situation analogous to analbuminemia; like analbuminemia, AFPD is presumably a benign genetic trait. Molecular Genetics In affected members of 2 Arab families with congenital deficiency of AFP, Sharony et al. (2004) identified a homozygous 2-bp deletion in the AFP gene (104150.0002). The affected individuals were asymptomatic and developed normally. Petit et al. (2009) identified a homozygous truncating mutation in the AFP gene (104150.0003) in an Algerian infant who showed normal growth and development. The deficiency was noted by the absence of AFP in the maternal serum and amniotic fluid during the second trimester of pregnancy. Animal Model Gabant et al. (2002) used gene targeting to show that AFP is not required for embryonic development. AFP-null embryos developed normally, and individually transplanted homozygous embryos could develop in an AFP-deficient microenvironment. Whereas mutant homozygous adult males were viable and fertile, AFP-null females were infertile. Analysis of these mice indicated that the defect was caused by a dysfunction of the hypothalamic/pituitary system, leading to anovulation. INHERITANCE \- Autosomal recessive LABORATORY ABNORMALITIES \- Low serum alpha-fetoprotein MISCELLANEOUS \- Major fetal plasma protein produced by yolk sac and liver \- Benign condition MOLECULAR BASIS \- Caused by mutation in the alpha-fetoprotein gene (AFP, 104150.0002 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

ALPHA-FETOPROTEIN DEFICIENCY

c1863081

omim

https://www.omim.org/entry/615969

{"mesh": ["C566300"], "omim": ["615969"], "orphanet": ["168612"]}

A number sign (#) is used with this entry because severe congenital neutropenia-3 (SCN3), also known as Kostmann disease, is caused by homozygous or compound heterozygous mutation in the HAX1 gene (605998) on chromosome 1q21. Description Severe congenital neutropenia-3 is an autosomal recessive bone marrow failure disorder characterized by low numbers of neutrophils, increased susceptibility to bacterial and fungal infections, and increased risk of developing myelodysplastic syndrome or acute myeloid leukemia. In addition, patients with HAX1 mutations affecting both isoform A and B of the gene develop neurologic abnormalities (summary by Boztug et al., 2010). The Swedish physician Rolf Kostmann (1956) described an autosomal recessive hematologic disorder, termed infantile agranulocytosis, with severe neutropenia with an absolute neutrophil count below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disorder was later termed Kostmann syndrome (Skokowa et al., 2007). Lekstrom-Himes and Gallin (2000) discussed severe congenital neutropenia in a review of immunodeficiencies caused by defects in phagocytes. In addition to Kostmann agranulocytosis, recessively inherited neutropenic syndromes include congenital neutropenia with eosinophilia (257100), Chediak-Higashi syndrome (214500), and Fanconi pancytopenic syndrome (see 227650). For a phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700). Clinical Features Infantile agranulocytosis was first clearly delineated by Kostmann (1956). Starting with 19 sibships collected by Kostmann (1975), Iselius and Gustavson (1984) assembled evidence that a single founder was responsible for the cases observed in Sweden. The likely origin of the gene was thought to be the parish of Overkalix in the county of Norrbotten in the most northern part of Sweden. Carlsson et al. (2008) provided follow-up of 5 affected individuals from the original family reported by Kostmann (1956). All those who survived beyond infancy had evidence of neurologic involvement with developmental delay and decreased cognitive function. Two of 4 patients who reached age 10 years also developed epilepsy. Olofsson et al. (1976) reported 2 patients, a boy and his niece. In each instance the parents were consanguineous. On the first day of life, 1 of the 2 patients had granulocytopenia; complete agranulocytosis developed in 3 weeks after an interval during which the patient had normal or even increased neutrophil levels, due possibly to meningitis. In addition to persistent severe absolute neutropenia (500 neutrophils per microliter or fewer) and bone marrow morphology that suggests maturational arrest of neutrophil precursors at the promyelocyte stage, variable degrees of monocytosis, eosinophilia, hypergammaglobulinemia, and thrombocytosis may be found. In a retrospective survey of 162 patients in whom bone marrow transplantation was performed in 14 European centers between 1969 and 1985, Fischer et al. (1986) found 1 patient with Kostmann syndrome. Corcione et al. (1993) characterized a spontaneous lymphoblastoid cell line raised from the peripheral blood of a patient with Kostmann congenital neutropenia. Neutropenia had first been discovered at the age of 1 month. When examined at the age of 2 years and 9 months, the girl had a history of recurrent bacterial infections (pneumonitis, otitis media, cutaneous furuncles, and tonsillitis) since the age of 3 months. Her general condition was poor, and mild hepatosplenomegaly and diffuse lymph node enlargement were found. Corcione et al. (1993) found that the lymphoblastoid cell line was composed of EBV-infected polyclonal B cells. The supernatant contained a colony-inhibiting activity that was demonstrated to be transforming growth factor beta-1 (TGFB1; 190180). Corcione et al. (1993) hypothesized that the B cells latently infected by EBV in vivo, and possibly expanded as a consequence of the infection, contributed to the inhibition of the patient's granulopoiesis by releasing TGF-beta-1. Koren et al. (1989) reported a family in which a male and female sib with first-cousin parents had what was called congenital dysgranulopoietic neutropenia. The female suffered from omphalitis due to enterobacter at age 2 weeks and subsequently died from sepsis at age 1 month. The male was admitted at age 2 months with an abscess in the right inguinal region due to Pseudomonas aeruginosa. He suffered from frequent severe pyogenic infections. At the time of the report by Koren et al. (1994) he was 11 years old and had been treated successfully with granulocyte colony-stimulating factor (GCSF; 138970) from the age of 8. In 1992, the mother became pregnant and sonographically guided fetal blood sampling was performed by cordocentesis. The results of the blood studies indicated that the fetus was not at risk. The newborn baby was indeed healthy with normal neutrophil counts at 2 and 4 months of age. Germeshausen et al. (2008) reported 6 unrelated patients with SCN3, 5 of whom were of Turkish origin. All presented in infancy with recurrent bacterial infections associated with neutropenia. One patient developed acute lymphoblastic leukemia at age 7 months, and another developed a myelodysplastic syndrome at age 7 years. Two patients had neurologic involvement, including psychomotor retardation and seizures. Germeshausen et al. (2008) noted that some patients with SCN3 develop neurologic deficits. Boztug et al. (2010) reported a consanguineous Turkish family in which 2 girls had SCN3 and neurologic deficits. One patient was diagnosed with the disorder at age 19 years and was treated with recombinant GCSF. She had global developmental delay since early childhood. She had impaired motor function without evidence of spasticity or ataxia, mental retardation, combined conductive and inner ear hearing loss, and severe epilepsy. Examination at age 28 years suggested a peripheral neuropathy. The second patient was diagnosed with SCN at age 5 years. This patient showed delayed motor development, hearing loss, and mental retardation. At age 26 years, the clinical neurologic examination was normal except for clumsiness. Genetic analysis in both patients revealed a homozygous 2-kb deletion within the HAX1 gene that removed exons 4-7, and Western blot analysis showed complete absence of the HAX1 protein. Quantitative brain MRI showed a general reduction of cerebral proton density in the white and gray matter, although no major abnormalities were seen on MRI scans, except for mild cerebellar atrophy in 1 patient. Similar studies in another unrelated patient with SCN3 and severe neurologic deficits also showed a reduction of proton density both in the cerebral white and gray matter, but these changes were not observed in an SCN3 patient without neurologic involvement. Boztug et al. (2010) suggested that the decreased proton density may reflect a reduction in neuronal cell density and microstructural brain changes. The findings again confirmed that mutations that affect both isoforms of HAX1 result in SCN3 with neurologic deficits. Pathogenesis To investigate the potential role of apoptosis in severe congenital neutropenia, Carlsson et al. (2004) obtained bone marrow aspirates and biopsies from 4 patients belonging to the kindred originally described by Kostmann (1956) and 1 patient with severe congenital neutropenia of unknown inheritance. An elevated degree of apoptosis was observed in the bone marrow of these patients, and a selective decrease in B-cell lymphoma-2 (BCL2; 151430) expression was seen in myeloid progenitor cells. Furthermore, in vitro apoptosis of bone marrow-derived Kostmann progenitor cells was increased, and mitochondrial release of cytochrome c was detected in CD34+ and CD33+ progenitors from patients, but not in controls. Administration of GCSF restored BCL2 expression and improved survival of myeloid progenitor cells. In addition, cytochrome c release was partially reversed upon incubation of progenitor cells with GCSF. These studies established a role for mitochondria-dependent apoptosis in the pathogenesis of Kostmann syndrome and yielded a tentative explanation for the beneficial effect of growth factor administration in these patients. Molecular Genetics Autosomal recessive severe congenital neutropenia constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells. Using a positional cloning approach and candidate gene evaluation, Klein et al. (2007) identified a recurrent homozygous germline mutation in HAX1 (605998.0002) in 3 Kurdish pedigrees. Through molecular screening of other individuals with severe congenital neutropenia, they identified 19 additional affected individuals with homozygous HAX1 mutations, including 3 belonging to the original Swedish pedigree described by Kostmann (1956) (605988.0001). HAX1 encodes the mitochondrial HS1-associated protein X1, which functions in signal transduction and cytoskeletal control. Klein et al. (2007) showed that HAX1 is critical to maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Their findings suggested that HAX1 is a major regulator of myeloid homeostasis and underlined the significance of genetic control of apoptosis in neutrophil development. Klein et al. (2007) sequenced the ELA2 gene (130130), previously associated with cyclic (Horwitz et al., 1999) and congenital (Dale et al., 2000) neutropenia in all individuals. No affected individual was found with mutations in both ELA2 and HAX1, suggesting that these genes defined 2 mutually exclusive groups of individuals with severe congenital neutropenia. Severe congenital neutropenia is a premalignant condition, as up to 21% of affected individuals develop a clonal proliferative disease leading to myelodysplastic syndrome or overt acute leukemia, often preceded by mutations in the gene encoding the granulocyte colony-stimulating factor receptor (CSF3R; 138971) (Dong et al., 1995). To determine whether HAX1 mutations predispose to somatic CSF3R mutations, Klein et al. (2007) sequenced CSF3R in all affected individuals with documented HAX1 mutations and reanalyzed the data of the SCN Registry. In 3 HAX1-deficient individuals, they identified somatic mutations in CSF3R. In 5 (28%) of 18 Japanese patients with severe congenital neutropenia, Ishikawa et al. (2008) identified homozygous or compound heterozygous mutations in the HAX1 gene (605998.0005; 605998.0006). All had developmental delay, and 3 had seizures. These neurologic clinical findings were not observed in 11 (61%) patients who were found to have mutations in the ELA2 gene. Smith et al. (2008) identified homozygous mutations in the HAX1 gene (see, e.g., 605998.0007; 605998.0008) in 4 (4%) of 109 probands with SCN. Genotype/Phenotype Correlations Germeshausen et al. (2008) identified 5 different mutations in the HAX1 gene (see, e.g., 605998.0003; 605998.0004) in 6 unrelated patients with autosomal recessive SCN3. HAX1 mutations affecting exclusively the full-length isoform A only (see, e.g., 605998.0002) resulted in neutropenia without neurologic symptoms. In contrast, mutations affecting both HAX1 isoforms A and B (see, e.g., 605998.0001 and 605998.0003) were associated with an additional neurologic phenotype (p less than 0.001). INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Psychomotor retardation (in some patients) \- Seizures (in some patients) IMMUNOLOGY \- Neutropenia \- Recurrent bacterial infections NEOPLASIA \- Increased risk of myelodysplastic syndromes \- Increased risk of leukemia MISCELLANEOUS \- Onset in infancy \- Only some patients showed neurologic involvement MOLECULAR BASIS \- Caused by mutation in the HCLS1-associated protein X1 (HAX1, 605998.0001 ). ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

NEUTROPENIA, SEVERE CONGENITAL, 3, AUTOSOMAL RECESSIVE

c1853118

omim

https://www.omim.org/entry/610738

{"mesh": ["C537592"], "omim": ["610738"], "icd-10": ["D70.0"], "orphanet": ["99749"], "synonyms": ["AGRANULOCYTOSIS, INFANTILE", "KOSTMANN DISEASE", "Alternative titles", "Severe congenital neutropenia type 3", "Infantile agranulocytosis"]}

Exercise hypertension SpecialtyCardiologist Exercise hypertension is an excessive rise in blood pressure during exercise. Many of those with exercise hypertension have spikes in systolic pressure to 250 mmHg or greater. A rise in systolic blood pressure to over 200 mmHg when exercising at 100 W is pathological and a rise in pressure over 220 mmHg needs to be controlled by the appropriate drugs.[1] Similarly, in healthy individuals the response of the diastolic pressure to 'dynamic' exercise (e.g. walking, running or jogging) of moderate intensity is to remain constant or to fall slightly (due to the improved blood flow), but in some individuals a rise of 10 mmHg or greater is found. Recent work at Johns Hopkins involving a group of athletes aged 55 to 75 with mild hypertension has found a correlation of those with exercise hypertension to a reduced ability of the major blood vessels to change in size in response to increased blood flow (probably due to impaired function of the endothelial cells in the vessel walls). This is to be differentiated from stiffness of the blood-vessel walls, which was not found to be correlated with the effect.[2] ## References[edit] 1. ^ Klaus, D. (February 1989). "Management of Hypertension in Actively Exercising Patients: Implications for Drug Selection". Drugs. 37 (2): 212–8. doi:10.2165/00003495-198937020-00008. PMID 2649357. S2CID 46963184. 2. ^ Stewart, Kerry; et al. (April 2004). "Exaggerated Exercise Blood Pressure is Related to Impaired Endothelial Vasodilatory Function". Am. J. Hypertens. 17 (4): 314–320. doi:10.1016/S0895-7061(03)01003-3. PMID 15062884. This medical sign 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

Exercise hypertension

None

wikipedia

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

{"wikidata": ["Q5420056"]}

A number sign (#) is used with this entry because of evidence that juvenile cataract with microcornea (CTRCT47) is caused by heterozygous mutation in the SLC16A12 gene (611910) on chromosome 10q23. One such family has been reported. Clinical Features Vandekerckhove et al. (2007) described a Swiss family in which 11 of 17 living family members in 3 generations underwent ophthalmic assessment and urine analysis. Eleven members had progressive juvenile cataract. Eight members available for clinical examination had bilateral microcornea not associated with microphthalmos. In 6 of these persons renal glucosuria was demonstrated. Kloeckener-Gruissem et al. (2008) restudied the family of Vandekerckhove et al. (2007), noting that 9 of 12 cataract patients also showed elevated glucose in urine in the absence of other renal or metabolic abnormalities. Molecular Genetics In a Swiss family with juvenile cataract with microcornea and renal glucosuria, originally reported by Vandekerckhove et al. (2007), Kloeckener-Gruissem et al. (2008) demonstrated heterozygosity for a nonsense mutation in the SLC16A12 gene (Q215X; 611910.0001). They showed that SLC16A12 has high expression in the eye and kidney and hypothesized that SLC16A12 is important for lens and kidney homeostasis. They suggested that the mutation was responsible for the cataract/microcornea/glucosuria phenotype. Dhayat et al. (2016) restudied 16 members of the Swiss family reported by Vandekerckhove et al. (2007), and found that of 11 family members with SLC16A12-associated cataract for whom renal data were available, 5 had renal leak glucosuria. Dhayat et al. (2016) identified a heterozygous missense mutation in the renal glucosuria-associated gene SLC5A2 (A89T; 182381.0007) that segregated fully with renal leak glucosuria in the family. They concluded that the previously identified mutation in SLC16A12 was only responsible for the cataract/microcornea phenotype. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Cataract, juvenile-onset, progressive \- Microcornea, bilateral LABORATORY ABNORMALITIES \- Increased fractional renal excretion of guanidinoacetate MISCELLANEOUS \- Based on report of 1 family (last curated August 2016) MOLECULAR BASIS \- Caused by mutation in the solute carrier family 16 (monocarboxylic acid transporter), member-12 gene (SLC16A12, 611910.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

CATARACT 47

c4310806

omim

https://www.omim.org/entry/612018

{"omim": ["612018"], "orphanet": ["247794"], "synonyms": ["Alternative titles", "CATARACT, JUVENILE, WITH MICROCORNEA AND GLUCOSURIA, FORMERLY", "CATARACT, JUVENILE, WITH MICROCORNEA"]}

A number sign (#) is used with this entry because of evidence that macular dystrophy with central cone involvement (CCMD) is caused by compound heterozygous mutation in the MFSD8 gene (611124) on chromosome 4q28. Clinical Features Roosing et al. (2015) studied a Dutch family in which 5 sibs, ranging in age from 54 to 71 years, had macular dystrophy with central cone involvement. Affected individuals presented in the third to sixth decade of life with decreased visual acuity and only slight pigmentary changes and color vision abnormalities. Funduscopy findings were variable and included bull's eye maculopathy, severe atrophy of central fovea, relatively spared fovea with surrounding atrophic ring, central retinal pigment epithelium (RPE) and/or choroid changes, pale or atrophic peripapillary area, pale optic disc, relatively spared periphery, and slightly or moderately attenuated vessels. One sib showed only subtle macular changes with no other abnormalities at 50 years of age. Color vision testing showed a red-green defect, and visual field tests demonstrated decreased central vision with normal periphery. Fluorescein angiography in 4 patients revealed central hypofluorescence in 2 of them, 1 of whom had a surrounding hyperfluorescent ring and the other a mottled pattern of perimacular hypofluorescence; another patient showed hyperfluorescence in a small central area, whereas the fourth patient had symmetrical central alterations in the outer retinal layers. Photopic and scotopic responses were normal on full-field electroretinograms (ERGs), but multifocal studies (mfERGs) revealed severely reduced central responses. Roosing et al. (2015) also studied an unrelated 62-year-old Dutch man who was diagnosed with cone dystrophy at 27 years of age and whose visual acuity decreased to counting fingers by 40 years of age. Over the years, gradual enlargement of a central scotoma was documented. ERGs on 8 different occasions showed normal rod function with only mildly abnormal cone function; at 60 years of age, however, the results suggested a tendency toward a rod-cone pattern, consistent with progression of retinal atrophy toward the midperiphery. Color vision was normal at age 29 years but developed into a deutan (green) deficiency at 42 years of age. None of the Dutch patients experienced seizures, and all had normal mental and psychomotor abilities. Mapping In 4 affected sibs from a Dutch family with macular dystrophy with central cone involvement, Roosing et al. (2015) performed genomewide linkage analysis and identified 3 different linkage peaks, on chromosomes 1, 2, and 4. Microsatellite marker analysis revealed that only the haplotypes on chromosome 4 segregated with disease, and a maximum lod score of 3.4 was obtained. Molecular Genetics In a Dutch family in which 5 sibs had CCMD mapping to chromosome 4, Roosing et al. (2015) performed exome sequencing and identified compound heterozygosity for a missense mutation (E336Q; 611124.0008) and a nonsense mutation (E381X; 611124.0009) in the MFSD8 gene. Exome sequencing in an unrelated Dutch man with CCMD revealed compound heterozygosity for the E336Q mutation and a c.1102G-C transversion (611124.0010). Analysis of the effect of the latter mutation, which occurs in the last nucleotide of exon 11, revealed that it causes skipping of exon 11 and is thus predicted to result in a truncated protein. Neither truncating mutation was found in an in-house exome database or the Exome Variant Server or 1000 Genomes Project databases; both had previously been reported in patients with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951), but none of the Dutch patients exhibited any extraocular features. The E336Q missense variant, however, was present in 1 (0.3%) of 302 alleles from ethnically matched controls, in 9 (0.21%) of 4,190 alleles in an in-house exome database, and in 25 (0.19%) of 12,006 European American alleles in the Exome Variant Server database; it was not found in 2,184 alleles in the 1000 Genomes Project database. Screening for E336Q in a cohort of patients with inherited maculopathy and cone disorders (22 with achromatopsia, 110 with cone dystrophy, and 112 with cone-rod dystrophy) revealed 4 patients carrying the variant in heterozygous state; sequence analysis of MFSD8 did not identify a second variant on the other allele. Regarding the lack of neurologic features in the Dutch patients carrying 2 MFSD8 mutations, Roosing et al. (2015) hypothesized that E336Q represents a hypomorphic variant and proposed a threshold model in which residual activity of MFSD8 suffices for proper function in all organs except the eye, resulting in nonsyndromic eye disease. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Decreased visual acuity \- Bull's eye maculopathy (in some patients) \- Profound atrophy in fovea (in some patients) \- Relative sparing of fovea with surrounding atrophic ring (in some patients) \- Central retinal pigment epithelium changes \- Choroid atrophy (rare) \- Pale or atrophic peripapillary area \- Optic disc pallor (rare) \- Relative sparing of periphery \- Slightly or moderately attenuated vessels \- Central hypofluorescence or hyperfluorescence on fluorescein angiography \- Color vision deficit, green or red-green \- Central scotoma on visual field testing \- Normal photopic and scotopic responses on electroretinography (ERG) \- Severely reduced central responses on multifocal ERG \- Mildly abnormal cone function on ERG (rare) MISCELLANEOUS \- Onset of symptoms in third to sixth decade of life MOLECULAR BASIS \- Caused by mutation in the major facilitator superfamily domain-containing protein-8 gene (MFSD8, 611124.0008 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

MACULAR DYSTROPHY WITH CENTRAL CONE INVOLVEMENT

c4015371

omim

https://www.omim.org/entry/616170

{"omim": ["616170"]}

Riccardi (1982) described cases of neurofibromatosis that are sufficiently variant that they seem to warrant separation from the classic von Recklinghausen NF I (162200), the acoustic neuroma type, NF II (101000), and the mixed type, NF III (162260). The group still is undoubtedly heterogeneous. Iris Lisch nodules, one of the most specific features of NF I, are usually absent in NF IV. The importance of a separate category for these cases is related to the probable difference in prognosis and genetic counseling and the desirability of avoiding confusion of studies of the natural history and pathogenesis of NF I. Eyes \- Iris Lisch nodules usually absent Inheritance \- Autosomal dominant \- heterogeneous Skin \- Atypical neurofibromatosis ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

NEUROFIBROMATOSIS, TYPE IV, OF RICCARDI

c0220695

omim

https://www.omim.org/entry/162270

{"mesh": ["C537392"], "omim": ["162270"], "synonyms": ["Alternative titles", "NEUROFIBROMATOSIS, VARIANT FORM(S) OF", "NF IV", "NEUROFIBROMATOSIS, ATYPICAL"]}

A number sign (#) is used with this entry because of evidence that Camurati-Engelmann disease results from domain-specific heterozygous mutations in the transforming growth factor-beta-1 gene (TGFB1; 190180) on chromosome 19q13. Also see Camurati-Engelmann disease type 2 (606631) in which no mutation in the TGFB1 gene has been found. Description Camurati-Engelmann disease is a rare autosomal dominant type of bone bone dysplasia. The hallmark of the disorder is the cortical thickening of the diaphyses of the long bones. Hyperostosis is bilateral and symmetrical and usually starts at the diaphyses of the femora and tibiae, expanding to the fibulae, humeri, ulnae, and radii. As the disease progresses, the metaphyses may be affected as well, but the epiphyses are spared. Sclerotic changes at the skull base may be present. The onset of the disease is usually during childhood and almost always before the age of 30. Most patients present with limb pain, muscular weakness, a waddling gait, and easy fatigability. Systemic manifestations such as anemia, leukopenia, and hepatosplenomegaly occur occasionally (summary by Janssens et al., 2006). Clinical Features Camurati (1922) of Bologna described a rare type of 'symmetrical hereditary osteitis' involving the lower limbs in a father and son and several others in a total of 4 generations. Pain in the legs and fusiform swelling of the legs below the knees were noted. Engelmann (1929) of Vienna reported an isolated case of 'osteopathica hyperostotica (sclerotisans) multiplex infantilis.' The disorder is sometimes called Camurati-Engelmann disease in recognition of the earlier description. Cockayne (1920) described a probable case before the publications of Camurati and Engelmann. The nature of the condition and the possibility that it represented syphilitic osteitis were discussed. Lennon et al. (1961) described a case of Engelmann disease and reviewed the literature. Gross thickening of the cortex of bones, both on the periosteal surface and in the medullary canal, is characteristic. The process usually begins in the shaft of the femur or tibia but spreads to involve all bones. Onset is usually before age 30 years, often before age 10. All races and both sexes are affected. Nine examples of familial occurrence in 1 or 2 generations were mentioned. Severe bone pains, especially in the legs, and muscular hypoplasia are the distinctive features of this form of sclerotic bone disease. The bones of the base of the skull and rarely the mandible may be affected. The skeletal disorder is often associated with muscular weakness, peculiar gait, pains in the legs, fatigability, and apparent undernutrition. The muscular weakness is not necessarily progressive and typical bone changes may be found in asymptomatic persons. Because of the associated features, muscular dystrophy or poliomyelitis is sometimes diagnosed in these patients. The condition described by Ribbing and in the past sometimes referred to as Ribbing disease (601477) has been considered by some to be Engelmann disease. Ribbing (1949) described a family in which 4 of 6 sibs were affected. The diaphyseal osteosclerosis and hyperostosis were limited to one or more (up to 4) of the long bones, the tibia being affected in all. The father, who was dead, had complained for many years of pains in the legs. Thus, the condition may be dominant; no x-ray studies of the father were available and Ribbing (1949) noted that the body had been cremated. Paul (1953) reported the same entity in 2 of 4 sibs, one of whom also had otosclerosis, which was present in several other members of the kindred. In an addendum, Paul noted that the infant son of one of his patients had difficulty walking and was found to have multiple sclerosing lesions of long bones. Again dominant inheritance was suggested. Ribbing (1949) referred to the condition described as hereditary multiple diaphyseal sclerosis (rather than dysplasia), and the same term was used by Paul (1953) and Furia and Schwartz (1990). Seeger et al. (1996) insisted that Ribbing disease is a disorder separate from Engelmann disease. Although it may appear to be identical radiographically, many clinical differences exist. Camurati-Engelmann disease presents during childhood, whereas Ribbing disease was thought by Seeger et al. (1996) to present in middle age. (They wrote: 'patients contract Ribbing disease after puberty.') The disease is confined to the diaphyses of long bones, especially the tibia and the femur. Whereas Engelmann disease is bilateral and symmetric, Ribbing disease is either unilateral or asymmetric and asynchronously bilateral. In Engelmann disease, the skull is involved as well as the long bones. The gait and neurologic abnormalities and anemia with extramedullary hematopoiesis occurs only in Engelmann disease. Makita et al. (2000) reported a 3-generation Japanese family with Engelmann disease with a wide variation in phenotype among the affected family members. Of the 12 patients, 7 had full manifestations of Engelmann disease, while the other 5 exhibited only segmental (rhizomelic and/or mesomelic) involvement and asymmetric diaphyseal sclerosis without any clinical symptoms, resembling Ribbing disease. The authors proposed that Engelmann disease and Ribbing disease represent phenotypic variation of the same disorder. Crisp and Brenton (1982) emphasized systemic manifestations in Engelmann disease: anemia, leukopenia, hepatosplenomegaly, and raised erythrocyte sedimentation rate. Their patient also had the Raynaud phenomenon and multiple nail-fold infarcts. Clybouw et al. (1994) reported a 10-year-old girl with characteristic clinical and roentgenologic manifestations of Camurati-Engelmann disease. Scintigraphy with 99mTc showed increased osteoblastic activity in the diaphyseal portions of almost all long bones. Clinical and roentgenologic investigations of her parents produced normal results, but a clear focus of osteoblastic hyperactivity was demonstrated scintigraphically at the base of the skull of the proband's mother. Some persons with Camurati-Engelmann disease may have subclinical manifestations. According to Clybouw et al. (1994), a detailed study including x-ray examination and scintigraphy is necessary for genetic counseling in apparently sporadic cases. Grey et al. (1996) provided a 45-year follow-up on a patient with Engelmann disease initially described by Stronge and McDowell (1950) when he was 28 years of age. The disease had shown progression over the subsequent 45 years, characterized by the unique involvement of the femoral capital epiphyses. The patient had changed little in physical appearance, apart from aging. He was thin and tall with generalized underdevelopment and weakness of the muscles, particularly around the pelvic girdle and thighs. The legs were bowed and the lumbar lordosis had increased. Serum alkaline phosphatase levels had remained normal. In 1950 the disease involved only the diaphyses of the affected limbs. By 45 years later it had affected the metaphyses of all limbs, the epiphyses, and the articular surfaces of the femoral heads and acetabula, as well as the right tibial epiphysis. The spine and hands, unaffected in 1950, showed changes and there was some progression of the disease in the skull. Saraiva (2000) described anticipation as judged by age of onset of symptoms in successive generations of a large family with 15 affected members in 3 generations. Wallace et al. (2004) reported a 4-generation pedigree with 7 individuals affected by CED. The pedigree demonstrated autosomal dominant inheritance but with remarkable variation in expressivity and reduced penetrance. The most severely affected individual had progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over 30 years. His carrier father, on the other hand, remained asymptomatic into his ninth decade and had no radiographic hyperostosis or sclerosis of the bones. Symptomatic relatives presented with lower limb pain and weakness. They were initially diagnosed with a variety of other conditions. Two of the symptomatic individuals were treated successfully with prednisone. Linkage to 19q13.1-q13.3 was confirmed. The arg218-to-his mutation in the TGFB1 gene (R218H; 190180.0003) was identified in the affected individuals, the asymptomatic obligate carrier, and in another unaffected relative. Janssens et al. (2006) reported 41 individuals with CED confirmed by genetic analysis from 14 families and provided a detailed review of the disorder. Inheritance Girdany (1959) described a family with 6 affected persons in 3 generations (no male-to-male transmission). A case reported by Singleton et al. (1956) had strikingly similar clinical features. Restudy indicated that 3 generations were affected in that family also (Singleton, 1967). Father and 2 children (son and daughter) were affected in a family reported by Ramon and Buchner (1966). The father was much more severely affected than the offspring. Allen et al. (1970) presented a family in which 11 persons in 3 generations were known to have been affected. Sparkes and Graham (1972) reported a remarkable family with many affected persons in several successive generations. A particularly remarkable feature was lack of penetrance in persons who must have had the gene but, as adults at any rate, showed no abnormality by x-ray. Clinical Management The beneficial effects of corticosteroids were apparently first described by Royer et al. (1967), followed shortly by Allen et al. (1970) and by Lindstrom (1974). Minford et al. (1981) noted not only relief from pain but also return of radiologic findings toward normal during treatment with corticosteroids. Population Genetics Campos-Xavier et al. (2001) stated that 5 mutations in the TGFB1 gene had been identified in 21 families with CED. In 1 Australian family and 6 European families with CED, they found 3 of these mutations, R218H (190180.0002) in 1 family, R218C (190180.0003) in 3 families, and C225R (190180.0001) in 3 families, which had previously been observed in families of Japanese and Israeli origin. The R218C mutation appeared to be the most prevalent worldwide, having been found in 17 of 28 reported families. Heterogeneity Campos-Xavier et al. (2001) found no obvious correlation between the nature of TGFB1 mutations and the severity of the clinical manifestations of CED, but observed a marked intrafamilial clinical variability, supporting incomplete penetrance of CED. Xavier et al. (2000) suggested that DPD1 is genetically homogeneous; however, Hecht et al. (2001) excluded the TGFB1 gene as the site of mutation in a DPD1 family, thus indicating the existence of at least one other form. Also see Camurati-Engelmann disease type II (606631) in which no mutation in the TGFB1 gene has been found. Mapping Ghadami et al. (2000) performed a genomewide linkage analysis of 2 unrelated Japanese families with CED, in which a total of 27 members were available for study; 16 of them were affected with CED. Two-point linkage analysis showed a maximum lod score of 7.41 (recombination fraction 0.00; penetrance = 1.00) for the D19S918 microsatellite marker locus. Haplotype analysis revealed that all the affected individuals shared a common haplotype observed, in each family, between D19S881 and D19S606, at 19q13.1-q13.3 (within a genetic interval of 15.1 cM). This linkage was confirmed by Janssens et al. (2000) and Vaughn et al. (2000). Molecular Genetics Because the transforming growth factor-beta-1 gene (TGFB1; 190180) maps to the same region of chromosome 19, Kinoshita et al. (2000) screened it for mutations in Camurati-Engelmann disease in 7 unrelated Japanese families and 2 families of European descent. They detected 3 different heterozygous missense mutations in exon 4, near the carboxy terminus of the latency-associated peptide (LAP), in all 9 families examined. INHERITANCE \- Autosomal dominant GROWTH Other \- Asthenic habitus HEAD & NECK Ears \- Deafness Eyes \- Exophthalmos \- Optic nerve compression \- Diplopia Teeth \- Dental caries SKELETAL Skull \- Sclerosis of skull base \- Mandible involvement Spine \- Sclerosis of posterior part of vertebrae (body and arches) \- Scoliosis Limbs \- Progressive diaphyseal widening \- Thickened cortices \- Narrowing of medullary canal \- Erlenmeyer flask defect \- Genu varus deformity \- Genu valgum deformity MUSCLE, SOFT TISSUES \- Relative muscle weakness, especially in pelvic girdle \- Atrophic muscle fiber on biopsy NEUROLOGIC Central Nervous System \- Headaches ENDOCRINE FEATURES \- Delayed puberty HEMATOLOGY \- Bone marrow hypoplasia \- Anemia MISCELLANEOUS \- Waddling gait \- Leg pain \- Onset in childhood MOLECULAR BASIS \- Caused by mutations in the beta-1 transforming growth factor gene (TGFB1, 190180.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

CAMURATI-ENGELMANN DISEASE

c0011989

omim

https://www.omim.org/entry/131300

{"doid": ["4997"], "mesh": ["D003966"], "omim": ["131300"], "icd-10": ["Q78.3"], "orphanet": ["1328"], "synonyms": ["Alternative titles", "CED", "ENGELMANN DISEASE", "DIAPHYSEAL DYSPLASIA 1, PROGRESSIVE", "PROGRESSIVE DIAPHYSEAL DYSPLASIA"], "genereviews": ["NBK1156"]}

Stickler syndrome type 3 is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism (midface hypoplasia, depressed nasal bridge, small nose with upturned tip, cleft palate, Pierre Robin sequence), bilateral, pronounced sensorineural hearing loss, and skeletal/joint anomalies (including spondyloepiphyseal dysplasia, arthralgia/arthropathy), in the absence of ocular abnormalities. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Autosomal dominant otospondylomegaepiphyseal dysplasia

c1861481

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=166100

{"gard": ["5021"], "mesh": ["C537494"], "omim": ["184840"], "umls": ["C1861481"], "icd-10": ["Q77.7"], "synonyms": ["AD OSMED", "Stickler syndrome type 3", "Stickler syndrome, non-ocular type"]}

Carbamoyl phosphate synthetase I deficiency is an inherited disorder that causes ammonia to accumulate in the blood (hyperammonemia). Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The brain is especially sensitive to the effects of excess ammonia. In the first few days of life, infants with carbamoyl phosphate synthetase I deficiency typically exhibit the effects of hyperammonemia, which may include unusual sleepiness, poorly regulated breathing rate or body temperature, unwillingness to feed, vomiting after feeding, unusual body movements, seizures, or coma. Affected individuals who survive the newborn period may experience recurrence of these symptoms if diet is not carefully managed or if they experience infections or other stressors. They may also have delayed development and intellectual disability. In some people with carbamoyl phosphate synthetase I deficiency, signs and symptoms may be less severe and appear later in life. ## Frequency Carbamoyl phosphate synthetase I deficiency is a rare disorder; its overall incidence is unknown. Researchers in Japan have estimated that it occurs in 1 in 800,000 newborns in that country. ## Causes Mutations in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. The CPS1 gene provides instructions for making the enzyme carbamoyl phosphate synthetase I. This enzyme participates in the urea cycle, which is a sequence of biochemical reactions that occurs in liver cells. The urea cycle processes excess nitrogen, generated when protein is broken down by the body, to make a compound called urea that is excreted by the kidneys. The specific role of the carbamoyl phosphate synthetase I enzyme is to control the first step of the urea cycle, a reaction in which excess nitrogen compounds are incorporated into the cycle to be processed. Carbamoyl phosphate synthetase I deficiency belongs to a class of genetic diseases called urea cycle disorders. In this condition, the carbamoyl phosphate synthetase I enzyme is at low levels (deficient) or absent, and the urea cycle cannot proceed normally. As a result, nitrogen accumulates in the bloodstream in the form of toxic ammonia instead of being converted to less toxic urea and excreted. Ammonia is especially damaging to the brain, and excess ammonia causes neurological problems and other signs and symptoms of carbamoyl phosphate synthetase I deficiency. ### Learn more about the gene associated with Carbamoyl phosphate synthetase I deficiency * CPS1 ## 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

Carbamoyl phosphate synthetase I deficiency

c4082171

medlineplus

https://medlineplus.gov/genetics/condition/carbamoyl-phosphate-synthetase-i-deficiency/

{"gard": ["7269"], "mesh": ["D020165"], "omim": ["237300"], "synonyms": []}

For a phenotypic description and a discussion of genetic heterogeneity of Senior-Loken syndrome, see 266900. Mapping Omran et al. (2002) studied a kindred of German ancestry with extended consanguinity and typical findings of SLSN. They identified a locus for SLSN in the region of the nephronophthisis-3 locus on chromosome 3q21-q22 (NPHP3; 604387). Haplotype studies showed a result compatible with homozygosity by descent in all affected individuals, covering the whole NPHP3 region. Linkage analysis yielded a parametric maximum multipoint lod score of 3.14. Recombinants observed for D3S1587 and D3S621 defined the critical disease interval, which spans 14 cM. Olbrich et al. (2003) did not identify mutations in the NPHP3 gene (608002) in affected members of the German family reported by Omran et al. (2002). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Leber congenital amaurosis \- Nystagmus \- Absent electroretinogram \- Vision loss, profound \- Poor pupillary reflexes GENITOURINARY \- Secondary nocturnal enuresis Kidneys \- Nephronophthisis \- End stage renal disease \- Corticomedullary cysts METABOLIC FEATURES \- Polyuria \- Polydipsia ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

SENIOR-LOKEN SYNDROME 3

c0403553

omim

https://www.omim.org/entry/606995

{"doid": ["0050576"], "mesh": ["C537580"], "omim": ["606995"], "orphanet": ["3156"]}

A rare, small-vessel vasculitis characterized by skin purpura, arthritis, abdominal and/or renal involvement, IgA tissue deposits (arterioles, capillaries, and venules) and circulating IgA immune complexes. ## Epidemiology The disease usually affects children and is rare in adults. Annual incidence in children is estimated at between 1/4,880 and 1/6,660, whereas it is estimated at around 1/1,000,000 in adults. The male-to-female ratio is 1.5:1. ## Clinical description Patients present with vascular purpura that is usually symmetrical and primarily localized to the buttocks and legs. In adults it is more frequently complicated by necrotic or hemorrhagic bullous lesions. The lesions progressively regress, disappear after a few days and, in 80% of cases, never reappear. Patients also present with arthralgia, predominantly involving the knees and ankles. Abdominal pain is common and may be associated with life-threatening gastrointestinal bleeding. Renal involvement is more severe and frequent in adults. It usually consists of microscopic hematuria with varying degrees of proteinuria. Nephrotic syndrome, renal failure, and hypertension may also occur. Other manifestations are rare but may include headaches, seizures, paresis, orchiepididymitis, uretritis, pancreatitis, myositis, episcleritis, pulmonary bleeding and myocarditis. ## Etiology The disease is associated with deposition of IgA-dominant immune complexes in arterioles, capillaries, and venules, but the exact etiology remains unknown. Several different viral or bacterial organisms, drugs, foods, and insect bites have been implicated as the initiating factors of the disease. ## Diagnostic methods The diagnosis is based on clinical and histopathological findings. Examination of skin and kidney biopsies reveals tissue deposition of IgA with circulating IgA immune complexes. ## Differential diagnosis Differential diagnoses include other causes of purpura such as thrombopenia, hemopathy or infectious diseases. In adults, ANCA associated vasculitis, systemic lupus erythematosus, and mixed cryoglobulinemia should also be considered in the differential diagnosis. ## Management and treatment The treatment is symptomatic. The use of steroids and/or immunosuppressors is controversial but may be considered in case of severe gastrointestinal or renal manifestations. Renin-angiotensin-system blockers should be started as soon as the proteinuria/creatinine ratio is greater than 50 mg/mmol. ## Prognosis Gastrointestinal or pulmonary bleeding can be life-threatening. The long term prognosis depends on the extent of the renal involvement. Long term follow-up studies of adult series show that end-stage renal failure may occur in up to one-third of patients. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Immunoglobulin A vasculitis

c0034152

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=761

{"gard": ["8204"], "mesh": ["D011695"], "umls": ["C0034152", "C0086922"], "icd-10": ["D69.0"], "synonyms": ["Anaphylactoid purpura", "Henoch-Schönlein purpura", "IgA vasculitis", "Purpura rheumatica", "Rheumatoid purpura"]}

This article relies largely or entirely on a single source. Relevant discussion may be found on the talk page. Please help improve this article by introducing citations to additional sources. Find sources: "Primary fibrinogenolysis" – news · newspapers · books · scholar · JSTOR (December 2020) Primary fibrinogenolysis is the pathological lysis of fibrinogen characterized with a low fibrinogen, high fibrin degradation products, prolonged prothrombin time and activated partial thromboplastin time, a normal platelet count and absence of microcirculatory thrombosis.[1] ## Contents * 1 Diagnosis * 2 Management * 3 References ## Diagnosis[edit] The most important differential diagnosis is disseminated intravascular coagulation, which is characterized with similar features but presence of a low platelet count and microcirculatory thrombosis. Antifibrinolytic treatments are contraindicated in patients with disseminated intravascular coagulation while they are useful in the treatment of primary fibrinogenolysis. ## Management[edit] This section is empty. You can help by adding to it. (October 2017) ## References[edit] 1. ^ Biron-Andréani C, Morau E, Schved JF, Hédon B, Dechaud H. Amniotic fluid embolism with haemostasis complications: primary fibrinogenolysis or disseminated intravascular coagulation? Pathophysiol Haemost Thromb. 2003;33(3):170-171 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Primary fibrinogenolysis

None

wikipedia

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

{"wikidata": ["Q7243127"]}

A number sign (#) is used with this entry because autosomal recessive spastic paraplegia-56 (SPG56) is caused by homozygous or compound heterozygous mutation in the CYP2U1 gene (610670) on chromosome 4q25. Description SPG56 is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive lower-limb spasticity resulting in walking difficulties. Upper limbs are often also affected, and some patients may have a subclinical axonal neuropathy (summary by Tesson et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800. Clinical Features Tesson et al. (2012) reported 5 unrelated families with autosomal recessive spastic paraplegia. Two were consanguineous and of Saudi Arabian origin. The other families were of Italian, Egyptian, or mixed Spanish/Vietnamese descent. Affected individuals developed spastic paraplegia, often involving the upper limbs, in the first decade (range, birth to age 8 years). Features included delayed walking, toe walking, unsteady gait, spastic gait, hyperreflexia of the lower limbs, and extensor plantar responses. Two patients had dystonic posturing of the upper limbs, and 3 had cognitive impairment or mental retardation. Five patients also had evidence of a subclinical axonal neuropathy, predominantly in the lower limbs. Brain MRI showed white matter lesions in 3 patients and a thin corpus callosum in 1 patient. During follow-up, 2 sibs with white matter lesions developed calcifications in the globus pallidus. Symptom severity varied widely, even within the same family. Inheritance The transmission pattern of spastic paraplegia in the families reported by Tesson et al. (2012) was consistent with autosomal recessive inheritance. Mapping By genomewide linkage analysis of a large consanguineous Saudi Arabian kindred with autosomal recessive spastic paraplegia, Tesson et al. (2012) found linkage to a region on chromosome 4q25 (maximum multipoint lod score of 4.76). A second affected Saudi family also showed linkage to this region. Both families shared a homozygous haplotype, yielding a 3.8-Mb candidate region between markers D4S3256 and D4S2940. Molecular Genetics In affected members of 2 consanguineous Saudi Arabian families with autosomal recessive spastic paraplegia, Tesson et al. (2012) identified a homozygous mutation in the CYP2U1 gene (D316V; 610670.0001). The mutation was found by linkage analysis followed by exome sequencing of the candidate region. Sequencing of this gene in 94 additional SPG patients identified biallelic mutations in 3 families (610670.0002-610670.0005). In the same study, Tesson et al. (2012) identified pathogenic mutations in the DDHD1 gene (614603) as a cause of SPG28 (609340). Both the DDHD1 and CYP2U1 gene products were expressed concomitantly in the developing mouse brain, and both showed partial mitochondrial localization. Mutant cells from SPG28 and SPG56 patients showed significantly lower mitochondrial respiration activity, lower ATP levels, and increased cytosolic hydrogen peroxide compared to controls. However, isolated catalytic activities of each of the respiratory chain complexes, measured after disruption of the mitochondrial membrane, were similar to controls. SPG56 fibroblasts showed structural abnormalities, suggesting a defect in mitochondrial membrane organization. CYP2U1 can catalyze the hydroxylation of arachidonic acid and related long-chain fatty acids, which are mediators of signaling pathways and may affect signaling of hormones or neurotransmitters. In addition, accumulation of reactive oxygen species may contribute to neurodegeneration. The study indicated that both DDHD1 and CYP2U1 are involved in the same pathway related to lipid metabolism and disruption of mitochondrial function, suggesting a common disease pathway in SPG. Nomenclature Tesson et al. (2012) referred to this disorder as SPG49. However, Oz-Levi et al. (2012) also used the designation SPG49 (615031) to refer to SPG caused by mutation in the TECPR2 gene (615000). Because the study by Oz-Levi et al. (2012) was accepted for publication before that of Tesson et al. (2012), the disorder caused by mutation in the CYP2U1 gene is referred to here as SPG56. INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Delayed motor development \- Spastic paraplegia \- Unsteady gait \- Toe walking \- Upper limb hyperreflexia (in some patients) \- Dystonic posturing (rare) \- Lower limb hyperreflexia \- Extensor plantar responses \- Cognitive impairment (rare) \- Thin corpus callosum (rare) \- White matter abnormalities (rare) \- Basal ganglia calcifications (rare) Peripheral Nervous System \- Axonal neuropathy, subclinical MISCELLANEOUS \- Onset in the first decade (range birth to 8 years) \- Variable severity MOLECULAR BASIS \- Caused by mutation in the cytochrome P450, family 2, subfamily U, polypeptide 1 gene (CYP2U1, 610670.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

