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Duca et al. (1981) described mother and her 3 daughters with short stature, hip dislocation, minor vertebral and pelvic changes, and microtia with deafness. See Wettke-Schafer and Kantner (1983) for discussion of possible X-linked dominant inheritance with lethality in hemizygous males. Joints \- Hip dislocation Growth \- Short stature Inheritance \- Autosomal dominant vs. X-linked dominant with lethality in hemizygous males Ears \- Microtia \- Deafness Skel \- Minor vertebral and pelvic changes ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	COXOAURICULAR SYNDROME	c1852513	1,900	omim	https://www.omim.org/entry/122780	2019-09-22T16:42:48	{"mesh": ["C565148"], "omim": ["122780"], "orphanet": ["1508"]}
Injection site reactions are allergic reactions that result in cutaneous necrosis that may occur at sites of medication injection, typically presenting in one of two forms, (1) those associated with intravenous infusion or (2) those related to intramuscular injection.[1]:123–4 Intra muscular injections may produce a syndrome called livedo dermatitis.[1]:124 ## See also[edit] * Application site reaction * Vitamin K reactions * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ a b James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Injection site reaction	c0151735	1,901	wikipedia	https://en.wikipedia.org/wiki/Injection_site_reaction	2021-01-18T19:10:00	{"mesh": ["D000075662"], "umls": ["C0151735"], "wikidata": ["Q6034307"]}
Abortion in Cameroon is only legal if the abortion will save the woman's life, the pregnancy gravely endangers the woman's physical or mental health, or the pregnancy is a result of rape.[1] ## Statistics[edit] In 1997, a survey in Yaoundé found 20 percent of women aged 20–29 had had at least one abortion.[2][3] 80 percent of these procedures took place in a medical facility, but they were not always safe, and women often faced complications.[2] The odds that a pregnant woman would seek an abortion were increased if they were educated or had children.[2] Of women reporting past abortions, 40% had two or more.[2] The survey found that 35% of all reported pregnancies in the capital city ended in abortion.[3] ## Access to reproductive health care[edit] In 1990, the Cameroon government passed Act No. 90/035 to prohibit birth control education.[4] Reports found that abortion and secretive reproductive health services were widespread and made up 40 percent of OB/GYN emergency admissions.[4] However, most access to abortion clinics were limited to urban centers within the country.[4] ## References[edit] 1. ^ Division, United Nations Dept of Economic and Social Affairs Population; population, Nations Unies Division de la (2001). Abortion Policies: A Global Review. United Nations Publications. ISBN 9789211513653. 2. ^ a b c d "Although Abortion Is Highly Restricted in Cameroon, It Is Not Uncommon Among Young Urban Women". Guttmacher Institute. 2005-09-08. Retrieved 2016-06-21. 3. ^ a b Calvès, Anne-Emmanuèle (2002). "Abortion Risk and Decisionmaking among Young People in Urban Cameroon". 33 (3): 249–260. JSTOR 3181117. Cite journal requires `\|journal=` (help) 4. ^ a b c "Women's Reproductive Rights in Cameroon: A Shadow Report" (PDF). Center for Reproductive Law and Policy. 1999. Retrieved 21 June 2016. * v * t * e Abortion in Africa Sovereign states * Algeria * Angola * Benin * Botswana * Burkina Faso * Burundi * Cameroon * Cape Verde (Cabo Verde) * Central African Republic * Chad * Comoros * Democratic Republic of the Congo * Republic of the Congo * Djibouti * Egypt * Equatorial Guinea * Eritrea * Eswatini (Swaziland) * Ethiopia * Gabon * The Gambia * Ghana * Guinea * Guinea-Bissau * Ivory Coast (Côte d'Ivoire) * Kenya * Lesotho * Liberia * Libya * Madagascar * Malawi * Mali * Mauritania * Mauritius * Morocco * Mozambique * Namibia * Niger * Nigeria * Rwanda * São Tomé and Príncipe * Senegal * Seychelles * Sierra Leone * Somalia * South Africa * South Sudan * Sudan * Tanzania * Togo * Tunisia * Uganda * Zambia * Zimbabwe States with limited recognition * Sahrawi Arab Democratic Republic * Somaliland Dependencies and other territories * Canary Islands / Ceuta / Melilla (Spain) * Madeira (Portugal) * Mayotte / Réunion (France) * Saint Helena / Ascension Island / Tristan da Cunha (United Kingdom) * v * t * e Human rights in Cameroon Subjects * Child marriage * Human trafficking * LGBT rights * Polygamy See also * Abortion * Corruption * Demographics * v * t * e Cameroon articles History * Baka * Mandara kingdom * Colonial governors * Kamerun * West Africa Campaign (World War I) * Kamerun Campaign * French Cameroons * British Cameroons * Union of the Peoples of Cameroon Geography * Cities * Climate * Divisions * Regions * Rivers * Wildlife Politics * Constitution * Corruption * Elections * Human rights * LGBT rights * Foreign relations * Law enforcement * Military * Political parties * President * list * Prime Minister * list Economy * Agriculture * Currency * Companies * Mining * Telecommunications * Tourism * Transport Culture * Abortion * Child marriage * Cuisine * Demographics * Education * Ethnic groups * Flag * Health * Human trafficking * Languages * Media * Music * Polygamy * Public holidays * Refugees * Religion * Sport * Outline * Index * Category * Portal This abortion-related article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Abortion in Cameroon	None	1,902	wikipedia	https://en.wikipedia.org/wiki/Abortion_in_Cameroon	2021-01-18T18:34:08	{"wikidata": ["Q24896140"]}
## Description Acrocephalopolydactylous dysplasia, or Elejalde syndrome, is a lethal multiple congenital disorder characterized by increased birth weight, globular body with thick skin, organomegaly, and fibrosis in multiple tissues (summary by Phadke et al., 2011). Clinical Features Elejalde et al. (1977) described 2 sibs, born to consanguineous parents, who showed excessive birth weight, a swollen globular body with thick skin, apparently short limbs, polydactyly, craniosynostosis with acrocephaly, omphalocele, and abnormal face. Autopsy documented abdominal organomegaly, ascites, and cystic renal dysplasia, with excessive amounts of connective tissue and perivascular proliferation of nerve fibers in many organs. Lurie et al. (1991) described an infant with acrocephaly, a large cavernous lymphangioma of the neck, postaxial polydactyly, cystic renal dysplasia, and severe hypoplasia of the small intestine and colon. Polysplenia was present, the right lung was hypoplastic, and a left lung sequestrum was located on the diaphragm. Lurie et al. (1991) reviewed cerebrorenodigital syndromes, of which 19 were considered to be autosomal recessive. Nevin et al. (1994) reported an 18-week-old fetus with craniosynostosis, gross edema, short limbs, postaxial polydactyly, redundant connective tissue, and cystic renal dysplasia consistent with a diagnosis of Elejalde syndrome. Thornton and Stewart (1997) described another example of this disorder in a child born of nonconsanguineous parents. The mother developed marked polyhydramnios, and ultrasound scan showed a large-for-date fetus with probable hydrops fetalis, cystic hygroma, and omphalocele. The infant was born at 24-weeks' gestation but died after 2 hours. The infant weighed 1,500 g and the placenta 390 g, both almost twice the expected weight for the gestational age. The skin was thick, shiny, and taut. At autopsy, well-formed bile ductules were absent from most portal tracts of the liver. The pancreas showed mild interstitial fibrosis, and nerve trunks appeared somewhat prominently within the fibrous tissue. The external appearance closely resembled that reported by Elejalde et al. (1977), although there was no evidence of craniosynostosis or polydactyly. Silhanova et al. (2006) reported an affected child born to nonconsanguineous parents in Poland. Prenatal ultrasound at 17 weeks' gestation showed abnormal shape of the head, short long bones, and hygroma colli. At birth, the infant had a swollen acrocephalic head, small and abnormally modeled ears, small and flat nose, big mouth, hypertelorism, epicanthal folds, short thick neck with a soft tissue mass over the posterior scalp and nape of the neck, short limbs with brachydactyly, genua recurvata, and protuberant abdomen. She died from respiratory failure 11 hours after birth. Postmortem examination showed craniosynostosis, hypoplastic lungs, hepatomegaly, ascites, small kidneys with abnormal lobulation, and fibrosis of the pancreas. Histologic examination of several organs showed abnormal fibrotic changes. Silhanova et al. (2006) postulated that a defect in a fibroblast growth factor receptor gene may be responsible for the phenotype. Phadke et al. (2011) reported a 33-week-old fetus, born of unrelated Indian parents, with features consistent with Elejalde syndrome. The fetus had a globular external appearance with distended, thick skin, bloated face, and ascites. Birth weight was increased (greater than 95th percentile), and he had micromelia and anal atresia; there was no craniosynostosis. Pathologic examination showed multicystic kidneys, partial duplication of the ureters, hypoplastic lungs, a complex heart defect, and enlarged liver with periportal and perivenular fibrosis and perivascular nerve fiber proliferation. Radiographs showed partial rib fusion on the left and some hemivertebrae. Nomenclature This disorder is distinct from the similarly named Elejalde disease (256710), which is also known as neuroectodermal melanolysosomal disease. INHERITANCE \- Autosomal recessive GROWTH Weight \- Increased birth weight Other \- Swollen globular body HEAD & NECK Head \- Acrocephaly Face \- Bloated face Ears \- Dysplastic ears \- Low-set ears \- Abnormally folded ears Eyes \- Upslanting palpebral fissures \- Hypertelorism \- Epicanthal folds Nose \- Small nose Neck \- Short neck \- Skin folds around the neck RESPIRATORY Lung \- Hypoplastic lungs ABDOMEN External Features \- Ascites \- Omphalocele (in some patients) Liver \- Hepatomegaly \- Hepatic fibrosis \- Perivascular nerve fiber proliferation \- Periportal and perivenular fibrosis Pancreas \- Pancreatic fibrosis (in some patients) Gastrointestinal \- Bowel hypoplasia (less common) \- Bowel atresia (less common) GENITOURINARY Kidneys \- Cystic renal dysplasia \- Enlarged kidneys SKELETAL Skull \- Craniosynostosis (in some patients) Limbs \- Micromelia Hands \- Polydactyly (in some patients) SKIN, NAILS, & HAIR Skin \- Thick skin \- Redundant connective tissue PRENATAL MANIFESTATIONS Placenta & Umbilical Cord \- Increased placental weight MISCELLANEOUS \- Variable phenotype \- Perinatal lethality ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	ACROCEPHALOPOLYDACTYLOUS DYSPLASIA	c1860157	1,903	omim	https://www.omim.org/entry/200995	2019-09-22T16:31:37	{"mesh": ["C536203"], "omim": ["200995"], "orphanet": ["221054"], "synonyms": ["Alternative titles", "ELEJALDE SYNDROME"]}
Black heel and palm Other namesCalcaneal petechiae, Chromidrose plantaire, Post-traumatic punctate intraepidermal hemorrhage, Tache noir,[1] and Talon noir SpecialtyDermatology Black heel and palm is a skin condition characterized by a sudden shower of minute, black, punctate macules occurring most often on the posterior edge of the plantar surface of one or both heels.[2]:43 ## See also[edit] * Skin lesion * List of cutaneous conditions ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. 2. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Black heel and palm	None	1,904	wikipedia	https://en.wikipedia.org/wiki/Black_heel_and_palm	2021-01-18T18:47:11	{"umls": ["C0406178"], "wikidata": ["Q4922335"]}
A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is caused by homozygous mutation in the TDP1 gene (607198) on chromosome 14q31. One such family has been reported. Description Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is an autosomal recessive neurologic disorder characterized by onset of gait disturbances in the first or second decades of life. Affected individuals have cerebellar ataxia associated with cerebellar atrophy on brain imaging, as well as an axonal sensorimotor neuropathy with distal sensory impairment, hypo- or areflexia, pes cavus, and steppage gait (summary by Takashima et al., 2002). ### Genetic Heterogeneity of Spinocerebellar Ataxia with Axonal Neuropathy See also SCAN2 (606002), caused by mutation in the SETX gene (608465) on chromosome 9q34, and SCAN3 (618387), caused by mutation in the COA7 gene (615623) on chromosome 1p32. Clinical Features Takashima et al. (2002) investigated a large multigenerational consanguineous Saudi Arabian family segregating an autosomal recessive ataxia with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus, and steppage gait. Detailed evaluation of 3 of the 9 affected individuals confirmed that they had cerebellar ataxia and axonal neuropathy, a combination that the authors designated SCAN1. All had cerebellar atrophy on brain imaging, and 2 had mild cerebral atrophy. One patient had a history of seizures, but all had normal intelligence. All 3 individuals had mild hypercholesterolemia and borderline hypoalbuminemia. The patients tested negative for mutations in most genes known to be associated with ataxia and neuropathy. Inheritance The transmission pattern of SCAN1 in the family reported by Takashima et al. (2002) was consistent with autosomal recessive inheritance. Pathogenesis El-Khamisy et al. (2005) showed that in human cells TDP1 is required for repair of chromosomal single-strand breaks arising independently of DNA replication from abortive topoisomerase-1 (TOP1; 126420) activity or oxidative stress. They reported that TDP1 is sequestered into multiprotein single-strand break repair (SSBR) complexes by direct interaction with DNA ligase III-alpha (600940) and that these complexes are catalytically inactive in SCAN1 cells. El-Khamisy et al. (2005) concluded that their data identified a defect in SSBR in a neurodegenerative disease, and implicated this process in the maintenance of genetic integrity in postmitotic neurons. Molecular Genetics In affected members of a multigenerational consanguineous Saudi Arabian family with SCAN1, Takashima et al. (2002) identified a homozygous missense mutation in the TDP1 gene (H493R; 607198.0001). The mutation was found by genomewide linkage mapping and analysis of candidate genes. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggested that the mutation would disrupt the active site of the enzyme. INHERITANCE \- Autosomal recessive SKELETAL Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Distal muscle weakness due to sensory neuropathy NEUROLOGIC Central Nervous System \- Cerebellar ataxia \- Steppage gait \- Dysarthria \- Steppage gait \- Seizures (in some patients) \- Cerebellar atrophy \- Cerebral atrophy, mild Peripheral Nervous System \- Axonal sensorimotor neuropathy \- Distal sensory impairment \- Hyporeflexia \- Areflexia \- Sural nerve biopsy shows loss of myelinated fibers LABORATORY ABNORMALITIES \- Hypercholesterolemia, mild \- Hypoalbuminemia, mild MISCELLANEOUS \- Onset in the first or second decade \- One Saudi Arabian family has been reported (last curated April 2019) MOLECULAR BASIS \- Caused by mutation in the tyrosyl-DNA phosphodiesterase 1 gene (TDP1, 607198.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 1	c1846574	1,905	omim	https://www.omim.org/entry/607250	2019-09-22T16:09:29	{"doid": ["0090115"], "mesh": ["C537313"], "omim": ["607250"], "orphanet": ["94124"]}