SPASTIC PARAPLEGIA 56, AUTOSOMAL RECESSIVE

c3539507

omim

https://www.omim.org/entry/615030

{"doid": ["0110808"], "omim": ["615030"], "orphanet": ["320411"], "synonyms": ["SPG56"]}

## Clinical Features Abou Jamra et al. (2011) reported a consanguineous Syrian family (MR050) in which individuals had nonsyndromic severe mental retardation. Symptoms included neonatal muscular hypotonia, moderate motor delay, tremor, and severe intellectual disability with no speech. One patient later developed hypertonia of the upper extremities. Mapping By homozygosity mapping of a consanguineous Syrian family with severe mental retardation, Abou Jamra et al. (2011) found linkage to a 45.6-Mb interval in the pericentromeric region of chromosome 11 between SNPs rs604518 and rs10899421 (lod score of 3.03). INHERITANCE \- Autosomal recessive MUSCLE, SOFT TISSUES \- Neonatal muscular hypotonia NEUROLOGIC Central Nervous System \- Intellectual disability, severe \- Motor delay, moderate \- Hypertonia of upper extremities (in one patient) \- No speech \- Unremarkable CT scan MISCELLANEOUS \- Based on a report of 1 consanguineous Syrian family (last curated November 2011) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

MENTAL RETARDATION, AUTOSOMAL RECESSIVE 23

c3280542

omim

https://www.omim.org/entry/614344

{"doid": ["0060308"], "omim": ["614344"], "orphanet": ["88616"], "synonyms": ["AR-NSID", "NS-ARID"]}

Hemimegalencephaly is a rare malformation involving one side of the brain. It may occur alone or in association with other syndromes such as Proteus syndrome, tuberous sclerosis, linear sebaceous nevus syndrome, neurofibromatosis, Sturge-Weber syndrome, or Klippel-Trenaunay syndrome. Children with this disorder may have a large, asymmetrical head accompanied by seizures, partial paralysis, and impaired cognitive development. Because the seizures associated with hemimegalencephaly are difficult to treat with anticonvulsant medications, a surgery called hemispherectomy is often the most successful treatment. The cause of hemimegalencephaly is not fully understood, but involves a disturbance of cells early in development and likely involves genes involved in patterning and symmetry. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Hemimegalencephaly

c0431391

gard

https://rarediseases.info.nih.gov/diseases/2637/hemimegalencephaly

{"mesh": ["D065705"], "orphanet": ["99802"], "synonyms": ["Macrencephaly", "Unilateral Megalencephaly"]}

## Description African iron overload is a distinct iron-loading disorder prevalent in Africa. Formerly termed Bantu siderosis, the disorder results from a predisposition to iron loading that is exacerbated by excessive intake of dietary iron. It is particularly a problem among Africans who drink a traditional beer brewed in non-galvanized steel drums. Although the disorder was once attributed to dietary excess alone, serious iron overload does not develop in all beer drinkers, and not all patients with iron overload consume excessive amounts of the beer (summary by Andrews, 1999). Clinical Features The pattern of iron deposition among persons with African iron overload differs from that among those with hereditary hemochromatosis (see 235200) (Gangaidzo et al., 1999). In the former persons, there is marked iron loading of Kupffer cells as well as hepatocytes, resembling the pattern seen in patients with transfusional siderosis and suggesting a defect in erythroid iron recycling. Cirrhosis, occasionally complicated by hepatocellular carcinoma, is the predominant organ manifestation. Cardiomyopathy and diabetes, common features of hereditary hemochromatosis, are less frequent. Although serum ferritin levels are elevated, the transferrin saturation does not always reflect the true extent of iron overload in these patients (summary by Andrews, 1999). Patients with African iron overload are probably more susceptible than others to infection, and they appear to have an increased incidence of tuberculosis (Gordeuk et al., 1996; Moyo et al., 1997). Inheritance To examine the hypothesis that African iron overload also involves a genetic factor, Gordeuk et al. (1992) used likelihood analysis to test for an interaction between a hypothesized iron-loading locus and an environmental factor, namely increased dietary iron, to determine transferrin (190000) saturation and unsaturated iron-binding capacity. They studied 236 members of 36 African families chosen because they contained index subjects with iron overload. Among family members with increased dietary iron due to the consumption of traditional beer, transferrin saturation in serum was distributed bimodally, with 56 normal values and 44 elevated values; the mean serum ferritin concentration was 5 times higher in the subjects with elevated transferrin saturation. The pedigree analysis provided evidence of both a genetic effect (p less than 0.005) and an effect of increased dietary iron (p less than 0.005) on transferrin saturation and unsaturated iron-binding capacity. Gordeuk et al. (1992) found that, in the most likely model, increased dietary iron raised the mean transferrin saturation from 30 to 81% and lowered the mean unsaturated iron-binding capacity from 38 to 13 micro-mol per liter in subjects heterozygous for the iron-loading locus. Moyo et al. (1998) presented evidence that heterozygosity for an unidentified iron-loading gene confers susceptibility to African iron overload and suggested that homozygous persons may be more severely affected. Mapping Gordeuk et al. (1992) excluded linkage of African iron overload to the HLA region (see 142800) on chromosome 6p21.3. Molecular Genetics In a study of 1,042 African chromosomes, Merryweather-Clarke et al. (1997) found a prevalence of 0% for the HFE C282Y mutation (613609.0001), the most common cause of hereditary hemochromatosis in persons of European descent. PCR analysis of DNA from 25 southern Africans, identified by segregation analysis as having a high probability of carrying the putative African iron-loading gene, failed to identify any subjects with the C282Y mutation (McNamara et al., 1998). Clinically significant iron overload occurs in Americans of African descent (Barton et al., 1995; Wurapa et al., 1996; Baer, 1996), but such persons rarely have mutations in the HFE gene (Monaghan et al., 1998). Misc \- Increased dietary iron Lab \- Elevated transferrin saturation Inheritance \- Autosomal dominant plus dietary factor ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

IRON OVERLOAD IN AFRICA

c0268063

omim

https://www.omim.org/entry/601195

{"doid": ["0111033"], "mesh": ["C537904"], "omim": ["601195"], "orphanet": ["139507"], "synonyms": ["Alternative titles", "AFRICAN IRON OVERLOAD", "BANTU SIDEROSIS"]}

Infantile cerebellar retinal degeneration (ICRD) is a genetic condition present from birth (congenital) that involves the brain and eyes. Individuals with this condition usually develop symptoms around six months of age including developmental delays, low muscle tone (hypotonia), and seizures. Other symptoms may include head bobbing, abnormal muscle twitching and movement, and loss of brain cells in the main part of the brain called the cerebellum. Eye findings in individuals with this condition may include retinal degeneration (weakening of the layer of tissue in the back of the eye that senses light), strabismus (crossed eyes), and nystagmus (fast, uncontrollable movements of the eyes). ICRD is caused by mutations in the ACO2 gene and is inherited in an autosomal recessive manner. While there is still no cure for this condition, treatment options will depend on the type and severity of symptoms. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Infantile cerebellar retinal degeneration

c3281192

gard

https://rarediseases.info.nih.gov/diseases/13264/infantile-cerebellar-retinal-degeneration

{"omim": ["614559"], "orphanet": ["313850"], "synonyms": ["Infantile cerebellar-retinal degeneration", "ICRD"]}

Carnitine palmitoyltransferase I deficiency (CPT1A deficiency) is an inherited metabolic condition that prevents the body from converting certain fats (long-chain fatty acids) into energy, particularly during periods without food. Carnitine, a natural substance acquired mostly through the diet, is required by cells to process fats and produce energy. Symptoms of this condition often appear early in life and include low blood sugar (hypoglycemia) and low levels of ketones, which are produced when the body breaks down fat for energy (hypoketotic hypoglycemia). This can lead to a greater risk for loss of consciousness or seizures. People with this disorder typically also have an enlarged liver (hepatomegaly), muscle weakness, nervous system damage, and elevated levels of carnitine in the blood. CPT1A deficiency is caused by mutations in the CPT1A gene and is inherited in an autosomal recessive manner. Although there is no cure for CPT1A deficiency, symptoms can be managed using several strategies, such dietary changes and use of fat supplements. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Carnitine palmitoyl transferase 1A deficiency

c1829703

gard

https://rarediseases.info.nih.gov/diseases/1120/carnitine-palmitoyl-transferase-1a-deficiency

{"mesh": ["C535588"], "omim": ["255120"], "umls": ["C1829703"], "orphanet": ["156"], "synonyms": ["Carnitine palmitoyltransferase 1A deficiency", "CPT1A deficiency", "Hepatic CPT1", "Hepatic carnitine palmitoyltransferase 1 deficiency", "L-CPT 1 deficiency", "Carnitine palmitoyl transferase IA deficiency", "Hepatic carnitine palmitoyl transferase 1 deficiency", "Hepatic carnitine palmitoyl transferase I deficiency", "L-CPT1 deficiency", "L-CPTI deficiency"]}

James (1961, 1978) reported familial aggregation for reduced two-point discrimination, tested on the forearm. Normally, a person can distinguish two points of a divider when they are between 2 mm and 10 mm apart; affected persons averaged 220 mm as the distance of two-point appreciation (James, 1961). Later, James (1978) stated that normal discrimination was about 50 mm; autosomal dominant insensitivity was more than 100 mm and sometimes as high as 290 mm. He observed direct transmission through 3 generations and had observations in collateral branches of the family giving an indirect indication of passage of the trait through 6 generations. Father-to-son transmission occurred. Neuro \- Reduced two-point discrimination Inheritance \- Autosomal dominant ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

DISCRIMINATION, TWO-POINT, REDUCTION IN

c1852074

omim

https://www.omim.org/entry/126180

{"omim": ["126180"], "synonyms": ["Alternative titles", "SENSORY DISCRIMINATION"]}

A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-25 (SCAR25) is caused by homozygous mutation in the ATG5 gene (604261) on chromosome 6q21. One such family has been reported. Clinical Features Kim et al. (2016) reported 2 brothers, born of consanguineous Turkish parents, with SCAR25. The patients had delayed psychomotor development with delayed walking, truncal ataxia, dysmetria, nystagmus, and low IQ (68 and 70). Brain imaging showed cerebellar hypoplasia. The family had previously been reported by Yapici and Eraksoy (2005). Follow-up of the patients showed no progression of symptoms. Inheritance The transmission pattern of SCAR25 in the family reported by Kim et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 brothers, born of remotely consanguineous Turkish parents, with SCAR25, Kim et al. (2016) identified a homozygous missense mutation in the ATG5 gene (E122D; 604261.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed a reduced interaction between ATG5 and its partner ATG12 (609608) and impaired autophagic flux compared to controls. In vitro functional expression studies showed that the E122D mutant protein had normal expression levels, but impaired interaction with ATG12; interaction with ATG16L (610767) was not impaired. The corresponding mutation in yeast also resulted in a 30 to 50% reduction in induced autophagy, and the E122D mutant protein was unable to rescue motility defects in Atg5-null Drosophila. The findings suggested that the E122D mutation results in a hypomorphic allele with a particularly damaging effect on neurons, and supported the role of impaired autophagy in neurodegenerative diseases. Kim et al. (2016) noted that complete knockout of Atg5 in mice is perinatal lethal (Kuma et al., 2004). Animal Model Hara et al. (2006) reported that the loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-null cells, diffuse abnormal intracellular proteins accumulate, and then form aggregates and inclusions. Hara et al. (2006) concluded that continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Nystagmus NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Delayed walking \- Cognitive impairment \- Spinocerebellar ataxia \- Truncal ataxia \- Dysmetria \- Cerebellar hypoplasia MISCELLANEOUS \- Onset in early childhood \- Nonprogressive disorder \- One consanguineous Turkish family has been reported (last curated July 2017) MOLECULAR BASIS \- Caused by mutation in the autophagy related 5 gene (ATG5, 604261.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 25

c4539808

omim

https://www.omim.org/entry/617584

{"omim": ["617584"]}

Pierre Robin sequence is a condition present at birth, in which the infant has a smaller than normal lower jaw (micrognathia), a tongue that is placed further back than normal (glossoptosis), and an opening in the roof of the mouth (cleft palate). This combination of features can lead to difficulty breathing and problems with eating early in life. Pierre Robin sequence may occur alone (isolated) or be associated with a variety of other signs and symptoms (described as syndromic). In about 20 to 40 percent of cases, the condition occurs alone. The exact causes of Pierre Robin syndrome are unknown. Changes (mutations) in the DNA near the SOX9 gene are the most common genetic cause of isolated cases of Pierre Robin sequence. Treatment is focused on the specific needs of each patient, but may include surgery to assist with breathing and feeding modifications to prevent choking. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Pierre Robin sequence

c0031900

gard

https://rarediseases.info.nih.gov/diseases/4347/pierre-robin-sequence

{"mesh": ["D010855"], "omim": ["261800"], "umls": ["C0031900"], "orphanet": ["718"], "synonyms": ["Pierre-Robin syndrome", "Glossoptosis, micrognathia, and cleft palate"]}

Anhalt et al. (1995) described a boy with midthoracic hemivertebrae, flat vertebrae, narrow anterior-posterior (A-P) diameter of the vertebral bodies, and absence of normal spinous processes of the lower thoracic and lumbar vertebrae. At 32 months of age he was evaluated for short stature. His father was very short (131.6 cm) and had scoliosis of the thoracic and lumbar spine, multiple anomalies of vertebral bodies with a decrease of A-P dimension, arthritic changes of chondropathic type in his hands, and coxa vara. Although there was some similarity to dyssegmental dwarfism (224400) and Kniest dysplasia (156550), Anhalt et al. (1995) suggested that this was a 'new' type of autosomal dominant spinal dysplasia. Spine \- Spinal dysplasia \- Midthoracic hemivertebrae \- Flat vertebrae \- Narrow anterio-posterior (A-P) vertebral body diameter \- Absent spinous processes of lower thoracic and lumbar vertebrae \- Thoracolumbar scoliosis Limbs \- Arthritis of hands \- Coxa vara Growth \- Short stature Inheritance \- Autosomal dominant ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

SPINAL DYSPLASIA, ANHALT TYPE

c1832464

omim

https://www.omim.org/entry/601344

{"mesh": ["C563348"], "omim": ["601344"]}

Yersinia pestis Urban plague is an infectious disease among rodent species that live in close association with humans in urban areas. It is caused by the bacterium Yersinia pestis which is the same bacterium that causes bubonic and pneumonic plague in humans. Plague was first introduced into the United States in 1900 by rat–infested steamships that had sailed from affected areas, mostly from Asia. Urban plague spread from urban rats to rural rodent species, especially among prairie dogs in the western United States.[1][2] ## Contents * 1 Vector reservoir * 2 Transmission * 3 See also * 4 References * 5 External links ## Vector reservoir[edit] Common vectors for urban plague are house mice, black rats, and Norway rats.[3] ## Transmission[edit] Urban plague can be spread from animals to humans via flea bites and handling of infected fluids and tissues. Human to human infection occurs from droplets that contain plague bacteria which are produced when an infected person coughs.[4] ## See also[edit] * Sylvatic plague * Epizootic ## References[edit] 1. ^ "A Plague Epizootic In The Black-Tailed Prairie Dog (Cynomys Ludovicianus)". Jwildlifedis.org. 2006-01-01. Retrieved 2013-07-28. 2. ^ "CDC - Maps & Statistics - Plague". Cdc.gov. 2013-04-23. Retrieved 2013-07-28. 3. ^ Cockrum, E. Lendell, Rabies, Lyme Diseases, Hanta Virus and other Animal-Borne Human Diseases in the United States and Canada. Fisher Books, Tucson, Arizona. 1997. Page 36. 4. ^ "CDC - Ecology & Transmission - Plague". Cdc.gov. 2019-07-31. Retrieved 2020-03-23. ## External links[edit] * Black Death on In Our Time at the BBC * Black Death at BBC * v * t * e Black Death Thematic * Second plague pandemic * Migration * Causes * Consequences * Notable deaths * Persecution of Jews during the Black Death * Cronaca fiorentina di Marchionne di Coppo Stefani * In medieval culture By geography * In Denmark * In England * In France * In the Holy Roman Empire * In Italy * In Norway * In Spain * In Sweden * Category * Commons *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Urban plague

None

wikipedia

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

{"wikidata": ["Q16993341"]}

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: "Speech sound disorder" – news · newspapers · books · scholar · JSTOR (December 2013) (Learn how and when to remove this template message) Speech sound disorder SpecialtySpeech-language pathologist A speech sound disorder (SSD) is a speech disorder in which some speech sounds (called phonemes) in a child's (or, sometimes, an adult's) language are not produced, are not produced correctly, or are not used correctly. The term "protracted phonological development" is sometimes preferred when describing children's speech, to emphasize the continuing development while acknowledging the delay. ## Contents * 1 Classification * 1.1 Articulation disorders * 1.2 Phonemic disorders * 1.3 Mixed speech sound disorders * 1.4 Residual errors * 2 Presentation * 3 Causes * 4 Diagnosis * 5 Treatment * 6 See also * 7 References * 8 Further reading * 9 External links ## Classification[edit] Speech sound disorders may be subdivided into two primary types, articulation disorders (also called phonetic disorders) and phonemic disorders (also called phonological disorders). However, some may have a mixed disorder in which both articulation and phonological problems exist. Though speech sound disorders are associated with childhood, some residual errors may persist into adulthood. ### Articulation disorders[edit] Articulation disorders (also called phonetic disorders, or simply "artic disorders" for short) are based on difficulty learning to physically produce the intended phonemes. Articulation disorders have to do with the main articulators which are the lips, teeth, alveolar ridge, hard palate, velum, glottis, and the tongue. If the disorder has anything to do with any of these articulators, then it is an articulation disorder. There are usually fewer errors than with a phonemic disorder, and distortions are more likely (though any omissions, additions, and substitutions may also be present). They are often treated by teaching the child how to physically produce the sound and having them practice its production until it (hopefully) becomes natural. Articulation disorders should not be confused with motor speech disorders, such as dysarthria (in which there is actual paralysis of the speech musculature) or developmental verbal dyspraxia (in which motor planning is severely impaired). ### Phonemic disorders[edit] In a phonemic disorder (also called a phonological disorders) the child is having trouble learning the sound system of the language, failing to recognize which sound-contrasts also contrast meaning. For example, the sounds /k/ and /t/ may not be recognized as having different meanings, so "call" and "tall" might be treated as homophones, both being pronounced as "tall." This is called phoneme collapse, and in some cases many sounds may all be represented by one — e.g., /d/ might replace /t/, /k/, and /g/. As a result, the number of error sounds is often (though not always) greater than with articulation disorders and substitutions are usually the most common error. Phonemic disorders are often treated using minimal pairs (two words that differ by only one sound) to draw the child's attention to the difference and its effect on communication. Some children with phonemic disorders may seem to be able to hear phoneme distinctions in the speech of others but not their own. This is called the fis phenomenon based on scenario in which a speech pathologist will say, "Did you say 'fis,' don't you mean 'fish'?" To which the child responds, "No, I didn't say 'fis,' I said 'fis'." In some cases, the sounds produced by the child are actually acoustically different, but not significantly enough for others to distinguish[1] – because those sounds are not phonemically unique to speakers of the language. Though phonemic disorders are often considered language disorders in that it is the language system that is affected, they are also speech sound disorders in that the errors relate to use of phonemes. This makes them different from specific language impairment, which is primarily a disorder of the syntax (grammar) and usage of language rather than the sound system. However, the two can coexist, affecting the same person. Other disorders can deal with a variety of different ways to pronounce consonants. Some examples are glides and liquids. Glides occur when the articulatory posture changes gradually from consonant to vowel. Liquids can include /l/ and /ɹ/ . ### Mixed speech sound disorders[edit] In some cases phonetic and phonemic errors may coexist in the same person. In such case the primary focus is usually on the phonological component but articulation therapy may be needed as part of the process, since teaching a child how to use a sound is not practical if the child does not know how to produce it. ### Residual errors[edit] Even though most speech sound disorders can be successfully treated in childhood, and a few may even outgrow them on their own, errors may sometimes persist into adulthood rather than only being not age appropriate. Such persisting errors are referred to as "residual errors" and may remain for life. ## Presentation[edit] Errors produced by children with speech sound disorders are typically classified into four categories: * Omissions: Certain sounds are not produced — entire syllables or classes of sounds may be deleted; e.g., fi' for fish or 'at for cat. * Additions (or Epentheses/Commissions): an extra sound or sounds are added to the intended word; e.g. puh-lane for plane. * Distortions: Sounds are changed slightly so that the intended sound may be recognized but sounds "wrong," or may not sound like any sound in the language. * Substitutions: One or more sounds are substituted for another; e.g., wabbit for rabbit or tow for cow. Sometimes, even for experts, telling exactly which type has been made is not obvious — some distorted forms of /ɹ/ may be mistaken for /w/ by a casual observer, yet may not actually be either sound but somewhere in between. Further, children with severe speech sound disorders may be difficult to understand, making it hard to tell what word was actually intended and thus what is actually wrong with it. Some terms can be used to describe more than one of the above categories, such as lisp, which is often the replacement of /s/ with /θ/ (a substitution), but can be a distortion, producing /s/ just behind the teeth resulting in a sound somewhere between /s/ and /θ/. There are three different levels of classification when determining the magnitude and type of an error that is produced: 1. Sounds the patient can produce 1. A: Phonemic- can be produced easily; used meaningfully and contrastively 2. B: Phonetic- produced only upon request; not used consistently, meaningfully, or contrastively; not used in connected speech 2. Stimulable sounds 1. A: Easily stimulable 2. B: Stimulable after demonstration and probing (i.e. with a tongue depressor) 3. Cannot produce the sound 1. A: Cannot be produced voluntarily 2. B: No production ever observed Note that omissions do not mean the sound cannot be produced, and some sounds may be produced more easily or frequently when appearing with certain other sounds: someone might be able to say "s" and "t" separately, but not "st," or may be able to produce a sound at the beginning of a word but not at the end. The magnitude of the problem will often vary between different sounds from the same speaker. ## Causes[edit] Most speech sound disorders occur without a known cause. A child may not learn how to produce sounds correctly or may not learn the rules of speech sounds on his or her own. These children may have a problem with speech development, which does not always mean that they will simply outgrow it by themselves. Many children do develop speech sounds over time but those who do not often need the services of a Speech-Language Pathologist to learn correct speech sounds.[clarification needed] Some speech sound errors can result from other syndromes or disorders such as: * developmental disorders (e.g. autism) * genetic disorders (e.g. Down syndrome) * hearing loss, including temporary hearing loss, such as from ear infections * cleft palate or other physical anomalies of the mouth * illness * neurological disorders (e.g. cerebral palsy) ## Diagnosis[edit] In a typical 2-year-old child, about 50% of speech may be intelligible. A 4-year-old child's speech should be intelligible overall, and a 7-year-old should be able to clearly produce most words consistent with community norms for their age. Misarticulation of certain difficult sounds ([l], [ɹ], [s], [z], [θ], [ð], [t͡ʃ], [d͡ʒ], and [ʒ]) may be normal up to 8 years. Children with speech sound disorder have pronunciation difficulties inappropriate for their age, and the difficulties are not caused by hearing problems, congenital deformities, motor disorders or selective mutism.[2] The DSM-5 diagnostic criteria are as follows:[2] > * A. Persistent difficulty with speech sound production that interferes with speech intelligibility or prevents verbal communication of messages. > * B. The disturbance causes limitations in effective communication that interfere with social participation, academic achievement, or occupational performance, individually or in any combination. > * C. Onset of symptoms is in the early developmental period. > * D. The difficulties are not attributable to congenital or acquired conditions, such as cerebral palsy, cleft palate, deafness or hearing loss, traumatic brain injury, or other medical or neurological conditions. > ## Treatment[edit] For most children, the disorder is not lifelong and speech difficulties improve with time and speech-language treatment. Prognosis is poorer for children who also have a language disorder, as that may be indicative of a learning disorder.[2] ## See also[edit] * Accent (sociolinguistics) * Developmental verbal dyspraxia * FOXP2 * KE family * Infantile speech * Speech and language pathology * Treatment of Articulation Disorders in School Systems ## References[edit] 1. ^ Fromkin, Victoria. (2000). "Phonology". Linguistics : an introduction to linguistic theory. Malden, Mass.; Oxford, U.K.: Blackwell. ISBN 978-0-631-19711-9. OCLC 43577669. Missing or empty `|title=` (help) 2. ^ a b c American Psychiatric Association, ed. (2013). "Speech Sound Disorder, 315.39 (F80.0)". Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing. pp. 44–45. ## Further reading[edit] * Bauman-Wängler, Jacqueline Ann. (2004). Articulatory and phonological impairments : a clinical focus (2 ed.). Boston: Allyn and Bacon. ISBN 978-0-205-40248-9. OCLC 493612551. * Secord, Wayne.; Boyce, Suzanne.; Donahue, JoAnn; Fox, Robert; Shine, Richard (2007). Eliciting sounds : techniques and strategies for clinician. Clifton Park, NY: Thomson Delmar Learning. ISBN 978-1-4018-9725-3. OCLC 77708677. * Justice, Laura M. (2006). Communication sciences and disorders : an introduction. Upper Saddle River, NJ: Pearson/Merrill Prentice Hall. ISBN 978-0-13-113518-5. OCLC 58563236. * Shriberg, Lawrence D.; Kent, Raymond D. (2013). Clinical phonetics (4 ed.). Boston, MA: Pearson Education. ISBN 978-0-13-702106-2. OCLC 798389609. * Bowen, C. (2009). Children's speech sound disorders. Oxford: Wiley-Blackwell * Raz, M. (1992). How to Teach a Child to Say the "S" Sound in 15 Easy Lessons. GerstenWeitz Publishers ISBN 9780963542601 * Raz, M. (1996). How to Teach a Child to Say the "R" Sound in 15 Easy Lessons. GerstenWeitz Publishers ISBN 9780963542618 * Raz, M. (1999). How to Teach a Child to Say the "L" Sound in 15 Easy Lessons. GerstenWeitz Publishers ISBN 9780963542649 ## External links[edit] * Children's Speech Sound Disorders * v * t * e Dyslexia and related specific developmental disorders Conditions Speech, language, and communication * Expressive language disorder * Infantile speech * Landau–Kleffner syndrome * Language disorder * Lisp * Mixed receptive-expressive language disorder * Specific language impairment * Speech and language impairment * Speech disorder * Speech error * Speech sound disorder * Stuttering * Tip of the tongue Learning disability * Dyslexia * Dyscalculia * Dysgraphia * Disorder of written expression Motor * Developmental coordination disorder * Developmental verbal dyspraxia Sensory * Auditory processing disorder * Sensory processing disorder Related topics * Dyslexia research * Irlen filters * Learning Ally * Learning problems in childhood cancer * Literacy * Management of dyslexia * Multisensory integration * Neuropsychology * Reading acquisition * Spelling * Writing system Lists * Dyslexia in fiction * Languages by Writing System * People with dyslexia *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Speech sound disorder

c4019167

wikipedia

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

{"mesh": ["D066229"], "umls": ["C1838022"], "wikidata": ["Q4133283"]}

Cauda equina syndrome (CES) refers to a group of symptoms that occur when nerves in the cauda equina (a collection of nerve roots that spread out from the bottom of the spinal cord) become compressed or damaged. These nerves roots connect the central nervous system and peripheral nervous system. CES can lead to pain, numbness, and weakness in the lower back, pelvic area and legs; "foot drop"; problems with bowel or bladder control; sexual dysfunction; and even paralysis. CES is considered a medical emergency and requires hospitalization. Therefore, people with unexplained onset of symptoms should seek medical attention as soon as possible and consult with a neurologist or neurosurgeon. CES is most commonly caused by a herniated disk in the lumbar spine. Other causes of CES may include a birth abnormality (such as spina bifida), a spinal infection or tumor, trauma or injury to the lower back, spinal stenosis, a spinal arteriovenous malformation, and complications after spinal surgery. CES can be difficult to diagnose since symptoms vary and they may mimic other conditions. Tests that may be used to diagnose CES include MRI, CT scan, and myelogram (a special type of X-ray of the spinal canal). Treatment usually targets the underlying cause of CES (removing the cause of nerve pressure) and most often involves urgent surgery to prevent permanent neurologic impairment. How well a person recovers from CES often depends on the underlying cause and how promptly they are treated. Symptoms are more likely to improve or go away if the cause is identified quickly and treatment begins right away. Some people have significant improvement of symptoms and quality of life after treatment. However, others may have permanent neurologic impairment, chronic pain, and/or mental health problems due to the impact of symptoms on social life and relationships. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Cauda equina syndrome

c0392548

gard

https://rarediseases.info.nih.gov/diseases/10987/cauda-equina-syndrome

{"mesh": ["D000077684"], "synonyms": []}

## Clinical Features Najmabadi et al. (2007) reported a large consanguineous Iranian family (M025) in which 4 individuals had nonsyndromic moderate mental retardation. Kuss et al. (2011) reported another consanguineous Iranian family (8500156) in which 4 members had nonsyndromic moderate mental retardation. Mapping By linkage analysis in a large consanguineous Iranian family (M025) in which 4 individuals had nonsyndromic moderate mental retardation, Najmabadi et al. (2007) identified a candidate locus on chromosome 19q, termed MRT11, with a maximum lod score of 4.0. Haplotype analysis delineated a 5.4-Mb candidate region between SNPs rs2109075 and rs8101149. By homozygosity mapping of a consanguineous Iranian family (8500156) in which 4 individuals had moderate nonsyndromic mental retardation, Kuss et al. (2011) found linkage to a locus on chromosome 19q. The candidate interval spanned 11.3 Mb between SNPs 11881580 and rs17727484 (lod score of 4.0). INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Mental retardation, moderate MISCELLANEOUS \- Based on 2 consanguineous Iranian families ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

MENTAL RETARDATION, AUTOSOMAL RECESSIVE 11

c1970193

omim

https://www.omim.org/entry/611097

{"doid": ["0060308"], "mesh": ["C567012"], "omim": ["611097"], "orphanet": ["88616"], "synonyms": ["AR-NSID", "NS-ARID"]}

Nyhan et al. (1978) described a male patient with self-mutilation, mental retardation, choreoathetosis, spasticity and hyperuricemia, identical to the clinical picture of HGPRT deficiency (308000). Although HGPRT and purine salvage were normal, an abnormality in synthesis or catabolism of trinucleotides was suggested by an unusual accumulation of trinucleotides. Nyhan (1989) stated that since subsequent studies of cells from this patient failed to show consistent accumulation of trinucleotides, there is no real evidence of abnormality in purine metabolism. He reiterated that 'the phenotype was absolutely typical.' Misc \- Self-mutilation Neuro \- Mental retardation \- Choreoathetosis \- Spasticity Lab \- Hyperuricemia \- HGPRT and purine salvage normal Inheritance \- X-linked ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

LESCH-NYHAN PHENOTYPE WITH NORMAL HGPRT

c0023374

omim

https://www.omim.org/entry/308950

{"mesh": ["D007926"], "omim": ["308950"], "orphanet": ["510"]}

## Clinical Features Van den Berghe et al. (1978) described a family in which 4 males in 2 generations showed almost complete absence of the ulna and of fingers 2 to 5, together with lobster-claw deformity of the feet. Conductor females showed slight hypoplasia of the ulnar side of the hand and mild syndactyly of the toes. Inheritance Van den Berghe et al. (1978) suggested X-linked recessive or autosomal dominant sex-influenced transmission as the possible mode of inheritance in the family with 4 males affected with absence of the ulna and lobster-claw deformity of the feet. INHERITANCE \- X-linked recessive SKELETAL Limbs \- Ulnar hypoplasia Hands \- Hypoplastic ulna, severe \- Nearly complete absence of fingers 2 to 5 \- Fingers 2 to 5 hypoplastic (in carrier females) Feet \- Lobster-claw foot deformity \- Mild syndactyly (in carrier females) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

ULNAR HYPOPLASIA WITH LOBSTER-CLAW DEFORMITY OF FEET

c1839123

omim

https://www.omim.org/entry/314360

{"mesh": ["C536936"], "omim": ["314360"], "orphanet": ["1122"]}

Common viral infection of the upper respiratory tract Common cold Other namesCold, acute viral nasopharyngitis, nasopharyngitis, viral rhinitis, rhinopharyngitis, acute coryza, head cold[1]Upper respiratory tract infection (URTI)[2] A representation of the molecular surface of one variant of human rhinovirus SpecialtyInfectious disease SymptomsCough, sore throat, runny nose, fever[3][4] ComplicationsUsually none, but occasionally otitis media, sinusitis, pneumonia and sepsis can occur[5] Usual onset~2 days from exposure[6] Duration1–3 weeks[3][7] CausesViral (Usually Rhinovirus)[8] Diagnostic methodBased on symptoms Differential diagnosisAllergic rhinitis, bronchitis, pertussis, sinusitis[5] PreventionHand washing, face masks, cough etiquette, avoiding sick people[3][9] TreatmentSymptomatic therapy,[3] zinc[10] MedicationNSAIDs[11] Frequency2–4 per year (adults); 6–8 per year (young children)[12] The common cold, also known simply as a cold, is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx.[6][8] Signs and symptoms may appear less than two days after exposure to the virus.[6] These may include coughing, sore throat, runny nose, sneezing, headache, and fever.[3][4] People usually recover in seven to ten days,[3] but some symptoms may last up to three weeks.[7] Occasionally, those with other health problems may develop pneumonia.[3] Well over 200 virus strains are implicated in causing the common cold, with rhinoviruses being the most common.[13] They spread through the air during close contact with infected people or indirectly through contact with objects in the environment, followed by transfer to the mouth or nose.[3] Risk factors include going to child care facilities, not sleeping well, and psychological stress.[6] The symptoms are mostly due to the body's immune response to the infection rather than to tissue destruction by the viruses themselves.[14] The symptoms of influenza are similar to those of a cold, although usually more severe and less likely to include a runny nose.[6][15] There is no vaccine for the common cold.[3] The primary methods of prevention are handwashing; not touching the eyes, nose or mouth with unwashed hands; and staying away from sick people.[3] Some evidence supports the use of face masks.[9] There is also no cure, but the symptoms can be treated.[3] Zinc may reduce the duration and severity of symptoms if started shortly after the onset of symptoms.[10] Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen may help with pain.[11] Antibiotics, however, should not be used, as all colds are caused by viruses,[16] and there is no good evidence that cough medicines are effective.[6][17] The common cold is the most frequent infectious disease in humans.[18] Under normal circumstances, the average adult gets two to three colds a year, while the average child may get six to eight.[8][12] Infections occur more commonly during the winter.[3] These infections have existed throughout human history.[19] ## Contents * 1 Signs and symptoms * 1.1 Progression * 2 Cause * 2.1 Viruses * 2.2 Transmission * 2.3 Weather * 2.4 Other * 3 Pathophysiology * 4 Diagnosis * 5 Prevention * 6 Management * 6.1 Symptomatic * 6.2 Antibiotics and antivirals * 6.3 Zinc * 6.4 Alternative medicine * 6.5 Vitamins C and D * 7 Prognosis * 8 Epidemiology * 9 History * 10 Society and culture * 11 Research directions * 12 References * 12.1 Works cited * 13 External links ## Signs and symptoms Woman with symptoms of the common cold The typical symptoms of a cold include cough, runny nose, sneezing, nasal congestion, and a sore throat, sometimes accompanied by muscle ache, fatigue, headache, and loss of appetite.[20] A sore throat is present in about 40% of cases and a cough in about 50%,[8] while muscle ache occurs in about half.[4] In adults, a fever is generally not present but it is common in infants and young children.[4] The cough is usually mild compared to that accompanying influenza.[4] While a cough and a fever indicate a higher likelihood of influenza in adults, a great deal of similarity exists between these two conditions.[21] A number of the viruses that cause the common cold may also result in asymptomatic infections.[22][23] The color of the mucus or nasal secretion may vary from clear to yellow to green and does not indicate the class of agent causing the infection.[24] ### Progression A cold usually begins with fatigue, a feeling of being chilled, sneezing, and a headache, followed in a couple of days by a runny nose and cough.[20] Symptoms may begin within sixteen hours of exposure[25] and typically peak two to four days after onset.[4][26] They usually resolve in seven to ten days, but some can last for up to three weeks.[7] The average duration of cough is eighteen days[27] and in some cases people develop a post-viral cough which can linger after the infection is gone.[28] In children, the cough lasts for more than ten days in 35–40% of cases and continues for more than 25 days in 10%.[29] ## Cause ### Viruses Coronaviruses are a group of viruses known for causing the common cold. They have a halo or crown-like (corona) appearance when viewed under an electron microscope. The common cold is a viral infection of the upper respiratory tract. The most commonly implicated virus is a rhinovirus (30–80%), a type of picornavirus with 99 known serotypes.[30] Other commonly implicated viruses include human coronaviruses (≈ 15%),[31][32] influenza viruses (10–15%),[33] adenoviruses (5%),[33] human respiratory syncytial virus (orthopneumovirus), enteroviruses other than rhinoviruses, human parainfluenza viruses, and human metapneumovirus.[34] Frequently more than one virus is present.[35] In total, more than 200 viral types are associated with colds.[4] ### Transmission The common cold virus is typically transmitted via airborne droplets (aerosols), direct contact with infected nasal secretions, or fomites (contaminated objects).[8][36] Which of these routes is of primary importance has not been determined.[37] The viruses may survive for prolonged periods in the environment (over 18 hours for rhinoviruses) and can be picked up by people's hands and subsequently carried to their eyes or nose where infection occurs.[36] Transmission from animals is considered highly unlikely; an outbreak documented at a British scientific base on Adelaide Island after seventeen weeks of isolation was thought to have been caused by transmission from a contaminated object or an asymptomatic human carrier, rather than from the husky dogs which were also present at the base.[38] Transmission is common in daycare and at school due to the proximity of many children with little immunity and frequently poor hygiene.[39] These infections are then brought home to other members of the family.[39] There is no evidence that recirculated air during commercial flight is a method of transmission.[36] People sitting in close proximity appear to be at greater risk of infection.[37] Rhinovirus-caused colds are most infectious during the first three days of symptoms; they are much less infectious afterwards.[40] ### Weather A common misconception is that one can "catch a cold" simply through prolonged exposure to cold weather.[41] Although it is now known that colds are viral infections, the prevalence of many such viruses are indeed seasonal, occurring more frequently during cold weather.[42] The reason for the seasonality has not been conclusively determined.[43] Possible explanations may include cold temperature-induced changes in the respiratory system,[44] decreased immune response,[45] and low humidity causing an increase in viral transmission rates, perhaps due to dry air allowing small viral droplets to disperse farther and stay in the air longer.[46] The apparent seasonality may also be due to social factors, such as people spending more time indoors, near infected people,[44] and specifically children at school.[39][43] Although normal exposure to cold does not increase one's risk of infection, severe exposure leading to significant reduction of body temperature (hypothermia) may put one at a greater risk for the common cold; although controversial, the majority of evidence suggests that it may increase susceptibility to infection.[45] ### Other Herd immunity, generated from previous exposure to cold viruses, plays an important role in limiting viral spread, as seen with younger populations that have greater rates of respiratory infections.[47] Poor immune function is a risk factor for disease.[47][48] Insufficient sleep and malnutrition have been associated with a greater risk of developing infection following rhinovirus exposure; this is believed to be due to their effects on immune function.[49][50] Breast feeding decreases the risk of acute otitis media and lower respiratory tract infections among other diseases,[51] and it is recommended that breast feeding be continued when an infant has a cold.[52] In the developed world breast feeding may not be protective against the common cold in and of itself.[53] ## Pathophysiology The common cold is a disease of the upper respiratory tract. The symptoms of the common cold are believed to be primarily related to the immune response to the virus.[14] The mechanism of this immune response is virus specific. For example, the rhinovirus is typically acquired by direct contact; it binds to humans via ICAM-1 receptors and the CDHR3 receptor through unknown mechanisms to trigger the release of inflammatory mediators.[14] These inflammatory mediators then produce the symptoms.[14] It does not generally cause damage to the nasal epithelium.[4] The respiratory syncytial virus (RSV), on the other hand, is contracted by direct contact and airborne droplets. It then replicates in the nose and throat before frequently spreading to the lower respiratory tract.[54] RSV does cause epithelium damage.[54] Human parainfluenza virus typically results in inflammation of the nose, throat, and bronchi.[55] In young children when it affects the trachea it may produce the symptoms of croup due to the small size of their airways.[55] ## Diagnosis The distinction between viral upper respiratory tract infections is loosely based on the location of symptoms, with the common cold affecting primarily the nose (rhinitis), throat (pharyngitis), and lungs (bronchitis).[8] There can be significant overlap, and more than one area can be affected.[8] Self-diagnosis is frequent.[4] Isolation of the viral agent involved is rarely performed,[56] and it is generally not possible to identify the virus type through symptoms.[4] ## Prevention The only useful ways to reduce the spread of cold viruses are physical measures[9] such as using correct handwashing technique and face masks; in the healthcare environment, gowns and disposable gloves are also used.[9] Isolation or quarantine is not used as the disease is so widespread and symptoms are non-specific. There is no vaccine to protect against the common cold.[57] Vaccination has proven difficult as there are many viruses involved and they mutate rapidly.[9][58] Creation of a broadly effective vaccine is, therefore, highly improbable.[59] Regular hand washing appears to be effective in reducing the transmission of cold viruses, especially among children.[60] Whether the addition of antivirals or antibacterials to normal hand washing provides greater benefit is unknown.[60] Wearing face masks when around people who are infected may be beneficial; however, there is insufficient evidence for maintaining a greater social distance.[60] It is unclear if zinc supplements affect the likelihood of contracting a cold.[61] Routine vitamin C supplements do not reduce the risk or severity of the common cold, though they may reduce its duration.[62] Gargling with water was found useful in one small trial.[63] ## Management Poster from 1937 encouraging citizens to "consult your physician" for treatment of the common cold Treatments of the common cold primarily involve medications and other therapies for symptomatic relief.[12] Getting plenty of rest, drinking fluids to maintain hydration, and gargling with warm salt water are reasonable conservative measures.[34] Much of the benefit from symptomatic treatment is, however, attributed to the placebo effect.[64] As of 2010,[update] no medications or herbal remedies had been conclusively demonstrated to shorten the duration of infection.[65] ### Symptomatic Treatments that may help with symptoms include simple pain medication and medications for fevers such as ibuprofen[11] and acetaminophen (paracetamol).[66] It, however, is not clear if acetaminophen helps with symptoms.[67] It is not known if over the counter cough medications are effective for treating an acute cough.[68] Cough medicines are not recommended for use in children due to a lack of evidence supporting effectiveness and the potential for harm.[69][70] In 2009, Canada restricted the use of over-the-counter cough and cold medication in children six years and under due to concerns regarding risks and unproven benefits.[69] The misuse of dextromethorphan (an over-the-counter cough medicine) has led to its ban in a number of countries.[71] Intranasal corticosteroids have not been found to be useful.[72] In adults short term use of nasal decongestants may have a small benefit.[73] Antihistamines may improve symptoms in the first day or two; however, there is no longer-term benefit and they have adverse effects such as drowsiness.[74] Other decongestants such as pseudoephedrine appear effective in adults.[75][73] Combined oral analgesics, antihistaminics and decongestants are generally effective for older children and adults.[76] Ipratropium nasal spray may reduce the symptoms of a runny nose but has little effect on stuffiness.[77] Ipratropium may also help with cough in adults.[78] The safety and effectiveness of nasal decongestant use in children is unclear.[73] Due to lack of studies, it is not known whether increased fluid intake improves symptoms or shortens respiratory illness.[79] As of 2017 heated and humidified air, such as via RhinoTherm, is of unclear benefit.[80] One study has found chest vapor rub to provide some relief of nocturnal cough, congestion, and sleep difficulty.[81] Some advise to avoid physical exercise if there are symptoms such as fever, widespread muscle aches or fatigue.[82][83] It is regarded as safe to perform moderate exercise if the symptoms are confined to the head, including runny nose, nasal congestion, sneezing, or a minor sore throat.[82][83] There is an old wives tale that having a hot drink can help with cold symptoms, but evidence to support this is very limited.[84] ### Antibiotics and antivirals Antibiotics have no effect against viral infections, including the common cold.[85] Due to their side effects, antibiotics cause overall harm but are still frequently prescribed.[85][86] Some of the reasons that antibiotics are so commonly prescribed include people's expectations for them, physicians' desire to help, and the difficulty in excluding complications that may be amenable to antibiotics.[87] There are no effective antiviral drugs for the common cold even though some preliminary research has shown benefits.[12][88] ### Zinc Main article: Zinc and the common cold Zinc supplements may shorten the duration of colds by up to 33% and reduce the severity of symptoms if supplementation begins within 24 hours of the onset of symptoms.[10][61][89][90][91] Some zinc remedies directly applied to the inside of the nose have led to the loss of the sense of smell.[10][92] A 2017 review did not recommend the use of zinc for the common cold for various reasons;[17] whereas a 2017 and 2018 review both recommended the use of zinc, but also advocated further research on the topic.[89][90] ### Alternative medicine While there are many alternative medicine and Chinese herbal medicines supposed to treat the common cold, there is insufficient scientific evidence to support their use.[12][93] As of 2015, there is weak evidence to support nasal irrigation with saline.[94] There is no firm evidence that Echinacea products or garlic provide any meaningful benefit in treating or preventing colds.[95][96] ### Vitamins C and D Main article: Vitamin C and the common cold Vitamin C supplementation does not affect the incidence of the common cold, but may reduce its duration.[62] There is no conclusive evidence that vitamin D supplementation affects respiratory infections.[97] ## Prognosis The common cold is generally mild and self-limiting with most symptoms generally improving in a week.[8] In children, half of cases go away in 10 days and 90% in 15 days.[98] Severe complications, if they occur, are usually in the very old, the very young, or those who are immunosuppressed.[18] Secondary bacterial infections may occur resulting in sinusitis, pharyngitis, or an ear infection.[99] It is estimated that sinusitis occurs in 8% and ear infection in 30% of cases.[100] ## Epidemiology The common cold is the most common human disease[18] and affects people all over the globe.[39] Adults typically have two to three infections annually,[8] and children may have six to ten colds a year (and up to twelve colds a year for school children).[12] Rates of symptomatic infections increase in the elderly due to declining immunity.[47] Native Americans and Inuit are more likely to be infected with colds and develop complications such as otitis media than Caucasians.[33] This may be explained as much by issues such as poverty and overcrowding as by ethnicity.[33] ## History A British poster from World War II describing the cost of the common cold[101] While the cause of the common cold was identified in the 1950s, the disease appears to have been with humanity since its early history.[19] Its symptoms and treatment are described in the Egyptian Ebers papyrus, the oldest existing medical text, written before the 16th century BCE.[102] The name "cold" came into use in the 16th century, due to the similarity between its symptoms and those of exposure to cold weather.[103] In the United Kingdom, the Common Cold Unit was set up by the Medical Research Council in 1946 and it was where the rhinovirus was discovered in 1956.[104] In the 1970s, the CCU demonstrated that treatment with interferon during the incubation phase of rhinovirus infection protects somewhat against the disease,[105] but no practical treatment could be developed. The unit was closed in 1989, two years after it completed research of zinc gluconate lozenges in the prophylaxis and treatment of rhinovirus colds, the only successful treatment in the history of the unit.[106] ## Society and culture The economic impact of the common cold is not well understood in much of the world.[100] In the United States, the common cold leads to 75–100 million physician visits annually at a conservative cost estimate of $7.7 billion per year. Americans spend $2.9 billion on over-the-counter drugs and another $400 million on prescription medicines for symptom relief.[107] More than one-third of people who saw a doctor received an antibiotic prescription, which has implications for antibiotic resistance.[107] An estimated 22–189 million school days are missed annually due to a cold. As a result, parents missed 126 million workdays to stay home to care for their children. When added to the 150 million workdays missed by employees suffering from a cold, the total economic impact of cold-related work loss exceeds $20 billion per year.[34][107] This accounts for 40% of time lost from work in the United States.[108] ## Research directions Antivirals have been tested for effectiveness in the common cold; as of 2009, none had been both found effective and licensed for use.[88] There are ongoing trials of the anti-viral drug pleconaril which shows promise against picornaviruses as well as trials of BTA-798.[109] The oral form of pleconaril had safety issues and an aerosol form is being studied.[109] Double-stranded RNA activated caspase oligomerizer (DRACO), a broad-spectrum antiviral therapy, has shown preliminary effectiveness in treating rhinovirus, as well as other infectious viruses.[110] The genomes of all known human rhinovirus strains have been sequenced.[111] ## References 1. ^ John, Pramod R. John (2008). Textbook of Oral Medicine. Jaypee Brothers Publishers. p. 336. ISBN 978-81-8061-562-7. Archived from the original on 29 May 2016. 2. ^ Lee H, Kang B, Hong M, Lee HL, Choi JY, Lee JA (2020). "Eunkyosan for the common cold: A PRISMA-compliment systematic review of randomised, controlled trials". Medicine (Baltimore). 99 (31): e21415. doi:10.1097/MD.0000000000021415. PMC 7402720. PMID 32756141. 3. ^ a b c d e f g h i j k l "Common Colds: Protect Yourself and Others". CDC. 6 October 2015. Archived from the original on 5 February 2016. Retrieved 4 February 2016. 4. ^ a b c d e f g h i j Eccles R (November 2005). "Understanding the symptoms of the common cold and influenza". Lancet Infect Dis. 5 (11): 718–25. doi:10.1016/S1473-3099(05)70270-X. PMC 7185637. PMID 16253889. 5. ^ a b Bennett, John E.; Dolin, Raphael; Blaser, Martin J. (2014). Principles and Practice of Infectious Diseases. Elsevier Health Sciences. p. 750. ISBN 978-1-4557-4801-3. Archived from the original on 8 September 2017. 6. ^ a b c d e f Allan, GM; Arroll, B (18 February 2014). "Prevention and treatment of the common cold: making sense of the evidence". CMAJ : Canadian Medical Association Journal. 186 (3): 190–99. doi:10.1503/cmaj.121442. PMC 3928210. PMID 24468694. 7. ^ a b c Heikkinen T, Järvinen A (January 2003). "The common cold". Lancet. 361 (9351): 51–59. doi:10.1016/S0140-6736(03)12162-9. PMC 7112468. PMID 12517470. 8. ^ a b c d e f g h i Arroll, B (March 2011). "Common cold". Clinical Evidence. 2011 (3): 1510. PMC 3275147. PMID 21406124. "Common colds are defined as upper respiratory tract infections that affect the predominantly nasal part of the respiratory mucosa" 9. ^ a b c d e Eccles p. 209 10. ^ a b c d "Zinc – Fact Sheet for Health Professionals". Office of Dietary Supplements, US National Institutes of Health. 10 July 2019. Retrieved 27 December 2019. "Although studies examining the effect of zinc treatment on cold symptoms have had somewhat conflicting results, overall zinc appears to be beneficial under certain circumstances.... In September of 2007, Caruso and colleagues published a structured review of the effects of zinc lozenges, nasal sprays, and nasal gels on the common cold [69]. Of the 14 randomized, placebo-controlled studies included, 7 (5 using zinc lozenges, 2 using a nasal gel) showed that the zinc treatment had a beneficial effect and 7 (5 using zinc lozenges, 1 using a nasal spray, and 1 using lozenges and a nasal spray) showed no effect. More recently, a Cochrane review concluded that “zinc (lozenges or syrup) is beneficial in reducing the duration and severity of the common cold in healthy people, when taken within 24 hours of onset of symptoms” [73]. The author of another review completed in 2004 also concluded that zinc can reduce the duration and severity of cold symptoms [68]. However, more research is needed to determine the optimal dosage, zinc formulation and duration of treatment before a general recommendation for zinc in the treatment of the common cold can be made [73]. As previously noted, the safety of intranasal zinc has been called into question because of numerous reports of anosmia (loss of smell), in some cases long-lasting or permanent, from the use of zinc-containing nasal gels or sprays [17–19]." 11. ^ a b c Kim, SY; Chang, YJ; Cho, HM; Hwang, YW; Moon, YS (21 September 2015). "Non-steroidal anti-inflammatory drugs for the common cold". The Cochrane Database of Systematic Reviews. 9 (9): CD006362. doi:10.1002/14651858.CD006362.pub4. PMID 26387658. 12. ^ a b c d e f Simasek M, Blandino DA (2007). "Treatment of the common cold". American Family Physician. 75 (4): 515–20. PMID 17323712. Archived from the original on 26 September 2007. 13. ^ "Common Cold and Runny Nose" (17 April 2015). CDC. Archived from the original on 1 February 2016. Retrieved 4 February 2016. 14. ^ a b c d Eccles p. 112 15. ^ "Cold Versus Flu". 11 August 2016. Archived from the original on 6 January 2017. Retrieved 5 January 2017. 16. ^ Harris, AM; Hicks, LA; Qaseem, A; High Value Care Task Force of the American College of Physicians and for the Centers for Disease Control and, Prevention (19 January 2016). "Appropriate Antibiotic Use for Acute Respiratory Tract Infection in Adults: Advice for High-Value Care From the American College of Physicians and the Centers for Disease Control and Prevention". Annals of Internal Medicine. 164 (6): 425–34. doi:10.7326/M15-1840. PMID 26785402. 17. ^ a b Malesker, MA; Callahan-Lyon, P; Ireland, B; Irwin, RS; CHEST Expert Cough, Panel. (November 2017). "Pharmacologic and Nonpharmacologic Treatment for Acute Cough Associated With the Common Cold: CHEST Expert Panel Report". Chest. 152 (5): 1021–37. doi:10.1016/j.chest.2017.08.009. PMC 6026258. PMID 28837801. "A suggestion for the use of zinc lozenges in healthy adults with cough due to common cold was considered by the expert panel. However, due to weak evidence, the potential side effects of zinc, and the relatively benign and common nature of the condition being treated, the panel did not approve inclusion of this suggestion." 18. ^ a b c Eccles p. 1 19. ^ a b Eccles, Ronald; Weber, Olaf (2009). Common cold. Basel: Birkhäuser. p. 3. ISBN 978-3-7643-9894-1. Archived from the original on 8 May 2016. 20. ^ a b Eccles p. 24 21. ^ Eccles p. 26 22. ^ Eccles p. 129 23. ^ Eccles p. 50 24. ^ Eccles p. 30 25. ^ Richard A. Helms, ed. (2006). Textbook of therapeutics: drug and disease management (8. ed.). Philadelphia, Pa. [u.a.]: Lippincott Williams & Wilkins. p. 1882. ISBN 978-0-7817-5734-8. Archived from the original on 30 April 2016. 26. ^ Turner, Ronald B.; Hayden, Frederick G. (2003). "Rhinovirus". In Rübsamen-Waigmann, Helga; et al. (eds.). Viral Infections and Treatment. New York: CRC Press. p. 111. ISBN 978-0-8247-4247-8. Archived from the original on 4 May 2016. 27. ^ Ebell, M.H.; Lundgren, J.; Youngpairoj, S. (January–February 2013). "How long does a cough last? Comparing patients' expectations with data from a systematic review of the literature". Annals of Family Medicine. 11 (1): 5–13. doi:10.1370/afm.1430. PMC 3596033. PMID 23319500. 28. ^ Dicpinigaitis PV (May 2011). "Cough: an unmet clinical need". Br. J. Pharmacol. 163 (1): 116–24. doi:10.1111/j.1476-5381.2010.01198.x. PMC 3085873. PMID 21198555. 29. ^ Goldsobel AB, Chipps BE (March 2010). "Cough in the pediatric population". J. Pediatr. 156 (3): 352–58. doi:10.1016/j.jpeds.2009.12.004. PMID 20176183. 30. ^ Palmenberg AC, Spiro D, Kuzmickas R, Wang S, Djikeng A, Rathe JA, Fraser-Liggett CM, Liggett SB (2009). "Sequencing and Analyses of All Known Human Rhinovirus Genomes Reveals Structure and Evolution". Science. 324 (5923): 55–59. Bibcode:2009Sci...324...55P. doi:10.1126/science.1165557. PMC 3923423. PMID 19213880. 31. ^ Pelczar (2010). Microbiology: Application Based Approach. p. 656. ISBN 978-0-07-015147-5. Archived from the original on 16 May 2016. 32. ^ Russell La Fayette Cecil; Lee Goldman; Andrew I. Schafer (2012), Goldman's Cecil Medicine, Expert Consult Premium Edition (24 ed.), Elsevier Health Sciences, pp. 2103–, ISBN 978-1-4377-1604-7, archived from the original on 4 May 2016 33. ^ a b c d Michael Rajnik; Robert W Tolan (13 September 2013). "Rhinovirus Infection". Medscape Reference. Archived from the original on 8 March 2013. Retrieved 19 March 2013. 34. ^ a b c "Common Cold". National Institute of Allergy and Infectious Diseases. 27 November 2006. Archived from the original on 6 September 2008. Retrieved 11 June 2007. 35. ^ Eccles p. 107 36. ^ a b c Eccles, Ronald; Weber, Olaf (2009). Common cold (Online-Ausg. ed.). Basel: Birkhäuser. p. 197. ISBN 978-3-7643-9894-1. Archived from the original on 2 May 2016. 37. ^ a b Eccles pp. 211, 215 38. ^ Allen, T. R.; Bradburne, A. F.; Stott, E. J.; Goodwin, C. S.; Tyrrell, D. A. J. (December 1973). "An outbreak of common colds at an Antarctic base after seventeen weeks of complete isolation". Journal of Hygiene. 71 (4): 657–667. doi:10.1017/s0022172400022920. PMC 2130424. PMID 4520509. 39. ^ a b c d Nikolaos G. Papadopoulos; Maria Xatzipsaltis; Sebastian L. Johnston (2009), "Rhinoviruses", in Arie J. Zuckerman; et al. (eds.), Principles and Practice of Clinical Virology (6th ed.), John Wiley & Sons, p. 496, ISBN 978-0-470-74139-9, archived from the original on 3 June 2016 40. ^ Gwaltney JM Jr, Halstead SB (16 July 1997). "Contagiousness of the common cold". Questions and answers. Journal of the American Medical Association. 278 (3): 256–57. doi:10.1001/jama.1997.03550030096050. 41. ^ Zuger, Abigail (4 March 2003). "'You'll Catch Your Death!' An Old Wives' Tale? Well." The New York Times. Archived from the original on 22 March 2017. 42. ^ Eccles p. 79 43. ^ a b "Common cold – Background information". National Institute for Health and Clinical Excellence. Archived from the original on 15 November 2012. Retrieved 19 March 2013. 44. ^ a b Eccles p. 80 45. ^ a b Mourtzoukou EG, Falagas ME (September 2007). "Exposure to cold and respiratory tract infections". The International Journal of Tuberculosis and Lung Disease. 11 (9): 938–43. PMID 17705968. 46. ^ Eccles p. 157 47. ^ a b c Eccles p. 78 48. ^ Eccles p. 166 49. ^ Cohen S, Doyle WJ, Alper CM, Janicki-Deverts D, Turner RB (January 2009). "Sleep habits and susceptibility to the common cold". Arch. Intern. Med. 169 (1): 62–67. doi:10.1001/archinternmed.2008.505. PMC 2629403. PMID 19139325. 50. ^ Eccles pp. 160–65 51. ^ McNiel, ME; Labbok, MH; Abrahams, SW (July 2010). "What are the risks associated with formula feeding? A re-analysis and review". Breastfeeding Review. 18 (2): 25–32. PMID 20879657. 52. ^ Lawrence, Ruth A.; Lawrence, Robert M. (2010). Breastfeeding: A guide for the medical profession (7th ed.). Maryland Heights, Mo.: Mosby/Elsevier. p. 478. ISBN 978-1-4377-3590-1. Archived from the original on 17 June 2016. 53. ^ Kenrad E. Nelson; Carolyn Masters Williams (2007), Infectious Disease Epidemiology: Theory and Practice (2nd ed.), Jones & Bartlett Learning, pp. 724–, ISBN 978-0-7637-2879-3, archived from the original on 20 May 2016 54. ^ a b Eccles p. 116 55. ^ a b Eccles p. 122 56. ^ Eccles pp. 51–52 57. ^ CDC (11 February 2019). "Common Colds". Centers for Disease Control and Prevention. Retrieved 18 September 2020. 58. ^ Simancas-Racines, Daniel; Franco, Juan Va; Guerra, Claudia V.; Felix, Maria L.; Hidalgo, Ricardo; Martinez-Zapata, Maria José (May 2017). "Vaccines for the common cold". The Cochrane Database of Systematic Reviews. 5: CD002190. doi:10.1002/14651858.CD002190.pub5. ISSN 1469-493X. PMC 6481390. PMID 28516442. 59. ^ Lawrence DM (May 2009). "Gene studies shed light on rhinovirus diversity". Lancet Infect Dis. 9 (5): 278. doi:10.1016/S1473-3099(09)70123-9. 60. ^ a b c Jefferson, Tom; Del Mar, Chris B.; Dooley, Liz; Ferroni, Eliana; Al-Ansary, Lubna A.; Bawazeer, Ghada A.; van Driel, Mieke L.; Jones, Mark A.; Thorning, Sarah; Beller, Elaine M.; Clark, Justin (20 November 2020). "Physical interventions to interrupt or reduce the spread of respiratory viruses". The Cochrane Database of Systematic Reviews. 11: CD006207. doi:10.1002/14651858.CD006207.pub5. hdl:10072/399941. ISSN 1469-493X. PMID 33215698. 61. ^ a b Singh, M; Das, RR (18 June 2013). Singh, Meenu (ed.). "Zinc for the common cold". The Cochrane Database of Systematic Reviews (6): CD001364. doi:10.1002/14651858.CD001364.pub4. PMID 23775705. (Retracted) 62. ^ a b Hemilä, H; Chalker, E (31 January 2013). "Vitamin C for preventing and treating the common cold". The Cochrane Database of Systematic Reviews. 1 (1): CD000980. doi:10.1002/14651858.CD000980.pub4. PMC 1160577. PMID 23440782. 63. ^ Moyad, MA (2009). "Conventional and alternative medical advice for cold and flu prevention: what should be recommended and what should be avoided?". Urologic Nursing. 29 (6): 455–58. PMID 20088240. 64. ^ Eccles p. 261 65. ^ "Common Cold: Treatments and Drugs". Mayo Clinic. Archived from the original on 12 February 2010. Retrieved 9 January 2010. 66. ^ Eccles R (2006). "Efficacy and safety of over-the-counter analgesics in the treatment of common cold and flu". Journal of Clinical Pharmacy and Therapeutics. 31 (4): 309–19. doi:10.1111/j.1365-2710.2006.00754.x. PMID 16882099. S2CID 22793984. 67. ^ Li, Siyuan; Yue, Jirong; Dong, Bi Rong; Yang, Ming; Lin, Xiufang; Wu, Taixiang (1 July 2013). "Acetaminophen (paracetamol) for the common cold in adults". The Cochrane Database of Systematic Reviews (7): CD008800. doi:10.1002/14651858.CD008800.pub2. ISSN 1469-493X. PMC 7389565. PMID 23818046. 68. ^ Smith, SM; Schroeder, K; Fahey, T (24 November 2014). "Over-the-counter (OTC) medications for acute cough in children and adults in community settings". The Cochrane Database of Systematic Reviews. 11 (11): CD001831. doi:10.1002/14651858.CD001831.pub5. PMC 7061814. PMID 25420096. 69. ^ a b Shefrin AE, Goldman RD (November 2009). "Use of over-the-counter cough and cold medications in children" (PDF). Can Fam Physician. 55 (11): 1081–83. PMC 2776795. PMID 19910592. Archived (PDF) from the original on 23 September 2015. 70. ^ Vassilev ZP, Kabadi S, Villa R (March 2010). "Safety and efficacy of over-the-counter cough and cold medicines for use in children". Expert Opinion on Drug Safety. 9 (2): 233–42. doi:10.1517/14740330903496410. PMID 20001764. S2CID 12952868. 71. ^ Eccles p. 246 72. ^ Hayward, Gail; Thompson, Matthew J; Perera, Rafael; Del Mar, Chris B; Glasziou, Paul P; Heneghan, Carl J (13 October 2015). "Corticosteroids for the common cold" (PDF). Cochrane Database of Systematic Reviews (10): CD008116. doi:10.1002/14651858.cd008116.pub3. PMID 26461493. 73. ^ a b c Deckx, Laura; De Sutter, An Im; Guo, Linda; Mir, Nabiel A.; van Driel, Mieke L. (17 October 2016). "Nasal decongestants in monotherapy for the common cold". The Cochrane Database of Systematic Reviews. 10: CD009612. doi:10.1002/14651858.CD009612.pub2. PMC 6461189. PMID 27748955. 74. ^ De Sutter, AI; Saraswat, A; van Driel, ML (29 November 2015). "Antihistamines for the common cold". The Cochrane Database of Systematic Reviews. 11 (11): CD009345. doi:10.1002/14651858.CD009345.pub2. hdl:1854/LU-7237869. PMID 26615034. 75. ^ Taverner D, Latte GJ (2007). Latte, G. Jenny (ed.). "Nasal decongestants for the common cold". Cochrane Database Syst Rev (1): CD001953. doi:10.1002/14651858.CD001953.pub3. PMID 17253470. 76. ^ De Sutter, An IM; van Driel, Mieke L; Kumar, Anna A; Lesslar, Olivia; Skrt, Alja (15 February 2012). "Oral antihistamine-decongestant-analgesic combinations for the common cold" (PDF). Cochrane Database of Systematic Reviews (2): CD004976. doi:10.1002/14651858.CD004976.pub3. PMID 22336807. 77. ^ AlBalawi, Zaina H.; Othman, Sahar S.; Alfaleh, Khalid (19 June 2013). "Intranasal ipratropium bromide for the common cold". The Cochrane Database of Systematic Reviews (6): CD008231. doi:10.1002/14651858.CD008231.pub3. ISSN 1469-493X. PMC 6492479. PMID 23784858. 78. ^ DeGeorge, KC; Ring, DJ; Dalrymple, SN (1 September 2019). "Treatment of the Common Cold". American Family Physician. 100 (5): 281–289. PMID 31478634. 79. ^ Guppy MP, Mickan SM, Del Mar CB, Thorning S, Rack A (February 2011). Guppy MP (ed.). "Advising patients to increase fluid intake for treating acute respiratory infections". Cochrane Database of Systematic Reviews (2): CD004419. doi:10.1002/14651858.CD004419.pub3. PMC 7197045. PMID 21328268. 80. ^ Singh, Meenu; Singh, Manvi; Jaiswal, Nishant; Chauhan, Anil (August 2017). "Heated, humidified air for the common cold". The Cochrane Database of Systematic Reviews. 8: CD001728. doi:10.1002/14651858.CD001728.pub6. ISSN 1469-493X. PMC 6483632. PMID 28849871. 81. ^ Paul IM, Beiler JS, King TS, Clapp ER, Vallati J, Berlin CM (December 2010). "Vapor rub, petrolatum, and no treatment for children with nocturnal cough and cold symptoms". Pediatrics. 126 (6): 1092–99. doi:10.1542/peds.2010-1601. PMC 3600823. PMID 21059712. 82. ^ a b Edward R. Laskowski (9 February 2017). "Is it OK to exercise if I have a cold?". Mayo Clinic. Archived from the original on 19 July 2017. Retrieved 4 July 2017. 83. ^ a b "Clearing the Air on Exercise and the Common Cold". American College of Sports Medicine. Archived from the original on 22 July 2017. Retrieved 4 July 2017. 84. ^ "Hot drinks ease cold and flu". National Health Service. 10 December 2008. Retrieved 17 February 2019. 85. ^ a b Kenealy, T; Arroll, B (4 June 2013). "Antibiotics for the common cold and acute purulent rhinitis". The Cochrane Database of Systematic Reviews. 6 (6): CD000247. doi:10.1002/14651858.CD000247.pub3. PMC 7044720. PMID 23733381. 86. ^ Eccles p. 238 87. ^ Eccles p. 234 88. ^ a b Eccles p. 218 89. ^ a b Rondanelli M, Miccono A, Lamburghini S, Avanzato I, Riva A, Allegrini P, Faliva MA, Peroni G, Nichetti M, Perna S (2018). "Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds-Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds". Evidence-based Complementary and Alternative Medicine. 2018: 5813095. doi:10.1155/2018/5813095. PMC 5949172. PMID 29853961. "Considering zinc, the supplementation may shorten the duration of colds by approximately 33%. CC patients may be instructed to try zinc within 24 hours of onset of symptoms." 90. ^ a b Hemila, H.; Fitzgerald, J.; Petrus, E.; Prasad, A. (2017). "Zinc Acetate Lozenges May Improve the Recovery Rate of Common Cold Patients: An Individual Patient Data Meta-Analysis". Open Forum Infect Diseases. 4 (2): ofx059. doi:10.1093/ofid/ofx059. PMC 5410113. PMID 28480298. "The 3-fold increase in the rate of recovery from the common cold is a clinically important effect. The optimal formulation of zinc lozenges and an ideal frequency of their administration should be examined. Given the evidence of efficacy, common cold patients may be instructed to try zinc acetate lozenges within 24 hours of onset of symptoms." 91. ^ Hemila, H.; Petrus, E.; Fitzgerald, J.; Prasad, A. (2016). "Zinc acetate lozenges for treating the common cold: an individual patient data meta-analysis". British Journal of Clinical Pharmacology. 82 (5): 1393–98. doi:10.1111/bcp.13057. PMC 5061795. PMID 27378206. 92. ^ "Loss of Sense of Smell with Intranasal Cold Remedies Containing Zinc". 2009. Archived from the original on 4 June 2015. 93. ^ Zhang, Xiaoge; Wu, Taixiang; Zhang, Jing; Yan, Qiu; Xie, Lingxia; Liu, Guan J (24 January 2007). "Chinese medicinal herbs for the common cold". Cochrane Database of Systematic Reviews (1): CD004782. doi:10.1002/14651858.CD004782.pub2. PMID 17253524. 94. ^ King, D; Mitchell, B; Williams, CP; Spurling, GK (20 April 2015). "Saline nasal irrigation for acute upper respiratory tract infections" (PDF). The Cochrane Database of Systematic Reviews. 4 (4): CD006821. doi:10.1002/14651858.CD006821.pub3. PMID 25892369. 95. ^ Karsch-Völk M, Barrett B, Kiefer D, Bauer R, Ardjomand-Woelkart K, Linde K (2014). "Echinacea for preventing and treating the common cold". Cochrane Database Syst Rev (Systematic review). 2 (2): CD000530. doi:10.1002/14651858.CD000530.pub3. PMC 4068831. PMID 24554461. 96. ^ Lissiman E, Bhasale AL, Cohen M (2014). Lissiman E (ed.). "Garlic for the common cold". Cochrane Database Syst Rev. 11 (11): CD006206. doi:10.1002/14651858.CD006206.pub4. PMC 6465033. PMID 25386977. 97. ^ Bradley R, Schloss J, Brown D, Celis D, Finnell J, Hedo R, Honcharov V, Pantuso T, Peña H, Lauche R, Steel A (December 2020). "The effects of vitamin D on acute viral respiratory infections: A rapid review". Adv Integr Med. 7 (4): 192–202. doi:10.1016/j.aimed.2020.07.011. PMC 7397989. PMID 32837896. 98. ^ Thompson, M; Vodicka, TA; Blair, PS; Buckley, DI; Heneghan, C; Hay, AD; TARGET Programme, Team (11 December 2013). "Duration of symptoms of respiratory tract infections in children: systematic review". BMJ (Clinical Research Ed.). 347: f7027. doi:10.1136/bmj.f7027. PMC 3898587. PMID 24335668. 99. ^ Eccles p. 76 100. ^ a b Eccles p. 90 101. ^ "The Cost of the Common Cold and Influenza". Imperial War Museum: Posters of Conflict. vads. Archived from the original on 27 July 2011. 102. ^ Eccles p. 6 103. ^ "Cold". Online Etymology Dictionary. Archived from the original on 24 October 2007. Retrieved 12 January 2008. 104. ^ Eccles p. 20 105. ^ Tyrrell DA (1987). "Interferons and their clinical value". Rev. Infect. Dis. 9 (2): 243–49. doi:10.1093/clinids/9.2.243. PMID 2438740. 106. ^ Al-Nakib W; Higgins, P.G.; Barrow, I.; Batstone, G.; Tyrrell, D.A.J. (December 1987). "Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges". J Antimicrob Chemother. 20 (6): 893–901. doi:10.1093/jac/20.6.893. PMC 7110079. PMID 3440773. 107. ^ a b c Fendrick AM, Monto AS, Nightengale B, Sarnes M (2003). "The economic burden of non-influenza-related viral respiratory tract infection in the United States". Arch. Intern. Med. 163 (4): 487–94. doi:10.1001/archinte.163.4.487. PMID 12588210. 108. ^ Kirkpatrick GL (December 1996). "The common cold". Prim. Care. 23 (4): 657–75. doi:10.1016/S0095-4543(05)70355-9. PMC 7125839. PMID 8890137. 109. ^ a b Eccles p. 226 110. ^ Rider TH, Zook CE, Boettcher TL, Wick ST, Pancoast JS, Zusman BD (2011). Sambhara S (ed.). "Broad-spectrum antiviral therapeutics". PLoS ONE. 6 (7): e22572. Bibcode:2011PLoSO...622572R. doi:10.1371/journal.pone.0022572. PMC 3144912. PMID 21818340. 111. ^ Val Willingham (12 February 2009). "Genetic map of cold virus a step toward cure, scientists say". CNN. Archived from the original on 26 April 2009. Retrieved 28 April 2009. ### Works cited * Eccles, Ronald; Weber, Olaf, eds. (2009). Common Cold (Illustrated ed.). Springer Science & Business Media. ISBN 978-3-7643-9912-2. ## External links Wikipedia's health care articles can be viewed offline with the Medical Wikipedia app. Wikimedia Commons has media related to Common cold. * Common cold at Curlie Classification D * ICD-10: J00 * ICD-9-CM: 460 * MeSH: D003139 * DiseasesDB: 31088 External resources * MedlinePlus: 000678 * Patient UK: Common cold * Medicine portal * Viruses portal * v * t * e Common cold Viruses * Adenovirus * Coronavirus * Enterovirus * Rhinovirus Symptoms * Cough * Fatigue * Fever * Headache * Loss of appetite * Malaise * Muscle aches * Nasal congestion * Rhinorrhea * Sneezing * Sore throat * Weakness Complications * Acute bronchitis * Bronchiolitis * Croup * Otitis media * Pharyngitis * Pneumonia * Sinusitis * Strep throat Drugs * Antiviral drugs * Pleconaril (experimental) * 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 respiratory system Upper RT (including URTIs, common cold) Head sinuses Sinusitis nose Rhinitis Vasomotor rhinitis Atrophic rhinitis Hay fever Nasal polyp Rhinorrhea nasal septum Nasal septum deviation Nasal septum perforation Nasal septal hematoma tonsil Tonsillitis Adenoid hypertrophy Peritonsillar abscess Neck pharynx Pharyngitis Strep throat Laryngopharyngeal reflux (LPR) Retropharyngeal abscess larynx Croup Laryngomalacia Laryngeal cyst Laryngitis Laryngopharyngeal reflux (LPR) Laryngospasm vocal cords Laryngopharyngeal reflux (LPR) Vocal fold nodule Vocal fold paresis Vocal cord dysfunction epiglottis Epiglottitis trachea Tracheitis Laryngotracheal stenosis Lower RT/lung disease (including LRTIs) Bronchial/ obstructive acute Acute bronchitis chronic COPD Chronic bronchitis Acute exacerbation of COPD) Asthma (Status asthmaticus Aspirin-induced Exercise-induced Bronchiectasis Cystic fibrosis unspecified Bronchitis Bronchiolitis Bronchiolitis obliterans Diffuse panbronchiolitis Interstitial/ restrictive (fibrosis) External agents/ occupational lung disease Pneumoconiosis Aluminosis Asbestosis Baritosis Bauxite fibrosis Berylliosis Caplan's syndrome Chalicosis Coalworker's pneumoconiosis Siderosis Silicosis Talcosis Byssinosis Hypersensitivity pneumonitis Bagassosis Bird fancier's lung Farmer's lung Lycoperdonosis Other * ARDS * Combined pulmonary fibrosis and emphysema * Pulmonary edema * Löffler's syndrome/Eosinophilic pneumonia * Respiratory hypersensitivity * Allergic bronchopulmonary aspergillosis * Hamman-Rich syndrome * Idiopathic pulmonary fibrosis * Sarcoidosis * Vaping-associated pulmonary injury Obstructive / Restrictive Pneumonia/ pneumonitis By pathogen * Viral * Bacterial * Pneumococcal * Klebsiella * Atypical bacterial * Mycoplasma * Legionnaires' disease * Chlamydiae * Fungal * Pneumocystis * Parasitic * noninfectious * Chemical/Mendelson's syndrome * Aspiration/Lipid By vector/route * Community-acquired * Healthcare-associated * Hospital-acquired By distribution * Broncho- * Lobar IIP * UIP * DIP * BOOP-COP * NSIP * RB Other * Atelectasis * circulatory * Pulmonary hypertension * Pulmonary embolism * Lung abscess Pleural cavity/ mediastinum Pleural disease * Pleuritis/pleurisy * Pneumothorax/Hemopneumothorax Pleural effusion Hemothorax Hydrothorax Chylothorax Empyema/pyothorax Malignant Fibrothorax Mediastinal disease * Mediastinitis * Mediastinal emphysema Other/general * Respiratory failure * Influenza * Common cold * SARS * Coronavirus disease 2019 * Idiopathic pulmonary haemosiderosis * Pulmonary alveolar proteinosis Authority control * GND: 4136665-7 * LCCN: sh85027912 * NDL: 00564849 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Common cold

c0009443

wikipedia

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

{"mesh": ["D003139"], "umls": ["C0009443"], "wikidata": ["Q12125"]}

A number sign (#) is used with this entry because hypomyelinating leukodystrophy-6 (HLD6) is caused by heterozygous mutation in the TUBB4A gene (602662) on chromosome 19p13. Mutation in the TUBB4A gene can also cause dystonia-4 (DYT4; 128101). Description Hypomyelinating leukodystrophy-6, also known as hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum, is a neurologic disorder characterized by onset in infancy or early childhood of delayed motor development and gait instability, followed by extrapyramidal movement disorders, such as dystonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises, progressive spastic tetraplegia, ataxia, and, more rarely, seizures. Most patients have cognitive decline and speech delay, but some can function normally. Brain MRI shows a combination of hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen. The disorder usually shows sporadic occurrence, but sibs may be affected if a parent is somatic mosaic for the mutation (summary by Simons et al., 2013). Hypomyelinating leukodystrophies (HLD) comprise a genetically heterogeneous entity in which there is a substantial permanent deficit in myelin deposition within the brain, resulting in neurologic deficits (van der Knaap et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080. Clinical Features In a retrospective study of patients with leukodystrophy, van der Knaap et al. (2002) identified 7 unrelated patients with neurologic impairment associated with a distinct brain MRI pattern characterized by hypomyelination and atrophy of the basal ganglia and cerebellum. Clinical features included onset at 1 to 3 years of delayed motor development, difficulty walking without support with later deterioration of motor skills, spasticity, dystonia, ataxia, tremor, rigidity, choreoathetosis, dysarthria, and learning disability. Two patients were more severely affected with onset at age 2 months, poor vision with optic atrophy, little motor development, seizures, and mental retardation. Electrophysiologic studies indicated generalized EEG slowing, delayed visual evoked responses, and variable delays in auditory evoked potentials. Sural nerve biopsies of 2 patients were normal. Brain MRI in all patients showed a homogeneous picture, with diffuse myelin deficiency, atrophy of the cerebellar vermis, and small or absent putamen. Serial MRI studies showed variable progression. The myelination defect involved the cerebrum as well as the pyramidal tracts through the posterior limb of the internal capsule to the brainstem. Van der Knaap et al. (2002) postulated that the disease involved both the disturbance of normal myelin development and degeneration. None had a family history of the disorder, and none of the parents were consanguineous. Mercimek-Mahmutoglu et al. (2005) reported 1 additional patient with a phenotype that was similar to that reported by van der Knaap et al. (2002). A 42-month-old girl developed progressive dystonia, spasticity, and oculogyric eye movements at age 3 months. She also was hypotonic but had opisthotonic posturing. Brain MRI showed supratentorial hypomyelination and progressive atrophy of the basal ganglia and cerebellum. Van der Knaap et al. (2007) reported 11 additional unrelated patients with this disorder. All were sporadic, and the potential mode of inheritance was unclear, but 1 patient had consanguineous parents. Early psychomotor development was normal or delayed, followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity beginning between 8 months and 7 years. Almost all had very poor speech development and loss of unsupported walking later in life. Mental deficiency ranged from mild to severe. Other variable features included nystagmus, decreased hearing, short stature, and microcephaly. Brain MRI showed diffuse hypomyelination with evidence of further myelin loss or white matter atrophy on serial imaging. The putamen was small or absent, the head of the caudate was decreased in size, and there was cerebellar atrophy. Histopathologic analysis confirmed myelin deficiency and suggested that it was related to both lack of deposition and ongoing loss. Simons et al. (2013) reported 11 individuals with HLD and atrophy of the cerebellum. Two of the patients had previously been reported (van der Knaap et al., 2002; van der Knaap et al., 2007). The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed by motor deterioration and extrapyramidal signs. Six patients had cognitive decline and 2 had mild intellectual disability, but 3 had normal cognitive development. All patients except 1 had some sort of speech delay and dysarthria. Miyatake et al. (2014) reported 8 unrelated Japanese patients with HLD6. Patients 1 and 2 had a more protracted clinical course compared to the others and were previously reported by Sasaki et al. (2009) as having an unclassified hypomyelinating leukodystrophy. These 2 patients were the only ones who achieved unsupported but unsteady walking, but they later lost the ability to walk at ages 12 and 25 years, respectively. Patient 4 was previously reported by Wakusawa et al. (2006) as having HABC. The mean age at onset was 9.2 months (range, 1.5-19 months). Some patients showed some initial motor development (rolling over or walking a few steps) followed by regression, whereas 4 had essentially no motor development, including 3 who never even achieved head control. In addition to severely delayed motor development, all patients developed an extrapyramidal disorder with spasticity, dystonia, and rigidity. Some showed choreoathetosis, tremor, and/or ataxia. Five patients had severe intellectual disability with no language acquisition and 1 had a few words. The 2 patients with a more protracted course achieved some language. Four patients had evidence of brainstem dysfunction on auditory testing. Other more variable features included nystagmus, seizures, and optic atrophy. Brain imaging showed hypomyelination and atrophy of the basal ganglia, cerebellum, and corpus callosum. None of the patients had a family history of a similar disorder. Blumkin et al. (2014) reported a 9-year-old boy, born of unrelated parents, with a somewhat attenuated form of HLD6 showing slow progression. He had mildly delayed psychomotor development and developed lower limb spasticity with an unstable gait, toe walking, and frequent falls. He had hip and knee flexion, Achilles tendon shortening, hyperreflexia of the lower limbs, and extensor plantar responses. He also had signs and symptoms of cerebellar atrophy, including lack of smooth pursuit, dysarthria, tremor, and dysmetria. Mild dystonic posturing appeared during action and at rest. Language delay, mild intellectual disability, and severe attention deficit with hyperactivity were also noted. Brain MRI showed incomplete myelination of the cerebral hemispheric deep and subcortical white matter, and cerebellar atrophy. The patient had been treated with colchicine since age 5 years due to genetically confirmed familial Mediterranean fever (FMF; 249100). Purnell et al. (2014) reported a 4-year-old girl with HLD6. She was first noted to have hypotonia and rotary nystagmus at age 2 months. She had delayed psychomotor development with lack of speech, but had not developed spasticity, dystonia, or choreoathetoid movements by age 4 years. She also had difficulty swallowing foods, and received a gastrostomy tube. The nystagmus resolved by 1 year of age. Brain MRI showed hypomyelination of the dorsal midbrain, cerebellum, and corpus callosum with mild atrophy of the brainstem and cerebellum. The basal ganglia were normal. Pizzino et al. (2014) reported 5 patients, including 2 adult sibs, with HLD6 confirmed by genetic analysis. All carried a de novo heterozygous TUBB4A mutation, including the 2 adult sibs whose parents did not carry the mutation in peripheral blood, suggesting low-level mosaicism in 1 of the parents. All patients had onset of motor disabilities in early childhood, sometimes with cognitive impairment. Brain imaging showed hypomyelination in all patients, but only 1 had cerebellar atrophy, and the 2 adults had global atrophy. The remaining 2 patients had isolated hypomyelination. None of the patients had severe basal ganglia involvement as evidenced by lack of putamen atrophy even after 5 decades of disease progression. The findings expanded the neuropathologic phenotype associated with TUBB4A, and indicated that some patients may have isolated hypomyelination without additional brain abnormalities. Kancheva et al. (2015) reported a consanguineous Roma Gypsy family from Bulgaria in which 5 sibs had HLD6. The patients presented in the first year of life with delayed motor development. Three patients learned to walk but lost independent ambulation later in childhood or during the teenage years, and 2 never achieved ambulation. Symptoms included spastic paraparesis, hyperreflexia, weakness of the lower limbs, broken eye pursuit, and dysmetria. Three patients had cerebellar ataxia; nerve conduction studies performed in 2 patients showed axonal motor and sensory polyneuropathy. Two patients who underwent brain imaging showed periventricular hypomyelination and mild cerebellar atrophy. None of the patients had dystonia or cognitive impairment. Inheritance HLD6 usually results from de novo mutations and occurs sporadically. However, Simons et al. (2013) reported 2 sibs with the disorder who inherited the mutation from an unaffected mother who was somatic mosaic for the mutation. Molecular Genetics In 9 unrelated patients with hypomyelinating leukodystrophy-6, Simons et al. (2013) identified the same de novo heterozygous mutation in the TUBB4A gene (D249N; 602662.0002). Two sibs with the disorder inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation was found by exome sequencing, confirmed by Sanger sequencing, and was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and Simons et al. (2013) suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells. In a 9-year-old boy with slowly progressive HLD6, Blumkin et al. (2014) identified a de novo heterozygous missense mutation in the TUBB4A gene (E410K; 602662.0004). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. In a 4-year-old girl with HLD6, Purnell et al. (2014) identified a de novo heterozygous missense mutation in the TUBB4A gene (R156L; 602662.0005). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. In 8 unrelated Japanese patients with HLD6, Miyatake et al. (2014) identified heterozygous missense mutations in the TUBB4A gene (see, e.g., 602662.0002; 602662.0004; 602662.0006-602662.0007). The mutations, which were found by whole-exome sequencing, occurred de novo in all cases with available parental samples. Structural modeling suggested that the mutations could affect microtubule assembly, structure, or interaction with other proteins, but functional studies were not performed. In 5 sibs with HLD6 from a consanguineous Roma Gypsy family, Kancheva et al. (2015) identified a heterozygous missense mutation in the TUBB4A gene (H190Y; 602662.0008). Functional studies of the variant were not performed. INHERITANCE \- Autosomal dominant GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly Ears \- Hearing loss (uncommon) Eyes \- Optic atrophy \- Poor vision \- Oculogyric eye movements \- Nystagmus (uncommon) NEUROLOGIC Central Nervous System \- Delayed motor development \- Hypomyelination of the brain white matter, diffuse \- Leukodystrophy \- Truncal hypotonia \- Spasticity \- Choreoathetosis \- Ataxia \- Tremor \- Dystonia \- Rigidity \- Gait impairment \- Loss of independent ambulation \- Poor speech development \- Dysarthria \- Seizures \- Opisthotonic posturing \- Learning difficulties \- Mental retardation, moderate to severe (in some patients) \- Cerebellar atrophy \- Basal ganglia atrophy \- Absence or atrophy of the putamen \- Small caudate MISCELLANEOUS \- Most cases result from de novo mutation \- Initial development may appear normal \- Onset in infancy up to 3 years \- Variable severity \- Progressive disorder MOLECULAR BASIS \- Caused by mutation in the tubulin, beta-4A gene (TUBB4A, 602662.0002 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

LEUKODYSTROPHY, HYPOMYELINATING, 6

c2676244

omim

https://www.omim.org/entry/612438

{"doid": ["0060798"], "mesh": ["C567314"], "omim": ["612438"], "orphanet": ["139441"], "synonyms": ["LEUKODYSTROPHY, HYPOMYELINATING, WITH ATROPHY OF THE BASAL GANGLIA AND CEREBELLUM", "Alternative titles", "H-ABC"], "genereviews": ["NBK395611"]}

Gianotti Crosti syndrome (GCS) is a rare childhood skin condition characterized by a papular rash with blisters on the skin of the legs, buttocks, and arms. It typically affects children between 9 months and 9 years of age. Skin lesions typically last at least 10 days and often last for several weeks. The lesions are usually preceded by an underlying infection (usually a virus), which may cause associated symptoms such as low-grade fever, sore throat, or symptoms of an upper respiratory infection. When GCS is associated with hepatitis B, Epstein-Barr, or cytomegalovirus (CMV) infection, acute hepatitis may also occur. GCS is thought to be a hypersensitive response to the underlying infection. While in many countries the underlying cause is hepatitis B, this is rarely the cause in North America. GCS typically does not require treatment and goes away on its own within 1 to 3 months. In some cases, a mild topical steroid cream may be prescribed to relieve itching. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Gianotti Crosti syndrome

c0263372

gard

https://rarediseases.info.nih.gov/diseases/6499/gianotti-crosti-syndrome

{"mesh": ["D000169"], "synonyms": ["Acrodermatitis, infantile lichenoid", "Acrodermatitis, papular infantile", "Crosti-gianotti syndrome", "GCS", "PAC", "Papular acrodermatitis of childhood", "PAS"]}