Alpha-gal allergy Other namesRed meat allergy Mammalian Meat Allergy (MMA) SymptomsSymptoms Durationunknown Causesbites from certain species of ticks. (Predominantly the Lone Star tick.) TreatmentDesensitization Alpha-gal allergy — or mammalian meat allergy (MMA)[1] — is a type of red-meat allergy characterized by a delayed onset of symptoms (3-5 hours) after ingesting the provoking food and resulting from past exposure to tick bites. It was first reported in 2002. Alpha-gal allergy is a reaction to galactose-alpha-1,3-galactose ("alpha-gal"), whereby the body is overloaded with immunoglobulin E (IgE) antibodies on contact with the carbohydrate.[2] Anti-gal is a human natural antibody that interacts specifically with the mammalian carbohydrate structure gal alpha 1-3Gal beta 1-4GlcNAc-R, termed, the alpha-galactosyl epitope.[3] The alpha-gal molecule is found in all mammals except apes, humans, and Old World monkeys.[3] Bites from certain ticks, such as the lone star tick (Am. americanum) in the US, and the paralysis tick in Australia, which can transfer this carbohydrate to a victim, have been implicated in the development of this delayed allergic response to consumption of mammalian meat products.[4] Individuals with alpha-gal allergy do not need to become strict vegetarians, because poultry, fish, and in rare cases for some people, lean meat such as venison does not trigger a reaction.[5] Alpha-gal allergy has been reported in 17 countries on all 6 continents where humans are bitten by ticks, particularly the United States and Australia.[6] As of November 2019 Australia has the highest rate of mammalian meat allergy and tick anaphylaxis in the world.[7] In the US, the allergy most often occurs in the central and southern regions, which corresponds to the distribution of the lone star tick.[8] In the Southern United States, where the tick is most prevalent, allergy rates are 32% higher than elsewhere.[9] However, as doctors are not required to report the number of patients with alpha-gal allergy, the true number of affected individuals is unknown.[10] Alpha-gal has also been shown to exist in the saliva of Ix. scapularis but not Am. maculatum.[11] Alpha-gal allergies are the first known food allergies that present the possibility of delayed anaphylaxis.[12][13][14] It is also the first known food-related allergy associated with a carbohydrate, rather than a protein.[13][15] Other mammalian products containing alpha-gal other than meat such as milk and gelatin may also trigger an allergic reaction.[16] ## Contents * 1 Symptoms * 2 Cause * 3 Mechanism * 4 Diagnosis * 5 Prognosis * 6 Desensitization * 7 History * 8 See also * 9 References * 10 Further reading ## Symptoms[edit] A typical allergic reaction to alpha-gal has a delayed onset, occurring 3–8 hours after the consumption of mammalian meat products, in contrast to the typical rapid onset of most food allergies. After the delayed onset, the allergic response is like most food allergies, and especially an IgE-mediated allergy, including severe whole-body itching, hives, angioedema, gastrointestinal upset, and possible anaphylaxis.[17] In 70% of cases the reaction is accompanied by respiratory distress and as such is particularly harmful to those with asthma.[12] ## Cause[edit] Amblyomma americanum, a vector for the allergy Alpha-gal allergies develop after a person has been bitten by the lone star tick in the United States, the European castor bean tick, the paralysis tick and Ixodes (Endopalpiger) australiensis in Australia,[18][6] Haemaphysalis longicornis in Japan,[19] and a currently unknown tick in South Africa, possibly Amblyomma hebraeum.[20][21] Alpha-gal is not naturally present in apes, Old World monkeys, or humans, but is in all other mammals. If a tick feeds on another mammal, the alpha-gal remains in its alimentary tract.[5] The tick then injects the alpha-gal into a person's skin, which causes the immune system to release a flood of IgE antibodies to fight the foreign carbohydrate.[5][18] Researchers still do not know which specific component of tick saliva causes the reaction.[22] A 2012 preliminary study found unexpectedly high rates of alpha-gal allergy in the Western and North Central parts of the United States. This suggests that unknown tick species may spread the allergy.[9] The study even found alpha-gal allergy cases in Hawaii, where no ticks identified with the allergies live.[22] Human factors were suggested, but no specific examples were provided.[9] Alpha-gal is present in the anticancer drug cetuximab, as well as the intravenous fluid replacements Gelofusine and Haemaccel. Blood thinners derived from porcine intestine and replacement heart valves derived from porcine tissue may also contain alpha-gal.[18] At least one instance of a man with an alpha-gal allergy going into anaphylaxis after receiving a heart valve transplant has been reported.[18] Some researchers have suggested that the alpha-gal in pig's tissue that surgeons use for xenografts might contribute to organ rejection.[23] ## Mechanism[edit] Recent research has shown that saliva from the lone star tick contains alpha-gal,[24] and that saliva is injected into the blood stream. The immune system then releases IgE antibodies to fight this foreign sugar. After this reaction, the future intake of mammal meat with the same alpha-gal causes an allergic reaction. Symptoms of the allergy reaction are caused by too many IgE antibodies attacking the allergen, in this case the alpha-gal.[18][25] ## Diagnosis[edit] A traditional skin-prick allergy test for allergy to meat may give a false-negative answer.[14][26] Determination of specific IgE to alpha-gal testing is commercially available, as well as IgE testing to specific red meats.[27][17] Skin and basophil activation tests with cetuximab are the most sensitive, but high costs limit their use.[27] ## Prognosis[edit] Unlike most food allergies, in some people, the alpha-gal allergy may recede over time, as long as the person is not bitten by another tick. The recovery period can take 8 months to 5 years.[18][22][28] ## Desensitization[edit] So far, only two successful desensitizations have been performed on patients with an alpha-gal allergy.[29] ## History[edit] Ixodes holocyclus, the species of hard-bodied tick most likely to be responsible in Australia for instances of alpha-gal allergy. The allergy was first formally identified as originating from tick bites in the United States in 2002 by Thomas Platts-Mills,[30] and independently by Sheryl van Nunen in Australia in 2007.[31][32][33] Platts-Mills and Scott Commins were attempting to discover why some people were reacting negatively to the carbohydrate in the cancer drug cetuximab.[18][34] They had previously hypothesized that a fungal infection or parasite could lead to the allergy.[18][28] When Platts-Mills was bitten by a tick and developed alpha-gal allergies, his team came to the conclusion that a link existed between tick bites and the allergy.[28] They found that the IgE antibody response to the mammalian oligosaccharide epitope, alpha-gal, was associated with both the immediate-onset anaphylaxis during first exposure to intravenous cetuximab and the delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products, such as beef or pork.[35] Van Nunen, an immunologist specialising in allergies, had been practicing in a tick-prone area of Sydney, when 25 patients reported having allergic reactions to red meat after being bitten by ticks.[36][37] She later concluded that the relatively sudden rise in cases was the result of a local fox baiting program which began in 2003. Foxes were introduced to Australia and had decimated the local indigenous bandicoot population, hence the fox baiting program. However an unforeseen effect of the subsequent rise in the bandicoot population was the rise in ticks, as bandicoots are a major host for ticks, and thus the number of humans suffering tick bites.[38] Alpha-gal allergies are similar to pork–cat syndrome, hence misidentification can occur. Pork–cat syndrome usually elicits an immediate allergic response, while a true alpha-gal allergy typically features a delayed allergic reaction of 3 to 8 hours after ingestion of the allergen.[39] ## See also[edit] * Poultry allergy * Pork–cat syndrome ## References[edit] 1. ^ Catalyst (ABC-TV program) first aired 8 November 2016 2. ^ Commins SP, Platts-Mills TA (February 2013). "Delayed anaphylaxis to red meat in patients with IgE specific for galactose alpha-1,3-galactose (alpha-gal)". Current Allergy and Asthma Reports. 13 (1): 72–7. doi:10.1007/s11882-012-0315-y. PMC 3545071. PMID 23054628. 3. ^ a b Galili U (1993). "Evolution and pathophysiology of the human natural anti-alpha-galactosyl IgG (anti-Gal) antibody". Springer Seminars in Immunopathology. 15 (2–3): 155–71. doi:10.1007/bf00201098. PMID 7504839. 4. ^ "Alpha-Gal IgE Test - Galactose-alpha-1,3-galactose : Viracor-IBT Laboratories". Retrieved 9 January 2013. 5. ^ a b c Williams L (December 27, 2013). "Just one bite". Sydney Morning Herald. Australia. p. 20. 6. ^ a b Kwak M, Somerville C, van Nunen S (July 2018). "A novel Australian tick Ixodes (Endopalpiger) australiensis inducing mammalian meat allergy after tick bite". Asia Pacific Allergy. 8 (3): e31. doi:10.5415/apallergy.2018.8.e31. PMC 6073180. PMID 30079309. 7. ^ Lawson, Kirsten (20 Nov 2019). "Gluten 'lifestylers' undermine efforts on coeliac disease". The Canberra Times. p. 4. 8. ^ "Meat Allergy: Alpha-Gal Reaction From Lone-Star Ticks More Common In Central, Southern U.S. Regions". 2012-11-09. Retrieved 9 January 2013. 9. ^ a b c Chan AL (November 9, 2012). "Where Meat Allergy From Ticks Is Most Common". Healthy Living. 10. ^ Frazier A (March 20, 2014). "Tick bite makes Lusby woman allergic to meat". The Washington Post. pp. METRO, T20. Archived from the original on July 2, 2018. 11. ^ Crispell, Gary; Commins, Scott P.; Archer-Hartman, Stephanie A.; Choudhary, Shailesh; Dharmarajan, Guha; Azadi, Parastoo; Karim, Shahid (2019). "Discovery of Alpha-Gal-Containing Antigens in North American Tick Species Believed to Induce Red Meat Allergy". Frontiers in Immunology. 10. doi:10.3389/fimmu.2019.01056. ISSN 1664-3224. 12. ^ a b Wolver SE, Sun DR, Commins SP, Schwartz LB (February 2013). "A peculiar cause of anaphylaxis: no more steak? The journey to discovery of a newly recognized allergy to galactose-alpha-1,3-galactose found in mammalian meat". Journal of General Internal Medicine. 28 (2): 322–5. doi:10.1007/s11606-012-2144-z. PMC 3614139. PMID 22815061. Lay summary – ScienceDaily (July 24, 2012). 13. ^ a b Alvarez A (July 25, 2012). "Tick bite leads to curious meat allergy". Milwaukee Journal Sentinel. Retrieved March 24, 2014. 14. ^ a b "'Alpha-Gal' Syndrome". Cornell Cooperative Extension in Suffolk County. Cornell University. 15. ^ Smith O (June 20, 2012). "Ticks causing mysterious meat allergy". CNN. 16. ^ "Ingestion of mammalian meat and alpha-gal allergy: Clinical relevance in primary care". Retrieved 2020-07-02. "Mammalian meat and milk (cow and goat) contain alpha-gal." 17. ^ a b "Viracor-IBT Laboratories Launches the First Assay to Identify a New Type of Delayed, IgE-based Allergic Reaction to Certain Meats" (Press release). Viracor-IBT Laboratories. September 13, 2010. Retrieved October 17, 2016. 18. ^ a b c d e f g h Zaraska M (December 3, 2013). "Want hives with that burger?". The Washington Post. pp. HEALTH, E01. 19. ^ Cabezas-Cruz, Alejandro; Hodžić, Adnan; Román-Carrasco, Patricia; Mateos-Hernández, Lourdes; Duscher, Georg Gerhard; Sinha, Deepak Kumar; Hemmer, Wolfgang; Swoboda, Ines; Estrada-Peña, Agustín; de la Fuente, José (2019-05-31). "Environmental and Molecular Drivers of the α-Gal Syndrome". Frontiers in Immunology. 10: 1210. doi:10.3389/fimmu.2019.01210. ISSN 1664-3224. PMC 6554561. PMID 31214181. 20. ^ Facey-Thomas H (2018-01-08). "Alpha-Gal". Allergy Foundation South Africa. 21. ^ Mabelane (2018). "Predictive values of alpha-gal IgE levels and alpha-gal IgE:total IgE ratio and oral food challenge proven meat allergy in a population with a high prevalence of reported red meat allergy". Pediatric Allergy Immunology. 29 (8): 841–849. doi:10.1111/pai.12969. PMID 30144162. 22. ^ a b c Kroen GC (November 16, 2012), Ticked Off About a Growing Allergy to Meat, ScienceNOW, retrieved March 24, 2014 23. ^ Travis J (November 1995). "The xeno-solution: perils and promise of transplanting animal organs into people". Science News. 148 (19): 298–301. doi:10.2307/4018063. JSTOR 4018063. PMID 11653203. 24. ^ Crispell, Gary; Commins, Scott P.; Archer-Hartman, Stephanie A.; Choudhary, Shailesh; Dharmarajan, Guha; Azadi, Parastoo; Karim, Shahid (17 May 2019). "Discovery of Alpha-Gal-Containing Antigens in North American Tick Species Believed to Induce Red Meat Allergy". Frontiers in Immunology. 10: 1056. doi:10.3389/fimmu.2019.01056. PMC 6533943. PMID 31156631. 25. ^ "Hundreds on East End get meat allergy from Lone Star tick's bite". Newsday. Jul 30, 2017. Retrieved 2017-08-01. 26. ^ Krishna N, Krishna S, Krishna R (November 2017). "P112 Correlation between clinical findings and laboratory tests for alpha gal sensitivity". Annals of Allergy, Asthma & Immunology. 119 (5): S37. doi:10.1016/j.anai.2017.08.136. 27. ^ a b Bircher AJ, Hofmeier KS, Link S, Heijnen I (February 2017). "Food allergy to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal): four case reports and a review". European Journal of Dermatology. 27 (1): 3–9. doi:10.1684/ejd.2016.2908. PMID 27873733. 28. ^ a b c Goetz G (June 26, 2012). "Red Meat Allergy Likely Cause by Tick Bites". Food Safety News. 29. ^ Unal D, Coskun R, Demir S, Gelincik A, Colakoglu B, Buyukozturk S (2017). "Successful beef desensitization in 2 adult patients with a delayed-type reaction to red meat". The Journal of Allergy and Clinical Immunology. In Practice. 5 (2): 502–503. doi:10.1016/j.jaip.2016.12.008. PMID 28132797. 30. ^ "NIAID Scientists Link Cases of Unexplained Anaphylaxis to Red Meat Allergy". National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. U.S. Department of Health and Human Services. 28 November 2017. 31. ^ Velasquez-Manoff, Moises (2018-07-24). "What the Mystery of the Tick-Borne Meat Allergy Could Reveal". The New York Times. ISSN 0362-4331. Retrieved 2019-03-08. 32. ^ McKenna, Maryn (2018-12-11). "What is behind the spread of a mysterious allergy to meat?". The Guardian. ISSN 0261-3077. Retrieved 2019-03-08. 33. ^ "Mammalian meat allergy: People on the northern beaches becoming allergic to red meat after tick bites". www.news.com.au. 2016-06-13. Retrieved 2019-03-08. 34. ^ Commins SP, Platts-Mills TA (October 2009). "Anaphylaxis syndromes related to a new mammalian cross-reactive carbohydrate determinant". The Journal of Allergy and Clinical Immunology. 124 (4): 652–7. doi:10.1016/j.jaci.2009.08.026. PMC 2774206. PMID 19815111. 35. ^ Berg EA, Platts-Mills TA, Commins SP (February 2014). "Drug allergens and food--the cetuximab and galactose-α-1,3-galactose story". Annals of Allergy, Asthma & Immunology. 112 (2): 97–101. doi:10.1016/j.anai.2013.11.014. PMC 3964477. PMID 24468247. 36. ^ McMahon, Alle (2019-01-18). "How tick bites can make some people allergic to meat and milk". ABC News. Retrieved 2019-03-08. 37. ^ "Mammalian meat allergy: a tick-ing time bomb?". Australian Veterinary Association. Archived from the original on 2019-03-27. Retrieved 2019-03-08. 38. ^ "MJA Podcasts 2018 Episode 27: Tick-induced allergies, with A/Prof Sheryl van Nunen". www.mja.com.au. Retrieved 2019-03-08. 39. ^ Zaraska M (December 3, 2013). "Cat owners can also develop meat allergy". The Washington Post. pp. HEALTH, E05. Archived from the original on June 25, 2018. ## Further reading[edit] * McKenna M (December 11, 2018). "What is behind the spread of a mysterious allergy to meat?". The Guardian. Retrieved December 11, 2018. * v * t * e Tick-borne diseases and infestations Diseases Bacterial infections Rickettsiales * Anaplasmosis * Boutonneuse fever * Ehrlichiosis (Human granulocytic, Human monocytotropic, Human E. ewingii infection) * Scrub typhus * Spotted fever rickettsiosis * Pacific Coast tick fever * American tick bite fever * rickettsialpox * Rocky Mountain spotted fever) Spirochaete * Baggio–Yoshinari syndrome * Lyme disease * Relapsing fever borreliosis Thiotrichales * Tularemia Viral infections * Bhanja virus * Bourbon virus * Colorado tick fever * Crimean–Congo hemorrhagic fever * Heartland bandavirus * Kemerovo tickborne viral fever * Kyasanur Forest disease * Omsk hemorrhagic fever * Powassan encephalitis * Severe fever with thrombocytopenia syndrome * Tete orthobunyavirus * Tick-borne encephalitis Protozoan infections * Babesiosis Other diseases * Tick paralysis * Alpha-gal allergy * Southern tick-associated rash illness Infestations * Tick infestation Species and bites Amblyomma * Amblyomma americanum * Amblyomma cajennense * Amblyomma triguttatum Dermacentor * Dermacentor andersoni * Dermacentor variabilis Ixodes * Ixodes cornuatus * Ixodes holocyclus * Ixodes pacificus * Ixodes ricinus * Ixodes scapularis Ornithodoros * Ornithodoros gurneyi * Ornithodoros hermsi * Ornithodoros moubata Other * Rhipicephalus sanguineus [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Alpha-gal allergy	None	1,906	wikipedia	https://en.wikipedia.org/wiki/Alpha-gal_allergy	2021-01-18T18:50:34	{"wikidata": ["Q16242785"]}