A rare subtype of autosomal recessive limb-girdle muscular dystrophy disorder characterized by infantile to childhood-onset of slowly progressive, principally proximal, shoulder and/or pelvic-girdle muscular weakness that typically presents with positive Gowers' sign and is associated with elevated creatine kinase levels, hyporeflexia, joint and achilles tendon contractures, and muscle hypertrophy, usually of the thighs, calves and/or tongue. Other highly variable features include cerebellar, cardiac and ocular abnormalities. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

ISPD-related limb-girdle muscular dystrophy R20

c4015095

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=352479

{"omim": ["616052"], "icd-10": ["G71.0"], "synonyms": ["Autosomal recessive limb-girdle muscular dystrophy type 2U", "ISPD-related LGMD R20", "LGMD type 2U", "LGMD2U", "Limb-girdle muscular dystrophy type 2U"]}

Omodysplasia is a rare skeletal dysplasia characterized by severe limb shortening and facial dysmorphism. Two types of omodysplasia have been described: an autosomal recessive or generalized form (also referred to as micromelic dysplasia with dislocation of radius) marked by severe micromelic dwarfism with predominantly rhizomelic shortening of both the upper and lower limbs, and an autosomal dominant form in which stature is normal and shortening is limited to the upper limbs. ## Epidemiology In total, less than 40 cases of omodysplasia have been described in the literature so far, with the majority of reported cases concerning the autosomal recessive form of the disease. ## Clinical description The facial dysmorphism is characterized by frontal bossing, a depressed nasal bridge with a short nose and a long and prominent philtrum. Decreased mobility of the elbows and knees is also a common feature. Other less frequent manifestations include midline hemangiomas, congenital heart defects, craniosynostosis and cryptorchidism in males. ## Etiology The etiology remains unknown but a paternally-inherited paracentric inversion of 15q13 to q21.3 has been detected in one family. ## Diagnostic methods Diagnosis is based on the clinical and radiological phenotype with major radiological findings including shortening and club-like tapering of the humeri and femora, proximal radioulnar diastasis and proximal radial head dislocation. Although the hands are generally considered to be normal in omodysplasia, short first metacarpals have been reported in the majority of patients with the autosomal dominant form. ## Differential diagnosis The differential diagnosis for the autosomal recessive form should include diastrophic dysplasia, atelosteogenesis and Larsen syndrome (see these terms), whereas the major differential diagnosis for the autosomal dominant form is Robinow syndrome (see this term). ## Antenatal diagnosis For affected families, detection of long bone anomalies by ultrasonography may allow prenatal diagnosis as early as at 13 weeks of gestation. ## Genetic counseling Genetic counseling should be recommended. ## Management and treatment Treatment is symptomatic only, involving mainly orthopedic management for recurrent joint dislocation. ## Prognosis The prognosis is variable. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Omodysplasia

c2750355

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2733

{"mesh": ["C567664"], "omim": ["164745", "258315"], "icd-10": ["Q78.8"]}

Sarcomatoid carcinoma of the lung SpecialtyOncology/pulmonology Sarcomatoid carcinoma of the lung is a term that encompasses five distinct histological subtypes of lung cancer, including (1) pleomorphic carcinoma, (2) spindle cell carcinoma, (3) giant cell carcinoma, (4) carcinosarcoma, or (5) pulmonary blastoma.[1] ## Contents * 1 Genetics * 2 Diagnosis * 2.1 Classification * 3 Treatment * 4 Prognosis * 5 References * 6 External links ## Genetics[edit] Abnormal duplication of the EGFR gene is a relatively infrequent phenomenon in SCL (>/= 4 copies in >/= 40% of cells in 5/22)[2] Overexpression of the EGFR protein occurs in nearly all cases (22/22).[2] Mutations of the EGFR gene are relatively rare (0/23).[2] K-ras mutations found in 8/22 cases (Gly12Cys in 6 cases and Gly12Val in 2 cases)[2] SCL show intense immune infiltration which is predominantly neutrophillic. However the tumors evade the immune system by increased expression of a negative regulator of T-cells mainly programmed death ligand-1.[3] ## Diagnosis[edit] ### Classification[edit] Lung cancer is a large and exceptionally heterogeneous family of malignancies.[4] Over 50 different histological variants are explicitly recognized within the 2004 revision of the World Health Organization (WHO) typing system ("WHO-2004"), currently the most widely used lung cancer classification scheme.[1] Many of these entities are rare, recently described, and poorly understood.[5] However, since different forms of malignant tumors generally exhibit diverse genetic, biological, and clinical properties, including response to treatment, accurate classification of lung cancer cases are critical to assuring that patients with lung cancer receive optimum management.[6][7] Approximately 98% of lung cancers are carcinoma, a term for malignant neoplasms derived from cells of epithelial lineage, and/or that exhibit cytological or tissue architectural features characteristically found in epithelial cells.[8] Under WHO-2004, lung carcinomas are divided into 8 major taxa:[1] * Squamous cell carcinoma * Small cell carcinoma * Adenocarcinoma * Large cell carcinoma * Adenosquamous carcinoma * Sarcomatoid carcinoma * Carcinoid tumor * Salivary gland-like carcinoma Sarcomatoid carcinomas are unique among lung carcinomas in that, although they are considered carcinomas, they contain cytological and tissue architectural features that are usually characteristic of sarcoma.[1] ## Treatment[edit] Because these tumors are so rare, there have been no randomized clinical trials yet conducted with respect to specific treatment regimens for any subtype.[9][10] Very few histospecific studies of individual subtypes SCL have been published in the literature; most data has been small retrospective case series or case reports. In many cases, SCL are generally treated like other NSCLC. However, as SCL are considered particularly aggressive non-small cell lung cancers,[2] some experts recommend particularly aggressive treatment approach to these tumors. Little is known about the effects of EGFR inhibitors in SC, although some evidence suggests that these tumors are not likely to be highly responsive.[2] ## Prognosis[edit] As a group, SCL prognosis is considered to be worse than that of most types of NSCLC.[citation needed] ## References[edit] 1. ^ a b c d Travis, William D; Brambilla, Elisabeth; Muller-Hermelink, H Konrad; et al., eds. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (PDF). World Health Organization Classification of Tumours. Lyon: IARC Press. ISBN 978-92-832-2418-1. Retrieved 27 March 2010. 2. ^ a b c d e f Italiano A, Cortot AB, Ilie M, et al. (November 2009). "EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: implications for anti-EGFR treatment of a rare lung malignancy". Int. J. Cancer. 125 (10): 2479–82. doi:10.1002/ijc.24610. PMID 19681124. S2CID 205938398. 3. ^ Velcheti, V.; Rimm, D. L.; Schalper, K. A. (2013). "Sarcomatoid Lung Carcinomas Show High Levels of Programmed Death Ligand-1 (PD-L1)". Journal of Thoracic Oncology. 8 (6): 803–805. doi:10.1097/JTO.0b013e318292be18. PMC 3703468. PMID 23676558. 4. ^ Roggli VL, Vollmer RT, Greenberg SD, McGavran MH, Spjut HJ, Yesner R (June 1985). "Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases". Hum. Pathol. 16 (6): 569–79. doi:10.1016/S0046-8177(85)80106-4. PMID 2987102. 5. ^ Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y (December 2001). "The new World Health Organization classification of lung tumours". Eur. Respir. J. 18 (6): 1059–68. doi:10.1183/09031936.01.00275301. PMID 11829087. 6. ^ Rossi G, Marchioni A, Sartori1 G, Longo L, Piccinini S, Cavazza A (2007). "Histotype in non-small cell lung cancer therapy and staging: The emerging role of an old and underrated factor". Curr Resp Med Rev. 3: 69–77. doi:10.2174/157339807779941820.CS1 maint: multiple names: authors list (link) 7. ^ Vincent MD (August 2009). "Optimizing the management of advanced non-small-cell lung cancer: a personal view". Curr Oncol. 16 (4): 9–21. doi:10.3747/co.v16i4.465. PMC 2722061. PMID 19672420. 8. ^ Travis WD, Travis LB, Devesa SS (January 1995). "Lung cancer". Cancer. 75 (1 Suppl): 191–202. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. PMID 8000996. 9. ^ National Library of Medicine. Available at http://www.pubmed.com 10. ^ National Institutes of Health. Clinical Trials Search Engine. Available at http://www.clinicaltrials.gov/ct2/results?term=sarcomatoid+carcinoma ## External links[edit] * Lung Cancer Home Page. The National Cancer Institute site containing further reading and resources about lung cancer. * World Health Organization Histological Classification of Lung and Pleural Tumours. 4th Edition * v * t * e Cancer involving the respiratory tract Upper RT Nasal cavity Esthesioneuroblastoma Nasopharynx Nasopharyngeal carcinoma Nasopharyngeal angiofibroma Larynx Laryngeal cancer Laryngeal papillomatosis Lower RT Trachea * Tracheal tumor Lung Non-small-cell lung carcinoma * Squamous-cell carcinoma * Adenocarcinoma (Mucinous cystadenocarcinoma) * Large-cell lung carcinoma * Rhabdoid carcinoma * Sarcomatoid carcinoma * Carcinoid * Salivary gland–like carcinoma * Adenosquamous carcinoma * Papillary adenocarcinoma * Giant-cell carcinoma Small-cell carcinoma * Combined small-cell carcinoma Non-carcinoma * Sarcoma * Lymphoma * Immature teratoma * Melanoma By location * Pancoast tumor * Solitary pulmonary nodule * Central lung * Peripheral lung * Bronchial leiomyoma Pleura * Mesothelioma * Malignant solitary fibrous tumor *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Sarcomatoid carcinoma of the lung

c1708781

wikipedia

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

{"umls": ["C1708781"], "wikidata": ["Q7423600"]}

## Clinical Features Carmel and Herbert (1969) reported 2 adult brothers from a Puerto Rican-Corsican family with decreased serum cobalamin (vitamin B12) due to congenital absence of the R-type binders of cobalamin in serum, saliva, cerebrospinal fluid, gastric juice, and granulocytes. The saliva contained no immunologic R binder, but a small amount of cross-reacting material was found in the serum. Partial deficiency was found in all 3 offspring of the affected males tested. The defect appeared to be clinically benign. Hall and Begley (1977) reported follow-up of the family reported by Carmel and Herbert (1969). One of the brothers had a slowly progressive neurologic disease characterized by spastic paraparesis and dementia, but the authors thought that it was unrelated to the transcobalamin defect as no other family members with R binder deficiency were affected. Lin et al. (2001) provided further follow-up of the brother followed by Hall and Begley (1977). His neurologic condition had deteriorated despite intermittent cobalamin injections, and he died in 1983 of an unknown cause. Laboratory studies late in his life showed decreased serum cobalamin and borderline low serum iron with no megaloblastic changes. Further laboratory studies confirmed decreased TCN1 levels and identified a serum and salivary deficiency of lactoferrin (LTF; 150210), a protein that coexists with R binder in specific granules of neutrophils and in secretions. His son and the son of his older R-deficient brother, both presumptive heterozygotes, also had mild deficiency of both R binder and lactoferrin. None of the patients had a predisposition to infections, as seen in specific granule deficiency (SGD; 245480). In contrast, serum and salivary lactoferrin levels were normal in 4 additional unrelated patients with TCN1 deficiency. Lin et al. (2001) postulated that the deficiencies of both TCN1 and lactoferrin constituted a unique hereditary disorder that was distinct from that of isolated R binder deficiency. Carmel (1982) reported a 77-year-old man with low serum cobalamin due to transcobalamin I deficiency. In addition, salivary cobalamin R binder protein was virtually undetectable, thus establishing the diagnosis. Laboratory studies showed that almost all of his cobalamin was carried by TCN2 (613441). Megaloblastic anemia was not present and the patient was able to maintain normal serum cobalamin levels while receiving monthly injections. The patient also had chronic anemia, atrophic gastritis, mild congestive heart failure, and mild distal vibratory loss, the last of which the authors attributed to coexisting folate deficiency and alcohol abuse. Carmel (1982) concluded that transcobalamin I deficiency is a benign disorder, in marked contrast to transcobalamin II deficiency (275350). Carmel (1983) reported a 64-year-old man with decreased serum cobalamin, normal serum folate, and no megaloblastic changes. No methylmalonic acid or homocystine was found in the urine. No R binder was detected in serum, gastric juices, saliva, or granulocytes by radioimmunoassay. The patient had no neurologic dysfunction related to low serum cobalamin. Sigal et al. (1987) described a previously healthy man with plasma R binder deficiency who was evaluated at 45 years of age for paresthesias in both hands. Paresthesias and numbness gradually developed in his legs and his gait became unsteady. Two years later he had moderate to severe loss of proprioceptive sensation in all limbs, mild loss of perception of pain and touch, hypoactive to absent deep tendon reflexes, but intact strength. Seven years after onset the patient had marked difficulty in manipulating objects with his hands, his gait had become wide-based, and proprioception was absent at the elbows and knees. Pinprick and temperature sensations were slightly reduced at the wrist and ankles, and deep tendon reflexes were absent. By 10 years after onset (age 55), he was confined to a wheelchair. Vitamin B12 appeared to have no therapeutic value. Serum B12 levels were decreased, and serum R binder levels were absent, but low levels of R binder were detectable in saliva. Adcock and McKnight (2002) reported a 48-year-old woman who was found on routine testing to have decreased serum cobalamin and mildly increased mean corpuscular volume. Serum folate, homocysteine, and methylmalonic acid were normal. Vitamin B12 injections resulted in only transient improvement in serum cobalamin levels. Laboratory findings and the absence of neurologic, gastrointestinal, and hematologic abnormalities suggested TCN1 deficiency. Adcock and McKnight (2002) emphasized the importance of correct diagnosis of TCN1 deficiency in the setting of decreased cobalamin because unnecessary treatment can be avoided. Molecular Genetics In 1 of the brothers with TCN1 deficiency originally reported by Carmel and Herbert (1969), Lin et al. (2001) did not identify any mutations in the promoter region of the initial coding sequence of the TCN1 gene (189905). However, shortage of material prevented further sequencing. INHERITANCE \- Autosomal recessive HEMATOLOGY \- Mean corpuscular volume may mildly increased or normal LABORATORY ABNORMALITIES \- Decreased serum cobalamin \- Decreased transcobalamin I in saliva, serum, gastric juice, and cerebrospinal fluid \- Decreased serum and salivary lactoferrin has been described in 1 family MISCELLANEOUS \- Considered a benign disorder ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

TRANSCOBALAMIN I DEFICIENCY

c0342700

omim

https://www.omim.org/entry/193090

{"mesh": ["C562798"], "omim": ["193090"], "orphanet": ["2967"], "synonyms": ["Alternative titles", "TCN1 DEFICIENCY", "COBALAMIN PSEUDODEFICIENCY DUE TO TRANSCOBALAMIN DEFICIENCY", "COBALAMIN R BINDER PROTEIN DEFICIENCY"]}

Glycogen storage disease type III (also known as GSDIII or Cori disease) is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body's cells. The accumulated glycogen is structurally abnormal and impairs the function of certain organs and tissues, especially the liver and muscles. GSDIII is divided into types IIIa, IIIb, IIIc, and IIId, which are distinguished by their pattern of signs and symptoms. GSD types IIIa and IIIc mainly affect the liver and muscles, and GSD types IIIb and IIId typically affect only the liver. It is very difficult to distinguish between the types of GSDIII that affect the same tissues. GSD types IIIa and IIIb are the most common forms of this condition. Beginning in infancy, individuals with any type of GSDIII may have low blood sugar (hypoglycemia), excess amounts of fats in the blood (hyperlipidemia), and elevated blood levels of liver enzymes. As they get older, children with this condition typically develop an enlarged liver (hepatomegaly). Liver size usually returns to normal during adolescence, but some affected individuals develop chronic liver disease (cirrhosis) and liver failure later in life. People with GSDIII often have slow growth because of their liver problems, which can lead to short stature. In a small percentage of people with GSDIII, noncancerous (benign) tumors called adenomas may form in the liver. Individuals with GSDIIIa may develop muscle weakness (myopathy) later in life. These muscle problems can affect both heart (cardiac) muscle and the muscles that are used for movement (skeletal muscles). Muscle involvement varies greatly among affected individuals. The first signs and symptoms are typically poor muscle tone (hypotonia) and mild myopathy in early childhood. The myopathy may become severe by early to mid-adulthood. Some people with GSDIIIa have a weakened heart muscle (cardiomyopathy), but affected individuals usually do not experience heart failure. Other people affected with GSDIIIa have no cardiac muscle problems. ## Frequency The incidence of GSDIII in the United States is 1 in 100,000 individuals. This condition is seen more frequently in people of North African Jewish ancestry; in this population, 1 in 5,400 individuals are estimated to be affected. GSDIIIa is the most common form of GSDIII, accounting for about 85 percent of all cases. GSDIIIb accounts for about 15 percent of cases. GSD types IIIc and IIId are very rare, and their signs and symptoms are poorly defined. Only a small number of affected individuals have been suspected to have GSD types IIIc and IIId. ## Causes Mutations in the AGL gene cause GSDIII. The AGL gene provides instructions for making the glycogen debranching enzyme. This enzyme is involved in the breakdown of glycogen, which is a major source of stored energy in the body. Between meals the body breaks down stores of energy, such as glycogen, to use for fuel. Most AGL gene mutations lead to the production of a nonfunctional glycogen debranching enzyme. These mutations typically cause GSD types IIIa and IIIb. The mutations that cause GSD types IIIc and IIId are thought to lead to the production of an enzyme with reduced function. All AGL gene mutations lead to storage of abnormal, partially broken down glycogen molecules within cells. A buildup of abnormal glycogen damages organs and tissues throughout the body, particularly the liver and muscles, leading to the signs and symptoms of GSDIII. ### Learn more about the gene associated with Glycogen storage disease type III * AGL ## 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

Glycogen storage disease type III

c0017922

medlineplus

https://medlineplus.gov/genetics/condition/glycogen-storage-disease-type-iii/

{"gard": ["9442"], "mesh": ["D006010"], "omim": ["232400"], "synonyms": []}

Coats plus syndrome is an inherited condition characterized by an eye disorder called Coats disease plus abnormalities of the brain, bones, gastrointestinal system, and other parts of the body. Coats disease affects the retina, which is the tissue at the back of the eye that detects light and color. The disorder causes blood vessels in the retina to be abnormally enlarged (dilated) and twisted. The abnormal vessels leak fluid, which can eventually cause the layers of the retina to separate (retinal detachment). These eye abnormalities often result in vision loss. People with Coats plus syndrome also have brain abnormalities including abnormal deposits of calcium (calcification), the development of fluid-filled pockets called cysts, and loss of a type of brain tissue known as white matter (leukodystrophy). These brain abnormalities worsen over time, causing slow growth, movement disorders, seizures, and a decline in intellectual function. Other features of Coats plus syndrome include low bone density (osteopenia), which causes bones to be fragile and break easily, and a shortage of red blood cells (anemia), which can lead to unusually pale skin (pallor) and extreme tiredness (fatigue). Affected individuals can also have serious or life-threatening complications including abnormal bleeding in the gastrointestinal tract, high blood pressure in the vein that supplies blood to the liver (portal hypertension), and liver failure. Less common features of Coats plus syndrome can include sparse, prematurely gray hair; malformations of the fingernails and toenails; and abnormalities of skin coloring (pigmentation), such as light brown patches called café-au-lait spots. Coats plus syndrome and a disorder called leukoencephalopathy with calcifications and cysts (LCC; also called Labrune syndrome) have sometimes been grouped together under the umbrella term cerebroretinal microangiopathy with calcifications and cysts (CRMCC) because they feature very similar brain abnormalities. However, researchers recently found that Coats plus syndrome and LCC have different genetic causes, and they are now generally described as separate disorders instead of variants of a single condition. ## Frequency Coats plus syndrome appears to be a rare disorder. Its prevalence is unknown. ## Causes Coats plus syndrome results from mutations in the CTC1 gene. This gene provides instructions for making a protein that plays an important role in structures known as telomeres, which are found at the ends of chromosomes. Telomeres are short, repetitive segments of DNA that help protect chromosomes from abnormally sticking together or breaking down (degrading). In most cells, telomeres become progressively shorter as the cell divides. After a certain number of cell divisions, the telomeres become so short that they trigger the cell to stop dividing or to self-destruct (undergo apoptosis). The CTC1 protein works as part of a group of proteins known as the CST complex, which is involved in the copying (replication) of telomeres. The CST complex helps prevent telomeres from being degraded in some cells as the cells divide. Mutations in the CTC1 gene impair the function of the CST complex, which affects the replication of telomeres. However, it is unclear how CTC1 gene mutations impact telomere structure and function. Some studies have found that people with CTC1 gene mutations have abnormally short telomeres, while other studies have found no change in telomere length. Researchers are working to determine how telomeres are different in people with CTC1 gene mutations and how these changes could underlie the varied signs and symptoms of Coats plus syndrome. ### Learn more about the gene associated with Coats plus syndrome * CTC1 ## 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

Coats plus syndrome

c2677299

medlineplus

https://medlineplus.gov/genetics/condition/coats-plus-syndrome/

{"gard": ["6121"], "mesh": ["C567401"], "omim": ["612199"], "synonyms": []}

A number sign (#) is used with this entry because of evidence that at least some cases of the wrinkly skin syndrome are caused by homozygous or compound heterozygous mutations in the ATP6V0A2 gene (611716) on chromosome 12q24. The occurrence of mutations in the same gene in autosomal recessive cutis laxa type IIA (ARCL2A; 219200) indicates that wrinkly skin syndrome and some cases of autosomal recessive cutis laxa type IIA represent variable manifestations of the same genetic defect. Clinical Features In 2 and possibly 3 offspring of first-cousin parents, Gazit et al. (1973) described a disorder they called the wrinkly skin syndrome. It was characterized at birth by wrinkled skin of the hands and feet with an increased number of wrinkles on the palms and soles. Skeletal musculature was poorly developed and hypotonic with winging of the scapulas. The venous pattern was prominent over the anterior thorax. The patients of Gazit et al. (1973) were Iraqi Jews. Karrar et al. (1983) described WSS in 2 Saudi Arabian sibs, a brother and sister whose parents were first cousins. Casamassima et al. (1987) reported a case indicating that mental retardation and microcephaly are components of the syndrome. Skin biopsy showed elastic fiber abnormalities. An atrial septal aneurysm was demonstrated on echocardiography. Hurvitz et al. (1990) reported another case. Kreuz and Wittwer (1993) reported a mother and her 2 sons with an interstitial deletion involving band q32 of chromosome 2 and compared their phenotypes with those of 20 previously reported individuals with the same deletion. All individuals had small size at birth, retarded growth and development, craniofacial dysmorphism, and skeletal and ocular anomalies. The mother and sons reported by Kreuz and Wittwer (1993), however, also showed features of the wrinkly skin syndrome, including wrinkling of the abdominal skin and the skin of the dorsum of the hands and feet, decreased elastic recoil of the skin, an increased number of palmar and plantar creases, musculoskeletal anomalies, microcephaly, mental retardation, and an old appearance. Broken elastic fibers were evident on light microscopy of the skin biopsies. The boys demonstrated a peculiar grimacing. Their serum copper and ceruloplasmin (117700) levels were slightly raised. The occurrence of WSS in association with heterozygosity for the deletion may be inconsistent with the presumed recessive inheritance of WSS. Azuri et al. (1999) found reports of 9 cases of wrinkly skin syndrome and also pointed to the 3 patients reported by Kreuz and Wittwer (1993) who showed some manifestations of WSS. They presented the case of a 2.5-year-old girl, the daughter of healthy, first-cousin Muslim parents, who had WSS associated with prominent neurologic involvement manifested by mental retardation, microcephaly, and an episode of epilepticus. In a letter, Zlotogora (1999) noted that Gazit et al. (1973) described the wrinkly skin syndrome in 2 girls and their newborn brother born to consanguineous Jews originating from Iraq. This report was written without the knowledge that the same 2 girls had been reported by Reisner et al. (1971) as one of the first examples of the syndrome of cutis laxa with growth and developmental delay (219200). The report of affected sibs by Ogur et al. (1990) supported the suggestion that the 2 disorders represent variable presentations of the same syndrome. A boy was severely affected with the classic form of cutis laxa and developmental delay, while his sister showed improvement over the years and at the age of 6.5 years presented with a relatively mild disease, including cutaneous manifestations similar to those found in the wrinkly skin syndrome. Kornak et al. (2008) noted that an association of a cutis laxa phenotype with a congenital disorder of glycosylation (CDG) had been described (Morava et al., 2005) and that wrinkly skin had been observed in an individual with a defect in the conserved oligomeric Golgi (COG) complex (Wu et al., 2004). On the basis of these observations, Kornak et al. (2008) investigated glycosylation of serum proteins isolated form individuals with ARCL2 and WSS and found that they showed a CDG type II pattern, which corresponds to a defect of N-glycosylation at the level of processing in the Golgi apparatus. Reduced sialic acid content of the glycans from affected individuals indicated that sialylation, a terminal step of glycan synthesis, was particularly impaired. A strict correlation between phenotype and degree of glycan abnormality was not seen. ### Phenotypic Overlap with Geroderma Osteodysplasticum Rajab et al. (2008) reported on 22 Omani patients from 11 consanguineous families with the diagnosis of wrinkly skin syndrome or geroderma osteodysplastica (231070) and concluded that the 2 disorders are distinct. Fourteen patients from 8 families had WSS. The WSS phenotype includes generalized, excessive skin wrinkling, dental problems (small teeth, delayed eruption, caries), hernia, congenital hip dislocation, failure to thrive, and large anterior fontanel. Isoelectric focusing of serum transferring revealed a sialotransferrin type 2 pattern in all 4 WSS patients studied, suggesting that WSS is related to an N-protein glycosylation defect, probably at the level of processing (CDG II). Mapping By homozygosity mapping in consanguineous families diagnosed with WSS or ARCL2, Kornak et al. (2008) found linkage to chromosome 12q24 (maximum lod = 3.2) in 12 families, including 4 with WSS. Molecular Genetics Kornak et al. (2008) found loss-of-function mutations in the ATP6V0A2 gene (see 611716.0003) in affected members of 4 consanguineous families from Oman diagnosed with wrinkly skin syndrome. They also found 8 different mutations in this gene (see 611716.0001-611716.0002) in patients diagnosed with autosomal recessive cutis laxa type II in 8 families living in other areas. The findings indicated a mechanism leading to a congenital glycosylation defect and showed that WSS and ARCL2 are variable manifestations of the same genetic defect. Rajab et al. (2008) stated that they reported the clinical features of 5 Omani families (families D, E, F, G, and H) with WSS that were found to have a mutation in the ATP6V0A2 gene by Kornak et al. (2008). In 1 of the Omani families originally reported by Rajab et al. (2008) with clinical features consistent with GO, Reversade et al. (2009) identified homozygosity for a missense mutation in the PYCR1 gene (179035.0008; see ARCL2B, 612940). ### Exclusion Studies In 3 families segregating WSS and 2 families segregating geroderma osteodysplastica, Rajab et al. (2008) excluded loci that had been described in cutis laxa and WSS phenotypes on 2q31, 5q23-q31 (LOX, 153455 and ADAMTS2, 604539); 7q11 (ELN, 130160), 11q13 (EFEMP2, 604633), and 14q32 (FBLN5, 604580). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Failure to thrive HEAD & NECK Head \- Large anterior fontanel \- Delayed closure of fontanels \- Normal birth head circumference \- Progressive microcephaly Face \- Sagging cheeks \- Long philtrum \- Smooth philtrum Ears \- Low-set ears Eyes \- Hypertelorism \- Downslanting palpebral fissures \- Epicanthal folds Nose \- Broad nasal bridge Mouth \- High-arched palate Teeth \- Small teeth \- Delayed tooth eruption \- Dental caries RESPIRATORY \- Recurrent lower respiratory infections CHEST Ribs Sternum Clavicles & Scapulae \- Pectus excavatum ABDOMEN External Features \- Umbilical hernia GENITOURINARY External Genitalia (Male) \- Inguinal hernia Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Osteopenia Skull \- Wormian bones Spine \- Scoliosis \- Kyphosis Pelvis \- Congenital hip dislocation \- Coxa vara Limbs \- Slender long bones Hands \- Deep palmar creases \- Hyperextensible joints Feet \- Deep plantar creases \- Club feet \- Pes planus SKIN, NAILS, & HAIR Skin \- Generalized skin wrinkling \- Deep palmar creases \- Deep plantar creases \- Skin laxity Skin Histology \- Frayed, broken, and shortened elastic fibers Nails \- Short nails \- Brittle nails Hair \- Sparse hair MUSCLE, SOFT TISSUES \- Reduced muscle mass \- Abnormal subcutaneous fat distribution NEUROLOGIC Central Nervous System \- Speech delay VOICE \- Nasal voice PRENATAL MANIFESTATIONS Delivery \- Premature rupture of membranes LABORATORY ABNORMALITIES \- Abnormal isoelectric focusing of serum transferrin \- Normal isoelectric focusing of apolipoprotein CIII MISCELLANEOUS \- Skin wrinkling improves with age MOLECULAR BASIS \- Caused by mutation in the ATPase, H+ transporting, lysosomal, V0 subunit A2 gene (ATP6V0A2, 611716.0003 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

WRINKLY SKIN SYNDROME

c0406587

omim

https://www.omim.org/entry/278250

{"mesh": ["C536750"], "omim": ["278250"], "orphanet": ["2834", "357058"], "genereviews": ["NBK5200"]}

Deformity of the finger or toe nails associated with a number of diseases Clubbing Other namesDrumstick fingers, Hippocratic fingers, digital clubbing, watch-glass nails[1] Clubbing SpecialtyPulmonology Nail clubbing, also known as digital clubbing or clubbing, is a deformity of the finger or toe nails associated with a number of diseases, mostly of the heart and lungs.[2][3] When it occurs together with joint effusions, joint pains, and abnormal skin and bone growth it is known as hypertrophic osteoarthropathy.[4] Clubbing is associated with lung cancer, lung infections, interstitial lung disease, cystic fibrosis, or cardiovascular disease.[5] Clubbing may also run in families,[5] and occur unassociated with other medical problems.[6][7] The incidence of clubbing is unknown; it was present in about 1% of people admitted to an internal medicine unit of a hospital.[5] Clubbing has been recognized as a sign of disease since the time of Hippocrates.[5] ## Contents * 1 Causes * 1.1 Hypertrophic pulmonary osteoarthropathy * 1.2 Primary hypertrophic osteoarthropathy * 2 Pathophysiology * 3 Diagnosis * 3.1 Stages * 4 Epidemiology * 5 History * 6 See also * 7 References ## Causes[edit] Clubbing is associated with * Lung disease: * Lung cancer, mainly non-small-cell (54% of all cases), not seen frequently in small-cell lung cancer (< 5% of cases)[8] * Interstitial lung disease most commonly idiopathic pulmonary fibrosis * Complicated tuberculosis * Suppurative lung disease: lung abscess, empyema, bronchiectasis, cystic fibrosis * Mesothelioma of the pleura * Arteriovenous fistula or malformation * Sarcoidosis * Heart disease: * Any disease featuring chronic hypoxia * Congenital cyanotic heart disease (most common cardiac cause) * Subacute bacterial endocarditis * Atrial myxoma (benign tumor) * Tetralogy of Fallot * Gastrointestinal and hepatobiliary: * Malabsorption * Crohn's disease and ulcerative colitis * Cirrhosis, especially in primary biliary cholangitis[9] * Hepatopulmonary syndrome, a complication of cirrhosis[10] * Others: * Graves' disease (autoimmune hyperthyroidism) – in this case it is known as thyroid acropachy[11] * Familial and hereditary clubbing and "pseudoclubbing" (people of African descent often have what appears to be clubbing) * Vascular anomalies of the affected arm such as an axillary artery aneurysm (in unilateral clubbing) Nail clubbing is not specific to chronic obstructive pulmonary disease (COPD). Therefore, in patients with COPD and significant degrees of clubbing, a search for signs of bronchogenic carcinoma (or other causes of clubbing) might still be indicated.[12] A congenital form has also been recognized.[13] ### Hypertrophic pulmonary osteoarthropathy[edit] Main article: Periosteal reaction Bone scan of a patient with HPOA A special form of clubbing is hypertrophic pulmonary osteoarthropathy (HPOA), known in continental Europe as Pierre Marie-Bamberger syndrome. This is the combination of clubbing and thickening of periosteum (connective tissue lining of the bones) and synovium (lining of joints), and is often initially diagnosed as arthritis. It is commonly associated with lung cancer.[citation needed] ### Primary hypertrophic osteoarthropathy[edit] Primary hypertrophic osteoarthropathy is HPOA without signs of pulmonary disease. This form has a hereditary component, although subtle cardiac abnormalities can occasionally be found. It is known eponymously as the Touraine–Solente–Golé syndrome. This condition has been linked to mutations in the gene on the fourth chromosome (4q33-q34) coding for the enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD); this leads to decreased breakdown of prostaglandin E2 and elevated levels of this substance.[14] ## Pathophysiology[edit] The exact cause for sporadic clubbing is unknown. Theories as to its cause include: * Vasodilation (i.e., distended blood vessels). * Secretion of growth factors (e.g., platelet-derived growth factor and hepatocyte growth factor) from the lungs. * Overproduction of prostaglandin E2 by other tissues.[14] * Increased entry of megakaryocytes into the systemic circulation. Under normal circumstances in healthy individuals, megakaryocytes that arise from the bone marrow are trapped in the pulmonary capillary bed and broken down before they enter the systemic circulation. It is thought that in disorders where there is right-to-left shunting or lung malignancy, the megakaryocytes can bypass the breakdown within the pulmonary circulation and enter the systemic circulation. They are then trapped within the capillary beds within the extremities, such as the digits, and release platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). PDGF and VEGF have growth promoting properties and cause connective tissue hypertrophy and capillary permeability.[15] ## Diagnosis[edit] Clubbing of the fingernail: The red line shows the outline of a clubbed nail. When clubbing is observed, pseudoclubbing should be excluded before making the diagnosis. Associated conditions may be identified by taking a detailed medical history—particular attention is paid to lung, heart, and gastrointestinal conditions—and conducting a thorough clinical examination, which may disclose associated features relevant to the underlying diagnosis. Additional studies such as a chest X-ray and a chest CT-scan may reveal otherwise asymptomatic cardiopulmonary disease.[12] ### Stages[edit] Clubbing is present in one of five stages:[12] * No visible clubbing \- Fluctuation (increased ballotability) and softening of the nail bed only. No visible changes of nails. * Mild clubbing \- Loss of the normal <165° angle (Lovibond angle) between the nailbed and the fold (cuticula). Schamroth's window (see below) is obliterated. Clubbing is not obvious at a glance. * Moderate clubbing \- Increased convexity of the nail fold. Clubbing is apparent at a glance. * Gross clubbing \- Thickening of the whole distal (end part of the) finger (resembling a drumstick) * Hypertrophic osteoarthropathy \- Shiny aspect and striation of the nail and skin Schamroth's test or Schamroth's window test (originally demonstrated by South African cardiologist Leo Schamroth on himself)[16] is a popular test for clubbing. When the distal phalanges (bones nearest the fingertips) of corresponding fingers of opposite hands are directly opposed (place fingernails of same finger on opposite hands against each other, nail to nail), a small diamond-shaped "window" is normally apparent between the nailbeds. If this window is obliterated, the test is positive and clubbing is present. * Severe clubbing * Front view * Side views * Cyanotic nail beds ## Epidemiology[edit] The exact frequency of clubbing in the population is not known. A 2008 study found clubbing in 1%, or 15 patients, of 1511 patients admitted to a department of internal medicine in Belgium. Of these, 40%, or 6 patients, turned out to have significant underlying disease of various causes, while 60%, or 9 patients, had no medical problems on further investigations and remained well over the subsequent year.[7] ## History[edit] At least since the time of Hippocrates, clubbing has been recognized as a sign of disease.[5] The phenomenon has been called "Hippocratic fingers". ## See also[edit] * Clubbed thumb (unrelated congenital deformity) ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ Rutherford, JD (14 May 2013). "Digital clubbing". Circulation. 127 (19): 1997–9. doi:10.1161/circulationaha.112.000163. PMID 23671180. 3. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0. :656 4. ^ Krugh, M; Vaidya, PN (January 2019). "Osteoarthropathy Hypertrophic". PMID 31082012. Cite journal requires `|journal=` (help) 5. ^ a b c d e Burcovschii, S; Aboeed, A (January 2019). "Nail Clubbing". PMID 30969535. Cite journal requires `|journal=` (help) 6. ^ Schwatz, RA. "Clubbing of the Nails". Medscape. Medscape. Retrieved 14 August 2014. 7. ^ a b Vandemergel X, Renneboog B (July 2008). "Prevalence, aetiologies and significance of clubbing in a department of general internal medicine". Eur. J. Intern. Med. 19 (5): 325–9. doi:10.1016/j.ejim.2007.05.015. PMID 18549933. 8. ^ Sridhar KS, Lobo CF, Altman RD (1998). "Digital clubbing and lung cancer". Chest. 114 (6): 1535–37. doi:10.1378/chest.114.6.1535. PMID 9872183. Archived from the original (PDF) on 2003-11-01. 9. ^ Epstein O, Dick R, Sherlock S (1981). "Prospective study of periostitis and finger clubbing in primary biliary cirrhosis and other forms of chronic liver disease". Gut. 22 (3): 203–6. doi:10.1136/gut.22.3.203. PMC 1419499. PMID 7227854. 10. ^ Naeije R (March 2003). "Hepatopulmonary syndrome and portopulmonary hypertension". Swiss Med Wkly. 133 (11–12): 163–9. PMID 12715285. 11. ^ "acropachy". GPnotebook. 12. ^ a b c Myers KA, Farquhar DR (2001). "The rational clinical examination: does this patient have clubbing?". JAMA. 286 (3): 341–7. doi:10.1001/jama.286.3.341. PMID 11466101. 13. ^ Shah K, Ferrara TM, Jan A, Umair M, Irfanullah, Khan S, Ahmad W, Spritz RA (August 2017). "Homozygous SLCO2A1 translation initiation codon mutation in a Pakistani family with recessive isolated congenital nail clubbing". Br. J. Dermatol. 177 (2): 546–548. doi:10.1111/bjd.15094. PMID 27681482. 14. ^ a b Uppal S, Diggle CP, Carr IM, et al. (June 2008). "Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy". Nat. Genet. 40 (6): 789–93. doi:10.1038/ng.153. PMID 18500342. 15. ^ Dickinson, CJ; Martin, JF (19 December 1987). "Megakaryocytes and platelet clumps as the cause of finger clubbing". Lancet. 2 (8573): 1434–5. doi:10.1016/s0140-6736(87)91132-9. PMID 2891996. 16. ^ Schamroth L (February 1976). "Personal experience". S. Afr. Med. J. 50 (9): 297–300. PMID 1265563. Classification D * ICD-10: R68.3 * ICD-9-CM: 781.5 * 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 Symptoms and signs relating to the respiratory system Auscultation * Stethoscope * Respiratory sounds * Stridor * Wheeze * Crackles * Rhonchi * Stertor * Squawk * Pleural friction rub * Fremitus * Bronchophony * Terminal secretions * Elicited findings * Percussion * Pectoriloquy * Whispered pectoriloquy * Egophony Breathing Rate * Apnea * Prematurity * Dyspnea * Hyperventilation * Hypoventilation * Hyperpnea * Tachypnea * Hypopnea * Bradypnea Pattern * Agonal respiration * Biot's respiration * Cheyne–Stokes respiration * Kussmaul breathing * Ataxic respiration Other * Respiratory distress * Respiratory arrest * Orthopnea/Platypnea * Trepopnea * Aerophagia * Asphyxia * Breath holding * Mouth breathing * Snoring Other * Chest pain * In children * Precordial catch syndrome * Pleurisy * Nail clubbing * Cyanosis * Cough * Sputum * Hemoptysis * Epistaxis * Silhouette sign * Post-nasal drip * Hiccup * COPD * Hoover's sign * asthma * Curschmann's spirals * Charcot–Leyden crystals * chronic bronchitis * Reid index * sarcoidosis * Kveim test * pulmonary embolism * Hampton hump * Westermark sign * pulmonary edema * Kerley lines * Hamman's sign * Golden S sign *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Nail clubbing

c0263538

wikipedia

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

{"icd-10": ["R68.3"], "wikidata": ["Q1340669"]}

Abortion in Japan is available to women in limited circumstances, including endangerment of their health or economic hardship. Chapter XXIX of the Penal Code of Japan makes abortion de jure illegal in the country, but exceptions to the law are broad enough that it is widely accepted and practiced. Meanwhile, the Maternal Health Protection Law allows approved doctors to practice abortion with the consent of the mother and her spouse, if the pregnancy has resulted from rape, or if the continuation of the pregnancy may severely endanger the maternal health because of physical reasons or economic reasons. Anyone trying to practice abortion without the consent of the woman will be punished, including the doctors. No abortifacient has been approved in Japan. Approved doctors, however, can choose to use imported abortifacient under the same terms above. Any other people who abort the fetus using abortifacients will be punished. Emergency contraceptive pills were approved by the Ministry of Health, Labour and Welfare of Japan in 2011.[1] ## Contents * 1 History * 2 Statistics * 3 Contraceptive use * 4 See also * 5 References ## History[edit] In 1842, the Shogunate in Japan banned induced abortion in Edo, but the law did not affect the rest of the country until 1869, when abortion was banned nationwide.[2][3] However, the crime was rarely punished unless the conception was a result of adultery or the woman died as a result of the abortion procedure.[2] According to the scholar Tiana Norgern, the abortion policy under the Meiji government was similar to that of the Edo period, and was fueled by the belief that a large population would yield more military and political influence on the international stage.[2] In 1868, the emperor banned midwives from performing abortions, and in 1880, Japan's first penal code declared abortion a crime.[2] The punishments for abortion grew more severe in 1907 when the penal code revised: women could be incarcerated for up to a year for having an abortion; practitioners could be jailed for up to seven.[2] The Criminal Abortion Law of 1907 is still technically in effect today, but other legislation has overridden its effects.[2] In 1923, doctors were granted legal permission to perform emergency abortions to save the mother's life; abortions performed under different, less life-threatening circumstances were still prosecuted.[2] In 1931, the Alliance for Reform of the Anti-Abortion Law (Datai Hō Kaisei Kiseikai) was formed by Abe Isoo and argued that "it is a woman's right not to bear a child she does not want, and abortion is an exercise of this right".[2] This organization believed that abortion should be made legal in circumstances in which there was a high chance of genetic disorder; in which a woman was poor, on public assistance, or divorced; in which it endangered the woman's health; and in which the pregnancy was a result of rape.[2] In 1934, the Fifth All-Japan Women's Suffrage Congress wrote up resolutions calling for the legalization of abortion as well as contraception.[2] This did not result in any immediate reaction from the government at the time, but after the war, these resolutions were consulted when drafting legislation legalizing abortion. In 1940, the National Eugenic Law stopped short of explicitly calling abortion legal by outlining a set of procedures a doctor had to follow in order to perform an abortion; these procedures included getting second opinions and submitting reports, though these could be ignored when it was an emergency.[2] This was a daunting and complicated process that many physicians did not want to deal with, and some sources attribute the fall in abortion rate between 1941 and 1944 from 18,000 to 1,800 to this legislation.[2] After World War II, Japan found itself in a population crisis. In 1946, 10 million people were declared at risk of starvation, and between the years 1945 and 1950, the population increased by 11 million.[2] In 1948, in the wake if the Miyuki Ishikawa case, Japan legalized abortion under special circumstances.[4] The Eugenic Protection Law of 1948 made Japan one of the first countries to legalize induced abortion. This law was revised as the Maternal Body Protection Law in 1996.[5] Currently, abortion is widely accepted in Japan. According to a 1998 survey, 79 percent of unmarried and 85 percent of married women approved of abortion.[6] According to researchers at Osaka University in 2001, 341,588 legal abortions were carried out in Japan, a 2.5 percent increase from 1998 to 2001.[7] However, in 2007 the figure had decreased to around 256,000.[5] ## Statistics[edit] Abortion statistics showed that the abortion rate (the number of cases of induced abortions per 1,000 women per year) increased for women younger than 20 from 1975 to 1995. The abortion ratio (number of cases per 1,000 live births) remained the highest amongst women aged 40–44. An increase in the abortion ratio was seen in the two youngest groups (younger than 20 and 20–24), especially among those who were born after 1955. The proportion of abortions that were experienced by women younger than 25 increased from 18 percent between 1976 and 1980 to 30 percent between 1991 and 1995, and a slight increase was also observed among women aged 40–44.[8] Overall, in 1995, the total number of abortions reported was 343,024, representing a 49 percent decrease from the number reported for 1975. The overall abortion rate changed from 22 to 11 abortions per 1,000 women in 1975 and 1995, respectively; and the overall abortion ratio changed from 353 to 289 abortions per 1,000 live births in the same 20-year period. In more than 99 percent of cases, the reason reported for performing an abortion was to protect the woman's health; this percentage remained constant during 1975–1995.[8] The official Japanese government statistics on abortion, however, cannot be considered as very accurate, since physicians tend to under-report the number of abortions they perform as a way of avoiding income tax payments (Coleman 1991), and because of social pressures to protect women's confidentiality, especially that of girls who are junior high or high school students. ## Contraceptive use[edit] A scenario study was conducted to assess the extent to which the unintended pregnancy rate in Japan, where oral contraceptives (OC) have not been legalized for family planning purposes and couples rely mainly on condoms, might change if more women were to use OC. Because current rates of unintended pregnancy and abortion in Japan are not known, data provided by the 1994 Japanese National Survey on Family Planning were used to construct scenarios for national contraceptive use. Annual failure rates of contraceptive methods and nonuse were applied to the contraceptive use scenarios, to obtain estimates of the annual number of contraceptive failure-related pregnancies. Subsequently, contraceptive practice situations assuming higher OC use rates were defined, and the associated change in the number of contraceptive failure-related pregnancies was estimated for each situation. It emerged that OC use rates of 15% decreased the expected number of unintended pregnancies by 13–17%, whereas use rates of 25% resulted in decreases of 22–29% and use rates of 50% in decreases of 45–58%. The findings were reasonably robust to variation in the assumptions that were made. In conclusion, each theoretical percentage increase in the OC use rate in Japan was found to lead to a roughly equivalent percentage decrease in the number of unintended pregnancies.[9] ## See also[edit] * Abortion * Abortion law * Mizuko kuyo * Birth Control in Japan ## References[edit] Wikimedia Commons has media related to Abortion in Japan. 1. ^ “Sosei Receives Approval From Japan MHLW for NorLevo(R) TABLETS 0.75mg Emergency Contraceptive Pill”, Sosei Group Corporation press release, 23 February 2011 2. ^ a b c d e f g h i j k l m Norgren, Tiana. Abortion before Birth Control: The Politics of Reproduction in Postwar Japan Princeton, NJ: Princeton University Press, 2001. 3. ^ Obayashi, M. (1982). Historical background of the acceptance of induced abortion. Josanpu Zasshi 36(12), 1011-6. Retrieved April 12, 2006. 4. ^ "Archived copy" 第１４７回国会 国民福祉委員会 第１０号 (in Japanese). National Diet Library. 2000-03-15. Archived from the original on 2008-10-22. Retrieved 2008-03-18.CS1 maint: archived copy as title (link) 5. ^ a b Kato, Mariko (October 20, 2009). "FYI: Abortion and the Pill: Abortion Still Key Birth Control". FYI (column). The Japan Times. 6. ^ Population Problems Research Council of the Mainichi Newspapers. 1996. Report on the 23rd National Survey on Family Planning. Tokyo; Mainichi Newspapers. 7. ^ J Stage Environmental Health and Preventative Medicine vol. 10 2005[permanent dead link] 8. ^ a b Goto, A., Fujiyama-Koriyama, C., Fukao, A., & Reich, M. "Abortion Trends in Japan, 1975–95". Studies in Family Planning, Vol. 31, No. 4 (December 2000), pp. 301–308. Population Council. 9. ^ Oddens B.J. & Lolkema, A. "A scenario study of oral contraceptive use in Japan: Toward fewer unintended pregnancies". Contraception, Volume 58, Issue 1, July 1998, pages 13–19. * v * t * e Abortion in Asia Sovereign states * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor (Timor-Leste) * Egypt * Georgia * India * Indonesia * Iran * Iraq * Israel * Japan * Jordan * Kazakhstan * North Korea * South Korea * Kuwait * Kyrgyzstan * Laos * Lebanon * Malaysia * Maldives * Mongolia * Myanmar * Nepal * Oman * Pakistan * Philippines * Qatar * Russia * Saudi Arabia * Singapore * Sri Lanka * Syria * Tajikistan * Thailand * Turkey * Turkmenistan * United Arab Emirates * Uzbekistan * Vietnam * Yemen States with limited recognition * Abkhazia * Artsakh * Northern Cyprus * Palestine * South Ossetia * Taiwan Dependencies and other territories * British Indian Ocean Territory * Christmas Island * Cocos (Keeling) Islands * Hong Kong * Macau * Book * Category * Asia portal * v * t * e Abortion Main topics * Definitions * History * Methods * Abortion debate * Philosophical aspects * Abortion law Movements * Abortion-rights movements * Anti-abortion movements Issues * Abortion and mental health * Beginning of human personhood * Beginning of pregnancy controversy * Abortion-breast cancer hypothesis * Anti-abortion violence * Abortion under communism * Birth control * Crisis pregnancy center * Ethical aspects of abortion * Eugenics * Fetal rights * Forced abortion * Genetics and abortion * Late-term abortion * Legalized abortion and crime effect * Libertarian perspectives on abortion * Limit of viability * Malthusianism * Men's rights * Minors and abortion * Natalism * One-child policy * Paternal rights and abortion * Prenatal development * Reproductive rights * Self-induced abortion * Sex-selective abortion * Sidewalk counseling * Societal attitudes towards abortion * Socialism * Toxic abortion * Unsafe abortion * Women's rights By country Africa * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde * Central African Republic * Chad * Egypt * Ghana * Kenya * Namibia * Nigeria * South Africa * Uganda * Zimbabwe Asia * Afghanistan * Armenia * Azerbaijan * Bahrain * Bangladesh * Bhutan * Brunei * Cambodia * China * Cyprus * East Timor * Georgia * India * Iran * Israel * Japan * Kazakhstan * South Korea * Malaysia * Nepal * Northern Cyprus * Philippines * Qatar * Saudi Arabia * Singapore * Turkey * United Arab Emirates * Vietnam * Yemen Europe * Albania * Andorra * Austria * Belarus * Belgium * Bosnia and Herzegovina * Bulgaria * Croatia * Czech Republic * Denmark * Estonia * Finland * France * Germany * Greece * Hungary * Iceland * Ireland * Italy * Kazakhstan * Latvia * Liechtenstein * Lithuania * Luxembourg * Malta * Moldova * Monaco * Montenegro * Netherlands * North Macedonia * Norway * Poland * Portugal * Romania * Russia * San Marino * Serbia * Slovakia * Slovenia * Spain * Sweden * Switzerland * Ukraine * United Kingdom North America * Belize * Canada * Costa Rica * Cuba * Dominican Republic * El Salvador * Guatemala * Mexico * Nicaragua * Panama * Trinidad and Tobago * United States Oceania * Australia * Micronesia * Fiji * Kiribati * Marshall Islands * New Zealand * Papua New Guinea * Samoa * Solomon Islands * Tonga * Tuvalu * Vanuatu South America * Argentina * Bolivia * Brazil * Chile * Colombia * Ecuador * Guyana * Paraguay * Peru * Suriname * Uruguay * Venezuela Law * Case law * Constitutional law * History of abortion law * Laws by country * Buffer zones * Conscientious objection * Fetal protection * Heartbeat bills * Informed consent * Late-term restrictions * Parental involvement * Spousal consent Methods * Vacuum aspiration * Dilation and evacuation * Dilation and curettage * Intact D&X * Hysterotomy * Instillation * Menstrual extraction * Abortifacient drugs * Methotrexate * Mifepristone * Misoprostol * Oxytocin * Self-induced abortion * Unsafe abortion Religion * Buddhism * Christianity * Catholicism * Hinduism * Islam * Judaism * Scientology * Category *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Abortion in Japan

None

wikipedia

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

{"wikidata": ["Q4668474"]}

Autosomal recessive spastic paraplegia type 48 is a form of hereditary spastic paraplegia usually characterized by a pure phenotype of a slowly progressive spastic paraplegia associated with urinary incontinence with an onset in mid- to late-adulthood. A complex phenotype, with the additional findings of cognitive impairment, sensorimotor polyneuropathy, ataxia and parkinsonism, as well as thin corpus callosum and white matter lesions (seen on magnetic resonance imaging), has also been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Autosomal recessive spastic paraplegia type 48

c3150901

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=306511

{"omim": ["613647"], "icd-10": ["G11.4"], "synonyms": ["SPG48"]}

Keratoderma with woolly hair is a group of related conditions that affect the skin and hair and in many cases increase the risk of potentially life-threatening heart problems. People with these conditions have hair that is unusually coarse, dry, fine, and tightly curled. In some cases, the hair is also sparse. The woolly hair texture typically affects only scalp hair and is present from birth. Starting early in life, affected individuals also develop palmoplantar keratoderma, a condition that causes skin on the palms of the hands and the soles of the feet to become thick, scaly, and calloused. Cardiomyopathy, which is a disease of the heart muscle, is a life-threatening health problem that can develop in people with keratoderma with woolly hair. Unlike the other features of this condition, signs and symptoms of cardiomyopathy may not appear until adolescence or later. Complications of cardiomyopathy can include an abnormal heartbeat (arrhythmia), heart failure, and sudden death. Keratoderma with woolly hair comprises several related conditions with overlapping signs and symptoms. Researchers have recently proposed classifying keratoderma with woolly hair into four types, based on the underlying genetic cause. Type I, also known as Naxos disease, is characterized by palmoplantar keratoderma, woolly hair, and a form of cardiomyopathy called arrhythmogenic right ventricular cardiomyopathy (ARVC). Type II, also known as Carvajal syndrome, has hair and skin abnormalities similar to type I but features a different form of cardiomyopathy, called dilated left ventricular cardiomyopathy. Type III also has signs and symptoms similar to those of type I, including ARVC, although the hair and skin abnormalities are often milder. Type IV is characterized by palmoplantar keratoderma and woolly and sparse hair, as well as abnormal fingernails and toenails. Type IV does not appear to cause cardiomyopathy. ## Frequency Keratoderma with woolly hair is rare; its prevalence worldwide is unknown. Type I (Naxos disease) was first described in families from the Greek island of Naxos. Since then, affected families have been found in other Greek islands, Turkey, and the Middle East. This form of the condition may affect up to 1 in 1,000 people from the Greek islands. Type II (Carvajal syndrome), type III, and type IV have each been identified in only a small number of families worldwide. ## Causes Mutations in the JUP, DSP, DSC2, and KANK2 genes cause keratoderma with woolly hair types I through IV, respectively. The JUP, DSP, and DSC2 genes provide instructions for making components of specialized cell structures called desmosomes. Desmosomes are located in the membrane surrounding certain cells, including skin and heart muscle cells. Desmosomes help attach cells to one another, which provides strength and stability to tissues. They also play a role in signaling between cells. Mutations in the JUP, DSP, or DSC2 gene alter the structure and impair the function of desmosomes. Abnormal or missing desmosomes prevent cells from sticking to one another effectively, which likely makes the hair, skin, and heart muscle more fragile. Over time, as these tissues are exposed to mechanical stress (for example, friction on the surface of the skin or the constant contraction and relaxation of the heart muscle), they become damaged and can no longer function normally. This mechanism probably underlies the skin, hair, and heart problems that occur in keratoderma with woolly hair. Some studies suggest that abnormal cell signaling may also contribute to cardiomyopathy in people with this group of conditions. Unlike the other genes associated with keratoderma with woolly hair, the KANK2 gene provides instructions for making a protein that is not part of desmosomes. Instead, it regulates other proteins called steroid receptor coactivators (SRCs), whose function is to help turn on (activate) certain genes. SRCs play important roles in tissues throughout the body, including the skin. Studies suggest that mutations in the KANK2 gene disrupt the regulation of SRCs, which leads to abnormal gene activity. However, it is unclear how these changes underlie the skin and hair abnormalities in keratoderma with woolly hair type IV. ### Learn more about the genes associated with Keratoderma with woolly hair * DSC2 * DSP * JUP * KANK2 ## Inheritance Pattern Most cases of keratoderma with woolly hair have an autosomal recessive pattern of inheritance, 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 usually do not show signs and symptoms of the condition. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Keratoderma with woolly hair

c1864850

medlineplus

https://medlineplus.gov/genetics/condition/keratoderma-with-woolly-hair/

{"gard": ["5595", "8167"], "mesh": ["C566471"], "omim": ["610476", "605676", "615821", "601214", "616099"], "synonyms": []}

Myotonic dystrophy type 1 (MD1), one of the two types of myotonic dystrophy, is an inherited type of muscular dystrophy that affects the muscles and other body systems (e.g., heart, eyes, endocrine system, and central nervous system). MD1 has three forms that somewhat overlap: the mild form, classic form, and congenital form (present at birth). The mild form has the least severe symptoms of the different forms of MD1 and is associated with a normal life span. The classic form is characterized by muscle weakness and wasting, prolonged muscle tensing (myotonia), cataract, and often, abnormal heart function. Adults with the classic form may become physically disabled and may have a shortened life span. The congenital form is characterized by severe generalized weakness at birth (hypotonia), often causing complications with breathing and early death. MD1 is inherited in an autosomal dominant manner and is caused by mutations in the DMPK gene. Treatment is based on the signs and symptoms present. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Myotonic dystrophy type 1

c3250443

gard

https://rarediseases.info.nih.gov/diseases/8310/myotonic-dystrophy-type-1

{"mesh": ["C538008"], "omim": ["160900"], "orphanet": ["273"], "synonyms": ["DM1", "Steinert myotonic dystrophy", "Dystrophia myotonica type 1", "Steinert's disease", "Myotonic dystrophy type 1", "MD1", "Steinert disease"]}

Focal facial dermal dysplasia type II (FFDD2) is a focal facial dermal dysplasia (FFDD; see this term), characterized by congenital bitemporal scar-like depressions and other facial and organ abnormalities. ## Epidemiology To date, FFDD2 has been reported in over 20 cases from 8 families. ## Clinical description FFDD2 is characterized by congenital bitemporal hypoplastic scar-like lesions resembling forceps marks with additional facial dysmorphic features. These frequently include low frontal hairline, sparse hair, periorbital puffiness, sparse lateral and upward lifting eyebrows, distichiasis (upper lashes), lack of lower lashes, flattened and/or bulbous nasal tip, and a prominent upper lip (with an inverted ''V'' contour). Occasionally epicanthal folds , linear grooves on forehead, skin dimples lateral to lips and redundant skin are reported. Cardiac and genital or urinary abnormalities have been rarely noted. Developmental delay, severe intellectual disability, behavioral problems, and learning difficulties may be observed. ## Etiology The etiology of FFDD2 is unknown. ## Diagnostic methods FFDD2 is diagnosed in patients bearing autosomal dominant bitemporal scar-like lesions and multiple FFDD2 features. ## Differential diagnosis Differential diagnosis includes focal facial dermal dysplasia type I (FFDD1) and focal facial dermal dysplasia type III (FFDD3; see these terms). ## Genetic counseling FFDD2 is transmitted in an autosomal dominant manner with variable expressivity and incomplete penetrance. ## Management and treatment Management comprises opthalmologic evaluations periodically. There is limited experience with plastic surgery for the facial scar-like lesions. ## Prognosis Affected individuals have a normal life span, but involvement of other organ systems may alter the prognosis. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Focal facial dermal dysplasia type II

c1744559

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=398173

{"mesh": ["C536385"], "omim": ["614973"], "umls": ["C1744559"], "icd-10": ["Q82.8"], "synonyms": ["FFDD type II", "FFDD2", "Focal facial dermal dysplasia 2, Brauer-Setleis type"]}

A number sign (#) is used with this entry because of evidence that lethal congenital contracture syndrome-10 (LCCS10) is caused by homozygous mutation in the NEK9 gene (609798) on chromosome 14q24. For a general phenotypic description and a discussion of genetic heterogeneity of lethal congenital contracture syndrome, see LCCS1 (253310). Clinical Features Casey et al. (2016) studied 2 Irish Traveller families with a recessive lethal skeletal dysplasia. In the first family, there were 2 offspring with fetal akinesia, multiple contractures, shortening of upper and lower limbs, short broad ribs, narrow chest and thorax, pulmonary hypoplasia, and protruding abdomen. In the second family, 3 offspring had the same features, and 2 of the 3 also exhibited bowed femurs. None of the affected infants survived past birth: 1 died 1 hour after birth, resuscitation failed in 2, 1 died in utero, and in 1 case the pregnancy was terminated. Molecular Genetics In an Irish Traveller family in which 2 offspring had lethal skeletal dysplasia, Casey et al. (2016) performed exome sequencing and identified a homozygous nonsense mutation in the NEK9 gene (R497X; 609798.0001) that segregated with disease. Analysis of a second Irish Traveller family with 3 similarly affected offspring showed that the R497X mutation segregated with disease in that family as well. The 2 families were likely distantly related. Casey et al. (2016) noted 'considerable overlap' between the features of these patients and those with short-rib thoracic dysplasia (SRTD6; 263520) due to mutations in the NEK1 gene (604588); however, the patients with the NEK9 mutation did not exhibit certain SRTD features such as polysyndactyly and renal cysts, but rather presented with fetal akinesia, multiple contractures, and short bowed femurs, which are not seen in the NEK1-associated disorder. INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation HEAD & NECK Face \- Long philtrum \- Micrognathia Mouth \- High-arched palate \- Narrow palate Neck \- Small thymus \- Short neck \- Stiff neck \- Reduced flexion of neck \- Torticollis, right CARDIOVASCULAR Heart \- Double outlet ventricles (in 1 patient) \- Overriding aorta (in 1 patient) \- Ventricular septal defect (in 1 patient) \- Enlarged heart (in 1 patient) RESPIRATORY Lung \- Hypoplastic lungs CHEST External Features \- Narrow chest and thorax Ribs Sternum Clavicles & Scapulae \- Short broad ribs \- Narrow rib cage Diaphragm \- Intact diaphragm but bulging upwards (in 1 patient) ABDOMEN External Features \- Protruding abdomen (in 1 patient) \- Omphalocele (in 1 patient) Spleen \- Small spleen SKELETAL Spine \- Thoracic scoliosis Limbs \- Multiple contractures \- Shortening of upper and lower limbs \- Bowed short femurs (in 1 family) Hands \- Overlapping fingers \- Adducted thumbs \- Lateral deviation of fingers Feet \- Talipes equinovarus MUSCLE, SOFT TISSUES \- Variation in fiber size with some very small fibers (in 1 patient) \- Changes compatible with central denervation (in 1 patient) PRENATAL MANIFESTATIONS Movement \- Fetal akinesia Amniotic Fluid \- Oligohydramnios (in 1 patient) \- Hydrops fetalis (in 1 patient) MISCELLANEOUS \- Based on report of 5 patients from 2 likely related Irish Traveler families (last curated July 2016) MOLECULAR BASIS \- Caused by mutation in the never in mitosis gene A-related kinase-9 gene (NEK9, 609798.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

LETHAL CONGENITAL CONTRACTURE SYNDROME 10

c4310760

omim

https://www.omim.org/entry/617022

{"omim": ["617022"], "orphanet": ["464366"], "synonyms": ["Lethal skeletal dysplasia-fetal akinesia-contractures-thoracic dysplasia-pulmonary hypoplasia syndrome"]}

A number sign (#) is used with this entry because an expansion of a CAG repeat in a brain-specific regulatory subunit of the protein phosphatase PP2A (PPP2R2B; 604325) is the cause of the disorder. Normal alleles carry 7 to 32 triplets, whereas disease alleles carry 51 to 78 triplets (Bahl et al., 2005). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). Clinical Features Holmes et al. (1999) identified a novel form of autosomal dominant spinocerebellar ataxia (SCA), termed SCA12, in a large pedigree, 'R,' of German descent. The phenotype was variable, but the prototypic phenotype was that of a classic spinocerebellar ataxia, and the disease resembled the spinocerebellar ataxias more closely than any other form of neurodegenerative disorder. Age of onset ranged from 8 to 55 years. Most individuals presented in the fourth decade with upper extremity tremor, progressing over several decades to include head tremor, gait ataxia, dysmetria, dysdiadokinesis, hyperreflexia, paucity of movement, abnormal eye movements, and, in the oldest subjects, dementia. MRI or CT scans of 5 cases indicated both cortical and cerebellar atrophy. O'Hearn et al. (2001) further characterized the phenotype of the 'R' pedigree and found that action tremor of the head and arms was the most distinguishing feature in comparison to other dominant SCAs. Bahl et al. (2005) reported 25 patients from 20 Indian families with SCA12 who were all members of an endogamous group with origins in the state of Haryana in northern India. Five of the families had been previously reported by Srivastava et al. (2001). Age at onset ranged from 26 to 56 years (mean of 40.2 years), and most presented with upper extremity tremor. Other features included hyperreflexia, dysarthria, and mild or no gait ataxia. Two individuals had axial dystonia, and 3 had facial myokymia. Almost half of patients had a subclinical sensory or sensorimotor neuropathy. Brain MRI or CT scan showed cerebellar and cerebral cortical atrophy. Anticipation was not observed. Molecular Genetics Holmes et al. (1999) used repeat expansion detection (RED), as described by Schalling et al. (1993), to identify an expanded CAG repeat in the PPP2R2B gene (604325.0001) in the proband and other affected family members. Using PCR analysis, they demonstrated that the expression was not 1 of 8 CAG repeats associated with a neurodegenerative disease or 1 of 3 CAG repeats known to undergo nonpathogenic expansion. From the proband, they cloned a 2.5-kb genomic clone that contained a repeat of 93 uninterrupted CAGs. There was no apparent correlation between repeat size and age of onset, although the range of expanded alleles was relatively narrow (66 to 78 repeats) and the precise age of onset of tremor, typically the first symptom, was difficult to define in this disorder. Holmes et al. (1999) assessed the PPP2R2B CAG repeat length in 394 unrelated neurologically normal individuals and 1,099 individuals with neurologic diseases; no expansion was detected, suggesting that SCA12 is rare. The CAG tract lies 133 nucleotides upstream of the reported transcription start site of the PPP2R2B gene (604325), encoding a brain-specific regulatory subunit of the protein phosphatase PP2A. The PPP2R2B gene had been mapped to 5q31-q33 between markers D5S436 and D5S470. Although the possibility that the CAG tract may lie within an unidentified gene overlapping or adjacent to PPP2R2B, an antibody probe did not detect polyglutamine expansions in protein derived from lymphoblastoid cell lines of affected family members. A lod score of 4.61 at theta = 0.0 was obtained for linkage between the expanded repeat and the disorder. It was possible that the expansion was in linkage disequilibrium with a second, as-yet-unidentified, causative mutation. However, the correlation between repeat expansion and disease in pedigree R, the lack of expansions in controls, and the known capacity of expansion mutations outside of protein-coding regions to cause disease indicated that the expansion was causative. Population Genetics In a study of 145 families with autosomal dominant cerebellar ataxia (ADCA), Fujigasaki et al. (2001) identified a family from India in which 6 affected and 3 unaffected members had an expanded CAG repeat in the PPP2R2B gene (604325.0001). They determined the distribution of normal PPP2R2B repeat length in 157 French and 100 Indian control subjects. In the French population normal alleles contained 9 to 18 CAG triplets, most frequently 10. In the Indian population, lengths of up to 45 CAG triplets were observed, but the most common allele also carried 10 triplets. Among 293 individuals with ADCA from 77 Indian families, Srivastava et al. (2001) found an expanded SCA12 repeat in 6 patients and 3 asymptomatic at-risk individuals from 5 families, which accounted for 7% of the ADCA cases. The expanded allele length ranged from 55 to 69 repeat units. Notable clinical features included age of onset from 26 to 50 years, initial presentation of hand tremor, lack of dementia, and evidence of a subclinical sensory and motor neuropathy. Of the 77 families, SCA1 (164400) mutation was found in 15.6%, SCA2 (183090) in 24.7%, and SCA3 (109150) and SCA7 (164500) in 2.6% each. SCA6 (183086), SCA8 (603680), and DRPLA (607462) mutations were not found. In an ataxia clinic in California, Cholfin et al. (2001) screened 180 kindreds for the SCA12 mutation. The patients were of highly diverse ethnic origins. None was found to carry the SCA12 expansion. The authors concluded that the SCA12 mutation is a rare cause of spinocerebellar degeneration but that it should be considered in patients with an atypical clinical phenotype, especially when tremor is initially present. Among 20 families from northern India with SCA12, Bahl et al. (2005) identified expanded CAG repeats ranging from 51 to 69 triplets. Unaffected individuals had repeats ranging from 8 to 23 triplets. Of note, 1 asymptomatic individual was homozygous for an expanded repeat (52 and 59 triplets). Haplotype analysis identified 1 haplotype that was associated with the disease alleles, indicating a common founder. Bahl et al. (2005) estimated that SCA12 accounts for about 16% of all ADCA cases in northern India. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Facial myokymia Eyes \- Ocular movement abnormalities NEUROLOGIC Central Nervous System \- Progressive cerebellar ataxia \- Upper extremity action tremor \- Head tremor \- Dysarthria \- Dysmetria \- Dysdiadochokinesis \- Hyperreflexia \- Parkinsonism \- Axial dystonia \- Dementia \- Cortical atrophy \- Cerebellar atrophy Peripheral Nervous System \- Subclinical sensory or sensorimotor neuropathy Behavioral Psychiatric Manifestations \- Depression \- Anxiety \- Delusions MISCELLANEOUS \- Age at onset 8 to 55 years (mean 40 years) \- Normal CAG repeat length is 7 to 32 triplets \- Pathogenic CAG repeat length is 51 to 78 triplets MOLECULAR BASIS \- Caused by expanded CAG trinucleotide repeats in the beta subunit of the protein phosphatase 2 gene (PPP2R2B, 604325.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

SPINOCEREBELLAR ATAXIA 12

c1858501

omim

https://www.omim.org/entry/604326

{"doid": ["0050962"], "mesh": ["C565790"], "omim": ["604326"], "orphanet": ["98762"]}

Rhabdomyosarcoma of the cervix uteri is a rare, highly malignant soft tissue sarcoma located in the uterine cervix and arising from primitive mesenchymal cells displaying skeletal muscle differentiation. It most often presents with abnormal vaginal discharge or dysfunctional uterine bleeding, abdominal pain and/or a cervical mass protruding into the vagina. Association with DICER1 syndrome has been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Rhabdomyosarcoma of the cervix uteri

c4289809

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=213802

{"icd-10": ["C53.0", "C53.1", "C53.8"], "synonyms": ["Cervical rhabdomyosarcoma"]}

Sporadic infantile bilateral necrosis is the sporadic form of infantile bilateral striatal necrosis (IBSN; see this term), a syndrome of bilateral symmetric spongy degeneration of the caudate nucleaus, putamen and globus pallidus characterized by developmental regression, choreoathetosis and dystonia progressing to spastic quadriparesis. ## Epidemiology Prevalence has been estimated at 1-9/1,000,000. ## Clinical description Sporadic IBSN can occur any time from the neonatal period through childhood and even in adolescence. Clinical features include choreoathetosis, dystonia, rigidity, spasticity, dysphagia, optic atrophy, intellectual deficit, developmental regression of motor and verbal skills, failure to thrive, myoclonus, quadriparesis, cerebellar ataxia and nystagmus. ## Etiology The disease is associated with abrupt neurologic dysfunction following an acute systemic febrile illness such as a mycoplasma, measles or streptococcus infection. ## Diagnostic methods Diagnosis is based on clinical observation of choreoathetoid movements of the face, trunk and extremities and evidence of basal ganglia degeneration on CT and MRI images. ## Differential diagnosis Differential diagnoses include Wilson's disease, acute disseminated encephalomyelitis, neurodegeneration with brain iron accumulation, Leigh disease, juvenile Huntington chorea, methylmalonic aciduria, guanidinoacetate methyltransferase deficiency, glutaric acidemia I (see these terms), carbon monoxide intoxication, small vessel arteritis and trauma. ## Management and treatment Treatment is based on treatment of the causal infection. ## Prognosis Prognosis is variable, with either gradual improvement in symptoms and complete recovery, observed after recovery from the infection, or severe neurological sequelae. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Sporadic infantile bilateral striatal necrosis

c4087175

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=225147

{"icd-10": ["G23.2"], "synonyms": ["ABSN", "Acute bilateral striatal necrosis", "Sporadic IBSN", "Sporadic infantile striatonigral degeneration", "Sporadic infantile striatonigral necrosis"]}

A number sign (#) is used with this entry because of evidence that in some instances familial gestational hyperthyroidism is caused by heterozygous mutation in the gene encoding the thyroid-stimulating hormone receptor (TSHR; 603372) on chromosome 14q31. Description Some degree of stimulation of the thyroid gland by chorionic gonadotropin (see 118860) is common during early pregnancy. When serum chorionic gonadotropin concentrations are abnormally high, e.g., in women with molar pregnancies (231090), overt hyperthyroidism may ensue. The pathophysiologic mechanism appears to be promiscuous stimulation of the thyrotropin receptor by the excess chorionic gonadotropin. The explanation for this stimulation is the close structural relations between chorionic gonadotropin and thyrotropin and between their receptors (Grossmann et al., 1997). Clinical Features Hyperemesis gravidarum is characterized by excessive vomiting in early pregnancy, leading to the loss of 5% or more of body weight. It is usually self-limited and therefore of little clinical consequence. Some women with the disorder have high serum thyroid hormone concentrations, and a few have sufficient clinical manifestations of hyperthyroidism to warrant short-term treatment with antithyroid drugs. Many, but not all, women with hyperemesis gravidarum and hyperthyroidism have high serum chorionic gonadotropin concentrations. Rodien et al. (1998) described mother and daughter with hyperemesis gravidarum associated with hyperthyroidism and normal serum concentrations of chorionic gonadotropin. They demonstrated that the thyrotropin receptor gene in the 2 women carried a heterozygous mutation, K183R (603372.0024), which rendered the thyrotropin receptor hypersensitive to chorionic gonadotropin. The daughter was a 27-year-old woman who was 10 weeks' pregnant when referred for the evaluation and treatment of hyperthyroidism. This was her third pregnancy, the first and second having resulted in early miscarriage accompanied by severe nausea and vomiting. In the third pregnancy, she again suffered severe nausea and vomiting and had a weight loss of 5 kg. She had tachycardia, excessive sweating, and tremor of the hands with a small, diffuse goiter and no ophthalmopathy. She was treated with propylthiouracil for 8 weeks with good results. After delivery of a normal girl at 38 weeks' gestation, propylthiouracil was discontinued. After an asymptomatic period, she returned 18 months later with recurrence of hyperthyroidism associated with hyperemesis gravidarum and was found to be pregnant again. Treatment with propylthiouracil was accompanied by a good response and delivery of a normal boy at 38 weeks' gestation. The mother was 27 years old when she gave birth to her daughter, 2 years after having a miscarriage. Both pregnancies were complicated by nausea, vomiting, and weight loss. The same symptoms recurred during a subsequent pregnancy, and the woman was treated with carbimazole for what was believed to be hyperthyroidism due to Graves disease, despite the absence of goiter and ophthalmopathy. After a normal delivery, the medication was discontinued and the patient remained euthyroid and had no further pregnancies. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

HYPERTHYROIDISM, FAMILIAL GESTATIONAL

c1863959

omim

https://www.omim.org/entry/603373

{"doid": ["7998"], "mesh": ["C566384"], "omim": ["603373"], "orphanet": ["99819"]}

A number sign (#) is used with this entry because Muenke craniosynostosis syndrome is caused by a specific heterozygous mutation of the fibroblast growth factor receptor-3 gene (FGFR3; 134934), pro250 to arg (P250R; 134934.0014), on chromosome 4p16. Description Muenke syndrome is an autosomal dominant disorder characterized by uni- or bicoronal synostosis, macrocephaly, midfacial hypoplasia, and developmental delay. Other more variable features include thimble-shaped middle phalanges, brachydactyly, carpal/tarsal fusion, and deafness. The phenotype is variable and can range from no detectable clinical manifestations to complex findings (summary by Abdel-Salam et al., 2011). Clinical Features On the basis of 61 individuals from 20 unrelated families where coronal synostosis was caused by the P250R mutation in the FGFR3 gene, Muenke et al. (1997) defined a new clinical syndrome distinct from previously defined craniosynostosis syndromes, including the Pfeiffer (101600), Crouzon (123500), Jackson-Weiss (123150), and Apert (101200) syndromes. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe to suggest Apert syndrome or Pfeiffer syndrome, respectively. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiologic findings of hands and feet can be helpful in the recognition of this syndrome, it was not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, Muenke et al. (1997) suggested that all patients with coronal synostosis, a particularly frequent and distinctive feature of the disorder, should be tested for this specific mutation. In a report of 9 individuals with the P250R mutation of the FGFR3 gene, Reardon et al. (1997) noted unisutural craniosynostosis in 3. They documented a variable clinical presentation. In 4 of the 9 cases, they noted mental retardation, which was unrelated to the management of the craniosynostosis. In a large German family, Golla et al. (1997) noted considerable phenotypic variability among individuals with the identical mutation. Gripp et al. (1998) found the P250R mutation in 4 of 37 patients with synostotic anterior plagiocephaly (literally 'oblique head'). In 3 mutation-positive patients with full parental studies, a parent with an extremely mild phenotype was found to carry the same mutation. None of the 6 patients with nonsynostotic plagiocephaly and none of the 4 patients with additional suture synostosis had the FGFR3 mutation. Hollway et al. (1998) reported a family in which the P250R mutation was associated with autosomal dominant congenital bilateral sensorineural deafness of moderate degree. Some of the family members also had craniosynostosis, which is a known manifestation of the P250R mutation. The low penetrance of symptomatic craniosynostosis in this 5-generation family raised the possibility that some families with the P250R mutation may present with deafness alone. Lajeunie et al. (1999) studied 62 patients with sporadic or familial forms of coronal craniosynostosis. The P250R mutation was identified in 20 probands from 27 unrelated families (74%), while only 6 of 35 sporadic cases (17%) were found to have this mutation. In both familial and sporadic cases, females were more severely affected, with 68% of females but only 35% of males having brachycephaly. In the most severely affected individuals, bicoronal craniosynostosis was associated with hypertelorism and marked bulging of the temporal fossae, features that Lajeunie et al. (1999) concluded might be helpful for clinical diagnosis. Lajeunie et al. (1999) concluded that the P250R mutation is most often familial and is associated with a more severe phenotype in females than in males. Lowry et al. (2001) reported a family in which members with coronal craniosynostosis, skeletal abnormalities of the hands, and sensorineural hearing loss had the P250R mutation. One female family member also had a Sprengel shoulder anomaly (184400) and multiple cervical spine anomalies consistent with Klippel-Feil anomaly (118100). The authors reported an additional case with an identical phenotype without the mutation. Like Muenke syndrome, hypochondroplasia (HCH; 146000) is caused by mutations in the FGFR3 gene. FGFR3 is known to play a role in controlling nervous system development. Grosso et al. (2003) described the clinical and neuroradiologic findings of a patient with Muenke syndrome and a patient with hypochondroplasia, each of whom had bilateral dysgenesis of the medial temporal lobe structures. Both were mentally normal and showed similarities in early-onset temporal lobe-related seizures. In both patients, EEG recorded bilateral temporal region discharges. MRI detected temporal lobe anomalies with inadequate differentiation between white and gray matter, defective gyri, and abnormally shaped hippocampus. The patient with hypochondroplasia carried the asn540-to-lys missense mutation (134934.0010); the patient with Muenke syndrome carried the P250R mutation. Kress et al. (2006) provided a phenotypic comparison between 42 patients from 24 kindreds with Muenke syndrome caused by the FGFR3 P250R mutation and 71 patients from 39 families with Saethre-Chotzen syndrome (SCS; 101400) caused by mutations in the TWIST1 gene (601622). Patients with classic SCS could be distinguished from the Muenke phenotype by presence of low-set frontal hairline, gross ptosis of the eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and broad great toe with bifid distal phalanx. Patients with SCS also tended to have intracranial hypertension as a consequence of early progressive multisutural fusion and normal mental development; those with Muenke syndrome tended to have mental delay and sensorineural hearing loss. Kress et al. (2006) concluded that SCS and Muenke should be considered separate syndromes. Shah et al. (2006) reported a family in which a female infant with Muenke syndrome due to the P250R mutation died suddenly on day 3 of life, most likely due to respiratory insufficiency resulting from upper airway obstruction associated with craniosynostosis. Her affected mother, who also had the mutation, had been diagnosed in infancy with Treacher Collins syndrome (154500). A second-born female child also had the P250R mutation but did not display respiratory compromise. In a male infant with trigonocephaly, van der Meulen et al. (2006) identified the P250R mutation, which was also present in the mother, who had barely detectable sequelae of a bicoronal synostosis. The authors suggested that mutation analysis of the FGFR1, FGFR2, and FGFR3 genes should be routinely performed in children with nonsyndromic trigonocephaly. Doherty et al. (2007) evaluated 9 patients, 5 children and 4 adults, with Muenke syndrome due to the P250R mutation. Six patients had bicoronal synostosis, and 3 had unicoronal synostosis. Feeding and/or swallowing difficulties were found in all of the children. The most common ocular complication was strabismus, which was found in 4 of the 9 patients. Oral findings consisted primarily of dental malocclusion and highly arched palate. A review of audiograms from these patients and an additional 13 patients with Muenke syndrome showed that 95% had mild to moderate, low frequency sensorineural hearing loss. Doherty et al. (2007) suggested that the hearing loss is a direct result of the FGFR3 mutation, not a secondary effect of craniosynostosis. Data from their patients and 312 previously reported cases of Muenke syndrome showed that females with the P250R mutation were significantly more likely to be reported with craniosynostosis than males (p less than 0.01). Mansour et al. (2009) evaluated hearing in 37 patients with Muenke syndrome due to the P250R mutation. The Muenke syndrome patients showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss. The finding was confirmed in a mouse model of Muenke syndrome. Escobar et al. (2009) reported a pair of identical female twins with variable manifestations of Muenke syndrome despite having the same de novo P250R mutation. They were born at 35 weeks' gestation and were noted to have abnormal head shape at birth. The less severely affected twin, who showed no abnormalities on prenatal ultrasound, had acrocephaly with a prominent forehead, wide-open anterior fontanel, coronal craniosynostosis, significant midface hypoplasia with malar hypoplasia, a short upturned nose, low-set ears, and a high-arched palate. She also had brachydactyly with shortening of the fifth finger and mild clinodactyly. Behavioral abnormalities included developmental delay, generalized anxiety disorder, and ADHD. The more severely affected twin was noted to have hydrocephaly due to aqueductal stenosis at 25 weeks' gestation. She had neonatal apnea and bradycardia requiring bag mask ventilation. Brain MRI showed a large poroencephalic cyst of the occipital horn of the left ventricle, hydrocephaly, and absence of the corpus callosum. She had atrial and ventricular septal defects and esophageal atresia with a tracheoesophageal fistula requiring surgery. Skull and facial features were similar to the other twin. Cognitive defects included pervasive developmental disorder, developmental delay, and ADHD. Both patients developed developed bilateral sensorineural hearing loss. Although the pregnancy was complicated by prenatal exposure to nortriptyline, the Escobar et al. (2009) did not believe that this affected the phenotype. Abdel-Salam et al. (2011) reported a boy, born of consanguineous parents, with craniosynostosis due to a heterozygous P250R mutation in the FGFR3 gene. In addition to right coronal, sagittal, and lambdoid suture synostosis, he had left hemimegalencephaly with poor differentiation of white and gray matter, an underdeveloped corpus callosum, and an abnormal hippocampus. Despite these cranial findings, he had mild developmental delay and symmetric strength, tone, and reflexes, with hyperreflexia. Dysmorphic features included craniofacial asymmetry with left frontal bossing, midface hypoplasia, proptosis, low-set ears, and brachydactyly. At age 18 months, he developed asymmetric hydrocephalus requiring third ventriculostomy. Postoperative cranial MRI showed a Chiari I-like malformation, but less dysplastic cerebral cortex. In addition, he had curly, light hair, and oval hypomelanotic patches on the abdomen, lower limbs, and back, with 1 hyperpigmented patch in the groin. Some of these features had not previously been reported in Muenke syndrome, but Abdel-Salam et al. (2011) noted that additional genetic effects could not be ruled out because of the consanguinity in this family. Inheritance Muenke syndrome is an autosomal dominant disorder (Muenke et al., 1997). Rannan-Eliya et al. (2004) studied 19 cases of Muenke syndrome due to heterozygous de novo P250R mutations in FGFR3. All 10 informative cases were of paternal origin; the average paternal age at birth for all 19 cases was 34.7 years. Population Genetics The birth rate for the Muenke FGFR3 P250R mutation is estimated to be 7.6 per 1,000,000 (Wilkie, 1997). Animal Model Mansour et al. (2009) generated mice homozygous and heterozygous for a P244R mutation in the Fgfr3 gene, which is the equivalent of the human P250R mutation, as a mouse model of Muenke syndrome. Fgfr3 P244R/+ and P244R/P244R mice showed dominant, fully penetrant low-frequency hearing loss that was similar but more severe than in Muenke syndrome patients. Mouse hearing loss correlated with an alteration in the fate of supporting cells (Deiters-to-pillar cells) along the entire length of the cochlear duct, especially at the apical or low-frequency end. There was excess outer hair cell development in the apical region. Hearing loss was dosage sensitive as homozygotes were more severely affected than heterozygotes. INHERITANCE \- Autosomal dominant GROWTH Height \- Normal height HEAD & NECK Head \- Brachycephaly \- Macrocephaly \- Plagiocephaly Face \- Midface hypoplasia \- Low-set frontal hairline Ears \- Hearing loss, sensorineural Eyes \- Hypertelorism \- Downslanting palpebral fissures \- Ptosis \- Strabismus Mouth \- High-arched palate \- Dental malocclusion SKELETAL Skull \- Coronal craniosynostosis (unicoronal or bicoronal, unilateral or bilateral) \- Bulging of temporal fossae Hands \- Clinodactyly \- Brachydactyly \- Coned epiphyses \- Broad, thimble-like middle phalanges \- Capitate-hamate fusions Feet \- Broad halluces \- Short middle phalanges \- Calcaneocuboidal fusions \- Coned epiphyses SKIN, NAILS, & HAIR Hair \- Low-set frontal hairline NEUROLOGIC Central Nervous System \- Developmental delay \- Mental retardation MISCELLANEOUS \- Females more severely affected than males \- Significant phenotypic variability \- Birth rate of 7.6 per 1,000,000 MOLECULAR BASIS \- Caused by mutation in the fibroblast growth factor receptor 3 gene (FGFR3, 134934.0014 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

MUENKE SYNDROME

c1864436

omim

https://www.omim.org/entry/602849

{"doid": ["0060703"], "mesh": ["C537369"], "omim": ["602849"], "orphanet": ["53271"], "synonyms": ["Alternative titles", "MUENKE NONSYNDROMIC CORONAL CRANIOSYNOSTOSIS"], "genereviews": ["NBK1415", "NBK1455"]}

Human disease MBL deficiency SpecialtyImmunology MBL deficiency is a pathology of the innate immune system involving Mannan-binding lectin pathway components such as MBL2. It is thought that 5–10% of the population have an MBL deficiency of some degree.[1] There are varying degrees of MBL deficiency; some people will not even know they have the deficiency, while others may have such low levels that they experience infections with great frequency. Babies and young children are most at risk. ## References[edit] 1. ^ "Mannose-binding lectin deficiency". Genetics Home Reference. U.S. National Library of Medicine. ## External links[edit] Classification D * OMIM: 154545 * MeSH: C563602 * v * t * e Lymphoid and complement disorders causing immunodeficiency Primary Antibody/humoral (B) Hypogammaglobulinemia * X-linked agammaglobulinemia * Transient hypogammaglobulinemia of infancy Dysgammaglobulinemia * IgA deficiency * IgG deficiency * IgM deficiency * Hyper IgM syndrome (1 * 2 * 3 * 4 * 5) * Wiskott–Aldrich syndrome * Hyper-IgE syndrome Other * Common variable immunodeficiency * ICF syndrome T cell deficiency (T) * thymic hypoplasia: hypoparathyroid (Di George's syndrome) * euparathyroid (Nezelof syndrome * Ataxia–telangiectasia) peripheral: Purine nucleoside phosphorylase deficiency * Hyper IgM syndrome (1) Severe combined (B+T) * x-linked: X-SCID autosomal: Adenosine deaminase deficiency * Omenn syndrome * ZAP70 deficiency * Bare lymphocyte syndrome Acquired * HIV/AIDS Leukopenia: Lymphocytopenia * Idiopathic CD4+ lymphocytopenia Complement deficiency * C1-inhibitor (Angioedema/Hereditary angioedema) * Complement 2 deficiency/Complement 4 deficiency * MBL deficiency * Properdin deficiency * Complement 3 deficiency * Terminal complement pathway deficiency * Paroxysmal nocturnal hemoglobinuria * Complement receptor deficiency This article about a medical condition affecting the circulatory 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

MBL deficiency

c3280586

wikipedia

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

{"gard": ["10309"], "mesh": ["C563602"], "umls": ["C3280586"], "wikidata": ["Q16994031"]}

A rare systemic autoimmune disease characterized by cholestasis and diffuse cholangiographic abnormalities with circular and symmetrical bile duct wall thickening, and elevated serum IgG4 levels. Characteristic histopathological findings include dense infiltration of IgG4-positive plasma cells and extensive fibrosis in the bile duct wall. A marked response to steroid therapy is typical. Patients present with jaundice, cholangitis, pruritis, and sometimes associated findings of autoimmune pancreatitis, sialadenitis, and retroperitoneal fibrosis. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