PUNLMP (Papillary Urothelial Neoplasm of Low Malignant Potential) Micrograph of a PUNLMP. Intermediate magnification. H&E stain. SpecialtyUrology, pathology Papillary urothelial neoplasm of low malignant potential (PUNLMP) is an exophytic (outward growing), (microscopically) nipple-shaped (or papillary) pre-malignant growth of the lining of the upper genitourinary tract (the urothelium), which includes the renal pelvis, ureters, urinary bladder and part of the urethra. PUNLMP is pronounced pun-lump, like the words pun and lump. As their name suggests, PUNLMPs are neoplasms, i.e. clonal cellular proliferations, that are thought to have a low probability of developing into urothelial cancer, i.e. a malignancy such as bladder cancer. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 2.1 Differential diagnosis * 3 Treatment * 4 References ## Signs and symptoms[edit] PUNLMPs can lead to blood in the urine (hematuria) or may be asymptomatic. ## Diagnosis[edit] Micrograph of a PUNLMP showing characteristic features (see text). H&E stain. PUNLMPs are exophytic lesions that appear friable to the naked eye and when imaged during cystoscopy. They are definitively diagnosed after removal by microscopic examination by pathologists. Histologically, they have a papillary architecture with slender fibrovascular cores and rare basal mitoses. The papillae rarely fuse and uncommonly branch. Cytologically, they have uniform nuclear enlargement. They cannot be reliably differentiated from low grade papillary urothelial carcinomas using cytology,[1] and their diagnosis (vis-a-vis low grade papillary urothelial carcinoma) has a poor inter-rater reliability.[2] Pathologic grading and staging tumors are: graded by the degree of cellular atypia (G1->G3), and staged: * papilloma * papillary tumor of low malignant potential (PTLMP) * papillary urothelial carcinomas low grade * papillary urothelial carcinomas high grade. ### Differential diagnosis[edit] * Papilloma. * Low grade papillary urothelial carcinoma. ## Treatment[edit] PUNLMPs are treated like non-invasive low grade papillary urothelial carcinomas,[1] excision and regular follow-up cystoscopies. There is a rare occurrence of a pelvic recurrence of a low-grade superficial TCC after cystectomy. Delayed presentation with recurrent low-grade urothelial carcinoma is an unusual entity and potential mechanism of traumatic implantation should be considered. Characteristically low-grade tumors are resistant to systemic chemotherapy and curative-intent surgical resection of the tumor should be considered. ## References[edit] 1. ^ a b Jones TD, Cheng L (June 2006). "Papillary urothelial neoplasm of low malignant potential: evolving terminology and concepts". J. Urol. 175 (6): 1995–2003. doi:10.1016/S0022-5347(06)00267-9. PMID 16697785. 2. ^ MacLennan GT, Kirkali Z, Cheng L (April 2007). "Histologic grading of noninvasive papillary urothelial neoplasms". Eur. Urol. 51 (4): 889–97, discussion 897–8. doi:10.1016/j.eururo.2006.10.037. PMID 17095142. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Papillary urothelial neoplasm of low malignant potential	c1266010	1,907	wikipedia	https://en.wikipedia.org/wiki/Papillary_urothelial_neoplasm_of_low_malignant_potential	2021-01-18T19:01:56	{"umls": ["C1266010", "C1518358"], "wikidata": ["Q7132990"]}
This article is about the condition currently classified as CHED. For the condition previously classified as CHED1, see posterior polymorphous corneal dystrophy. Congenital hereditary endothelial dystrophy Other namesMaumenee corneal dystrophy[1] A markedly opaque cornea due to corneal edema secondary to defective endothelial cells (Courtesy of Dr. Ahmed A. Hidajat) SpecialtyOphthalmology Congenital hereditary corneal dystrophy (CHED) is a form of corneal endothelial dystrophy that presents at birth. CHED was previously subclassified into two subtypes: CHED1 and CHED2. However in 2015, the International Classification of Corneal Dystrophies (IC3D) renamed the condition "CHED1" to become posterior polymorphous corneal dystrophy, and renamed the condition "CHED2" to become, simply, CHED.[2] Consequently, the scope of this article is restricted to the condition currently referred to as CHED ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Pathology * 4 Management * 5 See also * 6 References ## Signs and symptoms[edit] CHED presents congenitally, but has a stationary course. The cornea exhibits a variable degree of clouding: from a diffuse haze, to a "ground glass" appearance, with occasional focal gray spots. The cornea thickens to between two and three times is normal thickness. Rarely, sub-epithelial band keratopathy and elevated intraocular pressure occur. Patients have blurred vision and nystagmus, however it is rare for the condition to be associated with either epiphora or photophobia with this.[1] ## Genetics[edit] CHED exhibits autosomal recessive inheritance, with 80% of cases linked to mutations in SLC4A11 gene. The SLC4A11 gene encodes solute carrier family 4, sodium borate transporter, member 11.[1] ## Pathology[edit] Histologically, the Descemet's membrane in CHED becomes diffusely thickened and laminated. Multiple layers of basement membrane-like material appear to form on the posterior part of Descemet's membrane. The endothelial cells are sparse - they become atrophic and degenerated, with many vacuoles. The corneal stroma becomes severely disorganised; the lamellar arrangement of the fibrils becomes disrupted. ## Management[edit] Management of CHED primarily involves corneal transplantation. The age that corneal transplantation is required is variable, however, it is usually necessary fairly early in life.[1] ## See also[edit] * Posterior polymorphous corneal dystrophy (for the condition previously referred to as CHED1) * Corneal dystrophy ## References[edit] 1. ^ a b c d Bowes Hamill, M. (2015). 2015-2016 Basic and Clinical Science Course (BCSC): Refractive Surgery Section 13. ISBN 978-1615256570. 2. ^ Weiss, Jayne S.; Møller, Hans Ulrik; Aldave, Anthony J.; Seitz, Berthold; Bredrup, Cecilie; Kivelä, Tero; Munier, Francis L.; Rapuano, Christopher J.; Nischal, Kanwal K.; Kim, Eung Kweon; Sutphin, John; Busin, Massimo; Labbé, Antoine; Kenyon, Kenneth R.; Kinoshita, Shigeru; Lisch, Walter (February 21, 2015). "IC3D classification of corneal dystrophies--edition 2". Cornea. 34 (2): 117–159. doi:10.1097/ICO.0000000000000307. hdl:11392/2380137. PMID 25564336. 3. ^ Vithana EN; et al. (July 2006). "Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2)". Nat. Genet. 38 (7): 755–7. doi:10.1038/ng1824. PMID 16767101. 4. ^ Online Mendelian Inheritance in Man (OMIM): 217700 5. ^ Online Mendelian Inheritance in Man (OMIM): 121700 * v * t * e Types of corneal dystrophy Epithelial and subepithelial * Epithelial basement membrane dystrophy * Gelatinous drop-like corneal dystrophy * Lisch epithelial corneal dystrophy * Meesmann corneal dystrophy * Subepithelial mucinous corneal dystrophy Bowman's membrane * Reis–Bucklers corneal dystrophy * Thiel-Behnke dystrophy Stroma * Congenital stromal corneal dystrophy * Fleck corneal dystrophy * Granular corneal dystrophy * Lattice corneal dystrophy * Macular corneal dystrophy * Posterior amorphous corneal dystrophy * Schnyder crystalline corneal dystrophy Descemet's membrane and endothelial * Congenital hereditary endothelial dystrophy * Fuchs' dystrophy * Posterior polymorphous corneal dystrophy * X-linked endothelial corneal dystrophy Classification D * OMIM: 217700 * MeSH: C536439 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Congenital hereditary endothelial dystrophy	c1857569	1,908	wikipedia	https://en.wikipedia.org/wiki/Congenital_hereditary_endothelial_dystrophy	2021-01-18T18:37:06	{"gard": ["6196"], "mesh": ["C536439"], "umls": ["C1857569"], "orphanet": ["293603"], "wikidata": ["Q4127191"]}
A malformation syndrome that is characterized by facial dysmorphism, severe hypoplasia of the nasal bones and frontal sinuses, ocular involvement, early-onset hearing loss, skeletal and anhidrotic ectodermal anomalies and short stature with spondyloepiphyseal dysplasia and early-onset osteoarthritis. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Marshall syndrome	c0265235	1,909	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=560	2021-01-23T18:07:50	{"gard": ["6984"], "mesh": ["C536025"], "omim": ["154780"], "umls": ["C0265235"], "icd-10": ["Q87.0"]}
A number sign (#) is used with this entry because of evidence that combined pituitary hormone deficiency-3 (CPHD3) is caused by homozygous mutation in the LHX3 gene (601538) on chromosome 9q34. For a discussion of phenotypic and genetic heterogeneity of combined pituitary hormone deficiency, see CPHD1 (613038). Clinical Features Winkelmann et al. (1972) described 2 sisters with inner ear deafness and asexual ateleiotic dwarfism. Deficiency of growth hormone and gonadotropin was demonstrated by radioimmunoassay. The parents were not known to be related. Netchine et al. (2000) reported 2 unrelated consanguineous families with CPHD in which affected members exhibited severe growth retardation and deficiency of all but 1 of the anterior pituitary hormones, including growth hormone (GH; 139250), thyrotropin (TSH; see 188540), prolactin (PRL; 176760), luteinizing hormone (LH; see 152780), and follicle-stimulating hormone (FSH; see 136530); levels of adrenocorticotrophic hormone (ACTH; see 176830) were normal. Affected individuals also had elevated and anteverted shoulders leading to the clinical appearance of a stubby neck associated with a severe restriction of rotation of the cervical spine, preventing dissociation of head and trunk movements. Cervical x-rays did not reveal any vertebral malformation, and magnetic resonance imaging (MRI) showed the abnormal steepness of the cervical spine but normal soft tissue structures, without evidence of muscle fibrosis or atrophy. Electromyelograms in 2 patients did not reveal any signs of denervation or myopathic changes. In both families, all other members tested had normal neck rotation. Two affected individuals from 1 family had severe anterior pituitary hypoplasia by MRI, whereas the affected individual from the other family had an enlarged anterior pituitary by MRI at age 19 years that was not documented on a computer-assisted tomography (CT) scan performed 10 years earlier. Bhangoo et al. (2006) studied a 6.75-year-old boy, born of consanguineous parents, who had CPHD associated with rigid cervical spine causing limited head rotation. The child had presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T4, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency, were consistent with hypopituitarism. MRI revealed an apparently structurally normal cervical spine and a post-contrast hypointense lesion in the anterior pituitary consistent with microadenoma; pituitary volume was calculated to be 570.15 cubic millimeters, more than twice the normal mean. On school assessment, the boy was diagnosed with mental retardation resulting in severe speech delay. Neurologic exam revealed mild hypotonia and immature prehensile skills. EMG findings were suggestive of an anterior horn cell disease process; nerve conduction studies were normal. The clinically unaffected parents had normal anterior pituitary hormone panels. Rajab et al. (2008) described 3 sibs from a consanguineous Middle Eastern family who exhibited an unusual phenotype of panhypopituitarism with severe anterior pituitary hypoplasia, skeletal abnormalities including short neck with limited neck rotation and lumbar kyphosis and/or lordosis, hyperextensible joints and hyperelastic skin, deep palmar and plantar creases, hypoplastic nails, and dental caries. The 3 sibs also had mild (30 dB) sensorineural hearing loss bilaterally. Rajab et al. (2008) subsequently ascertained an unrelated boy, born of consanguineous parents, with a very similar phenotype: he had CPHD diagnosed in infancy with anterior pituitary hypoplasia on MRI, and later developed the appearance of skeletal dysplasia with a short neck, stiff back, and thoracic kyphosis; audiologic assessment revealed profound (96 dB) sensorineural hearing loss bilaterally. A presumptive diagnosis of ACTH deficiency was made in the first family based on clinical phenotype as well as low random cortisol concentrations; ACTH stimulation performed in the proband of the second family unequivocally established a diagnosis of ACTH deficiency. Rajab et al. (2008) reevaluated 3 affected individuals from the families previously described by Netchine et al. (2000), and found moderate (60 dB) and mild (30 dB) sensorineural hearing loss in 2 patients from 1 family; the single patient from the second family, who was extremely mentally retarded, was diagnosed to be completely deaf on the basis of the absence of any acoustic evoked potential (AEP). Mapping Rajab et al. (2008) performed homozygosity mapping in members of a family with CPHD, cervical rigidity, and sensorineural deafness, and identified 3 significant regions of shared homozygosity in the 3 affected individuals. Two of the regions contained no candidate genes of interest, but the locus on 9q34-qter encompassed the transcription factor LHX3, in which mutations had previously been associated with CPHD. Molecular Genetics Using a candidate-gene approach based on mouse studies involving the LHX3 gene (see 600577 and Sheng et al., 1996), Netchine et al. (2000) screened LHX3 in affected members of 2 unrelated consanguineous families with CPHD involving all of the anterior pituitary hormones except ACTH, who also displayed rigidity of the cervical spine and in whom mutation in the PROP1 gene (601538) had been excluded: homozygosity for a nonsense mutation (600577.0001) and an intragenic deletion (600577.0002) in the LHX3 gene were identified in the 2 families, respectively. The data were considered consistent with the known involvement of LHX3 in the development of all anterior pituitary cell types except corticotropes, and of extrapituitary structures as well. In a 6.75-year-old boy with CPHD and rigid cervical spine, Bhangoo et al. (2006) identified homozygosity for a 1-bp deletion mutation in the LHX3 gene (600577.0003). Pfaeffle et al. (2007) analyzed the LHX3 gene in 366 patients from 342 families with pituitary insufficiency and identified mutations in 7 affected individuals (1.9%) from 4 CPHD families (600577.0004-600577.0007, respectively). None of the 48 patients with isolated GH deficiency had an LHX3 mutation. The authors concluded that LHX3 mutations are a rare cause of CPHD and involve deficiencies of GH, PRL, TSH, and LH/FSH in all cases. Whereas most patients have a severe hormone deficiency manifesting after birth, milder forms can be observed. Pfaeffle et al. (2007) noted that limited neck rotation is not a universal feature in these patients, since it was not present in 3 sibs with CPHD who had a nonsense mutation in LHX3 (600577.0007). Rajab et al. (2008) sequenced the LHX3 gene in 4 patients from 2 unrelated consanguineous families, who presented with early-onset hypopituitarism with neonatal hypoglycemia, short neck with limited rotation, and mild sensorineural hearing loss, and identified homozygosity for a large intragenic deletion (600577.0008) and a nonsense mutation (600577.0009), respectively. Noting that sensorineural hearing loss was found upon reexamination of 3 of the mutation-positive patients studied by Netchine et al. (2000) and that ACTH deficiency was unequivocally confirmed in 1 of their own patients, Rajab et al. (2008) stated that the phenotypic spectrum associated with LHX3 mutations should be extended to encompass these features. Regarding the skin laxity and skeletal abnormalities seen in the 3 affected members of their family with the large deletion, Rajab et al. (2008) suggested that a second recessive mutation might be segregating in that family. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature (if untreated) HEAD & NECK Ears \- Deafness, sensorineural, variable Neck \- Short neck with limited rotation NEUROLOGIC Central Nervous System \- Mental retardation (if untreated) ENDOCRINE FEATURES \- Anterior pituitary hypoplasia \- Anterior pituitary enlargement LABORATORY ABNORMALITIES \- Low or absent growth hormone (GH) \- Low or absent thyroid-stimulating hormone (TSH) \- Low or absent follicle-stimulating hormone (FSH) \- Low or absent luteinizing hormone (LH) \- Low or absent prolactin (PL) \- Low or absent adrenocorticotropic hormone (ACTH) in some patients MOLECULAR BASIS \- Caused by mutations in the LIM/homeodomain protein LHX3 gene (LHX3, 600577.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	PITUITARY HORMONE DEFICIENCY, COMBINED, 3	c3489787	1,910	omim	https://www.omim.org/entry/221750	2019-09-22T16:28:52	{"doid": ["9406"], "mesh": ["C536710"], "omim": ["221750"], "orphanet": ["231720"], "synonyms": ["DEAFNESS, SENSORINEURAL, WITH PITUITARY DWARFISM", "Alternative titles", "PITUITARY HORMONE DEFICIENCY, COMBINED, WITH RIGID CERVICAL SPINE", "Non-acquired combined pituitary hormone deficiency-deafness-rigid cervical spine syndrome"]}