IgG4-related sclerosing cholangitis

c4302109

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=447764

{"icd-10": ["K83.0"]}

Austrian syndrome is a medical condition first described by Robert Austrian in 1957. The classical triad consists of pneumonia, endocarditis, and meningitis, all caused by Streptococcus pneumoniae. It is associated with alcoholism, due to the presence of hyposplenia (reduced splenic functioning), and can be seen in males between 40 and 60 years old.[1] ## Contents * 1 Signs and symptoms * 2 Mechanism/Pathophysiology * 3 Causes * 4 Diagnosis * 5 Prevention/Treatment * 6 Prognosis * 7 Epidemiology * 8 Research * 9 References ## Signs and symptoms[edit] Signs of Austrian syndrome usually begin in Caucasian males over 40. Austrian syndrome triad include pneumonia, endocarditis, and meningitis. A study showed that middle aged men with alcohol issues made up the majority of patients with Austrian Syndrome.[2] Symptoms of pneumonia include cough producing mucus, shortness of breath, chest pains during cough. Symptoms of endocarditis include fever, muscle aches, swollen feet, shortness of breath. Symptoms of meningitis include headache, confusion, sudden fever, sensitivity to light. ## Mechanism/Pathophysiology[edit] Osler's triad also known as Austrian Syndrome was first introduced in the 19th century. Streptococcus Pneumoniae is what causes an Osler’s triad of meningitis, pneumonia and endocarditis. The portal of entry for this triad is said to be the lungs which was then followed by meningitis and endocarditis. The major risk factors are heavy alcohol use, old age, splenectomy, immunosuppression, etc. Endocarditis typically involves the aortic valve. The native aortic valve is the most frequent site of vegetation for streptococcus pneumoniae, and is considered the most common cardiac lesion.[3] ## Causes[edit] The main cause of Osler’s triad (Austrian Syndrome) is streptococcus pneumoniae which is usually associated with heavy alcohol use. Named Osler's triad because it's an association of pneumonia, meningitis, and endocarditis. Drinking excessive amounts of alcohol puts an individual at risk. It was determined that alcoholism completed the tetrad of associated conditions. The patient who was the oldest recorded patient with Austrian syndrome had a history of health concerns such as hypertension, diabetes malleus, etc. increased her risk for Austrian syndrome.[4][3] ## Diagnosis[edit] Early diagnosis of Austrian syndrome is recommended. The disease is usually diagnosed later in an individual’s life, because it mostly affects older Caucasian men. To determine if an individual has Austrian Syndrome, a series of tests are performed. Bacterial cultivation was the main method in determining the diagnosis of Streptococcus pneumoniae. Rapid Diagnostic Test is when a liquid sample of ear or nasal discharge is collected. In terms of streptococcus pneumoniae, it also used to confirm the causative bacterium.[5] X-Ray Imaging of the chest is performed to determine lung inflammation and aortic regurgitation. Electrocardiogram is used to measure the sound waves of the heart. A physical exam is performed on lung and heart cavities and a spinal tap is also performed to collect cerebrospinal fluid. ## Prevention/Treatment[edit] Less consumption of alcohol or no consumption at all are effective ways to decrease the chances of getting Austrian Syndrome. 14% of patients don't have risk factors.[4] Since Austrian Syndrome consists of meningitis, pneumonia and endocarditis, there are separate treatments for each. Streptococcus pneumoniae and endocarditis are usually treated with penicillin, which has said to be the most effective but sources have said that some strains are resistant to penicillin. High doses of penicillin have no effect on pneumonia. Before penicillin was used for treatment, pneumococcus was a cause of a number of endocarditis cases.[3] Also, for endocarditis, a valve replacement would be performed to avoid cardiogenic shock. For meningitis, intravenous antibiotics are used. Earlier studies suggest that dexamethasone improved the outcome of adults with pneumococcal meningitis.[3] In a specific case study, a patient who had symptoms of a fever and headache was treated with cetotaxime, ampicllin, and dexamethasone and had to undergo an emergency valve surgery since the EKG showed mitral vegatation.[6] Researchers say a balanced diet and a healthy diet is beneficial for many aspects in an individual’s life. ## Prognosis[edit] In the 19th century, the mortality rate of Austrian Syndrome was about 75% and has decreased to approximately 32%. [4]The mortality percentage is increased in immunocompromised individuals.The long term effects are eventually death. The older you are, Austrian syndrome consists of pneumonia, endocarditis, and meningitis which all have high mortality rates. ## Epidemiology[edit] Austrian syndrome is a rare disease and it affects mostly males in their 50-60’s with a long history of alcohol abuse. ## Research[edit] Since Austrian Syndrome is extremely rare with less than 60 cases reported, there hasn't been lots of research done on the disease. But there have been multiple case studies that discuss certain treatments, preventions, diagnosis, depending on the individual. In a case study, a patient who had absolutely no history of alcohol abuse presented symptoms of the triad, such as low fever, myalgia, cough, breathlessness. He had abnormal pupils which indicated injury to the brain. A CT scan was performed and CSF analysis results showed 78 cells mm/3^3, a low glucose concentration and positive latex agglutination. The patient was treated with Cenftriaxone which caused the aortic valve to swell up so Vancomycin and Carbapenam was used next in the treatment process and the patient responded well and was able to recover at home with intensive therapy.[7] So antibiotics are used as tools of treatment. There have been no further reports on the Austrian syndrome, because there is a lack of knowledge on the subject. Some researchers refer to it as a 'disease of the past'. ## References[edit] 1. ^ Chest. 2009 Nov;136(5 Suppl):e30. 2. ^ Atkinson, Kate; Augustine, Daniel Xavier; Easaw, Jacob (2009-09-15). "Austrian syndrome: a case report and review of the literature". BMJ Case Reports. 2009: bcr0320091724. doi:10.1136/bcr.03.2009.1724. ISSN 1757-790X. PMC 3028387. PMID 21918664. 3. ^ a b c d Rakočević, Rastko; Shapouran, Sara; Pergament, Kathleen M (2019). "Austrian Syndrome – A Devastating Osler's Triad: Case Report and Literature Review". Cureus. 11 (4): e4486. doi:10.7759/cureus.4486. ISSN 2168-8184. PMC 6581326. PMID 31259104. 4. ^ a b c Rodríguez Nogué, M.; Gómez Arraiz, I.; Ara Martín, G.; Fraj Valle, M. M.; Gómez Peligros, A. (2019). "[Austrian syndrome: A rare manifestation of invasive pneumococcal disease. A case report and bibliographic review]". Revista Espanola de Quimioterapia: Publicacion Oficial de la Sociedad Espanola de Quimioterapia. 32 (2): 98–113. ISSN 1988-9518. PMC 6441982. PMID 30880376. 5. ^ "Streptococcus pneumoniae: diagnosis and treatment". Otsuka Pharmaceutical Co., Ltd. Retrieved 2020-12-11. 6. ^ Munoz, P (1999). "Austrian Syndrome Caused by Highly Penicillin-Resistant Streptococcus pneumoniae". Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 29 (6): 1591–2. doi:10.1086/313542. PMID 10585831. 7. ^ Midon, Márcio Estevão; Goldoni, Fernando; Souza, Sylvian Greicy Rocha; Miyasato, Jan Norimitsu Schiemann (2011). "Austrian Syndrome: case report". Arquivos Brasileiros de Cardiologia. 97 (3): e50–52. ISSN 1678-4170. PMID 22030703. * Schandl, Christian (March 2020). "Austrian syndrome". Clinical Medicine. 20 (2): e1.1–e1. doi:10.7861/clinmed.Let.20.2.1. PMC 7081815. PMID 32188672. * v * t * e Alcohol and health Alcohol use Alcohol-related crimes * Drunk drivers * Alcohol-related traffic crashes in the United States * Driving under the influence (DUI) * Drunk driving in the United States * Public intoxication * Rum-running * Adulterated moonshine/Denatured alcohol * List of methanol poisoning incidents Alcoholism * Alcohol and Native Americans * Alcoholism in adolescence * Alcoholism in family systems * Collaborative Study on the Genetics of Alcoholism * College student alcoholism * Disease theory of alcoholism * High-functioning alcoholic (HFA) * Seeing pink elephants Chemistry * Beer chemistry * Congener * Alcohol congener analysis * Ethanol * Blood alcohol content * Breathalyzer * Fusel alcohol * Wine chemistry Effects * Short-term effects of alcohol consumption * Long-term effects of alcohol * On memory * Subjective response to alcohol Interactions * Aging * Brain * Cancer * breast cancer * Cortisol * Pregnancy * Sleep * Tolerance/intolerance * Weight * Beverage-specific * Beer: Potomania * Red wine: Red wine headache Social issues * Alcohol advertising * on college campuses * Sex * Alcohol myopia * Alcohol abuse among college students * Binge drinking * Epidemiology * Blackout (alcohol-related amnesia) * Blackout Wednesday * Drinking game * list * pregaming * Drinking in public * Drunk dialing * Drunk walking * Drunkorexia * Dry drunk * French paradox * Hair of the dog * Nightcap * Pantsdrunk * Passive drinking * Binge drinking devices * Beer bong * Yard of ale * Routes of administration * Alcohol enema * Alcohol inhalation * Sconcing * Surrogate alcohol * Related issues * Balconing * Suicide History * Dionysian Mysteries * Dipsomania * Gin Craze * List of deaths through alcohol * Rum ration * Speakeasy General * Beer day * Drinking culture * Apéritif and digestif * Hangover remedies * Health effects of wine * Wine and food matching * Long-distance race involving alcohol * List of countries by alcohol consumption per capita * Alcohol consumption by youth in the United States * Nip joint Alcohol control Alcohol law * Administrative license suspension (ALS) * Alcohol packaging warning messages * Drunk driving law by country * DWI court * Field sobriety testing * Hip flask defence * Ignition interlock device * Legal drinking age * Age controversy in US * Underage drinking in US * List of alcohol laws of US Alcohol prohibition * List of countries with alcohol prohibition * Neo-prohibitionism * Temperance movement Sobriety * Alcohol detoxification * Alcohol-free zone * Dry campus * United States open-container laws * Designated driver * Alcohol rehabilitation * Drunk tank * Managed alcohol program * Non-alcoholic drink * List of cocktails * List of mixed drinks * Spritzer * Malt drinks * Teetotalism * Temperance bar * Twelve-step groups * Al-Anon/Alateen * Alcoholics Anonymous (AA): * Adult Children of Alcoholics (ACA) Alcohol limitation * 0-0-1-3 * Alcohol education * Alcohol server training * FRAMES * Dry January * Foundation for Advancing Alcohol Responsibility * Campaigns * Get Your Sexy Back * Liquor license * Low-alcohol drinks * Fermented tea * Low-alcohol beer * Low-alcoholic malt drinks * Small beer * Measurement * Alcoholic spirits measure * Standard drink * Recommended maximum intake of alcoholic beverages Addiction medicine * Disulfiram-like drugs: disulfiram, calcium carbimide, cyanamide. Sulfonic acids: Acamprosate Religion and alcohol * Christian views on alcohol * alcohol in the Bible * Islam and alcohol History * Bratt System Related * Index of alcohol-related articles * Austrian syndrome * Ban on caffeinated alcoholic beverages * Brief intervention * Gateway drug effect * Last call * Mood disorder * Non-alcoholic fatty liver disease * Self-medication * Spins * Sober companion * Sober living houses * Sobering center * Town drunk * Category This article about a disease, disorder, or medical condition is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Austrian syndrome

None

wikipedia

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

{"wikidata": ["Q3961667"]}

Growth retardation-mild developmental delay-chronic hepatitis syndrome is a rare, genetic, parenchymatous liver disease characterized by pre- and postnatal growth retardation, mild global developmental delay, chronic hepatitis with hepatosplenomegaly, Hashimoto thyroiditis, thrombocytopenia, anemia, and B-precursor acute lymphoblastic leukemia. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Growth retardation-mild developmental delay-chronic hepatitis syndrome

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=391366

{}

A canine vector-borne disease (CVBD) is one of "a group of globally distributed and rapidly spreading illnesses that are caused by a range of pathogens transmitted by arthropods including ticks, fleas, mosquitoes and phlebotomine sandflies."[1] CVBDs are important in the fields of veterinary medicine, animal welfare, and public health.[1] Some CVBDs are of zoonotic concern.[1] Many CVBD are transmissible to humans as well as companion animals. Some CVBD are fatal; most can only be controlled, not cured.[citation needed] Therefore, infection should be avoided by preventing arthropod vectors from feeding on the blood of their preferred hosts. While it is well known that arthropods transmit bacteria and protozoa during blood feeds, viruses are also becoming recognized as another group of transmitted pathogens of both animals and humans.[2] Some canine vector-borne pathogens of major zoonotic concern are found worldwide, while others are localized by continent.[1] Listed by vector, some such pathogens and their associated diseases are the following:[1] Phlebotomine sandflies (Psychodidae): * Leishmania amazonensis, L. colombiensis, and L. infantum cause visceral leishmaniasis (see also canine leishmaniasis). * L. braziliensis causes mucocutaneous leishmaniasis. * L. tropica causes cutaneous leishmaniasis. * L. peruviana and L. major cause localized cutaneous leishmaniasis. Triatomine bugs (Reduviidae): * Trypanosoma cruzi causes trypanosomiasis (Chagas disease). Ticks (Ixodidae): * Babesia canis subspecies (Babesia canis canis, B. canis vogeli, B. canis rossi, and B. canis gibsoni cause babesiosis. * Ehrlichia canis and E. chaffeensis cause monocytic ehrlichiosis. * Anaplasma phagocytophilum causes granulocytic anaplasmosis. * Borrelia burgdorferi causes Lyme disease. * Rickettsia rickettsii causes Rocky Mountain spotted fever. * Rickettsia conorii causes Mediterranean spotted fever. Mosquitoes (Culicidae): * Dirofilaria immitis and D. repens cause dirofilariasis.[1] ## References[edit] 1. ^ a b c d e f Domenico Otranto, Filipe Dantas-Torres & Edward B. Breitschwerdt, Managing canine vector-borne diseases of zoonotic concern: part one, Trends in Parasitology Vol. 25, Issue 4, pp. 157–163 (April 2009). 2. ^ "First Canine Vector-Borne Disease Symposium in Billesley, UK" (Press release). Bayer HealthCare. April 2006. Archived from the original on 2006-10-18. Retrieved 2005-11-16. This veterinary medicine–related article is a stub. You can help Wikipedia by expanding it. * v * t * e This infectious disease 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

Canine vector-borne disease

None

wikipedia

https://en.wikipedia.org/wiki/Canine_vector-borne_disease

{"wikidata": ["Q1024563"]}

A number sign (#) is used with this entry because of evidence that sideroblastic anemia-2 (SIDBA2), which is refractory to pyridoxine treatment, is caused by homozygous or compound heterozygous mutation in the SLC25A38 gene (610819) on chromosome 3p22. For a discussion of genetic heterogeneity of sideroblastic anemia, see SIDBA1 (300751). See 206000 for a possible pyridoxine-responsive form of autosomal sideroblastic anemia. Clinical Features Manabe et al. (1982) reported a female Japanese infant who was pale from birth and was found to have marked microcytic hypochromic anemia with 29 ringed sideroblasts per 100 nucleated cells in the bone marrow. The M:E ratio was 0.35 and the total sideroblast count was 89%. Delta-aminolevulinic acid synthetase (ALAS2; 301300) was very low in erythroblasts of this patient. The addition of pyridoxal phosphate had no clinical benefit. The mother had an intermediate level of the enzyme. The father could not be studied, but the authors suspected that both parents were heterozygous, consistent with possible autosomal recessive inheritance. Jardine et al. (1994) reported a brother and sister with transfusion-dependent, pyridoxine-refractory sideroblastic anemia from birth. Clinical features included microcytic, hypochromic anemia and hepatosplenomegaly. Genetic studies excluded linkage to and mutation in the ALAS2 gene, thus excluding the more common X-linked form of the disorder (SIDBA1; 300751). Inheritance was postulated to be autosomal recessive. Guernsey et al. (2009) reported 18 patients with autosomal recessive pyridoxine-refractory sideroblastic anemia. Most patients had onset in infancy of severe microcytic anemia and increased serum ferritin. Bone marrow aspirate showed ringed sideroblasts. The phenotype was similar to that seen in X-linked sideroblastic anemia. Molecular Genetics In 18 patients with autosomal recessive pyridoxine-refractory sideroblastic anemia, Guernsey et al. (2009) identified 11 different homozygous or compound heterozygous mutations in the SLC25A38 gene (see, e.g., 610819.0001-610819.0005). Three unrelated patients who were of Acadian descent from the Maritime Canadian provinces carried the same mutation (R117X; 610819.0001). The other patients were of northern European, Greek, Hispanic, and Asian Indian descent. INHERITANCE \- Autosomal recessive HEMATOLOGY \- Anemia (not responsive to pyridoxine supplementation) \- Microcytosis \- Hypochromia \- Ringed sideroblasts on bone marrow aspirate LABORATORY ABNORMALITIES \- Increased serum ferritin MISCELLANEOUS \- Genetic heterogeneity \- Onset in infancy MOLECULAR BASIS \- Caused by mutation in the solute carrier family 25, member 38 gene (SLC25A38, 610819.0001 ) \- Caused by mutation in the glutaredoxin 5 gene (GLRX5, 609588.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

ANEMIA, SIDEROBLASTIC, 2, PYRIDOXINE-REFRACTORY

c4225425

omim

https://www.omim.org/entry/205950

{"doid": ["0060065"], "omim": ["205950"], "orphanet": ["260305"], "synonyms": ["ARSA", "Congenital sideroblastic anemia"]}

Calcium pyrophosphate dihydrate disease Other namesPseudogout Polarized light microscopy of CPPD, showing rhombus-shaped calcium pyrophosphate crystals with positive birefringence. Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, also known as pseudogout and pyrophosphate arthropathy, is a rheumatologic disease which is thought to be secondary to abnormal accumulation of calcium pyrophosphate dihydrate crystals within joint soft tissues.[1] The knee joint is most commonly affected.[2] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 History * 7 Terminology * 8 References * 9 External links ## Signs and symptoms[edit] When symptomatic, the disease classically begins with symptoms that are similar to a gout attack (thus the monicker "pseudogout"). These include:[citation needed] * severe pain * warmth * swelling of one or more joints The symptoms can be monoarticular (involving a single joint) or polyarticular (involving several joints).[1] Symptoms usually last for days to weeks, and often recur. Although any joint may be affected, the knees, wrists, and hips are most common.[3] X-ray, CT, or other imaging usually shows accumulation of calcium within the joint cartilage, known as chondrocalcinosis. There can also be findings of osteoarthritis.[4][3] The white blood cell count is often raised.[3] In many instances, patients may also have signs of carpal tunnel syndrome.[3] This condition can also be associated with Milwaukee shoulder syndrome.[citation needed] ## Cause[edit] Calcium pyrophosphate The cause of CPPD disease is unknown. Increased breakdown of adenosine triphosphate (ATP; the molecule used as energy currency in all living things), which results in increased pyrophosphate levels in joints, is thought to be one reason why crystals may develop.[3] Familial forms are rare.[5] One genetic study found an association between CPPD and a region of chromosome 8q.[6] The gene ANKH is involved in crystal-related inflammatory reactions and inorganic phosphate transport.[4][3] ## Diagnosis[edit] The disease is defined by presence of joint inflammation and the presence of CPPD crystals within the joint. The crystals are usually detected by imaging and/or joint fluid analysis.[citation needed] X-ray of a knee with chondrocalcinosis. Medical imaging, consisting of x-ray, CT, MRI, or ultrasound may detect chondrocalcinosis within the affected joint, indicating a substantial amount of calcium crystal deposition within the cartilage or ligaments.[2] Ultrasound is a reliable method to diagnose CPPD.[7] Using ultrasound, chondrocalcinosis may be depicted as echogenic foci with no acoustic shadow within the hyaline cartilage[8] or fibrocartilage.[7] By x-ray, CPPD can appear similar to other diseases such as ankylosing spondylitis and gout.[2][3] Micrograph showing crystal deposition in an intervertebral disc. H&E stain. Arthrocentesis, or removing synovial fluid from the affected joint, is performed to test the synovial fluid for the calcium pyrophosphate crystals that are present in CPPD. When stained with H&E stain, calcium pyrophosphate crystals appears deeply blue ("basophilic").[9][10] However, CPP crystals are much better known for their rhomboid shape and weak positive Birefringence on polarized light microscopy, and this method remains the most reliable method of identifying the crystals under the microscope.[11] However, even this method suffers from poor sensitivity, specificity, and inter-operator agreement.[11] These two modalities currently define CPPD disease, but lack diagnostic accuracy.[12] Thus, the diagnosis of CPPD disease is potentially epiphenomenological. ## Treatment[edit] Because any medication that could reduce the inflammation of CPPD bears a risk of causing organ damage, treatment is not advised if the condition is not causing pain.[3] For acute pseudogout, treatments include intra-articular corticosteroid injection, systemic corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), or, on occasion, high-dose colchicine.[3] In general, NSAIDs are administered in low doses to help prevent CPPD. However, if an acute attack is already occurring, higher doses are administered.[3] If nothing else works, hydroxychloroquine or methotrexate may provide relief.[13] Research into surgical removal of calcifications is underway, however, this still remains an experimental procedure.[3] ## Epidemiology[edit] The condition is more common in older adults.[4] CPPD is estimated to affect 4% to 7% of the adult populations of Europe and the United States.[14] Previous studies have overestimated the prevalence by simply estimating the prevalence of chondrocalcinosis, which is found in many other conditions as well.[14] It may cause considerable pain, but it is never fatal.[3] Women are at a slightly higher risk than men, with an estimated ratio of occurrence of 1.4:1.[3] ## History[edit] CPPD crystal deposition disease was originally described over 50 years ago.[12] ## Terminology[edit] Calcium pyrophosphate dihydrate crystals are associated with a range of clinical syndromes, which have been given various names, based upon which clinical symptoms or radiographic findings are most prominent.[12] A task force of the European League Against Rheumatism (EULAR) made recommendations on preferred terminology.[5] Accordingly, calcium pyrophosphate deposition (CPPD) is an umbrella term for the various clinical subsets, whose naming reflects an emphasis on particular features. For example, pseudogout refers to the acute symptoms of joint inflammation or synovitis: red, tender, and swollen joints that may resemble gouty arthritis (a similar condition in which monosodium urate crystals are deposited within the joints). Chondrocalcinosis,[2][3] on the other hand, refers to the radiographic evidence of calcification in hyaline and/or fibrocartilage. "Osteoarthritis (OA) with CPPD" reflects a situation where osteoarthritis features are the most apparent. Pyrophosphate arthropathy refers to several of these situations.[15] ## References[edit] 1. ^ a b Wright GD, Doherty M (1997). "Calcium pyrophosphate crystal deposition is not always 'wear and tear' or aging". Ann. Rheum. Dis. 56 (10): 586–8. doi:10.1136/ard.56.10.586. PMC 1752269. PMID 9389218. 2. ^ a b c d Rothschild, Bruce M Calcium Pyrophosphate Deposition Disease (radiology) 3. ^ a b c d e f g h i j k l m n Rothschild, Bruce M Calcium Pyrophosphate Deposition Disease (rheumatology) at eMedicine 4. ^ a b c Tsui FW (Apr 2012). "Genetics and mechanisms of crystal deposition in calcium pyrophosphate deposition disease". Curr Rheumatol Rep. 14 (2): 155–60. doi:10.1007/s11926-011-0230-6. PMID 22198832. 5. ^ a b Zhang W, Doherty M, Bardin T, Barskova V, Guerne PA, Jansen TL, Leeb BF, Perez-Ruiz F, Pimentao J, Punzi L, Richette P, Sivera F, Uhlig T, Watt I, Pascual E. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011;70(4):563. 6. ^ Baldwin CT, Farrer LA, Adair R, Dharmavaram R, Jimenez S, Anderson L (March 1995). "Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q". Am. J. Hum. Genet. 56 (3): 692–7. PMC 1801178. PMID 7887424. 7. ^ a b Filippou, G.; Adinolfi, A.; Iagnocco, A.; Filippucci, E.; Cimmino, M.A.; Bertoldi, I.; Di Sabatino, V.; Picerno, V.; Delle Sedie, A.; Sconfienza, L.M.; Frediani, B. (June 2016). "Ultrasound in the diagnosis of calcium pyrophosphate dihydrate deposition disease. A systematic literature review and a meta-analysis". Osteoarthritis and Cartilage. 24 (6): 973–981. doi:10.1016/j.joca.2016.01.136. 8. ^ Arend CF. Ultrasound of the Shoulder. Master Medical Books, 2013. Free chapter on acromioclavicular chondrocalcinosis is available at ShoulderUS.com 9. ^ Hosler, Greg. "calcinosis_cutis_2_060122". Derm Atlas. Archived from the original on 5 February 2007. Retrieved 13 March 2012. 10. ^ "Calcium Pyrophosphate Dihydrate Deposition Disease: Synovial Biopsy, Wrist". Rheumatology Image Bank. American College of Rheumatology. Retrieved 13 March 2012. 11. ^ a b Dieppe, P.; Swan, A. (1 May 1999). "Identification of crystals in synovial fluid". Annals of the Rheumatic Diseases. 58 (5): 261–3. doi:10.1136/ard.58.5.261. PMC 1752883. PMID 10225806. 12. ^ a b c Rosenthal, AK; Ryan, LM (May 2011). "Crystal arthritis: Calcium pyrophosphate deposition—nothing 'pseudo' about it!". Nat Rev Rheumatol. 7 (5): 257–8. doi:10.1038/nrrheum.2011.50. PMID 21532639. 13. ^ Emkey GR, Reginato AM (2009). "All about gout and pseudogout". Journal of Musculoskeletal Medicine. 26 (10). 14. ^ a b Ann K. Rosenthal. "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease". UpToDate. This topic last updated: Jul 24, 2018. 15. ^ Longmore, Murray; Ian Wilkinson; Tom Turmezei; Chee Kay Cheung (2007). Oxford Handbook of Clinical Medicine. Oxford. p. 841. ISBN 978-0-19-856837-7. ## External links[edit] Classification D * ICD-10: M11.1-M11.2 * ICD-9-CM: [712.3 275.49 [712.3]] * OMIM: 600668 118600 * MeSH: D002805 * DiseasesDB: 10832 External resources * MedlinePlus: 000421 * eMedicine: med/1938 radio/125 orthoped/382 emerg/221 * v * t * e Diseases of joints General * Arthritis * Monoarthritis * Oligoarthritis * Polyarthritis Symptoms * Joint pain * Joint stiffness Inflammatory Infectious * Septic arthritis * Tuberculosis arthritis Crystal * Chondrocalcinosis * CPPD (Psudogout) * Gout Seronegative * Reactive arthritis * Psoriatic arthritis * Ankylosing spondylitis Other * Juvenile idiopathic arthritis * Rheumatoid arthritis * Felty's syndrome * Palindromic rheumatism * Adult-onset Still's disease Noninflammatory * Hemarthrosis * Osteoarthritis * Heberden's node * Bouchard's nodes * Osteophyte *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Calcium pyrophosphate dihydrate crystal deposition disease

c0856830

wikipedia

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

{"mesh": ["C563162"], "umls": ["C0856830"], "wikidata": ["Q64348505"]}

Herpes esophagitis Endoscopic image of Herpes esophagitis SpecialtyInfectious disease, gastroenterology Herpes esophagitis is a viral infection of the esophagus caused by Herpes simplex virus (HSV). While the disease most often occurs in immunocompromised patients, including post-chemotherapy, immunosuppression with organ transplants[1] and in AIDS,[2] herpes esophagitis can also occur in immunocompetent individuals.[3] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 Differential diagnosis * 3 Prevention * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] People with herpes esophagitis experience pain with eating and trouble swallowing. Other symptoms can include food impaction,[4] hiccups,[5] weight loss, fever,[3] and on rare occasions upper gastrointestinal bleeding as noted in the image above[6] and tracheoesophageal fistula.[7] Frequently one can see herpetiform lesions in the mouth and lips. ## Diagnosis[edit] Micrograph of an esophageal biopsy showing herpes eosphagitis, with the characteristic nuclear changes (nuclear moulding, chromatin clumping at the nuclear membrane (margination) and multinucleation). H&E stain. Upper Endoscopy often reveals ulcers throughout the esophagus with intervening normal-appearing mucosa. In severe cases the ulcers can coalesce and on rare occasions have a black appearance known as black esophagus.[8] While the diagnosis of herpes esophagitis can be inferred clinically it can only be accurately diagnosed through endoscopically obtained biopsies with microscopic evaluation by a pathologist finding the appropriate inclusion bodies and diagnostic immunochemical staining.[9] False negative findings may occur if biopsies are taken from the ulcer rather than from the margin of the ulcer as the inclusion particles are to be found in viable epithelial cells. Viral tissue culture represents the most accurate means of diagnosing the precise cause. ### Differential diagnosis[edit] CMV, VZV as well as HIV infections of the esophagus can have a similar presentation. Tissue culture is the most accurate means of distinguishing between the different viral causes.[10] Caustic esophagitis, pill-induced esophagitis as well as yeast esophagitis can have a similar clinical presentation. ## Prevention[edit] Herpes simplex virus is commonly found in humans, yet uncommonly results in systemic manifestations. Suppression of HIV with antiretroviral medications, careful monitoring of immunosuppressive medications are important means of prevention. Antiviral prophylaxis such as daily acyclovir in immunocompromised individuals may be considered. ## Treatment[edit] Antivirals such as acyclovir, famciclovir, or valacyclovir may be used. Intravenous acyclovir is reserved for individuals who cannot swallow due to the pain, individuals with other systemic manifestations of herpes or severely immunocompromised individuals. ## References[edit] 1. ^ Miller GG, Dummer JS (April 2007). "Herpes simplex and varicella zoster viruses: forgotten but not gone". Am. J. Transplant. 7 (4): 741–7. doi:10.1111/j.1600-6143.2006.01718.x. PMID 17391119. 2. ^ McBane RD, Gross JB (1991). "Herpes esophagitis: clinical syndrome, endoscopic appearance, and diagnosis in 23 patients". Gastrointest. Endosc. 37 (6): 600–3. doi:10.1016/s0016-5107(91)70862-6. PMID 1756917. 3. ^ a b Kato S, Yamamoto R, Yoshimitsu S, et al. (2005). "Herpes simplex esophagitis in the immunocompetent host". Dis. Esophagus. 18 (5): 340–4. doi:10.1111/j.1442-2050.2005.00510.x. PMID 16197537. 4. ^ Marshall JB, Smart JR, Elmer C, Lillich MA, Diaz-Arias AA (September 1992). "Herpes esophagitis causing an unsuspected esophageal food bolus impaction in an institutionalized patient". J. Clin. Gastroenterol. 15 (2): 179–80. doi:10.1097/00004836-199209000-00032. PMID 1328357. 5. ^ Mulhall BP, Nelson B, Rogers L, Wong RK (May 2003). "Herpetic esophagitis and intractable hiccups (singultus) in an immunocompetent patient". Gastrointest. Endosc. 57 (6): 796–7. doi:10.1067/mge.2003.212. PMID 12739568. 6. ^ Takeno M, Adachi H, Nakahama T, Inagaki Y, Morimoto H, Watanabe K (August 2002). "[Herpes esophagitis presenting upper gastrointestinal bleeding: report of a case]". Nihon Shokakibyo Gakkai Zasshi (in Japanese). 99 (8): 935–40. PMID 12229166. 7. ^ Obrecht WF, Richter JE, Olympio GA, Gelfand DW (November 1984). "Tracheoesophageal fistula: a serious complication of infectious esophagitis". Gastroenterology. 87 (5): 1174–9. doi:10.1016/S0016-5085(84)80082-7. PMID 6592123. 8. ^ Nagri S, Hwang R, Anand S, Kurz J (February 2007). "Herpes simplex esophagitis presenting as acute necrotizing esophagitis ("black esophagus") in an immunocompetent patient". Endoscopy. 39 (Suppl 1): E169. doi:10.1055/s-2007-966619. PMID 17614059. 9. ^ Bennett WE, Tarr PI (January 2009). "Enteric infections and diagnostic testing". Curr. Opin. Gastroenterol. 25 (1): 1–7. doi:10.1097/MOG.0b013e32831ba094. PMID 19114768. 10. ^ Meinhard Classen; Guido N. J. Tytgat; M.D. Ph.D.; Charles J. Lightdale (2010). Gastroenterological Endoscopy. Thieme. pp. 490–. ISBN 978-3-13-125852-6. Retrieved 26 June 2010. ## External links[edit] Classification D * ICD-10: B00.9 * ICD-9-CM: 054.79 * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum * v * t * e Skin infections, symptoms and signs related to viruses DNA virus Herpesviridae Alpha HSV * Herpes simplex * Herpetic whitlow * Herpes gladiatorum * Herpes simplex keratitis * Herpetic sycosis * Neonatal herpes simplex * Herpes genitalis * Herpes labialis * Eczema herpeticum * Herpetiform esophagitis Herpes B virus * B virus infection VZV * Chickenpox * Herpes zoster * Herpes zoster oticus * Ophthalmic zoster * Disseminated herpes zoster * Zoster-associated pain * Modified varicella-like syndrome Beta * Human herpesvirus 6/Roseolovirus * Exanthema subitum * Roseola vaccinia * Cytomegalic inclusion disease Gamma * KSHV * Kaposi's sarcoma Poxviridae Ortho * Variola * Smallpox * Alastrim * MoxV * Monkeypox * CPXV * Cowpox * VV * Vaccinia * Generalized vaccinia * Eczema vaccinatum * Progressive vaccinia * Buffalopox Para * Farmyard pox: Milker's nodule * Bovine papular stomatitis * Pseudocowpox * Orf * Sealpox Other * Yatapoxvirus: Tanapox * Yaba monkey tumor virus * MCV * Molluscum contagiosum Papillomaviridae HPV * Wart/plantar wart * Heck's disease * Genital wart * giant * Laryngeal papillomatosis * Butcher's wart * Bowenoid papulosis * Epidermodysplasia verruciformis * Verruca plana * Pigmented wart * Verrucae palmares et plantares * BPV * Equine sarcoid Parvoviridae * Parvovirus B19 * Erythema infectiosum * Reticulocytopenia * Papular purpuric gloves and socks syndrome Polyomaviridae * Merkel cell polyomavirus * Merkel cell carcinoma RNA virus Paramyxoviridae * MeV * Measles Togaviridae * Rubella virus * Rubella * Congenital rubella syndrome ("German measles" ) * Alphavirus infection * Chikungunya fever Picornaviridae * CAV * Hand, foot, and mouth disease * Herpangina * FMDV * Foot-and-mouth disease * Boston exanthem disease Ungrouped * Asymmetric periflexural exanthem of childhood * Post-vaccination follicular eruption * Lipschütz ulcer * Eruptive pseudoangiomatosis * Viral-associated trichodysplasia * Gianotti–Crosti syndrome *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Herpes esophagitis

c0238112

wikipedia

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

{"icd-9": ["054.79"], "icd-10": ["B00.9"], "wikidata": ["Q2849596"]}

A number sign (#) is used with this entry because of evidence that RIDDLE syndrome (RIDL) is caused by homozygous or compound heterozygous mutation in the RNF168 gene (612688) on chromosome 3q29. Description RIDDLE is an acronym for the major features of this syndrome: radiosensitivity, immunodeficiency, dysmorphic facies, and learning difficulties (Stewart et al., 2007). Clinical Features Stewart et al. (2007) described a male Caucasian patient with a novel syndrome of increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature. They termed the disorder RIDDLE syndrome. The patient's parents were nonconsanguineous, and there was no family history of immunodeficiency. At age 1 year, the patient's IgG and IgM levels were below normal limits. His B cells produced no detectable IgG in vitro. The patient was treated with intramuscular IgG from age 3 years, and he was switched to subcutaneous Ig at age 22 years. The patient's cells lacked the ability to recruit TP53BP1 (605230) to sites of DNA double-strand breaks, resulting in hypersensitivity to ionizing radiation, cell cycle checkpoint abnormalities, and impaired end joining in the recombined switch regions. No mutations were identified in TP53BP1 or other genes that regulate ionizing radiation-induced TP53BP1 foci formation. Stewart et al. (2007) concluded that a double-strand break repair protein exists upstream of TP53BP1 that contributes to normal development of the immune system. Stewart et al. (2009) noted the pathologic similarities to the ataxia-telangiectasia syndrome (AT; 208900). Devgan et al. (2011) reported a Turkish man, born of unrelated parents, who presented with short stature and mild ataxia at age 16 years. He had microcephaly but displayed displayed normal intelligence. Other features included conjunctival telangiectasia, recurrent sinus infections, decreased serum IgA, and increased alpha-fetoprotein. At age 29 years, the patient presented with progressive pulmonary failure that resulted in death at age 30. Pulmonary work-up revealed restrictive lung disease with interstitial thickening, bronchial telangiectasia, and possible pulmonary fibrosis. Patient cells were radiosensitive and showed defects in the repair of DNA double-strand breakage. Molecular Genetics In the patient with RIDDLE syndrome reported by Stewart et al. (2007), Stewart et al. (2009) identified compound heterozygosity for truncating mutations in the RNF168 gene (612688.0001 and 612688.0002). The authors noted that the patient's father, who was heterozygous for 1 of the mutations, had developed chronic B-cell leukemia, suggesting that RNF168 may also act as a tumor suppressor gene. In a Turkish man with a phenotype consistent with RIDDLE syndrome, Devgan et al. (2011) identified a homozygous truncating mutation in the RNF168 gene (612688.0003). Ectopic expression of RNF168 in patient cells restored the DNA repair defect. Devgan et al. (2011) noted some phenotypic similarities to chromosome 3q29 deletion syndrome (609425). INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly (in some patients) Eyes \- Ocular telangiectasia RESPIRATORY \- Progressive pulmonary failure (1 patient) \- Interstitial pneumonia (1 patient) \- Pulmonary fibrosis (1 patient) \- Bronchial telangiectasia (1 patient) SKIN, NAILS, & HAIR Skin \- Dry skin NEUROLOGIC Central Nervous System \- Learning difficulties (in 1 patient) \- Impaired motor control, mild \- Ataxia IMMUNOLOGY \- Immunodeficiency \- Variably decreased serum IgA, IgG, and IgM LABORATORY ABNORMALITIES \- Cells show increased sensitivity to ionizing radiation \- Defect in double-stranded DNA repair \- Increased alpha-fetoprotein MISCELLANEOUS \- Two unrelated patients have been reported (last curated July 2014) Onset in infancy or childhood MOLECULAR BASIS \- Caused by mutation in the ring finger protein 168 gene (RNF168, 612688.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

RIDDLE SYNDROME

c2677792

omim

https://www.omim.org/entry/611943

{"doid": ["0090113"], "mesh": ["C567453"], "omim": ["611943"], "orphanet": ["420741"], "synonyms": ["Alternative titles", "RADIOSENSITIVITY, IMMUNODEFICIENCY, DYSMORPHIC FACIAL FEATURES, AND LEARNING DIFFICULTIES"]}

## Clinical Features Waggoner et al. (1942) described 6 sisters in a sibship of 11 with agenesis of the white matter and mental retardation, surviving to adulthood. The family was of Finnish extraction. No parental consanguinity was known. Also see 224250. Neuro \- White matter agenesis \- Mental retardation Inheritance \- Autosomal recessive ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

AGENESIS OF CEREBRAL WHITE MATTER

c1859969

omim

https://www.omim.org/entry/202600

{"omim": ["202600"]}

This article needs editing for compliance with Wikipedia's Manual of Style. In particular, it has problems with not using MOS. Please help improve it if you can. (February 2019) (Learn how and when to remove this template message) Pancreatic disease SpecialtyGastroenterology Pancreatic diseases include: ## Contents * 1 Pancreatitis * 2 Diabetes mellitus * 3 Exocrine pancreatic insufficiency * 4 Cystic fibrosis * 5 Pseudocysts * 6 Cysts * 7 Congenital malformations * 7.1 Pancreas divisum * 7.2 Annular pancreas * 8 Neoplasms * 8.1 Benign * 8.2 Tumor predisposition * 8.2.1 Zollinger-Ellison syndrome * 9 Hemosuccus pancreaticus * 10 See also * 11 References * 12 External links ## Pancreatitis[edit] Pancreatitis is inflammation of the pancreas. There are two forms of pancreatitis, which are different in causes and symptoms, and require different treatment: * Acute pancreatitis is a rapid-onset inflammation of the pancreas, most frequently caused by alcoholism or gallstones. Less frequent but important causes are hypertriglyceridemia, drugs, infections. * Chronic pancreatitis is a long-standing inflammation of the pancreas. ## Diabetes mellitus[edit] The pancreas is central in the pathophysiology of both major types of diabetes mellitus. In type 1 diabetes mellitus, there is direct damage to the endocrine pancreas that results in insufficient insulin synthesis and secretion. Type 2 diabetes mellitus, which begins with insulin resistance, is characterized by the ultimate failure of pancreatic β cells to match insulin production with insulin demand. ## Exocrine pancreatic insufficiency[edit] Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI is found in humans afflicted with cystic fibrosis and Shwachman–Diamond syndrome. It is caused by a progressive loss of the pancreatic cells that make digestive enzymes. Chronic pancreatitis is the most common cause of EPI in humans. Loss of digestive enzymes leads to maldigestion and malabsorption of nutrients. ## Cystic fibrosis[edit] Cystic fibrosis, is a hereditary disease that affects the entire body, causing progressive disability and early death. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The product of this gene helps create sweat, digestive juices, and mucus. The name cystic fibrosis refers to the characteristic 'fibrosis' (tissue scarring) and cyst formation within the pancreas, causing irreversible damage, and often resulting in painful inflammation (pancreatitis). ## Pseudocysts[edit] A pancreatic pseudocyst is a circumscribed collection of fluid rich in amylase and other pancreatic enzymes, blood and necrotic tissue, typically located in the lesser sac. ## Cysts[edit] X-ray computed tomography (CT scan) findings of cysts in the pancreas are common, and often are benign. In a study of 2,832 patients without pancreatic disease, 73 patients (2.6%) had cysts in the pancreas.[1] About 85% of these patients had a single cyst. Cysts ranged in size from 2 to 38 mm (mean, 8.9 mm). There was a strong correlation between the presence of cysts and age. No cysts were identified among patients less than 40 years of age, while 8.7 percent of the patients aged 80 to 89 years had a pancreatic cyst. Cysts also may be present due to intraductal papillary mucinous neoplasm. ## Congenital malformations[edit] ### Pancreas divisum[edit] Pancreas divisum is a malformation in which the pancreas fails to fuse. It is a rare condition that affects only 6% of the world's population, and of these few, only 1% ever have symptoms that require surgery. ### Annular pancreas[edit] Annular pancreas is characterized by a pancreas that encircles the duodenum. It results from an embryological malformation in which the early pancreatic buds undergo inappropriate rotation and fusion, which can lead to small bowel obstruction. ## Neoplasms[edit] See pancreatic tumors, benign or malignant (pancreatic cancer). ### Benign[edit] * Serous cystadenoma of the pancreas * Solid pseudopapillary neoplasm ### Tumor predisposition[edit] #### Zollinger-Ellison syndrome[edit] Zollinger-Ellison syndrome is a collection of findings in individuals with gastrinoma, a tumor of the gastrin-producing cells of the pancreas. Unbridled gastrin secretion results in elevated levels of the hormone, and increased hydrochloric acid secretion from parietal cells of the stomach. It can lead to ulceration and scarring of the stomach and intestinal mucosa. ## Hemosuccus pancreaticus[edit] Hemosuccus pancreaticus, also known as pseudohematobilia or Wirsungorrhage, is a rare cause of hemorrhage in the gastrointestinal tract. It is caused by a bleeding source in the pancreas, pancreatic duct, or structures adjacent to the pancreas, such as the splenic artery, that bleed into the pancreatic duct. Patients with hemosuccus may develop symptoms of gastrointestinal hemorrhage, such as blood in the stools, maroon stools, or melena. They may also develop abdominal pain. Hemosuccus pancreaticus is associated with pancreatitis, pancreatic cancer and aneurysms of the splenic artery. Angiography may be used to diagnose hemosuccus pancreaticus, where the celiac axis is injected to determine the blood vessel that is bleeding. Concomitant embolization of the end vessel may terminate the hemorrhage. Alternatively, a distal pancreatectomy may be required to stop the hemorrhage. ## See also[edit] * Pancreas * Pancreatic mass ## References[edit] 1. ^ Laffan T, Horton KM, Klein AP, et al. (Sep 2008). "Prevalence of unsuspected pancreatic cysts on MDCT". AJR Am J Roentgenol. 191 (3): 802–807. doi:10.2214/AJR.07.3340. PMC 2692243. PMID 18716113. ## External links[edit] Classification D * ICD-10: K85-K86, Q45.0-Q45.3 * ICD-9-CM: 577, 751.7 * MeSH: D010182 * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum * v * t * e Congenital malformations and deformations of digestive system Upper GI tract Tongue, mouth and pharynx * Cleft lip and palate * Van der Woude syndrome * tongue * Ankyloglossia * Macroglossia * Hypoglossia Esophagus * EA/TEF * Esophageal atresia: types A, B, C, and D * Tracheoesophageal fistula: types B, C, D and E * esophageal rings * Esophageal web (upper) * Schatzki ring (lower) Stomach * Pyloric stenosis * Hiatus hernia Lower GI tract Intestines * Intestinal atresia * Duodenal atresia * Meckel's diverticulum * Hirschsprung's disease * Intestinal malrotation * Dolichocolon * Enteric duplication cyst Rectum/anal canal * Imperforate anus * Rectovestibular fistula * Persistent cloaca * Rectal atresia Accessory Pancreas * Annular pancreas * Accessory pancreas * Johanson–Blizzard syndrome * Pancreas divisum Bile duct * Choledochal cysts * Caroli disease * Biliary atresia Liver * Alagille syndrome * Polycystic liver disease * v * t * e Disease of the pancreas and glucose metabolism Diabetes * Types * type 1 * type 2 * gestational * MODY 1 2 3 4 5 6 * Complications * See Template:Diabetes Abnormal blood glucose levels * Hyperglycaemia * Oxyhyperglycemia * Hypoglycaemia * Whipple's triad Insulin disorders * Insulin resistance * Hyperinsulinism * Rabson–Mendenhall syndrome Other pancreatic disorders * Insulinoma * Insulitis *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Pancreatic disease

c0030286

wikipedia

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

{"mesh": ["D010182"], "umls": ["C0030286"], "orphanet": ["101937"], "wikidata": ["Q7130407"]}