Barakat syndrome, also known as HDR syndrome, is a rare, genetic syndrome characterized by hypoparathyroidism, sensorineural deafness, and renal (kidney) disease. However, specific symptoms and severity can vary. About 65% of people with Barakat syndrome have all three of these features, while the others have various combinations of these features. Some people with Barakat syndrome have one or more of these as well as additional features. Hypoparathyroidism leads to low levels of calcium in the blood (hypocalcemia), which can cause symptoms such as muscle pain, muscle spasms, seizures, and rarely, cardiomyopathy. Hearing loss is the most consistent feature of Barakat syndrome. It is usually bilateral and can range from moderate to profound. The type of kidney disease present can vary from person to person. For example, some people with Barakat syndrome are born with structural kidney or urinary tract abnormalities (underdeveloped or abnormally-formed), while others may have functional abnormalities (such as nephrotic syndrome, hematuria, renal tubular acidosis, or chronic kidney disease). Various additional features have been reported in some people with Barakat syndrome such as polycystic ovaries, distinctive facial features, ischemic stroke, retinitis pigmentosa, intellectual disability, growth failure, congenital heart disease, and other birth defects. Most cases of Barakat syndrome are caused by mutations in the GATA3 gene, or by a missing piece (deletion) of genetic material on chromosome 10 that includes the GATA3 gene. Inheritance is autosomal dominant. In some cases, the genetic cause is unknown. Barakat syndrome can be clinically diagnosed (without genetic testing) in a person with the complete triad of hypoparathyroidism, sensorineural deafness, and renal disease; or, in a person with two of these features who also has a positive family history. For those who have only deafness or renal disease, and for others who do not fit this criteria, genetic testing that identifies a GATA3 mutation is needed to confirm the diagnosis. Treatment for Barakat syndrome depends on the symptoms present and the severity in each person. Hypocalcemia may be treated with oral calcium and calcitriol, intravenous calcium gluconate, or parathyroid hormone injection. Hearing loss may be treated with hearing amplification and/or cochlear implantation. Treatment of kidney disease depends on the abnormality present. Some minor abnormalities may not need to be treated while others may require medications, surgery, or kidney transplantation. The long-term outlook (prognosis) usually depends on the severity of kidney disease, and those with minor kidney problems have a normal life expectancy. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Barakat syndrome	c1840333	1,911	gard	https://rarediseases.info.nih.gov/diseases/2911/barakat-syndrome	2021-01-18T18:01:53	{"mesh": ["C537907"], "omim": ["146255"], "umls": ["C1840333"], "orphanet": ["2237"], "synonyms": ["Hypoparathyroidism, sensorineural deafness, and renal dysplasia", "HDR syndrome", "Nephrosis, nerve deafness, and hypoparathyroidism"]}
Anomalous left coronary artery from the pulmonary artery Other namesBland-White-Garland syndrome Possible communication between left coronary artery and pulmonary artery in a 45-year-old woman with Bland-White-Garland syndrome. SpecialtyMedical genetics Anomalous left coronary artery from the pulmonary artery (ALCAPA or Bland-White-Garland syndrome or White-Garland syndrome) is a rare congenital anomaly in which the left coronary artery (LCA) branches off the pulmonary artery instead of the aortic sinus.[1] After birth, the pressure in other coronary arteries (namely the RCA) will have a pressure that exceeds the LCA and collateral circulation will increase. This, ultimately, can lead to blood flowing from the RCA into the LCA (retrograde) and into the pulmonary artery, thus forming a left-to-right shunt. [2] The syndrome is named for Edward Franklin Bland, Paul Dudley White, and Joseph Garland. ## References[edit] 1. ^ "Anomalous left coronary artery from the pulmonary artery". A.D.A.M. Medical Encyclopedia. Retrieved June 9, 2012. 2. ^ Crawford, Michael; DiMarco, John; Paulus, Walter (September 24, 2009). Cardiology (3rd ed.). Mosby. p. 229. ISBN 978-0723434856. ## External links[edit] Classification D * MeSH: D063748 External resources * MedlinePlus: 007323 This article about a congenital malformation is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Anomalous left coronary artery from the pulmonary artery	c1735886	1,912	wikipedia	https://en.wikipedia.org/wiki/Anomalous_left_coronary_artery_from_the_pulmonary_artery	2021-01-18T19:00:30	{"mesh": ["D063748"], "icd-10": ["Q24.5"], "wikidata": ["Q881480"]}
Break in a rib bone Rib fracture Other namesBroken rib, cracked rib An X ray showing multiple old fractured ribs of the person's left side as marked by the oval. SpecialtyEmergency medicine SymptomsChest pain that is worse with breathing in[1] ComplicationsPulmonary contusion, pneumothorax, pneumonia[1][2] CausesChest trauma[2] Diagnostic methodBased on symptoms, medical imaging[3] MedicationParacetamol (acetaminophen), NSAIDs, opioids[2] PrognosisPain improves over 6 weeks[3] FrequencyCommon[2] A rib fracture is a break in a rib bone.[1] This typically results in chest pain that is worse with breathing in.[1] Bruising may occur at the site of the break.[3] When several ribs are broken in several places a flail chest results.[4] Potential complications include a pneumothorax, pulmonary contusion, and pneumonia.[2][1] Rib fractures usually occur from a direct blow to the chest such as during a motor vehicle collision or from a crush injury.[2][1] Coughing or metastatic cancer may also result in a broken rib.[1] The middle ribs are most commonly fractured.[5][1] Fractures of the first or second ribs are more likely to be associated with complications.[6] Diagnosis can be made based on symptoms and supported by medical imaging.[3] Pain control is an important part of treatment.[7] This may include the use of paracetamol (acetaminophen), NSAIDs, or opioids.[2] A nerve block may be another option.[1] While fractured ribs have been wrapped, this may increase complications.[1] In those with a flail chest, surgery may improve outcomes.[8][9] They are a common injury following trauma.[10] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Causes * 3 Diagnosis * 4 Treatment * 4.1 Nerve blocks * 4.2 Surgery * 5 See also * 6 References * 7 External links ## Signs and symptoms[edit] This typically results in chest pain that is worse with breathing in.[1] Bruising may occur at the site of the break.[3] ### Complications[edit] When several ribs are broken in several places a flail chest results.[4] Potential complications include a pneumothorax, pulmonary contusion, and pneumonia.[2][1] ## Causes[edit] Rib fractures can occur with or without direct trauma during recreational activity. Cardiopulmonary resuscitation (CPR) has also been known to cause thoracic injury, including but not limited to rib and sternum fractures. They can also occur as a consequence of diseases such as cancer or rheumatoid arthritis. While for elderly individuals a fall can cause a rib fracture, in adults automobile accidents are a common event for such an injury.[11] ## Diagnosis[edit] Signs of a broken rib may include:[12] * Pain on inhalation * Swelling in chest area * Bruise in chest area * Increasing shortness of breath * Coughing up blood (rib may have damaged lung) Plain X-rays often pick up displaced fractures but often miss undisplaced fractures.[13] CT scanning is generally able to pick up both types of fractures.[13] Because children have more flexible chest walls than adults do, their ribs are more likely to bend than to break; therefore the presence of rib fractures in children is evidence of a significant amount of force and may indicate severe thoracic injuries such as pulmonary contusion.[4] Rib fractures are also a sign of more serious injury in elderly people.[14] * Illustration showing rib fracture at 3rd, 4th and 5th rib. * Right sided pneumothorax and rib fractures * Two broken ribs as seen on parasagittal CT ## Treatment[edit] There is no specific treatment for rib fractures, but various supportive measures can be taken. In simple rib fractures, pain can lead to reduced movement and cough suppression; this can contribute to formation of secondary chest infection.[15] Flail chest is a potentially life-threatening injury and will often require a period of assisted ventilation.[16] Flail chest and first rib fractures are high-energy injuries and should prompt investigation of damage to underlying viscera (e.g., lung contusion) or remotely (e.g., cervical spine injury). Spontaneous fractures in athletes generally require a cessation of the cause, e.g., time off rowing, while maintaining cardiovascular fitness.[medical citation needed] ### Nerve blocks[edit] Nerve blocks that may be used to help with pain related to rib fractures include epidural anesthesia, paravertebral block, erector spinae plane block and serratus anterior plane block.[17][18][19] There is very little evidence to support the use of one nerve block over another on the basis of analgesia or safety[20] ### Surgery[edit] Treatment options for internal fixation/repair of rib fractures include: * Judet and/or sanchez plates/struts are a metal plate with strips that bend around the rib and then is further secured with sutures.[21] * There are different specialist rib fixation systems on the market. They have two options: a precontoured metal plate that uses screws to secure the plate to the rib; and/or an intramedullary splint which is tunneled into the rib and secured with a set screw.[22] * Anterior locking plates are metal plates that have holes for screws throughout the plate. The plate is positioned over the rib and screwed into the bone at the desired position. The plates may be bent to match the contour of the section.[23] * U-plates can also be used as they clamp on to the superior aspect of the ribs using locking screws.[24] ## See also[edit] * Pulmonary hygiene ## References[edit] 1. ^ a b c d e f g h i j k l Mosby's Medical Dictionary (E-Book). Elsevier Health Sciences. 2013. p. 1567. ISBN 978-0323112581. Archived from the original on 2017-10-13. 2. ^ a b c d e f g h May, L; Hillermann, C; Patil, S (January 2016). "Rib fracture management". BJA Education. 16 (1): 26–32. doi:10.1093/bjaceaccp/mkv011. 3. ^ a b c d e Adams, James G. (2012). Emergency Medicine E-Book: Clinical Essentials (Expert Consult – Online). Elsevier Health Sciences. p. 682. ISBN 978-1455733941. Archived from the original on 2017-10-13. 4. ^ a b c Wanek, Sandra; Mayberry, John C (2004). "Blunt thoracic trauma: flail chest, pulmonary contusion, and blast injury". Critical Care Clinics. 20 (1): 71–81. doi:10.1016/S0749-0704(03)00098-8. PMID 14979330. 5. ^ Nanni, Christina (2012). PET-CT: Rare Findings and Diseases. Springer. p. 257. ISBN 978-3-642-24698-2. 6. ^ Murphy CE, 4th; Raja, AS; Baumann, BM; Medak, AJ; Langdorf, MI; Nishijima, DK; Hendey, GW; Mower, WR; Rodriguez, RM (27 May 2017). "Rib Fracture Diagnosis in the Panscan Era" (PDF). Annals of Emergency Medicine. 70 (6): 904–909. doi:10.1016/j.annemergmed.2017.04.011. PMID 28559032. S2CID 23442272. 7. ^ Brown, SD; Walters, MR (2012). "Patients with rib fractures: use of incentive spirometry volumes to guide care". Journal of Trauma Nursing. 19 (2): 89–91, quiz 92–03. doi:10.1097/JTN.0b013e31825629ee. PMID 22673074. S2CID 45547470. 8. ^ Schuurmans, J; Goslings, JC; Schepers, T (April 2017). "Operative management versus non-operative management of rib fractures in flail chest injuries: a systematic review". European Journal of Trauma and Emergency Surgery. 43 (2): 163–68. doi:10.1007/s00068-016-0721-2. PMC 5378742. PMID 27572897. 9. ^ Coughlin, TA; Ng, JW; Rollins, KE; Forward, DP; Ollivere, BJ (August 2016). "Management of rib fractures in traumatic flail chest: a meta-analysis of randomised controlled trials". The Bone & Joint Journal. 98-B (8): 1119–25. doi:10.1302/0301-620X.98B8.37282. PMID 27482027. 10. ^ Senekjian, L; Nirula, R (January 2017). "Rib Fracture Fixation: Indications and Outcomes". Critical Care Clinics. 33 (1): 153–65. doi:10.1016/j.ccc.2016.08.009. PMID 27894495. 11. ^ Rib Fracture at eMedicine 12. ^ "Broken or bruised ribs". NHS.UK. 2015. Archived from the original on 20 August 2015. Retrieved 15 August 2015. 13. ^ a b Dennis, BM; Bellister, SA; Guillamondegui, OD (October 2017). "Thoracic Trauma". The Surgical Clinics of North America. 97 (5): 1047–1064. doi:10.1016/j.suc.2017.06.009. PMID 28958357. 14. ^ Kent, Richard; Woods, William; Bostrom, Ola (2008-01-01). "Fatality Risk and the Presence of Rib Fractures". Annals of Advances in Automotive Medicine / Annual Scientific Conference. 52: 73–84. ISSN 1943-2461. PMC 3256783. PMID 19026224. 15. ^ Morice, A H; McGarvey, L; Pavord, I (2006). "Recommendations for the management of cough in adults". Thorax. 61 (Suppl 1): i1–24. doi:10.1136/thx.2006.065144. PMC 2080754. PMID 16936230. 16. ^ Paul, Pauline; Williams, Beverly (2009-01-01). Brunner & Suddarth's Textbook of Canadian Medical-surgical Nursing. Lippincott Williams & Wil. p. 637. ISBN 9780781799898. Archived from the original on 2016-06-29. 17. ^ Wardhan, R (October 2013). "Assessment and management of rib fracture pain in geriatric population: an ode to old age". Current Opinion in Anesthesiology. 26 (5): 626–31. doi:10.1097/01.aco.0000432516.93715.a7. PMID 23995061. S2CID 35082310. 18. ^ Grant, Stuart A.; Auyong, David B. (2016). Ultrasound Guided Regional Anesthesia. Oxford University Press. p. PT388. ISBN 9780190630478. 19. ^ Riley, B.; Malla, U.; Snels, N.; Mitchell, A.; Abi-Fares, C.; Basson, W.; Anstey, C.; White, L. (2020). "Erector spinae and serratus anterior blocks for the management of rib fractures: A retrospective exploratory matched study". The American Journal of Emergency Medicine. 38 (8): 1689–1691. doi:10.1016/j.ajem.2020.01.007. PMID 31932127. 20. ^ White, L.; Riley, B.; Malla, U.; Snels, N.; Mitchell, A.; Abi-Fares, C.; Basson, W.; Anstey, C. (2020-08-15). "ESB vs SAB in chest wall trauma, which is better?: A response and decision making guide". The American Journal of Emergency Medicine. 0 (10): 2221–2223. doi:10.1016/j.ajem.2020.08.004. ISSN 0735-6757. PMID 32843243. 21. ^ Fitzpatrick, D. C.; Denard, P. J.; Phelan, D.; Long, W. B.; Madey, S. M.; Bottlang, M. (2010). "Operative stabilization of flail chest injuries: review of literature and fixation options". European Journal of Trauma and Emergency Surgery. 36 (5): 427–33. doi:10.1007/s00068-010-0027-8. PMC 3150812. PMID 21841954. 22. ^ Mathison, Douglas (2014). Master Techniques in Surgery: Thoracic Surgery: Transplantation, Tracheal Resections, Mediastinal Tumors, Extended Thoracic Resections. Walters-Kluwer Health. ISBN 978-1-46988-903-0. Archived from the original on 12 May 2016. Retrieved 15 August 2015.Rib fracture at Google Books 23. ^ Browner, Bruce D. (2009-01-01). Skeletal Trauma: Basic Science, Management, and Reconstruction. Elsevier Health Scien. p. 1418. ISBN 978-1416022206. Archived from the original on 2016-05-08. 24. ^ de Jong, M. B.; Kokke, M. C.; Hietbrink, F.; Leenen, L. P. H. (2014). "Surgical Management of Rib Fractures: Strategies and Literature Review". Scandinavian Journal of Surgery. 103 (2): 120–25. doi:10.1177/1457496914531928. PMID 24782038. S2CID 11113635. ## External links[edit] Classification D * ICD-10: S22.3-S22.4 * ICD-9-CM: 807.0, 807.1 * MeSH: D012253 * DiseasesDB: 11553 External resources * eMedicine: emerg/204 radio/609 Scholia has a topic profile for Rib fracture. * 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 * v * t * e Chest injury, excluding fractures Cardiac and circulatory system injuries * vascular: Traumatic aortic rupture * Thoracic aorta injury * heart: Myocardial contusion/Commotio cordis * Cardiac tamponade * Hemopericardium * Myocardial rupture Lung and lower respiratory tract injuries * Pneumothorax * Hemothorax * Hemopneumothorax * Pulmonary contusion * Pulmonary laceration * Tracheobronchial injury * Diaphragmatic rupture [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Rib fracture	c0035522	1,913	wikipedia	https://en.wikipedia.org/wiki/Rib_fracture	2021-01-18T19:02:59	{"mesh": ["D012253"], "icd-9": ["807.1", "807.0"], "icd-10": ["S22.3", "S22.4"], "wikidata": ["Q1974017"]}
Oligoastrocytoma is a brain tumor that forms when two types of cells in the brain, called oligodendrocytes and astrocytes, rapidly increase in number to form a mass. These brain cells are known as glial cells, which normally protect and support nerve cells in the brain. Because an oligoastrocytoma is made up of a combination of two cell types, it is known as a mixed glioma. Oligoastrocytomas usually occur in a part of the brain called the cerebrum and are diagnosed in adults between the ages of 30 and 50. The exact cause of this condition is unknown. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Oligoastrocytoma	c0280793	1,914	gard	https://rarediseases.info.nih.gov/diseases/9769/oligoastrocytoma	2021-01-18T17:58:37	{"mesh": ["D009837"], "umls": ["C0280793"], "orphanet": ["251656"], "synonyms": []}
For a general phenotypic description and a discussion of genetic heterogeneity of migraine headaches, see MGR1 (157300). Mapping Anttila et al. (2008) provided evidence for a migraine susceptibility locus on chromosome 10q22-q23. The authors used alternative migraine phenotyping methods, including latent-class analysis and trait-component analysis, which are more inclusive than the strict criteria of the International Headache Society (IHS), to perform genomewide linkage analysis. The study included 3 cohorts: 690 Finnish patients, 661 Australian patients, and a replication cohort of 324 Finnish patients (a total of 1,675 individuals from 210 families). The initial Finnish study yielded highly significant lod scores ranging from 3.90 to 5.18 at 10q22-q23. Female-specific analysis strengthened the results to a lod score of 7.68. The Australian sample showed a lod score of 3.50, and the independent Finnish replication study yielded a lod score 2.41 at the same locus. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6- to 9.5-cM segment, centered on 101 cM, which showed in-family homology in 95% of affected Finns. Linkage was found with symptoms including formal IHS diagnosis, unilaterality, pulsation, and phonophobia, among others. The consistency of the linkage across studies with different ascertainment schemes and phenotyping methods provided strength for the findings. Anttila et al. (2008) concluded that the findings supported the use of symptomatology-based phenotyping in migraine, and suggested that the 10q22-q23 locus probably contains 1 or more migraine susceptibility variants. INHERITANCE \- Autosomal dominant HEAD & NECK Ears \- Phonophobia Eyes \- Photophobia ABDOMEN Gastrointestinal \- Nausea \- Vomiting NEUROLOGIC Central Nervous System \- Migraine with or without aura, may be pulsating and/or unilateral \- Headache MISCELLANEOUS \- Predominantly female-dominated inheritance pattern in Finnish families ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	MIGRAINE WITH OR WITHOUT AURA, SUSCEPTIBILITY TO, 12	c2673676	1,915	omim	https://www.omim.org/entry/611706	2019-09-22T16:03:03	{"omim": ["611706"]}
Vitamin B12-unresponsive methylmalonic acidemia type mut- is an inborn error of metabolism characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12. ## Epidemiology Prevalence of this form of the disorder is not known. More than 450 cases have been reported to date. ## Clinical description The disease typically presents very early in life (<1 to 4 weeks), although later onset cases have been observed, with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, developmental delay, intellectual deficit, hepatomegaly and coma. Patients may show signs of anemia. They may also have potentially life-threatening ketoacidosis and/or hyperammonemia, renal and neurological complications, metabolic stroke and cardiomyopathy. mut- is generally less severe than vitamin B12-unresponsive methylmalonic acidemia type mut0 (see this term) and may in some cases respond to vitamin B12 therapy. Long term complications include metabolic stroke and development of end stage renal failure. These complications are more frequent in mut0 than in mut-. ## Etiology The disease is caused by partial deficiency in the activity of the mitochondrial vitamin B12-dependent enzyme methylmalonyl-CoA mutase which is a result of mutations in the MUT gene (6p21). ## Genetic counseling It is transmitted as an autosomal recessive trait. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Vitamin B12-unresponsive methylmalonic acidemia type mut-	c1855114	1,916	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79312	2021-01-23T17:51:02	{"mesh": ["C565390"], "omim": ["251000"], "icd-10": ["E71.1"], "synonyms": ["Partial deficiency of methylmalonyl-CoA mutase", "Vitamin B12-unresponsive methylmalonic aciduria type mut-"]}
## Cloning and Expression Kobilka et al. (1987) reported the cloning and complete nucleotide sequence of the cDNA for human beta-2-adrenergic receptor. The deduced amino acid sequence (413 residues) encodes a protein containing 7 clusters of hydrophobic amino acids suggestive of membrane-spanning domains. While the protein shows 87% identity overall with the previously cloned hamster beta-2-adrenergic receptor, the most highly conserved regions are the putative transmembrane helices (95% identical) and cytoplasmic loops (93% identical), suggesting that these regions of the molecule harbor important functional domains. Gene Structure Whereas the rhodopsin gene (180380) consists of 5 exons interrupted by 4 introns, the beta-adrenergic receptor genes contain no introns in either their coding or untranslated sequences (Kobilka et al., 1987). Emorine et al. (1987) characterized the promoter region of the gene. Mapping Because of a lack of beta-adrenergic receptors, Chinese hamster fibroblasts do not respond to the beta-adrenergic agonist with an increase in cellular cAMP. Thus, by study of hamster-human somatic cell hybrids, Sheppard et al. (1983) could assign to human chromosome 5 the structural gene for the beta-2-adrenergic receptor. By studies in somatic cell hybrids and by in situ hybridization, Kobilka et al. (1987) localized the gene to 5q31-q32. This position is the same as that for the gene coding for platelet-derived growth factor receptor (173410) and is adjacent to the site of the FMS oncogene (164770), the receptor for CSF1 (120420). By in situ hybridization, Yang-Feng et al. (1990) regionalized the assignment to 5q32-q34. By analysis of interspecific backcrosses, Oakey et al. (1991) mapped the corresponding mouse gene, symbolized Adrb2, to the proximal portion of chromosome 18. Biochemical Features ### Crystal Structure Cherezov et al. (2007) reported the crystal structure of a human beta-2 adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4-angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the beta-2-adrenergic receptor is very similar to that of retinal in rhodopsin (180380), structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family. Rosenbaum et al. (2007) reported that to overcome the structural flexibility of the beta-2-adrenergic receptor and to facilitate its crystallization, they engineered a beta-2-adrenergic receptor fusion protein in which T4 lysozyme replaces most of the third intracellular loop of the G protein-coupled receptor and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of the fusion protein provided insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting a conformational pathway from the ligand-binding pocket to regions that interact with G proteins. Rasmussen et al. (2007) reported a structure of the human beta-2 adrenoceptor (beta-2-AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4-angstrom/3.7-angstrom resolution. The cytoplasmic ends of the beta-2-AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta-2-AR are not seen. The beta-2-AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane domains 3 and 6, involving the conserved E/DRY sequences. Rasmussen et al. (2007) concluded that these differences may be responsible for the relatively high basal activity and structural instability of the beta-2-AR, and contribute to the challenges of obtaining diffraction-quality crystals of non-rhodopsin G protein-coupled receptors. Rasmussen et al. (2011) generated a camelid antibody fragment, which they called a nanobody, to the beta-2-AR that exhibits G protein-like behavior, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive beta-2-AR structure revealed subtle changes in the binding pocket; however, these small changes were associated with an 11-angstrom outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that were remarkably similar to those observed in opsin, an active form of rhodopsin. Rosenbaum et al. (2011) used the inactive structure of the human beta-2-AR as a guide to design a beta-2-AR agonist that can be covalently tethered to a specific site on the receptor through a disulfide bond. The covalent beta-2-AR-agonist complex formed efficiently, and was capable of activating a heterotrimeric G protein. Rosenbaum et al. (2011) crystallized a covalent agonist-bound beta-2-AR-T4L fusion protein in lipid bilayers through the use of lipidic mesophase method, and determined its structure at 3.5-angstrom resolution. A comparison to the inactive structure and an antibody-stabilized active structure showed how binding events at both the extracellular and intracellular surfaces are required to stabilize an active conformation of the receptor. The structures were in agreement with long-timescale (up to 30 microseconds) molecular dynamics stimulations showing that an agonist-bound active conformation spontaneously relaxes to an inactive-like conformation in the absence of a G protein or stabilizing antibody. Rasmussen et al. (2011) presented the crystal structure of the active state ternary complex composed of agonist-occupied monomeric beta-2-AR and nucleotide-free Gs (139320) heterotrimer. The principal interactions between the beta-2-AR and Gs involve the amino- and carboxy-terminal alpha-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the beta-2-AR include a 14-angstrom outward movement at the cytoplasmic end of transmembrane segment 6 and an alpha-helical extension of the cytoplasmic end of transmembrane segment 5. The most surprising observation is a major displacement of the alpha-helical domain of G-alpha-s relative to the Ras-like GTPase domain. Chung et al. (2011) applied peptide amide hydrogen-deuterium exchange mass spectrometry to probe changes in the structure of the heterotrimeric bovine G protein, Gs, on formation of a complex with agonist-bound human beta-2-AR. They reported structural links between the receptor-binding surface and the nucleotide-binding pocket of Gs that undergo higher levels of hydrogen-deuterium exchange than would be predicted from the crystal structure of the beta-2-AR-Gs complex. Together with x-ray crystallographic and electron microscopic data of the beta-2-AR-Gs complex, Chung et al. (2011) provided a rationale for a mechanism of nucleotide exchange, whereby the receptor perturbs the structure of the amino-terminal region of the alpha-subunit of Gs and consequently alters the 'P-loop' that binds the beta-phosphate in GDP. Gene Function Using oligonucleotide directed site-specific mutagenesis, Fraser et al. (1988) accomplished point mutation at nucleotide 388 of the BAR gene. The mutation resulted in a guanine-to-adenine substitution, exchanging an asparagine for a highly conserved aspartic acid at residue 130 of the human beta-adrenergic receptor. The mutant beta-adrenergic receptor appeared capable of interacting with the stimulatory guanine nucleotide-binding regulatory protein, but the ability of guanine nucleotides to alter agonist affinity was attenuated. Luttrell et al. (1999) demonstrated that activated beta-2-adrenergic receptor binds beta-arrestin-1 (ARRB1; 107940), which then binds c-src (190090) at its amino terminus. This interaction targets the complex to clathrin-coated pits and allows for beta-2-adrenergic activation of the MAP kinases ERK1 (601795) and ERK2 (176948). Patients with nocturnal asthma represent a subset of asthmatics who experience a marked worsening of airway obstruction and symptoms while asleep. Nocturnal asthmatics display greater bronchial hyperreactivity than do nonnocturnal asthmatics. Several studies had suggested that autonomic function may be different in nocturnal asthma as compared to nonnocturnal asthma. Szefler et al. (1991) found that circulating neutrophil and lymphocyte beta-2-adrenergic receptors, which are potential markers for ADRB2s of bronchial smooth muscle and other lung cells, decrease at 4:00 a.m. as compared to 4:00 p.m. in patients with nocturnal asthma. No such downregulation of ADRB2 was found in nonnocturnal asthmatics or normal subjects. Davare et al. (2001) found that the beta-2 adrenergic receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel Ca(V)1.2 (114206). This complex also contains a G protein, an adenylyl cyclase (see 103070), cAMP-dependent kinase (see 601639), and the counterbalancing phosphatase PP2A (see 605997). Davare et al. (2001) used electrophysiologic recordings from hippocampal neurons to demonstrate highly localized signal transduction from the receptor to the channel. The assembly of this signaling complex provides a mechanism that ensures specific and rapid signaling by a G protein-coupled receptor. Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, the connection of ubiquitination with regulation of mammalian G protein-coupled receptor function has been unclear. Shenoy et al. (2001) demonstrated that agonist stimulation of endogenous or transfected beta-2 adrenergic receptors led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta-arrestin (ARRB2; 107941). Moreover, proteasome inhibitors reduced receptor internalization and degradation, thus implicating a role for the ubiquitination machinery in the trafficking of the beta-2 adrenergic receptor. Receptor ubiquitination required beta-arrestin, which bound the E3 ubiquitin ligase MDM2 (164785). Abrogation of beta-arrestin ubiquitination, either by expression in MDM2-null cells or by dominant-negative forms of MDM2 lacking E3 ligase activity, inhibited receptor internalization with marginal effects on receptor degradation. However, an ADRB2 mutant lacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. Shenoy et al. (2001) concluded that their results delineated an adaptor role of beta-arrestin in mediating the ubiquitination of the beta-2 adrenergic receptor and indicated that ubiquitination of the receptor and of beta-arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic G protein-coupled receptor. Harrison et al. (2003) demonstrated that signaling via the erythrocyte beta-2 adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (GNAS; 139320) regulated the entry of the human malaria parasite Plasmodium falciparum. Agonists that stimulate cAMP production led to an increase in malarial infection that could be blocked by specific receptor antagonists. Moreover, peptides designed to inhibit GNAS protein function reduced parasitemia in P. falciparum cultures in vitro, and beta-antagonists reduced parasitemia of P. berghei infections in an in vivo mouse model. Harrison et al. (2003) suggested that signaling via the erythrocyte beta-2-adrenergic receptor and GNAS may regulate malarial infection across parasite species. By analyzing Adrb2-deficient mice, Elefteriou et al. (2005) demonstrated that the sympathetic nervous system favors bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl (602642). This sympathetic function requires phosphorylation by protein kinase A (PKA; see 176911) of ATF4 (604064), a cell-specific CREB (123810)-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biologic importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART (602606), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Elefteriou et al. (2005) concluded that their study established that leptin-regulated neural pathways control both aspects of bone remodeling, and demonstrated that integrity of sympathetic signaling is necessary for the increase in bone resorption caused by gonadal failure. In HEK293 cells in vitro, Ni et al. (2006) found that activation of ADRB2 receptors stimulated gamma-secretase activity and beta-amyloid (APP; 104760) production. Stimulation involved the association of ADRB2 with PSEN1 (104311) and required agonist-induced endocytosis of ADRB2. Similar effects were observed after activation of the opioid receptor OPRD1 (165195). In mouse models of Alzheimer disease (AD; 104300), chronic treatment with ADRB2 agonists increased cerebral amyloid plaques, and treatment with ADRB2 antagonists reduced cerebral amyloid plaques. Ni et al. (2006) postulated that abnormal activation of ADRB2 receptors may contribute to beta-amyloid accumulation in AD. Using nanoscale