Pure red cell aplasia SpecialtyHematology Pure red cell aplasia (PRCA) or erythroblastopenia refers to a type of anemia affecting the precursors to red blood cells but not to white blood cells. In PRCA, the bone marrow ceases to produce red blood cells. There are multiple etiologies that can cause PRCA. The condition has been first described by Paul Kaznelson in 1922.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Treatment * 4 See also * 5 References * 6 External links ## Signs and symptoms[edit] Signs and symptoms may include: * Pale appearance * Fast heart rate * decreased activity ## Causes[edit] Causes of PRCA include: * Autoimmune disease. * Thymoma.[2] * Viral infections such as HIV, herpes, parvovirus B19 (Fifth disease),[3] or hepatitis.[citation needed] * Lymphoproliferative. Association of pure red cell aplasia with T-cell large granular lymphocyte leukemia is well recognized, especially in China.[4] * Idiopathic. Many cases of PRCA are considered idiopathic in that there is no discernible cause detected.[5] * Drugs such as mycophenolic acid[6] or erythropoietin.[7][citation needed] * Congenital. The term "hereditary pure red cell aplasia" has been used to refer to Diamond–Blackfan anemia.[8] ## Treatment[edit] PRCA is considered an autoimmune disease as it will respond to immunosuppressant treatment such as cyclosporin in many patients,[9] though this approach is not without risk.[10] It has also been shown to respond to treatments with rituximab and tacrolimus.[citation needed] ## See also[edit] * Diamond–Blackfan anemia (genetic red cell aplasia) * Aplastic anemia (aplasia affecting other bone marrow cells as well) ## References[edit] 1. ^ Kaznelson P (1922). "Zur Entstehung der Blutplättchen". Verh Dtsch Ges Inn Med. 34: 557–8. 2. ^ Hirokawa M, Sawada K, Fujishima N, et al. (January 2008). "Long-term response and outcome following immunosuppressive therapy in thymoma-associated pure red cell aplasia: a nationwide cohort study in Japan by the PRCA collaborative study group". Haematologica. 93 (1): 27–33. doi:10.3324/haematol.11655. PMID 18166782. 3. ^ Geetha D, Zachary JB, Baldado HM, Kronz JD, Kraus ES (December 2000). "Pure red cell aplasia caused by Parvovirus B19 infection in solid organ transplant recipients: a case report and review of literature". Clinical Transplantation. 14 (6): 586–91. doi:10.1034/j.1399-0012.2000.140612.x. PMID 11127313. 4. ^ Kwong YL, Wong KF (1998). "Association of pure red cell aplasia with T large granular lymphocyte leukaemia". J. Clin. Pathol. 51 (9): 672–5. doi:10.1136/jcp.51.9.672. PMC 500904. PMID 9930071. 5. ^ Miller AC, Rashid RM (2008). "Three episodes of acquired pure red cell aplasia restricted to pregnancy". Journal of Perinatal Medicine. 36 (3): 270–1. doi:10.1515/JPM.2008.041. PMID 18576941. 6. ^ Petrochko C (2009). "FDA Strengthens Warning on Transplant Drug." Medpage Today. 14 August 2009. Accessed 19 August 2009. 7. ^ Macdougall, IC (November 2007). "Epoetin-induced pure red cell aplasia: diagnosis and treatment". Current Opinion in Nephrology and Hypertension. 16 (6): 585–8. doi:10.1097/MNH.0b013e3282f0c4bf. PMID 18089975. 8. ^ Online Mendelian Inheritance in Man (OMIM): 105650 9. ^ Sawada K, Hirokawa M, Fujishima N, et al. (August 2007). "Long-term outcome of patients with acquired primary idiopathic pure red cell aplasia receiving cyclosporine A. A nationwide cohort study in Japan for the PRCA Collaborative Study Group". Haematologica. 92 (8): 1021–8. doi:10.3324/haematol.11192. PMID 17640861. 10. ^ Sawada K, Fujishima N, Hirokawa M (August 2008). "Acquired pure red cell aplasia: updated review of treatment". Br. J. Haematol. 142 (4): 505–14. doi:10.1111/j.1365-2141.2008.07216.x. PMC 2592349. PMID 18510682. ## External links[edit] Classification D * ICD-10: D60 * ICD-9-CM: 284.8 * MeSH: D012010 * DiseasesDB: 29063 External resources * eMedicine: med/1967 * v * t * e Diseases of red blood cells ↑ Polycythemia * Polycythemia vera ↓ Anemia Nutritional * Micro-: Iron-deficiency anemia * Plummer–Vinson syndrome * Macro-: Megaloblastic anemia * Pernicious anemia Hemolytic (mostly normo-) Hereditary * enzymopathy: Glucose-6-phosphate dehydrogenase deficiency * glycolysis * pyruvate kinase deficiency * triosephosphate isomerase deficiency * hexokinase deficiency * hemoglobinopathy: Thalassemia * alpha * beta * delta * Sickle cell disease/trait * Hereditary persistence of fetal hemoglobin * membrane: Hereditary spherocytosis * Minkowski–Chauffard syndrome * Hereditary elliptocytosis * Southeast Asian ovalocytosis * Hereditary stomatocytosis Acquired AIHA * Warm antibody autoimmune hemolytic anemia * Cold agglutinin disease * Donath–Landsteiner hemolytic anemia * Paroxysmal cold hemoglobinuria * Mixed autoimmune hemolytic anemia * membrane * paroxysmal nocturnal hemoglobinuria * Microangiopathic hemolytic anemia * Thrombotic microangiopathy * Hemolytic–uremic syndrome * Drug-induced autoimmune * Drug-induced nonautoimmune * Hemolytic disease of the newborn Aplastic (mostly normo-) * Hereditary: Fanconi anemia * Diamond–Blackfan anemia * Acquired: Pure red cell aplasia * Sideroblastic anemia * Myelophthisic Blood tests * Mean corpuscular volume * normocytic * microcytic * macrocytic * Mean corpuscular hemoglobin concentration * normochromic * hypochromic Other * Methemoglobinemia * Sulfhemoglobinemia * Reticulocytopenia *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa

Pure red cell aplasia

c0034902

wikipedia

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

{"gard": ["10898", "7504"], "mesh": ["D012010"], "umls": ["C0034902"], "icd-9": ["284.8"], "icd-10": ["D60"], "orphanet": ["98872"], "wikidata": ["Q751631"]}

Nicotine dependence Other namestobacco dependence; tobacco use disorder Play media Video explanation Nicotine dependence[notes 1] is a state of dependence upon nicotine.[1] Nicotine dependence is a chronic, relapsing disease defined as a compulsive craving to use the drug, despite harmful social consequences.[5] Tolerance is another component of drug dependence.[6] Nicotine dependence develops over time as a person continues to use nicotine.[6] Nicotine dependence is a serious public health concern due to it being one of the leading causes of avoidable deaths worldwide. [7] There are different ways of measuring nicotine dependence.[3] The five common dependence assessment scales are the Fagerström Test for Nicotine Dependence, the Diagnostic and Statistical Manual of Mental Disorders, the Cigarette Dependence Scale, the Nicotine Dependence Syndrome Scale, and the Wisconsin Inventory of Smoking Dependence Motives.[3] The long use of Fagerström Test for Nicotine Dependence is supported by the existence of significant preexisting research, and its conciseness.[3] There are approximately 976 million smokers in the world.[8] There is an increased frequency of nicotine dependence in people with anxiety disorders.[9] Nicotine is a sympathomimetic stimulant[10] that attaches to nicotinic acetylcholine receptors in the brain.[11] Neuroplasticity within the brain's reward system occurs as a result of long-term nicotine use, leading to nicotine dependence.[1] There are genetic risk factors for developing dependence.[12] For instance, genetic markers for a specific type of nicotinic receptor (the α5-α3-β4 nicotine receptors) have been linked to increased risk for dependence.[12] Evidence-based medicine can double or triple a smoker's chances of quitting successfully.[13] ## Contents * 1 Definition * 2 Diagnosis * 3 Mechanisms * 3.1 Biomolecular * 3.2 Psychosocial * 4 Treatment * 4.1 Medication * 4.2 Psychosocial * 5 Epidemiology * 6 Concerns * 7 Notes * 8 See also * 9 Bibliography * 10 References * 11 External links ## Definition[edit] Play media A National Institute on Drug Abuse video entitled Anyone Can Become Addicted to Drugs.[14] Nicotine dependence is defined as a neurobiological adaptation to repeated drug exposure that is manifested behaviorally by highly controlled or compulsive use; psychoactive effects such as tolerance, physical dependence, and pleasant effect; and nicotine-reinforced behavior, including an inability to quit despite harmful effects, a desire to quit, and repeated cessation attempts.[15] Nicotine dependence is a chronic, relapsing disease defined as a compulsive craving to use the drug, despite harmful social consequences; inability to control drug use; and onset of withdrawal-like symptoms when the drug is discontinued.[5] A 1988 Surgeon General report states, "Tolerance" is another aspect of drug addiction [dependence] whereby a given dose of a drug produces less effect or increasing doses are required to achieve a specified intensity of response. Physical dependence on the drug can also occur, and is characterized by a withdrawal syndrome that usually accompanies drug abstinence. After cessation of drug use, there is a strong tendency to relapse."[6] Nicotine dependence leads to heavy smoking and causes severe withdrawal symptoms and relapse back to smoking.[6] Nicotine dependence develops over time as a person continues to use nicotine.[6] Teenagers do not have to be daily or long-term smokers to show withdrawal symptoms.[16] Relapse should not frustrate the nicotine user from trying to quit again.[13] A 2015 review found "Avoiding withdrawal symptoms is one of the causes of continued smoking or relapses during attempts at cessation, and the severity and duration of nicotine withdrawal symptoms predict relapse."[17] Symptoms of nicotine dependence include irritability, anger, impatience, and problems in concentrating.[18] ## Diagnosis[edit] There are different ways of measuring nicotine dependence.[3] The five common dependence assessment scales are the Fagerström Test for Nicotine Dependence, the Diagnostic and Statistical Manual of Mental Disorders, the Cigarette Dependence Scale, the Nicotine Dependence Syndrome Scale, and the Wisconsin Inventory of Smoking Dependence Motives.[3] The Fagerström Test for Nicotine Dependence focuses on measuring physical dependence which is defined "as a state produced by chronic drug administration, which is revealed by the occurrence of signs of physiological dysfunction when the drug is withdrawn; further, this dysfunction can be reversed by the administration of drug".[3] The long use of Fagerström Test for Nicotine Dependence is supported by the existence of significant preexisting research, and its conciseness.[3] The 4th edition of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) had a nicotine dependence diagnosis which was defines as "...a cluster of cognitive, behavioral, and physiological symptoms..."[3] In the updated DSM-5 there is no nicotine dependence diagnosis, but rather Tobacco Use Disorder, which is defined as, "A problematic pattern of tobacco use leading to clinically significant impairment or distress, as manifested by at least 2 of the following [11 symptoms], occurring within a 12-month period."[19] The Cigarette Dependence Scale was developed "to index dependence outcomes and not dependence mechanisms".[3] The Nicotine Dependence Syndrome Scale, "a 19-item self-report measure, was developed as a multidimensional scale to assess nicotine dependence".[3] The Wisconsin Inventory of Smoking Dependence Motives "is a 68-item measure developed to assess dependence as a motivational state".[3] ## Mechanisms[edit] Traditional cigarettes are the most common delivery device for nicotine.[citation needed] However, electronic cigarettes are becoming more popular.[20] Nicotine can also be delivered via other tobacco products such as chewing tobacco, snus, pipe tobacco, hookah, all of which can produce nicotine dependence.[citation needed] ### Biomolecular[edit] Dopamine Pre-existing cognitive and mood disorders may influence the development and maintenance of nicotine dependence.[21] Nicotine is a parasympathomimetic stimulant[10] that binds to and activates nicotinic acetylcholine receptors in the brain,[11] which subsequently causes the release of dopamine and other neurotransmitters, such as norepinephrine, acetylcholine, serotonin, gamma-aminobutyric acid, glutamate, endorphins,[22] and several neuropeptides.[23] Repeated exposure to nicotine can cause an increase in the number of nicotinic receptors, which is believed to be a result of receptor desensitization and subsequent receptor upregulation.[22] This upregulation or increase in the number of nicotinic receptors significantly alters the functioning of the brain reward system.[24] With constant use of nicotine, tolerance occurs at least partially as a result of the development of new nicotinic acetylcholine receptors in the brain.[22] After several months of nicotine abstinence, the number of receptors go back to normal.[11] Nicotine also stimulates nicotinic acetylcholine receptors in the adrenal medulla, resulting in increased levels of adrenaline and beta-endorphin.[22] Its physiological effects stem from the stimulation of nicotinic acetylcholine receptors, which are located throughout the central and peripheral nervous systems.[25] Chronic nicotinic acetylcholine receptor activation from repeated nicotine exposure can induce strong effects on the brain, including changes in the brain's physiology, that result from the stimulation of regions of the brain associated with reward, pleasure, and anxiety.[26] These complex effects of nicotine on the brain are still not well understood.[26] When these receptors are not occupied by nicotine, they are believed to produce withdrawal symptoms.[27] These symptoms can include cravings for nicotine, anger, irritability, anxiety, depression, impatience, trouble sleeping, restlessness, hunger, weight gain, and difficulty concentrating.[28] Neuroplasticity within the brain's reward system occurs as a result of long-term nicotine use, leading to nicotine dependence.[1] There are genetic risk factors for developing dependence.[12] For instance, genetic markers for a specific type of nicotinic receptor (the α5-α3-β4 nicotine receptors) have been linked to increased risk for dependence.[12][29] The most well-known hereditary influence related to nicotine dependence is a mutation at rs16969968 in the nicotinic acetylcholine receptor CHRNA5, resulting in an amino acid alteration from aspartic acid to asparagine.[30] The single-nucleotide polymorphisms (SNPs) rs6474413 and rs10958726 in CHRNB3 are highly correlated with nicotine dependence.[31] Many other known variants within the CHRNB3–CHRNA6 nicotinic acetylcholine receptors are also correlated with nicotine dependence in certain ethnic groups.[31] There is a relationship between CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptors and complete smoking cessation.[32] Increasing evidence indicates that the genetic variant CHRNA5 predicts the response to smoking cessation medicine.[32] ### Psychosocial[edit] In addition to the specific neurological changes in nicotinic receptors, there are other changes that occur as dependence develops.[citation needed] Through various conditioning mechanisms (operant and cue/classical), smoking comes to be associated with different mood and cognitive states as well as external contexts and cues.[24] ## Treatment[edit] There are treatments for nicotine dependence, although the majority of the evidence focuses on treatments for cigarette smokers rather than people who use other forms of tobacco (e.g., chew, snus, pipes, hookah, e-cigarettes).[citation needed] Evidence-based medicine can double or triple a smoker's chances of quitting successfully.[13] ### Medication[edit] There are eight major evidence-based medications for treating nicotine dependence: bupropion, cytisine (not approved for use in some countries, including the US), nicotine gum, nicotine inhaler, nicotine lozenge/mini-lozenge, nicotine nasal spray, nicotine patch, and varenicline.[33] These medications have been shown to significantly improve long-term (i.e., 6-months post-quit day) abstinence rates, especially when used in combination with psychosocial treatment.[13] The nicotine replacement treatments (i.e., patch, lozenge, gum) are dosed based on how dependent a smoker is—people who smoke more cigarettes or who smoke earlier in the morning use higher doses of nicotine replacement treatments.[citation needed] There is no consensus for remedies for tobacco use disorder among pregnant smokers who also use alcohol and stimulants.[4] ### Psychosocial[edit] Psychosocial interventions delivered in-person (individually or in a group) or over the phone (including mobile phone interventions) have been shown to effectively treat nicotine dependence.[33] These interventions focus on providing support for quitting and helping with smokers with problem-solving and developing healthy responses for coping with cravings, negative moods, and other situations that typically lead to relapse.[citation needed] The combination of pharmacotherapy and psychosocial interventions has been shown to be especially effective.[13] ## Epidemiology[edit] First-time nicotine users develop a dependence about 32% of the time.[34] There are approximately 976 million smokers in the world.[8] Estimates are that half of smokers (and one-third of former smokers) are dependent based on DSM criteria, regardless of age, gender or country of origin, but this could be higher if different definitions of dependence were used.[35] Recent data suggest that, in the United States, the rates of daily smoking and the number of cigarettes smoked per day are declining, suggesting a reduction in population-wide dependence among current smokers.[36] However, there are different groups of people who are more likely to smoke than the average population, such as those with low education or low socio-economic status and those with mental illness.[36] There is also evidence that among smokers, some subgroups may be more dependent than other groups.[citation needed] Men smoke at higher rates than do women and score higher on dependence indices; however, women may be less likely to be successful in quitting, suggesting that women may be more dependent by that criterion.[36][37] There is an increased frequency of nicotine dependence in people with anxiety disorders.[9] 6% of smokers who want to quit smoking each year are successful at quitting.[7] Nicotine withdrawal is the main factor hindering smoking cessation.[38] A 2010 World Health Organization report states, "Greater nicotine dependence has been shown to be associated with lower motivation to quit, difficulty in trying to quit, and failure to quit, as well as with smoking the first cigarette earlier in the day and smoking more cigarettes per day."[39] E-cigarettes may result in starting nicotine dependence again.[40] Greater nicotine dependence may result from dual use of traditional cigarettes and e-cigarettes.[40] Like tobacco companies did in the last century, there is a possibility that e-cigarettes could result in a new form of dependency on nicotine across the world.[41] ## Concerns[edit] Play media Nicotine use and addiction. Nicotine dependence results in substantial mortality, morbidity, and socio-economic impacts.[7] Nicotine dependence is a serious public health concern due to it being one of the leading causes of avoidable deaths worldwide.[7] The medical community is concerned that e-cigarettes may escalate global nicotine dependence, particularly among adolescents who are attracted to many of the flavored e-cigarettes.[42] There is strong evidence that vaping induces symptoms of dependence in users.[43] Many organizations such the World Health Organization, American Lung Association, and Australian Medical Association do not approve of vaping for quitting smoking in youth, making reference to concerns about their safety and the potential that experimenting with vaping may result in nicotine dependence and later tobacco use.[44] ## Notes[edit] 1. ^ Nicotine dependence[1] is also variously known as cigarette dependence,[2] tobacco dependence,[3] or tobacco use disorder.[4] ## See also[edit] * Nicotine poisoning * Nicotine withdrawal ## Bibliography[edit] * Stratton, Kathleen; Kwan, Leslie Y.; Eaton, David L. (January 2018). Public Health Consequences of E-Cigarettes (PDF). National Academies of Sciences, Engineering, and Medicine. National Academies Press. pp. 1–774. doi:10.17226/24952. ISBN 978-0-309-46834-3. PMID 29894118. ## References[edit] 1. ^ a b c d D'Souza MS, Markou A (2011). "Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments". Addict Sci Clin Pract. 6 (1): 4–16. PMC 3188825. PMID 22003417.CS1 maint: uses authors parameter (link) 2. ^ Stratton 2018, p. Dependence and Abuse Liability, 256. 3. ^ a b c d e f g h i j k l Piper, Megan; McCarthy, Danielle; Baker, Timothy (2006). "Assessing tobacco dependence: A guide to measure evaluation and selection". Nicotine & Tobacco Research. 8 (3): 339–351. doi:10.1080/14622200600672765. ISSN 1462-2203. PMID 16801292. 4. ^ a b Akerman, Sarah C.; Brunette, Mary F.; Green, Alan I.; Goodman, Daisy J.; Blunt, Heather B.; Heil, Sarah H. (2015). "Treating Tobacco Use Disorder in Pregnant Women in Medication-Assisted Treatment for an Opioid Use Disorder: A Systematic Review". Journal of Substance Abuse Treatment. 52: 40–47. doi:10.1016/j.jsat.2014.12.002. ISSN 0740-5472. PMC 4382443. PMID 25592332. 5. ^ a b Falcone, Mary; Lee, Bridgin; Lerman, Caryn; Blendy, Julie A. (2015). "Translational Research on Nicotine Dependence". Translational Neuropsychopharmacology. Current Topics in Behavioral Neurosciences. 28. pp. 121–150. doi:10.1007/7854_2015_5005. ISBN 978-3-319-33911-5. ISSN 1866-3370. PMC 3579204. PMID 26873019. 6. ^ a b c d e U.S. Department of Health and Human Services (1988). The health consequences of smoking: Nicotine addiction: A report of the Surgeon General (PDF). U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Health Promotion and Education, Office on Smoking and Health. DHHS Publication No. (CDC) 88-8406. 7. ^ a b c d Rachid, Fady (2016). "Neurostimulation techniques in the treatment of nicotine dependence: A review". The American Journal on Addictions. 25 (6): 436–451. doi:10.1111/ajad.12405. ISSN 1055-0496. PMID 27442267. 8. ^ a b Ng, M; Freeman, MK; Fleming, TD; Robinson, M; Dwyer-Lindgren, L; Thomson, B; Wollum, A; Sanman, E; Wulf, S; Lopez, AD; Murray, CJ; Gakidou, E (8 January 2014). "Smoking prevalence and cigarette consumption in 187 countries, 1980-2012". JAMA. 311 (2): 183–92. doi:10.1001/jama.2013.284692. PMID 24399557. 9. ^ a b Moylan, Steven; Jacka, Felice N; Pasco, Julie A; Berk, Michael (2012). "Cigarette smoking, nicotine dependence and anxiety disorders: a systematic review of population-based, epidemiological studies". BMC Medicine. 10 (1): 123. doi:10.1186/1741-7015-10-123. ISSN 1741-7015. PMC 3523047. PMID 23083451. 10. ^ a b Richard Beebe; Jeff Myers (19 July 2012). Professional Paramedic, Volume I: Foundations of Paramedic Care. Cengage Learning. pp. 640–. ISBN 978-1-133-71465-1. 11. ^ a b c Bullen, Christopher (2014). "Electronic Cigarettes for Smoking Cessation". Current Cardiology Reports. 16 (11): 538. doi:10.1007/s11886-014-0538-8. ISSN 1523-3782. PMID 25303892. 12. ^ a b c d Saccone, NL; Culverhouse, RC; Schwantes-An, TH; Cannon, DS; Chen, X; Cichon, S; Giegling, I; Han, S; Han, Y; Keskitalo-Vuokko, K; Kong, X; Landi, MT; Ma, JZ; Short, SE; Stephens, SH; Stevens, VL; Sun, L; Wang, Y; Wenzlaff, AS; Aggen, SH; Breslau, N; Broderick, P; Chatterjee, N; Chen, J; Heath, AC; Heliövaara, M; Hoft, NR; Hunter, DJ; Jensen, MK; Martin, NG; Montgomery, GW; Niu, T; Payne, TJ; Peltonen, L; Pergadia, ML; Rice, JP; Sherva, R; Spitz, MR; Sun, J; Wang, JC; Weiss, RB; Wheeler, W; Witt, SH; Yang, BZ; Caporaso, NE; Ehringer, MA; Eisen, T; Gapstur, SM; Gelernter, J; Houlston, R; Kaprio, J; Kendler, KS; Kraft, P; Leppert, MF; Li, MD; Madden, PA; Nöthen, MM; Pillai, S; Rietschel, M; Rujescu, D; Schwartz, A; Amos, CI; Bierut, LJ (5 August 2010). "Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD". PLOS Genetics. 6 (8): e1001053. doi:10.1371/journal.pgen.1001053. PMC 2916847. PMID 20700436. 13. ^ a b c d e Fiore, MC; Jaen, CR; Baker, TB; et al. (2008). Treating tobacco use and dependence: 2008 update (PDF). Rockville, MD: U.S. Department of Health and Human Services, U.S. Public Health Service. Archived from the original (PDF) on 2016-03-27. Retrieved 2016-09-02. 14. ^ "Anyone Can Become Addicted to Drugs". National Institute on Drug Abuse. July 2015. 15. ^ "E-Cigarette Use Among Youth and Young Adults: A Report of the Surgeon General" (PDF). United States Department of Health and Human Services. Surgeon General of the United States. 2016. This article incorporates text from this source, which is in the public domain. 16. ^ Camenga, Deepa R.; Klein, Jonathan D. (2016). "Tobacco Use Disorders". Child and Adolescent Psychiatric Clinics of North America. 25 (3): 445–460. doi:10.1016/j.chc.2016.02.003. ISSN 1056-4993. PMC 4920978. PMID 27338966. 17. ^ Pistillo, Francesco; Clementi, Francesco; Zoli, Michele; Gotti, Cecilia (2015). "Nicotinic, glutamatergic and dopaminergic synaptic transmission and plasticity in the mesocorticolimbic system: Focus on nicotine effects". Progress in Neurobiology. 124: 1–27. doi:10.1016/j.pneurobio.2014.10.002. ISSN 0301-0082. PMID 25447802. 18. ^ Shaik, Sabiha Shaheen (2016). "Tobacco Use Cessation and Prevention – A Review". Journal of Clinical and Diagnostic Research. 10 (5): ZE13-7. doi:10.7860/JCDR/2016/19321.7803. ISSN 2249-782X. PMC 4948554. PMID 27437378. 19. ^ American Psychiatric Association (22 May 2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). American Psychiatric Pub. p. 571. ISBN 978-0-89042-557-2. 20. ^ Payne, JD; Orellana-Barrios, M; Medrano-Juarez, R; Buscemi, D; Nugent, K (2016). "Electronic cigarettes in the media". Proc (Bayl Univ Med Cent). 29 (3): 280–3. doi:10.1080/08998280.2016.11929436. PMC 4900769. PMID 27365871. 21. ^ Besson, Morgane; Forget, Benoît (2016). "Cognitive Dysfunction, Affective States, and Vulnerability to Nicotine Addiction: A Multifactorial Perspective". Frontiers in Psychiatry. 7: 160. doi:10.3389/fpsyt.2016.00160. ISSN 1664-0640. PMC 5030478. PMID 27708591. This article incorporates text by Morgane Besson and Benoît Forget available under the CC BY 4.0 license. 22. ^ a b c d "Republished: Nicotine and health". BMJ. 349 (nov26 9): 2014.7.0264rep. 2014. doi:10.1136/bmj.2014.7.0264rep. ISSN 1756-1833. PMID 25428425. 23. ^ Atta-ur- Rahman; Allen B. Reitz (1 January 2005). Frontiers in Medicinal Chemistry. Bentham Science Publishers. pp. 279–. ISBN 978-1-60805-205-9. 24. ^ a b Martin-Soelch, Chantal (2013). "Neuroadaptive Changes Associated with Smoking: Structural and Functional Neural Changes in Nicotine Dependence". Brain Sciences. 3 (1): 159–176. doi:10.3390/brainsci3010159. ISSN 2076-3425. PMC 4061825. PMID 24961312. 25. ^ National Center for Chronic Disease Prevention Health Promotion (US) Office on Smoking Health (2014). "The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General, Chapter 5 - Nicotine". Surgeon General of the United States: 107–138. PMID 24455788. Cite journal requires `|journal=` (help) 26. ^ a b Rowell, Temperance R; Tarran, Robert (2015). "Will Chronic E-Cigarette Use Cause Lung Disease?". American Journal of Physiology. Lung Cellular and Molecular Physiology. 309 (12): L1398–L1409. doi:10.1152/ajplung.00272.2015. ISSN 1040-0605. PMC 4683316. PMID 26408554. 27. ^ Benowitz, NL (17 June 2010). "Nicotine addiction". The New England Journal of Medicine. 362 (24): 2295–303. doi:10.1056/NEJMra0809890. PMC 2928221. PMID 20554984. 28. ^ Laura J. Martin, David Zieve, Isla Ogilvie, A.D.A.M. Editorial team (7 June 2016). "Nicotine and Tobacco". Medline Plus.CS1 maint: uses authors parameter (link) 29. ^ Ware, JJ; van den Bree, MB; Munafò, MR (2011). "Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: a meta-analysis". Nicotine & Tobacco Research. 13 (12): 1167–75. doi:10.1093/ntr/ntr118. PMC 3223575. PMID 22071378. 30. ^ Yu, Cassie; McClellan, Jon (2016). "Genetics of Substance Use Disorders". Child and Adolescent Psychiatric Clinics of North America. 25 (3): 377–385. doi:10.1016/j.chc.2016.02.002. ISSN 1056-4993. PMID 27338962. 31. ^ a b Wen, L; Yang, Z; Cui, W; Li, M D (2016). "Crucial roles of the CHRNB3–CHRNA6 gene cluster on chromosome 8 in nicotine dependence: update and subjects for future research". Translational Psychiatry. 6 (6): e843. doi:10.1038/tp.2016.103. ISSN 2158-3188. PMC 4931601. PMID 27327258. 32. ^ a b Chen, Li-Shiun; Horton, Amy; Bierut, Laura (2018). "Pathways to precision medicine in smoking cessation treatments". Neuroscience Letters. 669: 83–92. doi:10.1016/j.neulet.2016.05.033. ISSN 0304-3940. PMC 5115988. PMID 27208830. 33. ^ a b Hartmann-Boyce, J; Stead, LF; Cahill, K; Lancaster, T (October 2013). "Efficacy of interventions to combat tobacco addiction: Cochrane update of 2012 reviews". Addiction. 108 (10): 1711–21. doi:10.1111/add.12291. PMID 23834141. 34. ^ MacDonald, K; Pappa, K (April 2016). "WHY NOT POT?: A Review of the Brain-based Risks of Cannabis". Innov Clin Neurosci. 13 (3–4): 13–22. PMC 4911936. PMID 27354924. 35. ^ Hughes, JR; Helzer, JE; Lindberg, SA (8 November 2006). "Prevalence of DSM/ICD-defined nicotine dependence". Drug and Alcohol Dependence. 85 (2): 91–102. doi:10.1016/j.drugalcdep.2006.04.004. PMID 16704909. 36. ^ a b c "Current Cigarette Smoking Among Adults — United States, 2005–2013". Morbidity and Mortality Weekly Report. Centers for Disease Control and Prevention (63): 1108–1112. 2014. 37. ^ Weinberger, AH; Pilver, CE; Mazure, CM; McKee, SA (September 2014). "Stability of smoking status in the US population: a longitudinal investigation". Addiction. 109 (9): 1541–53. doi:10.1111/add.12647. PMC 4127136. PMID 24916157. 38. ^ Wadgave, U; Nagesh, L (2016). "Nicotine Replacement Therapy: An Overview". International Journal of Health Sciences. 10 (3): 425–435. doi:10.12816/0048737. PMC 5003586. PMID 27610066. 39. ^ "Gender, women, and the tobacco epidemic" (PDF). World Health Organization. 2010. 40. ^ a b DeVito, Elise E.; Krishnan-Sarin, Suchitra (2017). "E-cigarettes: Impact of E-Liquid Components and Device Characteristics on Nicotine Exposure". Current Neuropharmacology. 15 (4): 438–459. doi:10.2174/1570159X15666171016164430. ISSN 1570-159X. PMC 6018193. PMID 29046158. 41. ^ Schraufnagel, Dean E. (2015). "Electronic Cigarettes: Vulnerability of Youth". Pediatric Allergy, Immunology, and Pulmonology. 28 (1): 2–6. doi:10.1089/ped.2015.0490. ISSN 2151-321X. PMC 4359356. PMID 25830075. 42. ^ Palazzolo, Dominic L. (November 2013). "Electronic cigarettes and vaping: a new challenge in clinical medicine and public health. A literature review". Frontiers in Public Health. 1 (56): 56. doi:10.3389/fpubh.2013.00056. PMC 3859972. PMID 24350225. 43. ^ Stratton 2018, p. Chapter 8-52. 44. ^ Yoong, Sze Lin; Stockings, Emily; Chai, Li Kheng; Tzelepis, Flora; Wiggers, John; Oldmeadow, Christopher; Paul, Christine; Peruga, Armando; Kingsland, Melanie; Attia, John; Wolfenden, Luke (2018). "Prevalence of electronic nicotine delivery systems (ENDS) use among youth globally: a systematic review and meta-analysis of country level data". Australian and New Zealand Journal of Public Health. 42 (3): 303–308. doi:10.1111/1753-6405.12777. ISSN 1326-0200. PMID 29528527. ## External links[edit] Classification D * ICD-10: F17.2 * ICD-10-CM: F17.2 * ICD-9-CM: 305.1 * OMIM: 188890 * SNOMED CT: 56294008 * Fagerstrom Test of Nicotine Dependence (Heatherton et al., 1991) * Heaviness of Smoking Index (Heatherton et al., 1989) * Diagnostic and Statistical Manual of Mental Disorders V (DSM-V) * Tobacco Dependence Screener (Kawakami et al., 1999) * Nicotine Dependence Syndrome Scale (NDSS; Shiffman, Waters & Hickcox, 2004) * Cigarette Dependence Scale (Etter et al., 2003) * Wisconsin Inventory of Smoking Dependence Motives (Piper et al., 2004) * v * t * e Reinforcement disorders: Addiction and Dependence Addiction Drug * Alcohol * Amphetamine * Cocaine * Methamphetamine * Methylphenidate * Nicotine * Opioid Behavioral * Financial * Gambling * Shopping * Palatable food * Sex-related * Intercourse * Pornography * Internet-related * Internet addiction disorder * Internet sex addiction * Video game addiction * Digital media addictions Cellular mechanisms * Transcriptional * ΔFosB * c-Fos * Cdk5 * CREB * GluR2 * NF-κB * Epigenetic * G9a * G9a-like protein * HDAC1 * HDAC2 * HDAC3 * HDAC4 * HDAC5 * HDAC9 * HDAC10 * SIRT1 * SIRT2 * ... Dependence Concepts * Physical dependence * Psychological dependence * Withdrawal Disorders * Drugs * Alcoholism * Amphetamine * Barbiturate * Benzodiazepine * Caffeine * Cannabis * Cocaine * Nicotine * Opioid * Non-drug stimuli * Tanning dependence Treatment and management Detoxification * Alcohol detoxification * Drug detoxification Behavioral therapies * Cognitive behavioral therapy * Relapse prevention * Contingency management * Community reinforcement approach and family training * Motivational enhancement therapy * Motivational interviewing * Motivational therapy * Physical exercise Treatment programs * Drug rehab * Residential treatment center * Heroin-assisted treatment * Intensive outpatient program * Methadone maintenance * Smoking cessation * Nicotine replacement therapy * Tobacco cessation clinics in India * Twelve-step program Support groups * Addiction recovery groups * List of twelve-step groups Harm reduction * Category:Harm reduction * Drug checking * Reagent testing * Low-threshold treatment programs * Managed alcohol program * Moderation Management * Needle exchange program * Responsible drug use * Stimulant maintenance * Supervised injection site * Tobacco harm reduction See also * Addiction medicine * Allen Carr * Category:Addiction * Discrimination against drug addicts * Dopamine dysregulation syndrome * Cognitive control * Inhibitory control * Motivational salience * Incentive salience * Sober companion * Category * v * t * e Treatment of drug dependence (N07B) Nicotine dependence * Bupropion * Cytisine * Lobeline * Mecamylamine * Varenicline * AA (Clonidine) Alcohol dependence * AD inhibitor (Disulfiram * Calcium carbimide * Hydrogen cyanamide) * Acamprosate * Opioid antagonists * Naltrexone * Nalmefene) * κ-Opioid receptor antagonists * Aticaprant * Topiramate * AA (Clonidine) * Baclofen * Phenibut Opioid dependence * AA (Clonidine * Lofexidine) * Ibogaine * Opioids * Buprenorphine (+naloxone) * Levacetylmethadol * Methadone * Dihydrocodeine * Dihydroetorphine * Hydromorphone (extended-release) * Morphine (extended-release) * Opioid antagonists (Naltrexone * Nalmefene) Benzodiazepine dependence * AA (Clonidine) * Benzodiazepines (Diazepam * Lorazepam * Chlordiazepoxide * Oxazepam) * Barbiturates (Phenobarbital) Research Salvia divinorum * v * t * e Psychoactive substance-related disorder General * SID * Substance intoxication / Drug overdose * Substance-induced psychosis * Withdrawal: * Craving * Neonatal withdrawal * Post-acute-withdrawal syndrome (PAWS) * SUD * Substance abuse / Substance-related disorders * Physical dependence / Psychological dependence / Substance dependence Combined substance use * SUD * Polysubstance dependence * SID * Combined drug intoxication (CDI) Alcohol SID Cardiovascular diseases * Alcoholic cardiomyopathy * Alcohol flush reaction (AFR) Gastrointestinal diseases * Alcoholic liver disease (ALD): * Alcoholic hepatitis * Auto-brewery syndrome (ABS) Endocrine diseases * Alcoholic ketoacidosis (AKA) Nervous system diseases * Alcohol-related dementia (ARD) * Alcohol intoxication * Hangover Neurological disorders * Alcoholic hallucinosis * Alcoholic polyneuropathy * Alcohol-related brain damage * Alcohol withdrawal syndrome (AWS): * Alcoholic hallucinosis * Delirium tremens (DTs) * Fetal alcohol spectrum disorder (FASD) * Fetal alcohol syndrome (FAS) * Korsakoff syndrome * Positional alcohol nystagmus (PAN) * Wernicke–Korsakoff syndrome (WKS, Korsakoff psychosis) * Wernicke encephalopathy (WE) Respiratory tract diseases * Alcohol-induced respiratory reactions * Alcoholic lung disease SUD * Alcoholism (alcohol use disorder (AUD)) * Binge drinking Caffeine * SID * Caffeine-induced anxiety disorder * Caffeine-induced sleep disorder * Caffeinism * SUD * Caffeine dependence Cannabis * SID * Cannabis arteritis * Cannabinoid hyperemesis syndrome (CHS) * SUD * Amotivational syndrome * Cannabis use disorder (CUD) * Synthetic cannabinoid use disorder Cocaine * SID * Cocaine intoxication * Prenatal cocaine exposure (PCE) * SUD * Cocaine dependence Hallucinogen * SID * Acute intoxication from hallucinogens (bad trip) * Hallucinogen persisting perception disorder (HPPD) Nicotine * SID * Nicotine poisoning * Nicotine withdrawal * SUD * Nicotine dependence Opioids * SID * Opioid overdose * SUD * Opioid use disorder (OUD) Sedative / hypnotic * SID * Kindling (sedative–hypnotic withdrawal) * benzodiazepine: SID * Benzodiazepine overdose * Benzodiazepine withdrawal * SUD * Benzodiazepine use disorder (BUD) * Benzodiazepine dependence * barbiturate: SID * Barbiturate overdose * SUD * Barbiturate dependence Stimulants * SID * Stimulant psychosis * amphetamine: SUD * Amphetamine dependence Volatile solvent * SID * Sudden sniffing death syndrome (SSDS) * Toluene toxicity * SUD * Inhalant abuse *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Nicotine dependence

c0028043

wikipedia

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

{"mesh": ["D014029"], "umls": ["C0028043"], "wikidata": ["Q18553444"]}

Progressive nodular histiocytosis SpecialtyDermatology Progressive nodular histiocytosis is a cutaneous condition clinically characterized by the development of two types of skin lesions: superficial papules and deeper larger subcutaneous nodules.[1]:718 ## See also[edit] * Non-X histiocytosis ## References[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. * v * t * e Histiocytosis WHO-I/Langerhans cell histiocytosis/ X-type histiocytosis * Letterer–Siwe disease * Hand–Schüller–Christian disease * Eosinophilic granuloma * Congenital self-healing reticulohistiocytosis WHO-II/non-Langerhans cell histiocytosis/ Non-X histiocytosis * Juvenile xanthogranuloma * Hemophagocytic lymphohistiocytosis * Erdheim-Chester disease * Niemann–Pick disease * Sea-blue histiocyte * Benign cephalic histiocytosis * Generalized eruptive histiocytoma * Xanthoma disseminatum * Progressive nodular histiocytosis * Papular xanthoma * Hereditary progressive mucinous histiocytosis * Reticulohistiocytosis (Multicentric reticulohistiocytosis, Reticulohistiocytoma) * Indeterminate cell histiocytosis WHO-III/malignant histiocytosis * Histiocytic sarcoma * Langerhans cell sarcoma * Interdigitating dendritic cell sarcoma * Follicular dendritic cell sarcoma Ungrouped * Rosai–Dorfman disease This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Progressive nodular histiocytosis

c4707331

wikipedia

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

{"orphanet": ["158022"], "synonyms": [], "wikidata": ["Q7248852"]}

A number sign (#) is used with this entry because Bart-Pumphrey syndrome is caused by heterozygous mutation in the GJB2 gene (121011) on chromosome 13q12. Clinical Features Bart and Pumphrey (1967) described a kindred in which many members had knuckle pads, leukonychia, and deafness due to a lesion of the cochlea. Keratosis palmaris et plantaris was present in some. Male-to-male transmission was thought to have occurred in 2 instances. The condition described by Schwann (1963) was probably the same. The presence of leukonychia and the absence of digital constrictions appear to distinguish this disorder from Vohwinkel syndrome (124500). A family reported by Crosby and Vidurrizaga (1976) established that keratosis palmoplantaris, probably developing only in older affected persons, is part of the syndrome. Knuckle pads on the toes were pictured. Ramer et al. (1994) described this disorder in 5 members of a family and reviewed other disorders that are associated with knuckle pads. Richard et al. (2004) described a 3-generation Polish family with Bart-Pumphrey syndrome. All affected family members, including the maternal grandmother and uncle, presented with congenital deafness and developed diffuse, sharply demarcated thickening of palms and soles during early childhood. In the proband, an audiogram at 24 years of age demonstrated profound bilateral sensorineural hearing loss with normal middle ear function. Palmoplantar keratoderma had locally an almost punctate surface reminiscent of Vohwinkel syndrome, and was most profound over the heels and in interphalangeal folds, resulting there in the formation of hard, hyperkeratotic bands. Before puberty, 2 affected individuals had developed fixed, hyperkeratotic plaques with a verrucous surface over the metacarpo- and interphalangeal joints that regressed over time in 1. Two affected individuals had leukonychia. Light microscopic evaluation of skin biopsies revealed massive orthokeratotic hyperkeratosis without evidence for retained nuclei, hypergranulosis, acanthosis, and papillomatosis. Epidermal gap junctions appeared normal on electron microscopic evaluation. Molecular Genetics In a multigeneration Polish family with Bart-Pumphrey syndrome, Richard et al. (2004) reported a novel nonconservative missense GJB2 mutation (121011.0030) segregating with the disorder. This mutation, not detected in 110 control individuals of northern European ancestry, lies within a cluster of pathogenic GJB2 mutations affecting the evolutionarily conserved first extracellular loop of Cx26 important for docking of connexin hemichannels and voltage gating. Immunostaining of Cx26 in lesional palmar and knuckle skin was weak or absent, although its adnexal expression appeared normal and the punctate membrane staining of Cx26 and other epidermal connexins was not altered. Nevertheless, the widespread immunostaining of Cx30 (GJB6; 604418) throughout the spinous cell layers suggested a compensatory overexpression. In a 26-year-old male with Bart-Pumphrey syndrome, Alexandrino et al. (2005) identified heterozygosity for a missense mutation in the GJB2 gene (121011.0035). Limbs \- Knuckle pads Skin \- Keratosis palmaris et plantaris Inheritance \- Autosomal dominant Nails \- Leukonychia Ears \- Cochlear deafness ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

KNUCKLE PADS, LEUKONYCHIA, AND SENSORINEURAL DEAFNESS

c0266004

omim

https://www.omim.org/entry/149200

{"doid": ["0050658"], "mesh": ["C537210"], "omim": ["149200"], "orphanet": ["2698"], "synonyms": ["Alternative titles", "BART-PUMPHREY SYNDROME"]}

Rahim Adam et al. (1985) reported a hemorrhagic diathesis due to combined deficiency of factors V and VIII in a Syrian brother and sister. Unlike reported cases, no abnormality of protein C (612283) or its inhibitor was found. Both parents and 1 of 3 clinically normal sibs had levels of factors V and VIII greater than 10% but less than 50% of normal. Inheritance \- Autosomal recessive Misc \- Reduced factor V and VIII in heterozygotes Lab \- Factor V deficiency \- Factor VIII deficiency Heme \- Bleeding diathesis ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

FACTOR V AND FACTOR VIII, COMBINED DEFICIENCY OF, WITH NORMAL PROTEIN C AND PROTEIN C INHIBITOR

c1856883

omim

https://www.omim.org/entry/227310

{"mesh": ["C565577"], "omim": ["227310"], "orphanet": ["35909"]}

Feingold syndrome is a disorder that affects many parts of the body. There are two types of Feingold syndrome, distinguished by their genetic cause; both types have similar features that can vary among affected individuals. Individuals with Feingold syndrome type 1 or type 2 have characteristic abnormalities of their fingers and toes. Almost all people with this condition have a specific hand abnormality called brachymesophalangy, which refers to shortening of the second and fifth fingers. Other common abnormalities include fifth fingers that curve inward (clinodactyly), underdeveloped thumbs (thumb hypoplasia), and fusion (syndactyly) of the second and third toes or the fourth and fifth toes. Additional common features of both types of Feingold syndrome include an unusually small head size (microcephaly), a small jaw (micrognathia), a narrow opening of the eyelids (short palpebral fissures), and mild to moderate learning disabilities. Less often, affected individuals have hearing loss, short stature, or kidney or heart abnormalities. People with Feingold syndrome type 1 are frequently born with a blockage in part of their digestive system called gastrointestinal atresia. In most cases, the blockage occurs in the esophagus (esophageal atresia) or in part of the small intestine (duodenal atresia). Individuals with type 2 do not have gastrointestinal atresias. ## Frequency Feingold syndrome appears to be a rare condition, although its exact prevalence is unknown. Type 1 is more common than type 2. ## Causes Mutations in the MYCN gene cause Feingold syndrome type 1, and mutations in chromosome 13 that remove (delete) a region of the chromosome that includes the MIR17HG gene cause type 2. Both genes are involved in growth and development, particularly before birth. The MYCN gene provides instructions for making a protein that regulates the activity (expression) of other genes. The protein attaches (binds) to specific regions of DNA and controls the first step of protein production (transcription). Studies suggest that the MYCN protein is necessary for normal development of the limbs, heart, kidneys, lungs, nervous system, and digestive system. The MIR17HG gene provides instructions for making a set of microRNAs (miRNAs) known as the miR-17~92 cluster. MiRNAs are short pieces of RNA, a chemical cousin of DNA. These molecules control gene expression by blocking protein production. The miRNAs in the miR-17~92 cluster are involved in the development of many tissues and organs in the body. Mutations affecting the MYCN or MIR17HG gene that cause Feingold syndrome prevent one copy of the gene in each cell from producing any functional protein or miRNAs, respectively. As a result, only half the normal amount of the protein or miRNAs is available to control the activity of specific genes during development. It remains unclear how a reduced amount of the MYCN protein or miR-17~92 cluster miRNAs cause the specific features of Feingold syndrome. ### Learn more about the genes and chromosome associated with Feingold syndrome * MIR17HG * MYCN * chromosome 13 ## Inheritance Pattern This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Feingold syndrome

c0796068

medlineplus

https://medlineplus.gov/genetics/condition/feingold-syndrome/

{"gard": ["8407"], "mesh": ["C537734"], "omim": ["164280", "614326"], "synonyms": []}