live-cell scanning ion conductance and fluorescence resonance energy transfer microscopy in cardiomyocytes from healthy adult rats and mice, Nikolaev et al. (2010) found that spatially confined beta-2 adrenergic receptor-induced cAMP signals were localized exclusively to the deep transverse tubules, whereas functional beta-1 adrenergic receptors (ADRB1; 109630) were distributed across the entire cell surface. Using immunofluorescence microscopy, Coureuil et al. (2010) demonstrated that Neisseria meningitidis (Nm) colonies at the cell surface of human brain endothelial cells promoted translocation of ARRB1 and ARRB2 to the inner surface of the plasma membrane, facing the bacteria. ARRBs translocated under the colonies served as a scaffolding platform for signaling events elicited by Nm. ADRB2 was the only G protein-coupled receptor expressed in the cell line that played a permissive role in the formation of cortical plaques under colonies and in bacterial crossing of cell monolayers. Coureuil et al. (2010) concluded that the ADRB2/ARRB signaling pathway is required for Nm to promote stable adhesion to brain endothelial cells and subsequent crossing of the blood-brain barrier. Using an unbiased screen targeting endogenous gene expression, Mittal et al. (2017) discovered that the beta-2-adrenoreceptor (B2AR) is a regulator of the alpha-synuclein gene (SNCA; 163890). B2AR ligands modulate SNCA transcription through histone H3 lysine-27 acetylation (H3K27ac) of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the B2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing Parkinson disease (PD; see 168600) (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a B2AR antagonist, propanolol, correlated with increased risk. B2AR activation protected model mice and patient-derived cells. Thus, Mittal et al. (2017) concluded that B2AR is linked to transcription of alpha-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies. Molecular Genetics Reihsaus et al. (1993) found 6 different polymorphic forms of ADRB2. These polymorphisms consisted of amino acid substitutions. When they were mimicked by site-directed mutagenesis of the cloned human ADRB2 cDNA and expressed in Chinese hamster fibroblasts, some were found to display different pharmacologic properties. Specifically, they found that glycine at position 16 (R16G; 109690.0001), rather than arginine, imparted enhanced agonist-promoted downregulation. This prompted them to determine ADRB2 phenotypes of 2 well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34% nocturnal depression of peak expiratory flow rates and 22 nonnocturnal asthmatics with virtually no such depression (2.3%). The frequency of the gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the arg16 allele was present in 19.6% of the nocturnal group and 47.8% of the nonnocturnal group. Turki et al. (1995) hypothesized that gly16 may be overrepresented in nocturnal asthma. This overrepresentation of the gly16 allele in nocturnal asthma was significant at p = 0.007, with a 3.8 odds ratio for having both nocturnal asthma and the gly16 polymorphism. Comparisons of the 2 cohorts as to homozygosity for gly16, homozygosity for arg16, or heterozygosity were also consistent with segregation of gly16 with nocturnal asthma. There was no difference in the frequency of the gln27-to-glu (Q27E; 109690.0002) and thr164-to-ile (T164I; 109690.0003) polymorphisms between the 2 groups. In a metaanalysis of 28 published studies, Contopoulos-Ioannidis et al. (2005) confirmed the association between the gly16 polymorphism and nocturnal asthma, but found no association between the R16G or Q27E variants and asthma susceptibility overall or bronchial hyperresponsiveness. The beta-2-adrenergic receptor agonists are the most widely used agents in the treatment of asthma, but the genetic determinants of responsiveness to these agents are unknown. It had been reported that gly16 (see 109690.0001) is associated with increased agonist-promoted downregulation of ADRB2 as compared with arg16. A form of the receptor with glu27 had been shown to be resistant to downregulation when compared with gln27 (109690.0002), but only when coexpressed with arg16. In a group of 269 children in a longitudinal study of asthma, Martinez et al. (1997) performed spirometry before and after administration of albuterol and correlated the findings with the genotypes of these 2 polymorphisms. Two polymorphisms showed marked linkage disequilibrium, with 97.8% of all chromosomes that carried arg16 also carrying gln27. When compared to homozygotes for gly16, homozygotes for arg16 were 5.3 times and heterozygotes for gly16 were 2.3 times more likely to respond to albuterol, respectively. Similar trends were observed for asthmatic and nonasthmatic children, and results were independent of baseline lung function, ethnic origin, and previous use of antiasthma medication. No association was found between glu27 and response to albuterol. In a study of 190 asthmatics, Israel et al. (2001) found that the homozygous arg16 genotype of the ADRB2 gene was positively associated with an acute response to treatment, but was also associated with a significant decrease in response after regular use of beta-agonists, whereas the gly-gly genotype showed no change with regular use. In a discussion of genetic polymorphism of drug targets, one aspect of pharmacogenomics, Evans and McLeod (2003) discussed genetic polymorphisms of the ADRB2 gene that alter the process of signal transduction by the beta-2-adrenergic receptor. They stated that the R16G (109690.0001) and Q27E (109690.0002) substitutions are relatively common, with allele frequencies of 0.4 to 0.6. They noted that Drysdale et al. (2000) had identified 13 distinct SNPs in ADRB2, which were organized into 12 haplotypes and that this finding led to evaluation of the importance of haplotype structure as compared with individual SNPs in determining receptor function and pharmacologic response. ### Associations Pending Confirmation In a study of 65 healthy and drug-free subjects, Lonnqvist et al. (1992) demonstrated that some individuals have resistance to the lipolytic effects of catecholamines and that this is the result of decreased ADRB2 expression in fat cells. The resistance was studied in vivo and in isolated abdominal subcutaneous adipocytes. Some of the plotted data demonstrated bimodality consistent with a relatively simple genetic basis for the difference. Whether the genetic difference is located at the ADRB2 locus or at another site was unclear. The clinical consequence of catecholamine resistance in apparently healthy subjects was also not clear. It is well established that obesity is under strong genetic influence, with up to 40% of the variation in body fat content being attributed to genetic factors. Genes that are involved in the regulation of catecholamine function may be of particular importance for human obesity because of the central role catecholamines play in energy expenditure, both as hormones and as neurotransmitters. This regulation is in part affected by stimulating lipid mobilization through lipolysis in fat cells. The beta-2 adrenoceptor is a major lipolytic receptor in human fat cells. Large et al. (1997) investigated whether the common polymorphisms arg16 to gly and gln27 to glu are related to obesity. They found that gln27 to glu was indeed markedly associated with obesity with a relative risk for obesity of approximately 7 and an odds ratio of approximately 10. Homozygotes for glu27 had an average fat mass excess of 20 kg and approximately 50% larger fat cells than controls. However, no significant association with changes in ADRB2 function was observed. The polymorphism arg16gly was associated with altered ADRB2 function, with gly16 carriers showing a 5-fold increased agonist sensitivity without any change in ADRB2 expression. However, it was not significantly linked with obesity. The findings of Large et al. (1997) suggested that genetic variation in the ADRB2 gene may be of major importance for obesity, energy expenditure, and lipolytic ADRB2 function in adipose tissue, at least in women. By PCR-direct sequencing, Yamada et al. (1999) screened the 5-prime untranslated region of the ADRB2 gene from 40 obese subjects. They identified 2 polymorphic sites: a T-to-C transition at -47 and a T-to-C transition at -20. By PCR and restriction digestion, they further analyzed the association of these polymorphisms with obesity in 574 subjects. The -47T-C substitution was in tight linkage disequilibrium with the -20T-C substitution. These polymorphisms were also in linkage disequilibrium with codon 16 and codon 27 polymorphisms. Subjects carrying the -47C/-20C allele had greater body mass index (25.5 +/- 4.5 vs 24.4 +/- 4.1 kg/m2; p = 0.007) and higher serum triglyceride levels (166 +/- 160 vs 139 +/- 95 mg/dl; p = 0.015) than -47T/-20T homozygotes. The variant allele frequency was significantly higher in obese subjects than in nonobese subjects (0.18 vs 0.11; p = 0.0026). Furthermore, an increased frequency of the variant allele was shown in diabetic patients compared with nondiabetic subjects (0.19 vs 0.11; p = 0.0005). The authors pointed out that the association may be attributable to the greater proportion of diabetic patients in the obese group. They suggested that the exchange at -47 may alter the expression level of the ADRB2 gene, because the nucleotide substitution at -47 results in a cys-to-arg exchange at the C terminal of the leader peptide. The distal end of 5q, 5q31.1-qter, contains the genes for 2 adrenergic receptors, ADRB2 and ADRA1B (104220), and the dopamine receptor type 1A gene (DRD1A; 126449). Krushkal et al. (1998) used an efficient discordant sib-pair ascertainment scheme to investigate the impact of this region of the genome on variation in systolic blood pressure in young Caucasians. They measured 8 highly polymorphic markers spanning this positional candidate gene-rich region in 427 individuals from 55 3-generation pedigrees containing 69 discordant sib pairs, and calculated multipoint identity by descent probabilities. The results of genetic linkage and association tests indicated that the region between markers D5S2093 and D5S462 was significantly linked to one or more polymorphic genes influencing interindividual variation in systolic blood pressure levels. Since the ADRA1B and DRD1A genes are located close to these markers, the data suggested that genetic variation in one or both of these G protein-coupled receptors, which participate in the control of vascular tone, play an important role in influencing interindividual variation in systolic blood pressure levels. Dallongeville et al. (2003) studied the association between the G16R (109690.0001) and Q27E (109690.0002) polymorphisms of the ADRB2 receptor and metabolic syndrome (605552) in 276 male and female patients with metabolic syndrome and 872 controls. Metabolic syndrome was defined according to National Cholesterol Education Program Adult Treatment Panel III guidelines. The G16R (P less than 0.005) and Q27E (P less than 0.04) polymorphisms were associated with metabolic syndrome in men, but not in women. Because both variants were in linkage disequilibrium, a haplotype analysis was performed. There was no evidence of any statistically significant association between ADRB2 haplotypes and metabolic syndrome. Evolution Cagliani et al. (2009) analyzed the recent evolutionary history of the ADRB genes in humans, with particular concern to selective patterns. Although their data suggested neutral selection for the ADRB1 gene, most tests rejected neutral evolution for the ADRB2 and ADRB3 genes. Selection of specific ADRB2 alleles was found particularly in European, African, and Asian samples. The inferred ADRB2 haplotypes partitioned into 3 major clades with a coalescence time of 1 to 1.5 million years, suggesting that the ADRB2 gene is either subject to balanced selection or undergoing a selective sweep. Haplotype analysis also revealed ethnicity-specific differences. There was significant deviations from Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct European cohorts; HWE deviation depended on sex (females were in disequilibrium), and genotypes displaying maximum and minimum relative fitness differed across population samples, suggesting a complex situation possibly involving epistasis or maternal selection. Wilson et al. (2010) noted errors in the chimpanzee Adrb sequence used by Cagliani et al. (2009) to estimate the node for appearance of the human most recent common ancestor (MRCA). The correction suggested a significantly more ancient MRCA for this gene. Wilson et al. (2010) also reviewed haplotypes at the 3-prime end of the ADRB2 gene that were not addressed by Cagliani et al. (2009). In a response from the Cagliani group, Fumagalli et al. (2010) noted the data correction and recalculated the time to MRCA as 1.9 million years. They proposed that this increased depth provides further support that ADRB2 has been evolving under a balancing-selection regime. Animal Model Rohrer et al. (1999) found that mice lacking both Adrb1 and Adrb2 had normal basal heart rate, blood pressure, and metabolic rate. However, stimulation with beta-receptor agonists or exercise revealed significant impairment in chronotropic range, vascular reactivity, and metabolic rate; maximal exercise capacity was not affected. Beta-receptor stimulation of cardiac inotropy and chronotropy was mediated almost exclusively by Adrb1, whereas vascular relaxation and metabolic rate were controlled by all 3 beta receptors. Compensatory alterations in cardiac muscarinic receptor density and vascular Adrb3 responsiveness were also observed in Adrb1/Adrb2 double-knockout mice. Maurice et al. (1999) tested the hypothesis that genetic manipulation of the myocardial beta-adrenergic receptor system, which is impaired in heart failure, can enhance cardiac function. They delivered adenoviral transgenes, including human B2AR, to the myocardium of rabbits using an intracoronary approach. Catheter-mediated delivery of Adeno-B2AR produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. The delivery of the transgene reproducibly produced 5- to 10-fold B2AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function, compared with control rabbits that received an empty adenovirus. To determine whether the sympathetic nervous system is the efferent arm of diet-induced thermogenesis, Bachman et al. (2002) created mice that lacked the beta-adrenergic receptors ADRB1, ADRB2, and ADRB3. Beta-less mice on a chow diet had a reduced metabolic rate and were slightly obese. On a high-fat diet, beta-less mice, in contrast to wildtype mice, developed massive obesity that was due entirely to a failure of diet-induced thermogenesis. Bachman et al. (2002) concluded that the beta-adrenergic receptors are necessary for diet-induced thermogenesis and that this efferent pathway plays a critical role in the body's defense against diet-induced obesity. Odley et al. (2004) developed transgenic mice expressing constitutively active (GTPase-deficient) or dominant-inhibitory (non-GTP-binding) Rab4 (179511) mutants. Expression of constitutively active Rab4 had no effect on cardiac structure or function, but the dominant-inhibitory Rab4 mutant impaired the responsiveness of Adrb2 to endogenous and exogenous catecholamines. These defects were accompanied by bizarre vesicular structures and abnormal accumulation of Adrb2 in the sarcoplasm and subsarcolemma. Odley et al. (2004) presented further evidence that Rab4 is involved in bidirectional sarcolemmal-vesicular Adrb2 trafficking, which occurs continuously in healthy hearts and is necessary for normal baseline adrenergic responsiveness and resensitization after catecholamine exposure. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	BETA-2-ADRENERGIC RECEPTOR	c1862282	1,917	omim	https://www.omim.org/entry/109690	2019-09-22T16:44:28	{"omim": ["109690"], "synonyms": ["Alternative titles", "BETA-ADRENERGIC RECEPTOR", "BETA-2-ADRENOCEPTOR", "ADRB2R"]}
A number sign (#) is used with this entry because of evidence that bronchiectasis with or without elevated sweat chloride (BESC3) can be caused by mutation in the gene encoding the gamma subunit of the epithelial sodium channel (SCNN1G; 600761). For discussion of genetic heterogeneity of bronchiectasis with or without elevated sweat chloride, see BESC1 (211400). Molecular Genetics Fajac et al. (2008) screened the SCNN1G gene in 55 patients with idiopathic bronchiectasis who had 1 or no mutations in the CFTR gene (602421) and identified heterozygosity for 2 missense mutations in 3 patients without mutation in CFTR, G183S (600761.0005) and E197K (600761.0006), respectively. All 3 patients had normal sweat chlorides; 1 had an abnormal nasal potential difference (NPD), whereas the other 2 had normal NPDs. The authors noted that the 2 patients with the E197K mutation were among the most severely affected of the patients without mutation in CFTR, with forced expiratory volumes in 1 second (FEV1s) that were 64% and 35% of predicted, respectively. Mutesa et al. (2009) analyzed the CFTR gene in 60 unrelated Rwandan children who had CF-like symptoms and identified heterozygosity for a CFTR mutation in 5 patients (none were homozygous). Sequencing of the genes encoding the 3 subunits of the epithelial sodium channel (ENaC) revealed heterozygous mutations in SCNN1A (600228) and SCNN1B (600760) in 4 patients, respectively, whereas the remaining patient was heterozygous for a mutation in both SCNN1B and SCNN1G. Among the patients who were negative for mutation in CFTR, only known polymorphisms were found in the ENaC genes. Mutesa et al. (2009) concluded that some cases of CF-like syndrome in Africa may be associated with mutations in CFTR and ENaC genes. INHERITANCE \- Autosomal dominant RESPIRATORY Airways \- Chronic bronchitis Lung \- Bronchiectasis LABORATORY ABNORMALITIES \- Normal sweat chloride (3 of 3 patients) \- Increased nasal-potential difference (1 of 3 patients) MOLECULAR BASIS \- Caused by mutation in the sodium channel, nonvoltage-gated 1, gamma gene (SCNN1G, 600761.0005 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	BRONCHIECTASIS WITH OR WITHOUT ELEVATED SWEAT CHLORIDE 3	c0339985	1,918	omim	https://www.omim.org/entry/613071	2019-09-22T15:59:53	{"doid": ["9563", "0080528"], "omim": ["613071"], "orphanet": ["60033"], "synonyms": ["Alternative titles", "CYSTIC FIBROSIS-LIKE SYNDROME"]}
A number sign (#) is used with this entry because hemochromatosis type 1 (HFE1) is caused by homozygous or compound heterozygous mutation in the HFE gene (613609) on chromosome 6p22. Description Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism wherein the body accumulates excess iron (summary by Feder et al., 1996). Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. Removal of excess iron by therapeutic phlebotomy decreases morbidity and mortality if instituted early in the course of the disease. Classic hemochromatosis (HFE) is most often caused by mutation in a gene designated HFE on chromosome 6p21.3. Adams and Barton (2007) reviewed the clinical features, pathophysiology, and management of hemochromatosis. ### Genetic Heterogeneity of Hemochromatosis At least 4 additional iron overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Juvenile hemochromatosis, or hemochromatosis type 2 (HFE2), is autosomal recessive and is divided into 2 forms: HFE2A (602390), caused by mutation in the HJV gene (608374) on chromosome 1q21, and HFE2B (613313), caused by mutation in the HAMP gene (606464) on chromosome 19q13. Hemochromatosis type 3 (HFE3; 604250), an autosomal recessive disorder, is caused by mutation in the TFR2 gene (604720) on chromosome 7q22. Hemochromatosis type 4 (HFE4; 606069), an autosomal dominant disorder, is caused by mutation in the SLC40A1 gene (604653) on chromosome 2q32. Hemochromatosis type 5 (HFE5; 615517) is caused by mutation in the FTH1 gene (134770) on chromosome 11q12. Clinical Features Muir et al. (1984) recognized 4 different types of hereditary hemochromatosis which 'bred true' in families, suggesting that more than one genetic lesion in iron metabolism can lead to hereditary hemochromatosis. Group I was termed the classic form with elevated transferrin (190000) saturation, serum ferritin levels, and liver iron content; group II was characterized by severe iron overload and accelerated disease manifesting at an early age; group III was characterized by elevated total body iron stores, normal transferrin saturation and serum ferritin levels; and group IV was characterized by markedly elevated findings on serum biochemical tests, i.e., transferrin saturation and serum ferritin, with minimal elevation in total body iron stores. Milman et al. (1992) found no relationship between genetic subtypes of transferrin and the expression of disease in hemochromatosis patients. Edwards et al. (1980) identified 35 hemochromatosis homozygotes through pedigree studies, using the close linkage to HLA-A (142800) in the identification. Thirteen were asymptomatic. Arthropathy was present in 20, hepatomegaly in 19, transaminasemia in 16, skin pigmentation in 15, splenomegaly in 14, cirrhosis in 14, hypogonadism in 6, and diabetes in 2. None had congestive heart failure. Only 1 had the triad of hepatomegaly, hyperpigmentation, and diabetes. Serum iron was increased in 30 of 35, transferrin saturation was increased in all 35, serum ferritin in 23 of 32, urinary iron excretion after deferoxamine in 28 of 33, hepatic parenchymal cell stainable iron in 32 of 33, and hepatic iron in 27 of 27. Iron loading was 2.7 times greater in men than in women. No female had hepatic cirrhosis. By studying 1,058 individuals who were heterozygous for the HLA-linked hemochromatosis mutation, Bulaj et al. (1996) found that the mean serum iron concentrations and transferrin-saturation values were higher in heterozygotes than in normal subjects and did not increase with age. Initial transferrin-saturation levels exceeding the threshold associated with the homozygous genotype were found in 4% of males and 8% of female heterozygotes. The geometric mean serum ferritin concentration was higher in heterozygotes than in normal subjects and increased with age. Higher-than-normal values were found in 20% of males and 8% of female heterozygotes. The clinical and biochemical expression of hemochromatosis was more marked in heterozygotes with paternally transmitted mutations than in those with maternally transmitted mutations. Liver biopsy abnormalities were generally associated with alcohol abuse, hepatitis, or porphyria cutanea tarda. Bulaj et al. (1996) concluded that complications due to iron overload alone in hemochromatosis heterozygotes are 'extremely rare.' This was the first description of parent-of-origin effects in hemochromatosis. Escobar et al. (1987) established the diagnosis of hemochromatosis in a 7-year-old boy and his 29-month-old brother. These were said to be the youngest children with primary hemochromatosis reported to that time. They were members of a family in which 3 generations had affected individuals. Data from the literature on values of serum iron, serum ferritin, transferrin saturation, and hepatic iron were reviewed. Kaikov et al. (1992) described hemochromatosis in asymptomatic sibs in whom the diagnosis was made after an unexpected finding of elevated serum iron concentrations. The sibs were 7, 6, and 4 years of age. Elevated red cell mean corpuscular volume (MCV) was elevated in all 3, at 90 to 92 fL. In their review of the literature, they found 16 cases of symptomatic homozygous children at ages ranging from 4 to 19 years at the time of diagnosis. They suggested that normalization of the MCV may be an indirect index of adequate phlebotomy. The cases of Escobar et al. (1987) and Kaikov et al. (1992) may have been juvenile hemochromatosis (602390). Roldan et al. (1998) described acute liver failure after iron supplementation in a 29-year-old woman with unrecognized hemochromatosis. Roy and Andrews (2001) reviewed disorders of iron metabolism, with emphasis on aberrations in hemochromatosis, Friedreich ataxia (FRDA; 229300), aceruloplasminemia (604290), and other inherited disorders. McDermott and Walsh (2005) assessed the prevalence of hypogonadism in a large group of patients with hemochromatosis diagnosed in a single center over a 20-year period. Abnormally low plasma testosterone levels, with low luteinizing hormone (LH; see 152780) and follicle-stimulating hormone (FSH; see 136530) levels, were found in 9 of 141 (6.4%) male patients tested. Eight of nine (89%) had associated hepatic cirrhosis; 3 of 9 (33%) had diabetes. Inappropriately low LH and FSH levels were found in 2 of 38 females (5.2%) in whom the pituitary-gonadal axis could be assessed. McDermott and Walsh (2005) concluded that patients with lesser degrees of hepatic siderosis at diagnosis are unlikely to develop hypogonadism. ### Liver Cirrhosis and Liver Cancer Deugnier et al. (1993) analyzed the occurrence of primary liver cancer in hemochromatosis; there was 1 instance of cholangiocarcinoma and 53 instances of hepatocellular carcinoma (HCC; 114550). Of the 54 patients, 32 were untreated and 22 had been 'de-ironed.' Three of the patients had hepatocellular carcinoma in noncirrhotic but only fibrotic liver. Chronic alcoholism and tobacco smoking was higher in patients with hepatocellular carcinoma than in matched hemochromatosis patients without carcinoma. A common manifestation of tissue damage caused by iron accumulation in hereditary hemochromatosis is hepatic cirrhosis that may lead to hepatocellular carcinoma. Willis et al. (2000) determined the risk of developing such disease manifestations in individuals with HFE mutations in Norfolk, UK. The frequency of mutant HFE alleles in archived liver tissue blocks from patients with cirrhosis or liver cancer was compared with that in 1,000 control blood samples. This control group was derived from a number of sources; no sample was from an individual with diagnosed HH. Of 34 cases of liver cancer, 3 (8.8%) were homozygous for the C282Y (613609.0001) mutation (2 hepatocellular carcinomas, 1 undifferentiated liver carcinoma). None of these patients had been given a diagnosis of HH prior to the diagnosis of liver cancer. None were C282Y/H63D (613609.0002) compound heterozygotes. Five of 190 cirrhosis samples (2.6%) were homozygous for C282Y; 4 of these patients had been given a clinical diagnosis of HH at the time of biopsy, and the remaining case fell also into the liver cancer group. Six cirrhosis samples were from C282Y/H63D compound heterozygotes; none had been given a clinical diagnosis of HH. The frequency of C282Y homozygotes in the control group was 1 in 230, and of C282Y/H63D compound heterozygotes was 1 in 108. HFE mutations were significantly more common in disease than in control specimens. Willis et al. (2000) calculated that, in their population, 2.7% of C282Y homozygotes and 1% of C282Y/H63D compound heterozygotes develop liver disease at some point in their lives. Both Wilson disease (WND; 277900) and hemochromatosis, characterized by excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles (191170) in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, Hussain et al. (2000) determined the frequency of p53 mutated alleles in nontumorous liver tissue from WND and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249, and C:G to A:T transversions and C:G to T:A transitions at codon 250 were found in liver tissue from WND cases, and a higher frequency of G:C to T:A transversions at codon 249 was also found in liver tissue from hemochromatosis cases. Sixty percent of WND and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggested nitric oxide as a source of increased oxidative stress. The results were consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WND causes mutation in the p53 tumor suppressor gene. Other Features Chromium, an essential trace mineral required for normal insulin function, is transported bound to transferrin and competes with iron for that binding. Sargent et al. (1979) found that less chromium is retained in patients with hemochromatosis than in controls, and suggested that the diabetes of hemochromatosis may be due in part to chromium deficiency. Murphy (1987) noted that a considerable proportion of the patients who develop Vibrio vulnificus septicemia are persons with hemochromatosis. This organism thrives in an environment with abundant iron. It occurs naturally in many warm coastal waters and sometimes contaminates shellfish harvested from these areas. The organism can cause infection when ingested in raw or improperly cooked contaminated shellfish or when introduced into the open wounds of persons who handle contaminated seafood or bathe in contaminated waters. Bacteremia due to V. vulnificus in patients with hemochromatosis may be related to the availability of iron for microbial metabolism or to the presence of hepatic cirrhosis (Bullen et al., 1991) and is often fatal. Diamond et al. (1989) studied the prevalence and pathogenesis of osteopenia in 22 men with hemochromatosis. They concluded that a significant decrease in bone density is observed in this condition, particularly when hypogonadism is present. They speculated that low serum free-testosterone concentrations, rather than calciotrophic hormones, determine bone mass in this disorder. Barton et al. (1994) demonstrated that hemochromatosis homozygotes and, to a lesser extent, heterozygotes, both male and female, have increased blood levels of lead. In contrast, mean blood lead of subjects with transfusion-induced iron overload did not differ significantly from that of normal controls. The findings in homozygotes could not be related to age, presence or absence of iron loading, or the extent of therapeutic phlebotomy. Increased absorption of iron and cobalt, which may have the same absorptive pathway, had previously been documented in homozygotes; the new findings were interpreted as indicating increased absorption of lead as well. The findings suggested that patients with hemochromatosis, like children with iron deficiency, are more susceptible to lead poisoning. Anand et al. (1983) and Eriksson et al. (1986) described cases suggesting a possible relationship between alpha-1-antitrypsin deficiency (613490) and hemochromatosis. In a series of 15 patients referred to a liver transplantation center in the U.S., Rabinovitz et al. (1992) found a significant correlation between heterozygous PiZ (107400.0011) alpha-1-antitrypsin deficiency and hemochromatosis. Other studies, however, failed to show a relationship between the 2 inborn errors of metabolism. To investigate the matter further, Elzouki et al. (1995) used a monoclonal antibody against the PiZ variant of AAT in 67 consecutive patients with genetic hemochromatosis seen in 2 Swedish hospitals. In 3 of the patients with hemochromatosis, homozygosity for the PiZ variant was found. Liver biopsy was performed in 65 of the 67 patients; 2 of the 3 PiZ homozygotes were found to have cirrhosis, compared to 10% (6 of 59) of the noncarriers of the PiZ variant. None of the homozygous or heterozygous AAT-deficient patients had developed hepatocellular carcinoma compared with 2 of 59 of the non-PiZ gene carriers. Severe emphysema developed in 2 of the patients with the homozygous phenotype. Elzouki et al. (1995) concluded that the data suggested that the presence of the PiZ allele in double dose when associated with genetic hemochromatosis contributes to the earlier onset of cirrhosis, although it may not increase the risk of hepatocellular carcinoma. Grove et al. (1998) examined the hypothesis that mutations in the HFE gene determine hepatic iron status in alcoholics and predispose to advanced alcoholic liver disease. The sample population was derived from the northeast of England and consisted of 257 individuals with alcoholic liver disease and 117 controls from the local population. No significant excess of C282Y (613609.0001) or H63D (613609.0002) alleles was demonstrated in alcoholics with advanced liver disease compared to those with no liver disease. There was no difference in age at biopsy or presentation. No difference in allele distribution was noted between alcoholics and controls. No relationship between allele frequency and histologic evidence of iron overload was noted. The authors commented that HFE mutations did not predispose to advanced liver disease in alcoholics. Because ceruloplasmin (CP; 117700) seems to be involved in iron mobilization, Cairo et al. (2001) measured serum CP levels in 35 patients with hereditary hemochromatosis, 12 patients with acquired iron overload, and 36 healthy subjects. Ceruloplasmin was lower in HH patients than in controls; no difference was found between untreated HH patients and those on a phlebotomy program and between HH patients carrying the normal and mutated alleles of the HFE gene. CP levels in patients with acquired iron overload were significantly higher than in HH patients and similar to those of controls. No differences in albumin, alpha-1-acid glycoprotein, or copper serum levels were observed in the 3 groups. Cippa and