For a phenotypic description and a discussion of genetic heterogeneity of this disorder, see ARVD1 (107970). Clinical Features Li et al. (2000) reported a North American family with early-onset arrhythmogenic right ventricular dysplasia (ARVD) and high penetrance. All of the children with the disease haplotype had pathologic or clinical evidence of the disease at under 10 years of age. The family spanned 5 generations, having 10 living and 2 dead affected individuals, with ARVD segregating as an autosomal dominant. Mapping By linkage analysis in a North American family with early-onset arrhythmogenic right ventricular dysplasia, Li et al. (2000) first excluded the 5 previously known ARVD loci, and a novel locus was identified on 10p14-p12. A peak 2-point lod score of 3.92 was obtained with marker D10S1664 at a recombination fraction of 0.0. Additional genotyping and haplotype analysis identified a shared region of 10.6 cM between markers D10S547 and D10S1653. Molecular Genetics Li et al. (2000) investigated the involvement of the PTPLA gene (610467) in the family with ARVD mapped to 10p by Li et al. (2000). A lys64-to-gln missense mutation was identified in all affected members, but was also found in 1 unaffected family member and 3 unaffected, unrelated controls, and is, therefore, likely to represent a benign polymorphism. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 6

c1862511

omim

https://www.omim.org/entry/604401

{"doid": ["0110075"], "mesh": ["C566254"], "omim": ["107970", "604401"], "orphanet": ["217656"], "synonyms": ["Familial isolated ARVD", "Familial isolated ARVC", "Alternative titles", "Familial isolated arrhythmogenic ventricular dysplasia", "Familial isolated arrhythmogenic ventricular cardiomyopathy", "Familial isolated arrhythmogenic right ventricular cardiomyopathy", "ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY 6"], "genereviews": ["NBK1131"]}

Group of genetic diseases involving the harmful accumulation of lipids in cells Lipid storage disorder SpecialtyEndocrinology A lipid storage disorder (or lipidosis) is any one of a group of inherited metabolic disorders in which harmful amounts of fats or lipids accumulate in some of the body’s cells and tissues.[1] People with these disorders either do not produce enough of one of the enzymes needed to metabolize and break down lipids or they produce enzymes that do not work properly. Over time, the buildup of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen and bone marrow. Inside cells under normal conditions, lysosomes convert, or metabolize, lipids and proteins into smaller components to provide energy for the body. ## Contents * 1 Classification * 1.1 Sphingolipidoses * 1.2 Other * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Classification[edit] Disorders that store this intracellular material are part of the lysosomal storage diseases family of disorders. ### Sphingolipidoses[edit] Main article: Sphingolipidosis Many lipid storage disorders can be classified into the subgroup of sphingolipidoses, as they relate to sphingolipid metabolism. Members of this group include Niemann-Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay–Sachs disease, metachromatic leukodystrophy, multiple sulfatase deficiency and Farber disease. They are generally inherited in an autosomal recessive fashion, but Fabry disease is X-linked. Taken together, sphingolipidoses have an incidence of approximately 1 in 10,000. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.[citation needed] Some of the sphingolipidoses may alternatively be classified into either GM1 gangliosidoses or GM2 gangliosidoses. Tay–Sachs disease belongs to the latter. ### Other[edit] Other lipid storage disorders that are generally not classified as sphingolipidoses include fucosidosis, Schindler disease and Wolman disease. ## Genetics[edit] Lipid storage diseases can be inherited two ways: Autosomal recessive inheritance occurs when both parents carry and pass on a copy of the faulty gene, but neither parent show signs and symptoms of the condition and is not affected by the disorder. Each child born to these parents have a 25 percent chance of inheriting both copies of the defective gene, a 50 percent chance of being a carrier, and a 25 percent chance of not inheriting either copy of the defective gene. Children of either gender can be affected by an autosomal recessive this pattern of inheritance.[citation needed] X-linked recessive (or sex linked) inheritance occurs when the mother carries the affected gene on the X chromosome that determines the child’s gender and passes it to her son. Sons of carriers have a 50 percent chance of inheriting the disorder. Daughters have a 50 percent chance of inheriting the X-linked chromosome but usually are not severely affected by the disorder. Affected men do not pass the disorder to their sons but their daughters will be carriers for the disorder.[citation needed] ## Diagnosis[edit] Diagnosis of the lipid storage disorders can be achieved through the use of several tests. These tests include clinical examination, biopsy, genetic testing, molecular analysis of cells or tissues, and enzyme assays. Certain forms of this disease can also be diagnosed through urine testing, which detects the stored material. Prenatal testing is also available to determine if the fetus will have the disease or is a carrier.[1] ## Treatment[edit] There are no specific treatments for lipid storage disorders; however, there are some highly effective enzyme replacement therapies for people with type 1 Gaucher disease and some patients with type 3 Gaucher disease. There are other treatments such as the prescription of certain drugs like phenytoin and carbamazepine to treat pain for patients with Fabry disease. Furthermore, gene therapies and bone marrow transplantation may prove to be effective for certain lipid storage disorders.[2] Diet restrictions do not help prevent the buildup of lipids in the tissues.[1] ## See also[edit] * Xanthomatosis * Niemann–Pick disease ## References[edit] 1. ^ a b c "Lipid Storage Diseases Fact Sheet". National Institute of Neurological Disorders and Stroke. January 13, 2015. Archived from the original on January 11, 2015. Retrieved November 28, 2005. 2. ^ Lipid Storage Disorders at eMedicine ## External links[edit] Classification D * ICD-10: E75 * ICD-9-CM: 272.7 * MeSH: D008064 External resources * eMedicine: ped/1310 * v * t * e Lysosomal storage diseases: Inborn errors of lipid metabolism (Lipid storage disorders) Sphingolipidoses (to ceramide) From ganglioside (gangliosidoses) * Ganglioside: GM1 gangliosidoses * GM2 gangliosidoses (Sandhoff disease * Tay–Sachs disease * AB variant) From globoside * Globotriaosylceramide: Fabry's disease From sphingomyelin * Sphingomyelin: phospholipid: Niemann–Pick disease (SMPD1-associated * type C) * Glucocerebroside: Gaucher's disease From sulfatide (sulfatidoses * leukodystrophy) * Sulfatide: Metachromatic leukodystrophy * Multiple sulfatase deficiency * Galactocerebroside: Krabbe disease To sphingosine * Ceramide: Farber disease NCL * Infantile * Jansky–Bielschowsky disease * Batten disease Other * Cerebrotendineous xanthomatosis * Cholesteryl ester storage disease (Lysosomal acid lipase deficiency/Wolman disease) * Sea-blue histiocytosis *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Lipid storage disorder

c0023794

wikipedia

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

{"mesh": ["D008064"], "umls": ["C0023794", "C0029591"], "orphanet": ["79204"], "wikidata": ["Q3540902"]}

Tubulointerstitial nephritis and uveitis Other namesAcute tubulointerstitial nephritis and uveitis syndrome SpecialtyOphthalmology Tubulointerstitial nephritis and uveitis (TINU) is a rare medical condition in which there is uveitis (inflammation of the uvea in the eye) together with tubulointerstitial nephritis (inflammation of the tubules inside the kidney). ## Contents * 1 Symptoms and signs * 2 Diagnosis * 3 Management * 4 Prevalence * 5 History * 6 References * 7 External links ## Symptoms and signs[edit] Uveitis may cause pain of the affected eye together with changes in vision. It may be accompanied by nonspecific systemic symptoms such as fever, involuntary weight loss, fatigue, loss of appetite, abdominal pain, and joint pains.[1] ## Diagnosis[edit] This section is empty. You can help by adding to it. (August 2017) ## Management[edit] This section is empty. You can help by adding to it. (August 2017) ## Prevalence[edit] It is a very rare disease. Approximately 200 cases were reported in medical journals in the 35 years after its initial description.[1] Altogether, more than 100 cases have been reported in Japan.[2] ## History[edit] It was first described in 1975.[1][3] ## References[edit] 1. ^ a b c Mackensen, F; Billing, H (November 2009). "Tubulointerstitial nephritis and uveitis syndrome". Current Opinion in Ophthalmology. 20 (6): 525–31. doi:10.1097/ICU.0b013e3283318f9a. PMID 19752730. S2CID 11461472. 2. ^ Matsumoto, Keiichiro; Fukunari, Kenichi; Ikeda, Yuji; Miyazono, Motoaki; Kishi, Tomoya; Matsumoto, Ryoko; Fukuda, Makoto; Uchiumi, Saori; Yoshizaki, Mai (2015-01-01). "A report of an adult case of tubulointerstitial nephritis and uveitis (TINU) syndrome, with a review of 102 Japanese cases". The American Journal of Case Reports. 16: 119–123. doi:10.12659/AJCR.892788. ISSN 1941-5923. PMC 4347719. PMID 25725230. 3. ^ Dobrin, RS; Vernier, RL; Fish, AL (September 1975). "Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas and anterior uveitis. A new syndrome". The American Journal of Medicine. 59 (3): 325–33. doi:10.1016/0002-9343(75)90390-3. PMID 1163543. ## External links[edit] Classification D * ICD-10: Xxx.x * ICD-9-CM: xxx * OMIM: 607665 External resources * Orphanet: 91500 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Tubulointerstitial nephritis and uveitis

c1843273

wikipedia

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

{"gard": ["9252"], "mesh": ["C536922"], "umls": ["C1843273"], "orphanet": ["91500"], "wikidata": ["Q3961624"]}

A type of idiopathic inflammatory myopathy characterized by evocative skin lesions and symmetrical proximal muscle weakness. ## Epidemiology Annual incidence is estimated between 1 to 10 new cases/million population/year, and prevalence between 1/50,000 and 1/10,000. Dermatomyositis (DM) is more common in women than in men (2:1). In the United States, a Black-to-Caucasian ratio of 3:1 has been reported. ## Clinical description Onset is generally in adulthood, in some cases earlier (Juvenile DM, see this term). Patients typically present a heliotrope rash (erythema of eyelids with or without edema) and Gottron's papules (lichenoid papules over knuckles and sometimes knees, elbows), violaceous erythema (on extensor surfaces and face), poikiloderma (photoexposed areas), and periungual telangiectasias. In rare cases, cutaneous vasculitis, ulcerations, and calcinosis are observed. Subsequently, over weeks or months, they develop symmetrical proximal muscle weakness with a variable impact on physical capacities. Other systems may then become involved (vascular, pulmonary, gastrointestinal, and cardiac). Pulmonary manifestations range from aspiration pneumonia to interstitial lung disease (ILD), sometimes with complications such as pulmonary arterial hypertension (see these terms). Other features may include dysphagia, sinus tachycardia, diastolic dysfunction and myocarditis (often asymptomatic). About one third of patients develop malignancy, often within 0 to 3 years before or after disease onset (breast and ovarian cancers (see this term) in women, and lung and prostate cancer in men). Other less frequently reported neoplasms include colorectal cancer, or non-Hodgkin lymphoma, pancreatic, gastric and bladder cancer (see these terms). ## Etiology The exact pathogenesis has not yet been elucidated. DM is thought to be related to complement-mediated changes in small vessels in muscle tissue leading to vascular damage. Viruses and Toxoplasma and Borrelia species, have been suggested as possible triggers. ## Diagnostic methods Diagnosis is based on the characteristic skin findings with development of proximal muscle weakness, elevated muscle enzymes (serum creatine kinase, aldolasa) and myopathic findings on electromyography (EMG). It is generally confirmed by muscle biopsy showing inflammatory infiltrates around blood vessels and perifascicular atrophy. Patients frequently have circulating autoantibodies antinuclear antibodies (ANAs) and more specific antibodies may be present (e.g. anti-Mi2, anti-Tiff1gamma, anti-MDA5). ## Differential diagnosis The differential diagnoses include muscular dystrophies of late onset, as well as adult-onset nemaline myopathy, proximal myotonic myopathies and systemic lupus erythematosus, pityriasis rubra pilaris, lichen planus (see these terms), and polymorphous light eruption. ## Management and treatment The aim of treatment is to eliminate inflammation and restore muscle performance. Initial treatment includes high-dose corticosteroids. Dosage is then tapered to reach an appropriate maintenance dose. Immunosuppressive agents are also frequently used in combination, typically methotrexate, azathioprine, and mycophenolatemofetil. Intravenous immunoglobulin (IVIg) or intravenous methylprednisolone (IVMP) may be used in severe cases. Physical therapy is also recommended. Topical corticosteroid and tacrolimus have been used to treat skin manifestations. Patients should avoid direct UV light and use high-factor sunscreen. Monitoring for extramuscular involvement should include chest X-ray and pulmonary function testing. If cardiac involvement is suspected, echocardiography is recommended. Age-appropriate cancer screening is also recommended. ## Prognosis Prognosis is sometimes poor and depends on patient response to treatment, severity of disease manifestations and comorbidities (notably associated cancer). Long-term corticosteroids may be a source of morbidity. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Dermatomyositis

c0011633

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=221

{"gard": ["6263"], "mesh": ["D003882"], "umls": ["C0011633", "C0221056"], "icd-10": ["M33.0", "M33.1"], "synonyms": ["Adult dermatomyositis"]}

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-47 (SPG47) is caused by homozygous mutation in the AP4B1 gene (607245) on chromosome 1p13. Description Spastic paraplegia-47 is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (summary by Abou Jamra et al., 2011). Clinical Features Abou Jamra et al. (2011) reported a consanguineous Israeli Arab family (ID01) in which 3 sibs had severe mental retardation and spasticity. All presented at birth with microcephaly and muscular hypotonia, which later developed to hypertonia. Physical examination showed hyperreflexia, spastic paraplegia, and an inability to walk unaided. All had a severe cognitive deficit, marked speech delay, and adaptive impairment. Other features included high palate, wide nasal bridge, short stature, hyperlaxity, genu recurvatum, pes planus, and a waddling gait. They had stereotypic laughter and markedly shy character. None had seizures, vision or hearing impairments, or any anomalies of inner organs. Blumkin et al. (2011) reported 2 sibs, born of consanguineous Arab parents, with a severe neurodegenerative disorder beginning in infancy. The patients had delayed psychomotor development, mental retardation, and spastic paraplegia with increased tone in the lower limbs, hyperreflexia, and extensor plantar responses. Both had febrile seizures in early childhood. One child had dysarthria at age 5.5 years, and the other showed spastic tongue protrusion and jaw opening with hypersalivation. Brain imaging of both patients showed thinning of the corpus callosum and periventricular white matter changes. Dysmorphic features were not observed, although 1 had microcephaly. Tuysuz et al. (2014) reported 2 Turkish sisters with SPG47. The patients had delayed psychomotor development, severe intellectual disability with impaired speech, spastic tetraplegia with hypertonia and inability to walk independently, and infantile-onset seizures. Dysmorphic features included microcephaly, facial hypotonia, coarse face, bitemporal narrowing, broad nasal bridge with bulbous nose, short philtrum, everted upper lip, wide mouth, and high-arched palate. Brain imaging showed ventriculomegaly, thin corpus callosum, and white matter loss. Abdollahpour et al. (2015) reported 2 sibs, born of unrelated parents, with SPG47. The patients were 12 and 14 years old, respectively, at the time of the report. Both showed delayed psychomotor development in early infancy, followed by spasticity of the lower limbs and hyperreflexia. Both patients became wheelchair-bound around 12 years of age and had contractures. Additional features included poor or absent speech, microcephaly, short stature, valgosity of the hips with acetabular dysplasia, club foot, and dysmorphic facial features, including open mouth, tongue protrusion, and broad nasal root. Both patients developed febrile seizures at ages 10 and 12 years, respectively. Inheritance The transmission pattern of SPG47 in the family reported by Tuysuz et al. (2014) was consistent with autosomal recessive inheritance. Mapping By homozygosity mapping analysis of 2 sibs with complicated spastic paraplegia, Blumkin et al. (2011) found linkage to a 7.3-Mb region on chromosome 1p13-p12, which they designated SPG47. Molecular Genetics By linkage analysis followed by candidate gene sequencing of an Israeli Arab family with autosomal recessive mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4B1 gene (607245.0001). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function. In 2 sibs, born of consanguineous Arab parents, with SPG47, Bauer et al. (2012) identified a homozygous truncating mutation in the AP4B1 gene (607245.0002). The mutation was found by exome sequencing of the candidate region on chromosome 1p13-p12 identified by linkage analysis (Blumkin et al., 2011). Bauer et al. (2012) noted the phenotypic similarities to the patients reported by Abou Jamra et al. (2011). In 2 Turkish sisters with SPG47, Tuysuz et al. (2014) identified a homozygous truncating mutation in the AP4B1 gene (607245.0003). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies on patient cells were not reported. In 2 sibs, born of unrelated parents, with SPG47, Abdollahpour et al. (2015) identified a homozygous truncating mutation in the AP4B1 gene (607245.0004). Functional studies of the variant and studies on patient cells were not reported. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly Face \- Coarse face \- Hypotonia face \- Bitemporal narrowing \- Short philtrum Nose \- Wide nasal bridge \- Bulbous nose Mouth \- Everted upper vermilion \- Wide mouth \- High-arched palate SKELETAL \- Contractures \- Joint hyperlaxity (1 family) Pelvis \- Valgosity of the hips (1 family) \- Acetabular dysplasia (1 family) Limbs \- Genu recurvatum (1 family) Feet \- Pes planus (1 family) \- Club feet (1 family) MUSCLE, SOFT TISSUES \- Hypotonia, neonatal \- Hypertonia later NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Mental retardation, severe \- Spasticity \- Hyperreflexia \- Inability to walk unaided \- Waddling gait \- Extensor plantar responses \- Delayed speech development \- Dysarthria \- Seizures \- Dystonia \- Thin corpus callosum \- Periventricular white matter abnormalities \- White matter loss \- Ventriculomegaly Behavioral Psychiatric Manifestations \- Stereotypic laughter \- Shy character (1 family) MISCELLANEOUS \- Onset at birth \- Slowly progressive MOLECULAR BASIS \- Caused by mutation in the adaptor-related protein complex 4, beta-1 subunit gene (AP4B1, 607245.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPASTIC PARAPLEGIA 47, AUTOSOMAL RECESSIVE

c3279738

omim

https://www.omim.org/entry/614066

{"doid": ["0110799"], "omim": ["614066"], "orphanet": ["280763"], "synonyms": ["CEREBRAL PALSY, SPASTIC QUADRIPLEGIC, 5, FORMERLY", "Alternative titles", "AP4 deficiency syndrome"], "genereviews": ["NBK535153"]}

An extended form of Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome characterized by destruction and detachment of the skin epithelium and mucous membranes involving more than 30% of the body surface area. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Toxic epidermal necrolysis

c0014518

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=537

{"mesh": ["D013262"], "umls": ["C0014518"], "icd-10": ["L51.2"], "synonyms": ["Lyell syndrome"]}

This syndrome is characterised by the presence of a unilateral angioma on the face and autistic developmental problems characterised by language delay and atypical social interactions. ## Epidemiology So far, the syndrome has been described in four children. ## Diagnostic methods The initial diagnosis was Sturge-Weber syndrome (see this term), despite the absence of leptomeningeal angiomatosis which is one of the hallmarks of this disease. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Autism-facial port-wine stain syndrome

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137911

{"gard": ["10303"]}

Elbow fractures are any broken bone around the elbow joint.They include among others:[1] * Olecranon fractures * Supracondylar humerus fractures * Radial head fractures The terrible triad of the elbow (not to be confused with the terrible triad of the knee) is a combination of:[2] * A fracture of the head of radius * A fracture of the coronoid process of the ulna * Humeroulnar dislocation (generally posterior or posterolateral) The terrible triad of the elbow is confers joint instability and a major risk of developing osteoarthritis.[2] ## References[edit] 1. ^ Daniel K Nishijima. "Elbow Fracture". Retrieved 9 December 2014. 2. ^ a b Seijas R, Ares-Rodriguez O, Orellana A, Albareda D, Collado D, Llusa M (2009). "Terrible triad of the elbow" (PDF). J Orthop Surg (Hong Kong). 17 (3): 335–9. doi:10.1177/230949900901700319. * v * t * e Fractures and cartilage damage General * Avulsion fracture * Chalkstick fracture * Greenstick fracture * Open fracture * Pathologic fracture * Spiral fracture Head * Basilar skull fracture * Blowout fracture * Mandibular fracture * Nasal fracture * Le Fort fracture of skull * Zygomaticomaxillary complex fracture * Zygoma fracture Spinal fracture * Cervical fracture * Jefferson fracture * Hangman's fracture * Flexion teardrop fracture * Clay-shoveler fracture * Burst fracture * Compression fracture * Chance fracture * Holdsworth fracture Ribs * Rib fracture * Sternal fracture Shoulder fracture * Clavicle * Scapular Arm fracture Humerus fracture: * Proximal * Supracondylar * Holstein–Lewis fracture Forearm fracture: * Ulna fracture * Monteggia fracture * Hume fracture * Radius fracture/Distal radius * Galeazzi * Colles' * Smith's * Barton's * Essex-Lopresti fracture Hand fracture * Scaphoid * Rolando * Bennett's * Boxer's * Busch's Pelvic fracture * Duverney fracture * Pipkin fracture Leg Tibia fracture: * Bumper fracture * Segond fracture * Gosselin fracture * Toddler's fracture * Pilon fracture * Plafond fracture * Tillaux fracture Fibular fracture: * Maisonneuve fracture * Le Fort fracture of ankle * Bosworth fracture Combined tibia and fibula fracture: * Trimalleolar fracture * Bimalleolar fracture * Pott's fracture Crus fracture: * Patella fracture Femoral fracture: * Hip fracture Foot fracture * Lisfranc * Jones * March * Calcaneal This article about Orthopedic surgery 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

Elbow fracture

c0600106

wikipedia

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

{"umls": ["C0600106"], "icd-10": ["S52.0"], "wikidata": ["Q3752478"]}

CHARGE syndrome is a disorder that affects many areas of the body. CHARGE is an abbreviation for several of the features common in the disorder: coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities. The pattern of malformations varies among individuals with this disorder, and the multiple health problems can be life-threatening in infancy. Affected individuals usually have several major characteristics or a combination of major and minor characteristics. The major characteristics of CHARGE syndrome are common in this disorder and occur less frequently in other disorders. Most individuals with CHARGE syndrome have a gap or hole in one of the structures of the eye (coloboma), which forms during early development. A coloboma may be present in one or both eyes and may impair a person's vision, depending on its size and location. Some affected individuals also have abnormally small or underdeveloped eyes (microphthalmia). In many people with CHARGE syndrome, one or both nasal passages are narrowed (choanal stenosis) or completely blocked (choanal atresia), which can cause difficulty breathing. Affected individuals frequently have cranial nerve abnormalities. The cranial nerves emerge directly from the brain and extend to various areas of the head and neck, controlling muscle movement and transmitting sensory information. Abnormal function of certain cranial nerves can cause swallowing problems, facial paralysis, a sense of smell that is diminished (hyposmia) or completely absent (anosmia), and mild to profound hearing loss. People with CHARGE syndrome also typically have middle and inner ear abnormalities, which can contribute to hearing problems, and unusually shaped external ears. While the minor characteristics of CHARGE syndrome are common in this disorder, they are also frequently present in people without the disorder. The minor characteristics include heart defects; slow growth starting in late infancy; delayed development of motor skills, such as sitting unsupported and walking; and an opening in the lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate). Affected individuals frequently have hypogonadotropic hypogonadism, which affects the production of hormones that direct sexual development. As a result, males with CHARGE syndrome are often born with an unusually small penis (micropenis) and undescended testes (cryptorchidism). Abnormalities of external genitalia are seen less often in affected females. Puberty can be incomplete or delayed in affected males and females. Another minor feature of CHARGE syndrome is tracheoesophageal fistula, which is an abnormal connection (fistula) between the esophagus and the trachea. Most people with CHARGE syndrome also have distinctive facial features, including a square-shaped face and differences in appearance between the right and left sides of the face (facial asymmetry). Affected individuals have a wide range of cognitive function, from normal intelligence to major learning disabilities with absent speech and poor communication. Less common features of CHARGE syndrome include kidney abnormalities; immune system problems; abnormal curvature of the spine (scoliosis or kyphosis); and limb abnormalities, such as extra fingers or toes (polydactyly), missing fingers or toes (oligodactyly), an inward and upward turning foot (club foot), and abnormalities of the long bones of the arms and legs. ## Frequency CHARGE syndrome occurs in approximately 1 in 8,500 to 10,000 newborns. ## Causes Mutations in the CHD7 gene cause most cases of CHARGE syndrome. The CHD7 gene provides instructions for making a protein that regulates gene activity (expression) by a process known as chromatin remodeling. Chromatin is the complex of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. When DNA is tightly packed, gene expression is lower than when DNA is loosely packed. Chromatin remodeling is one way gene expression is regulated during development. Most mutations in the CHD7 gene lead to the production of an abnormal CHD7 protein that is broken down prematurely. Shortage of this protein is thought to disrupt chromatin remodeling and the regulation of gene expression. Changes in gene expression during embryonic development likely cause the signs and symptoms of CHARGE syndrome. A small percentage of individuals with CHARGE syndrome do not have an identified mutation in the CHD7 gene. Some of them may have a genetic change affecting the CHD7 gene that has not been found, and others may have a change in a different gene, although additional genes associated with CHARGE syndrome have not been identified. ### Learn more about the gene associated with CHARGE syndrome * CHD7 ## Inheritance Pattern When CHARGE syndrome is caused by mutations in the CHD7 gene, it follows an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family. In rare cases, an affected person inherits the mutation from an affected parent. The inheritance pattern of other cases of CHARGE syndrome is unknown. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CHARGE syndrome

c0265354

medlineplus

https://medlineplus.gov/genetics/condition/charge-syndrome/

{"gard": ["29"], "mesh": ["D058747"], "omim": ["214800"], "synonyms": []}

Combined oxidative phosphorylation defect type 13 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by normal early development followed by the sudden onset in infancy of poor feeding, dysphagia, truncal (followed by global) hypotonia, motor regression, abnormal movements (i.e. severe dystonia of limbs, choreoathetosis, facial dyskinesias) and reduced tendon reflexes. The disease course is severe but nonprogressive. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Combined oxidative phosphorylation defect type 13

c3554129

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319514

{"omim": ["614932"], "icd-10": ["G71.3"], "synonyms": ["COXPD13"]}

Congenital pulmonary lymphangiectasia (CPL) is a rare developmental disorder that affects the lungs. It is present from birth and usually becomes apparent in the first few days of life with respiratory failure. It sometimes is apparent before birth with non-immune hydrops fetalis and pleural effusion (fluid in the lung). Infants with CPL often develop severe, potentially life-threatening, respiratory distress shortly after birth. They may also develop cyanosis caused by low oxygen levels in the blood, which causes the skin to have a bluish tint. Symptoms are due to abnormally wide (dilated) lymphatic vessels within the lungs. These vessels drain a fluid called lymph from different areas of the body. They are an important part of the lymphatic system, which helps the immune system protect the body against infection and disease. The underlying cause of CPL is unknown. It can occur as a primary or secondary disorder (due to another underlying condition). Primary CPL occurs as an isolated defect or as part of a generalized form of lymphatic disease affecting the whole body. Secondary CPL can occur due to a variety of heart abnormalities or lymphatic obstruction. Some cases of CPL have been associated with genetic disorders. Treatment aims to relieve the symptoms of the disorder and may include CPAP, intubation, and/or fluid drainage. While much of the older literature suggests a very high mortality rate, recent studies suggest that CPL does not have as poor an outlook. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Congenital pulmonary lymphangiectasia

c1849554

gard

https://rarediseases.info.nih.gov/diseases/9900/congenital-pulmonary-lymphangiectasia

{"mesh": ["C537727"], "omim": ["265300"], "umls": ["C1849554"], "orphanet": ["2414"], "synonyms": ["CPL", "Lymphangiomatosis pulmonary", "Pulmonary cystic lymphangiectasis", "Lymphangiectasia pulmonary congenital"]}

A rare, genetic, slowly progressive neurodegenerative disease resulting from MGLUR1 deficiency characterized by global developmental delay (beginning in infancy), mild to severe intellectual deficit with poor or absent speech, moderate to severe stance and gait ataxia, pyramidal signs (e.g. hyperreflexia) and mild dysdiadochokinesia, dysmetria, tremors, and/or dysarthria. Oculomotor signs, such as nystagmus, strabismus, ptosis and hypometric saccades, may also be associated. Brain imaging reveals progressive, generalized, moderate to severe cerebellar atrophy, inferior vermian hypoplasia, and/or constitutionally small brain. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Autosomal recessive congenital cerebellar ataxia due to MGLUR1 deficiency

c3553816

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324262

{"omim": ["614831"], "icd-10": ["G11.1"], "synonyms": ["Autosomal recessive congenital cerebellar ataxia due to metabotropic glutamate receptor 1 deficiency", "Autosomal recessive spinocerebellar ataxia type 13", "SCAR13"]}

Premature thelarche SpecialtyGynecology, endocrinology Premature thelarche (PT) is a medical condition, characterised by isolated breast development in female infants. It occurs in females younger than 8 years, with the highest occurrence before the age of 2. PT is rare, occurring in 2.2-4.7% of females aged 0 to 2 years old.[1] The exact cause of the condition is still unknown, but it has been linked to a variety of genetic, dietary and physiological factors.[2] PT is a form of Incomplete Precocious Puberty (IPP). IPP is the presence of a secondary sex characteristic in an infant, without a change in their sex hormone levels. Central Precocious Puberty (CPP) is a more severe condition than IPP. CPP is the presentation of secondary sex characteristics, with a change in sex hormones due to alteration of the hypothalamic-pituitary-gonadal (HPG) axis.[1] }CPP is an aggressive endocrine disorder with harmful developmental consequences for the patient. At the presentation of PT, diagnostics are used to ensure it isn’t early stage CPP. CPP can be differentiated from PT through biochemical testing, ultrasounds and ongoing observation.[3] There is no treatment for PT but regular observation is important to ensure it doesn’t progress to CPP. CPP diagnosis is important as treatment is necessary.[1] ## Contents * 1 Symptoms and signs * 1.1 Patterns of PT * 1.2 Associated Symptoms * 2 Pathophysiology * 2.1 Estrogen * 2.2 Follicle stimulating hormone * 2.3 Other causes * 3 CPP and PT * 4 Diagnosis * 4.1 Pelvic Ultrasounds * 4.2 Biochemical tests * 4.3 Combined diagnostic approach * 5 Research * 5.1 Exposure to environmental agents * 5.2 Leptin * 5.3 GNAS1 gene mutation * 6 See also * 7 References * 8 External links ## Symptoms and signs[edit] Premature thelarche is breast hypertrophy before puberty. This form of hypertrophy is an increase in breast tissue. PT occurs in pre-pubescent females, under the age of 8, having a peak occurrence in the first two years of life.[4] The breast development is usually bi-lateral: both breasts show development. In some cases development may be unilateral: one breast develops.[citation needed] ### Patterns of PT[edit] There are four patterns of PT development. Most patients have hypertrophy followed by complete loss of the excess breast tissue (51% of cases) or loss of most excess tissue, but some remains until puberty (36% of cases). Less commonly patients have ongoing patterns of thelarche: 9.7% suffer from a cyclic pattern where the size of the breast tissue varies over time, and 3.2% experience continual increase in tissue size.[1] ### Associated Symptoms[edit] The main symptom of PT is enlarged breast tissue in infants. Estrogen’s role in PT, also leads to increased bone age and growth in some cases.[5] In PT these secondary symptoms are minimal: bone age only varies from actual age by a few months and growth velocity only slightly varies from the norm. Diagnostic tests will distinguish these PT secondary symptoms from the more severe bone aging and growth occurring in early CPP.[3] ## Pathophysiology[edit] The direct pathophysiology behind PT is still unknown, but there are many postulated causes.[2] ### Estrogen[edit] PT is linked to increased sensitivity of the breast tissue to estradiol, an estrogen derivative, in certain prepubertal individuals.[1] Sporadic estrogen or estradiol production in the adrenal glands, follicles or ovarian cysts is also linked to the condition.[2][6] ### Follicle stimulating hormone[edit] Follicle Stimulating Hormone (FSH) is secreted from the anterior pituitary. FSH plays a key role in development, growth and puberty, thus it is suspected to play a role in PT. Gondotropin-releasing hormone (GnRH) stimulation testing in some patients with PT has shown a dominant response from FSH. This response is linked to active mutations in the FSH receptor and Gs-a subunit in PT. Genetic investigation indicated these mutations only account for few cases of premature PT.[2][7] PT may also be caused by transient partial activation of the HPG axis. Partial activation would release a surplus of FSH from the anterior pituitary without further disruption of the HPG axis.[6] ### Other causes[edit] The consumption or exposure to certain endocrine disrupters have also been linked to PT.[2] ## CPP and PT[edit] PT is the benign growth of breasts in infants, while CPP is a condition that involves the frequent activation of the HPG axis in patients. PT does not require treatment, as the condition is limited to enlarged breast tissue that usually subsides with time. CPP is associated with a wider range of symptoms including thelarche, pubic hair growth, accelerated bone aging, increased growth velocity and early epiphyseal growth. If an individual is affected with CPP they will need to begin treatment immediately. CPP is treated with lutenizing hormone (LH) releasing hormone agonists. PT can impact growth velocity and bone age slightly, but CPP affects these characteristics to the point of detriment to the adult stature.[1] Patients with suspected PT must undergo diagnostic testing to ensure it isn’t CPP or exaggerated thelarche, the intermediate stage before CPP.[3] Notable hormone differences occur between CPP and PT patients, so studying these hormone levels is the main biochemical diagnostic used in CPP.[4] Individuals with CPP usually have a higher basal LH levels and LH:FSH ratios.[1][4] Few PT patients, 9 to 14%, are predicted to develop CPP.[1][4] Observation allows clinicians to identify the presentation of CPP indicative symptoms in PT patients. No diagnostics tests can indicate if a PT patient is at risk of developing CPP.[4] ## Diagnosis[edit] Premature thelarche does not require treatment. In PT, breast hypertrophy will usually stop completely and patients will experience regression of the breast tissue over 3 to 60 months. Less commonly, patients may remain with residual breast tissue or continue through cycles of breast hypertrophy and regression until puberty.[1] Diagnostics are utilised in individuals with PT, especially at the presentation of other secondary sex characteristics. Diagnostics aim to ensure PT patients are not suffering from CPP.[1] ### Pelvic Ultrasounds[edit] Pelvic ultrasounds are important in diagnosing CPP.[3] Patients with CPP have an increased ovary and uterus size. The ovary and uterus volume of CPP patients is similar to that of females undergoing puberty.[1] The pelvis ultrasound is problematic as a diagnostic, as there is not a specific cut-off for the uterine and ovary volumes that indicate the patient has CPP. Patients with PT should have a uterine and ovarian volume within the normal range for their age. Pelvic ultrasounds are a desirable diagnostic as they are non-invasive and easy to continually review. The pelvic ultrasound should be paired with biochemical tests to determine the presence of CPP.[3] ### Biochemical tests[edit] Biochemical tests study the hormone levels in patients. CPP patients have elevated LH levels and peak LH:FSH ratios when compared to PT patients. It is hard to use LH as a diagnostic for CPP, as the LH assay has varying sensitivity and specificity.[1] The GnRH stimulation test is the main diagnostic biochemical test used to distinguish PT from CPP.[3] The GnRH test demonstrates the pituitary responsiveness to GnRH. GnRH stimulates the release of LH and FSH from the anterior pituitary. The peak LH:FSH ratio in CPP patients is similar to the ratio of pubertal females. Females with PT demonstrated a LH:FSH ratio lower than pubertal females.[8] The disadvantages of the GnRH stimulation test is it takes a long time to perform and requires multiple collections from the patient, making the process time consuming and inconvenient. The test is highly specific but has low sensitivity as the LH hormone response is usually observed in later stages of CPP.[3] There are also overlaps in the expected value in the GnRH test results of individuals with CPP and PT.[1] ### Combined diagnostic approach[edit] The diagnostic inconsistency in CPP means that a combination of all of pelvic ultrasounds and biochemical tests should be paired with observation, to ensure PT doesn’t progress to CPP.[1] ## Research[edit] ### Exposure to environmental agents[edit] Natural commodities like fennel, lavender and tea tree oils have been linked to PT. Lavender and tea tree oil have weak estrogenic activities. These estrogenic properties may cause an imbalance in endocrine signalling pathways, leading to PT in regular users of these products.[1] Fennel tea has been studied as an endocrine disrupter linked to PT. Fennel seed oil contains anethole a compound with estrogenic effects. The tea contains fennel seed oil and regular use results in increased estradiol levels in the infant. Infants with fennel tea related PT, were given the tea as a homeopathic remedy for restlessness. The tea was consumed for at least four months before the presentation of PT symptoms. PT resulting from fennel tea subsides approximately six months after stopping the use of fennel tea.[9] ### Leptin[edit] Leptin is an adipocyte hormone that has important implications of puberty and sex hormone secretion. Increased leptin has been linked to estrogen and estradiol secretion. Leptin has key roles in maintaining age appropriate body composition and desired weight. Leptin receptors are also found in mammary epithelial cells and leptin has been observed as a growth factor in breast tissue. Increased leptin levels have been observed in some cases of PT. The increase in leptin levels cause increased estradiol levels and development of breast tissue.[6] ### GNAS1 gene mutation[edit] The form of PT with fluctuating hypertrophy in patients has been linked to activating mutations in the GNAS1 gene. This mutation accounts for a small number of cases of PT.[5][7] ## See also[edit] * Mammoplasia * Breast hypertrophy * Gynecomastia ## References[edit] 1. ^ a b c d e f g h i j k l m n o Khokar A, Mojia A (2018). "Premature Thelarche". Pediatric Annals. 47 (1): 12–15. 2. ^ a b c d e Rezkalla J, Von Wald T, Hansen KA (June 2017). "Premature Thelarche and the PURA Syndrome". Obstetrics and Gynecology. 129 (6): 1037–1039. doi:10.1097/AOG.0000000000002047. PMID 28486374. 3. ^ a b c d e f g Lee SH, Joo EY, Lee JE, Jun YH, Kim MY (January 2016). "The Diagnostic Value of Pelvic Ultrasound in Girls with Central Precocious Puberty". Chonnam Medical Journal. 52 (1): 70–4. doi:10.4068/cmj.2016.52.1.70. PMC 4742613. PMID 26866003. 4. ^ a b c d e Sømod ME, Vestergaard ET, Kristensen K, Birkebæk NH (2016-02-22). "Increasing incidence of premature thelarche in the Central Region of Denmark - Challenges in differentiating girls less than 7 years of age with premature thelarche from girls with precocious puberty in real-life practice". International Journal of Pediatric Endocrinology. 2016 (1): 4. doi:10.1186/s13633-016-0022-x. PMC 4763410. PMID 26909102. 5. ^ a b Codner E, Román R (March 2008). "Premature thelarche from phenotype to genotype". Pediatric Endocrinology Reviews. 5 (3): 760–5. PMID 18367996. 6. ^ a b c Dundar B, Pirgon O, Sangun O, Doguc DK (August 2013). "Elevated leptin levels in nonobese girls with premature thelarche". Journal of Investigative Medicine. 61 (6): 984–8. doi:10.2310/JIM.0b013e31829cbe20. PMID 23838698. S2CID 22270791. 7. ^ a b Román R, Johnson MC, Codner E, Boric MA, áVila A, Cassorla F (August 2004). "Activating GNAS1 gene mutations in patients with premature thelarche". The Journal of Pediatrics. 145 (2): 218–22. doi:10.1016/j.jpeds.2004.05.025. PMID 15289771. 8. ^ Zevenhuijzen H, Kelnar CJ, Crofton PM (2004). "Diagnostic utility of a low-dose gonadotropin-releasing hormone test in the context of puberty disorders". Hormone Research. 62 (4): 168–76. doi:10.1159/000080324. PMID 15331852. S2CID 23120189. 9. ^ Okdemir D, Hatipoglu N, Kurtoglu S, Akın L, Kendirci M (January 2014). "Premature thelarche related to fennel tea consumption?". Journal of Pediatric Endocrinology & Metabolism. 27 (1–2): 175–9. doi:10.1515/jpem-2013-0308. PMID 24030028. S2CID 20871881. ## External links[edit] Classification D * ICD-10: E30.8 * ICD-9-CM: 259.1 * v * t * e Gonadal disorder Ovarian * Polycystic ovary syndrome * Premature ovarian failure * Estrogen insensitivity syndrome * Hyperthecosis Testicular Enzymatic * 5α-reductase deficiency * 17β-hydroxysteroid dehydrogenase deficiency * aromatase excess syndrome Androgen receptor * Androgen insensitivity syndrome * Familial male-limited precocious puberty * Partial androgen insensitivity syndrome Other * Sertoli cell-only syndrome General * Hypogonadism * Delayed puberty * Hypergonadism * Precocious puberty * Hypoandrogenism * Hypoestrogenism * Hyperandrogenism * Hyperestrogenism * Postorgasmic illness syndrome * Cytochrome P450 oxidoreductase deficiency * Cytochrome b5 deficiency * Androgen-dependent condition * Aromatase deficiency * Complete androgen insensitivity syndrome * Mild androgen insensitivity syndrome * Hypergonadotropic hypogonadism * Hypogonadotropic hypogonadism * Fertile eunuch syndrome * Estrogen-dependent condition * Premature thelarche * Gonadotropin insensitivity * Hypergonadotropic hypergonadism * 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

Premature thelarche

c0425772

wikipedia

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

{"icd-10": ["E30.8"], "wikidata": ["Q26815924"]}

Osteoporosis-pseudoglioma syndrome is a rare condition characterized by severe thinning of the bones (osteoporosis) and eye abnormalities that lead to vision loss. In people with this condition, osteoporosis is usually recognized in early childhood. It is caused by a shortage of minerals, such as calcium, in bones (decreased bone mineral density), which makes the bones brittle and prone to fracture. Affected individuals often have multiple bone fractures, including in the bones that form the spine (vertebrae). Multiple fractures can cause collapse of the affected vertebrae (compressed vertebrae), abnormal side-to-side curvature of the spine (scoliosis), short stature, and limb deformities. Decreased bone mineral density can also cause softening or thinning of the skull (craniotabes). Most affected individuals have impaired vision at birth or by early infancy and are blind by young adulthood. Vision problems are usually caused by one of several eye conditions, grouped together as pseudoglioma, that affect the light-sensitive tissue at the back of the eye (the retina), although other eye conditions have been identified in affected individuals. Pseudogliomas are so named because, on examination, the conditions resemble an eye tumor known as a retinal glioma. Rarely, people with osteoporosis-pseudoglioma syndrome have additional signs or symptoms such as mild intellectual disability, weak muscle tone (hypotonia), abnormally flexible joints, or seizures. ## Frequency Osteoporosis-pseudoglioma syndrome is a rare disorder that occurs in approximately 1 in 2 million people. ## Causes Osteoporosis-pseudoglioma syndrome is caused by mutations in the LRP5 gene. This gene provides instructions for making a protein that participates in a chemical signaling pathway that affects the way cells and tissues develop. In particular, the LRP5 protein helps regulate bone mineral density and plays a critical role in development of the retina. LRP5 gene mutations that cause osteoporosis-pseudoglioma syndrome prevent cells from making any LRP5 protein or lead to a protein that cannot function. Loss of this protein's function disrupts the chemical signaling pathways that are needed for the formation of bone and for normal retinal development, leading to the bone and eye abnormalities characteristic of osteoporosis-pseudoglioma syndrome. ### Learn more about the gene associated with Osteoporosis-pseudoglioma syndrome * LRP5 ## Inheritance Pattern Osteoporosis-pseudoglioma syndrome is inherited in an autosomal recessive pattern, which means both copies of the LRP5 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. However, some carriers may have decreased bone mineral density. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Osteoporosis-pseudoglioma syndrome

c0432252

medlineplus

https://medlineplus.gov/genetics/condition/osteoporosis-pseudoglioma-syndrome/

{"gard": ["4160"], "mesh": ["C536063"], "omim": ["259770"], "synonyms": []}