Krayenbuehl (2013) hypothesized that sustained enhanced iron absorption in patients with HFE hemochromatosis may have a beneficial effect on growth. They assessed the height in a cohort of 176 patients with HFE hemochromatosis at the University Hospital Zurich. Homozygous C282Y (613609.0001) mutations were found in 93% of patients, whereas compound heterozygosity for H63D (613609.0002) and C282Y mutations was found in 7%. Height in patients with hemochromatosis was compared with that in an age- and sex-matched Swiss reference population, with the use of data reported in the registry of military conscription and by the Swiss Federal Statistical Office. The mean height in men with hemochromatosis (120) was 178.2 cm, versus 173.9 cm in controls (458,322), a difference of 4.3 cm (95% CI, 3.0 to 5.5; p less than 0.001). The mean height in women with hemochromatosis (56) was 167.1 cm, versus 163.8 cm in controls (10,260), a difference of 3.3 cm (95% CI, 1.3 to 5.3; p less than 0.001). Cippa and Krayenbuehl (2013) speculated that patients with HFE hemochromatosis may benefit in their first 2 decades from constantly enhanced iron absorption, providing a steadily sufficient supply of iron during physical development. Inheritance Debre et al. (1958) concluded that the biochemical defect of idiopathic hemochromatosis is present in heterozygotes and that whether the disease develops is dependent on other influences on iron metabolism. They suggested that juvenile hemochromatosis resulting from consanguineous marriages may represent the homozygous state of the gene. Bothwell et al. (1959), Debre et al. (1958), and several others concluded that 1 form of hemochromatosis is inherited as an autosomal dominant disorder with incomplete penetrance in females because of loss of blood in menstruation and pregnancy. Saddi and Feingold (1974) reported a study of 96 pedigrees which, they concluded, supported autosomal recessive inheritance. Consanguinity was increased among the parents. No parent or offspring was affected. Segregation analysis was consistent with autosomal recessive inheritance if reduced penetrance in females was assumed. Simon et al. (1977) concluded that idiopathic hemochromatosis is recessive, although polygenic (probably oligogenic) inheritance could not be excluded. Bassett et al. (1982) provided evidence that clarified some of the previous confusion of whether hemochromatosis is a recessive or a dominant. They observed 5 families with hemochromatosis in 2 successive generations. HLA typing of the subjects indicated that a homozygous-heterozygous mating almost certainly had occurred in 4 of the 5 families, resulting in homozygous offspring. Powell et al. (1987) restudied a family reported by Bassett et al. (1982) in which 2 children apparently homozygous for hemochromatosis did not manifest overt disease; alternative explanations such as dominant inheritance were postulated. Subsequent studies provided the correct explanation (pseudodominant inheritance) and added further evidence for the tight linkage of HFE to HLA-A. Borecki et al. (1989) performed a segregation analysis on 147 HH pedigrees from Brittany, France, indexed by the measurement of latent capacity of transferrin. No evidence for heterozygous expression was observed, either in the biochemical domain of latent capacity of transferrin, or in increased liability to overt disease. The analysis allowed clear resolution of the recessive single gene inheritance pattern in these families. Borecki et al. (1990) concluded that the hemochromatosis gene is completely recessive with respect to both clinical manifestations and serum iron abnormalities, with significant differences in expression by sex. Clinical manifestations were present in all male homozygotes, suggesting that the recessive hemochromatosis genotype is fully penetrant at all ages in males. This was not the case for younger females, however. Mapping Simon et al. (1976) found HLA-A3 in 78.4% of hemochromatosis patients and 27% of controls; HLA-B14 was found in 25.5% of cases and 3.4% of controls. Among sibs with hemochromatosis, Simon et al. (1977) found a highly significant association between hemochromatosis and possession of the same 2 haplotypes. For 6 families a lod score of 2.239 at a recombination fraction of 0.005 supported linkage of HLA and hemochromatosis. Stevens et al. (1977) concluded that a gene for hemochromatosis may be on chromosome 6 close to the HLA-A locus in linkage disequilibrium with high frequency of A3 in patients with hemochromatosis. Cartwright et al. (1978) obtained lod scores well above the 3.0 for the HLA-hemochromatosis linkage. That the high lod score is not an artifact due to A3, B7 and B14 associations was supported by the finding of a lod score of 4.14 at theta 0.00 in 5 pedigrees in which these antigens were not present in the probands (Dadone et al., 1982). Skolnick (1983) contended that linkage disequilibrium cannot explain the HLA-hemochromatosis association because the association is with a haplotype, either A3-B7 or A3-B14. Edwards et al. (1985, 1986) presented the first known example of recombination between the HLA-A and hemochromatosis loci and proposed that the (or at least a) hemochromatosis locus lies between the HLA-A and HLA-B loci. David et al. (1986, 1987) studied an exceptional recombinant family with 3 HLA-identical sibs: 1 had hemochromatosis, whereas the other 2 were free of any clinical or biologic signs of the disease. The study of restriction patterns using 2 MHC class I probes showed 2 differences between the proband and his sibs which were attributed to an unbalanced crossover or a genetic conversion. The absence of a 7.7-kb HindIII fragment in the proband suggested that this segment is the location of at least part of the hemochromatosis gene. Furthermore, it appeared that the hemochromatosis gene lies telomeric to the HLA-A locus. Lucotte and Coulondre (1986) found that a specific PvuII restriction fragment correlates absolutely with the HLA-A3 serologic allele and with the hemochromatosis allele. Using pulsed field gel electrophoresis in conjunction with probes that map within, or in the vicinity of, the HLA class I region, Lord et al. (1990) did not detect any disease-specific differences in affected members of 3 HH pedigrees or in 6 unrelated patients with the disorder. The authors concluded that the lesion responsible for HH lies beyond the resolution of this technique and does not involve large structural deletions or extensive rearrangements. Boretto et al. (1992) reported linkage studies with restriction polymorphisms which were consistent with location of the hemochromatosis locus either less than 100 kb centromeric to the HLA-A locus or on its telomeric side. Jazwinska et al. (1993) found a maximum lod score of 9.90 at theta = 0.0 for HLA-A and 8.26 at theta = 0.0 for a microsatellite marker at D6S105. No recombination was observed with either marker. Other markers were separated from the hemochromatosis locus by recombination, thereby defining the centromeric and telomeric limits for the HFE gene as HLA-B and D6S109, respectively. A multipoint map indicated that hemochromatosis locus is located in a region less than 1 cM proximal to HLA-A and less than 1 cM telomeric of HLA-A. In a single family with hemochromatosis, Calandro et al. (1995) identified 2 recombinant individuals confirmed by analysis of 16 polymorphic markers located near HLA-A and D6S105. One of the recombinants provided evidence that the HH gene is telomeric to the 5-prime end of the HLA-F locus. The HLA-F locus was placed approximately 0.027 cM distal to HLA-A, which in turn was 0.01 cM distal of HLA-B. Raha-Chowdhury et al. (1996) showed that a highly polymorphic polypurine tract in the 5-prime untranslated region of HLA-F is as strongly associated with hemochromatosis as HLA-A3 or D6S105-8. The observed frequency of heterozygosity at the HLA-F polymorphism was 95% and the locus was found to be informative in pedigrees that are not informative at HLA-A and D6S105. By fluorescence in situ hybridization analysis, Hashimoto et al. (1995) mapped the HFE gene to chromosome 6p22. Heterogeneity Edwards et al. (1981) suggested that 2 families reported by Wands et al. (1976) and Rowe et al. (1977) may have had a rare distinct form of hemochromatosis. In these families, neither serum ferritin concentration nor transferrin saturation was a reliable indicator of hepatic siderosis and fibrosis. Hepatic fibrosis was observed in some individuals with a very modest increase in hepatic iron and in a few individuals with normal hepatic iron content. The disorder appeared to be transmitted as an autosomal dominant. No HLA data were reported in these families. In Australia, Jazwinska et al. (1996) found that all patients of northern European origin with hemochromatosis were homozygous for the cys282-to-tyr mutation (C282Y; 613609.0001). The frequency was greater than 90% in Brittany (Jouanolle et al., 1996). However, in Italy, Carella et al. (1997) performed mutation analysis on the HFE gene in patients from families with the 6p-linked disease but without the C282Y mutation and failed to find nucleotide abnormalities in coding sequences and intron/exon boundaries that could account for the disorder. The negative findings of RNA-SSCP were supported by the absence of mutations in the HFE gene by direct sequencing. Major deletions or rearrangements of the gene were excluded by Southern blotting. Carella et al. (1997) concluded that hemochromatosis in Italy appears to be more heterogeneous than reported in northern Europe, and suggested abnormalities in unexplored portions of introns, RNA untranslated regions, regulatory elements, or another tightly linked locus as alternative possibilities for the cause of the disorder. Studies by Carella et al. (1997) and Piperno et al. (1998) indicated that only 64% of patients with hemochromatosis in Italy were homozygous for the C282Y mutation. In commenting on the report of Carella et al. (1997), Beutler (1997) pointed to the 0.01 gene frequency in the Italian population, which is considerably lower than in persons of European ancestry who have been studied in the United States and in northern Europe. In agreement with the data from this southern European population, Beutler and Gelbart (1997) found that among nearly 400 Ashkenazi Jews the gene frequency of the C282Y mutation was only 0.013, compared with 0.07 in the non-Jewish American white population. These findings and those of Carella et al. (1997) seem consistent with the putative Celtic origin of the C282Y mutation (Jazwinska et al., 1995). Molecular Genetics In patients with hereditary hemochromatosis, Feder et al. (1996) identified 2 mutations in the HFE gene (C282Y; 613609.0001 and 613609.0002). The C282Y mutation was detected in 85% of all HFE chromosomes, indicating that in their population 83% of hemochromatosis cases are related to C282Y homozygosity. Beutler et al. (1997) pointed out that calreticulin (CALR; 109091), like beta-2-microglobulin (B2M; 109700), associates with class I HLA proteins and appears to be identical to mobilferrin, a putative iron transport protein. Thus these 2 proteins were considered candidates for mutations in patients with hemochromatosis. The investigators sequenced the coding region and parts of introns of the HFE gene (called by them HLA-H), the B2M gene, and the CALR gene in 10, 7, and 5 hemochromatosis patients, respectively, selecting those who were not homozygous for the common C282Y mutation. No additional mutations were found in the HLA-H gene and no disease related mutations in the other 2 genes. The authors noted that the basis for hemochromatosis in more than 10% of European patients and in most Asian patients awaits explanation. Beutler et al. (1997) speculated that the finding of some effects in heterozygotes (Bulaj et al., 1996) and the rarity of mutations other than C282Y and his63 to asp (H63D; 613609.0002) may point to a gain-of-function consequence of these mutations, similar, they suggested, to sickle cell anemia, which is caused by only 1 type of mutation (see 141900.0038) and represents in effect a gain-of-function mutation. The unique mutation causing achondroplasia, gly380 to arg (G380R; 134934.0001), might also be cited. By sequence analysis of exons 2, 3, 4, and 5, and portions of introns 2, 4, and 5 of the HFE gene, Barton et al. (1999) identified novel mutations in 4 of 20 hemochromatosis probands who lacked C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity. Probands 1 and 2 were heterozygous for the previously undescribed mutations ile105 to thr (I105T; 613609.0009) and gly93 to arg (G93R; 613609.0010). Probands 3 and 4 were heterozygous for the previously described but uncommon HFE mutation ser65 to cys (S65C; 613609.0003). Proband 3 was also heterozygous for C282Y and had porphyria cutanea tarda (see 176100), and proband 4 had hereditary stomatocytosis (185000). Each of these 4 probands had iron overload. In each proband with an uncommon HFE coding region mutation, I105T, G93R, and S65C occurred on separate chromosomes from those with the C282Y or H63D mutations. Neither I105T, G93R, nor S65C occurred as spontaneous mutations in these probands. In 176 normal control subjects, 2 were heterozygous for S65C, but I105T and G93R were not detected. Griffiths and Cox (2000) reviewed the molecular pathophysiology of iron metabolism. Pietrangelo (2004) reviewed the various forms of hemochromatosis. In a useful diagram, he illustrated the polygenic nature and phenotypic continuum of hereditary hemochromatosis. The continuum involves age at onset, clinical severity, and contribution of host or environmental factors to expressivity. Intermediate phenotypes can result from combined heterozygous mutations (compound heterozygosity) or homozygous mutations of more than 1 hemochromatosis gene. For instance, the relatively mild phenotype associated with homozygous mutation of HFE can be aggravated and accelerated by a coexisting heterozygous mutation in a gene associated with a juvenile form of the disease, such as HAMP. The latter mutation, combined with a normally silent heterozygous HFE mutation, can also result in unexpected expression of disease. Lee et al. (2004) identified a patient with adult-onset hemochromatosis who was compound heterozygous for mutations in the HJV gene (G320V, 608374.0001; 608374.0007). ### Genetic Modifiers In patients with 'atypical' hemochromatosis, defined as having a discordant iron phenotype despite having the same HFE genotype, Hofmann et al. (2002) performed mutation analysis of the transferrin receptor-2 gene (TFR2), which is mutated in HFE3. Sib pairs homozygous for HFE C282T had a discordant phenotype in serum transferrin concentration and/or significant differences in liver fibrosis and liver enzyme levels. Also included were individuals who were not homozygous for C282Y, but who had evidence of iron excess. In a pair of brothers homozygous for the C282Y mutation, Hofmann et al. (2002) found a mutation in the TFR2 only in the brother with liver fibrosis, suggesting that TFR2 functions as a modifier for penetrance of the hemochromatosis phenotype when present with homozygosity for C282Y. The screening for mutations in all 18 exons indicated that mutations of the TFR2 gene are rare. Merryweather-Clarke et al. (2003) described 2 families who exhibited digenic inheritance of hemochromatosis. In family A, the proband had a JH phenotype and was heterozygous for the C282Y mutation in the HFE gene as well as a frameshift mutation in the HAMP gene (606464.0003). The proband's unaffected mother was also heterozygous for the HAMP frameshift mutation, but lacked the HFE C282Y mutation and was heterozygous for the HFE H63D mutation (613609.0002). In family B, there was a correlation between severity of iron overload, heterozygosity for a HAMP G71D mutation (606464.0004), and heterozygosity or homozygosity for the HFE C282Y mutation. The authors proposed that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation. Among 310 C282Y homozygous HFE patients, Le Gac et al. (2004) found 9 patients with an additional heterozygous HJV mutation, including the L101P (608374.0006) and G320V mutations. Iron indices of 8 of these patients appeared to be more severe than those observed in sex- and age-matched C282Y homozygotes without an HJV mutation. Mean serum ferritin concentrations of the 6 males with an HJV mutation were significantly higher than those of C282Y homozygous males without an HJV mutation. Using pretherapeutic serum ferritin levels in C282Y homozygotes as a marker of penetrance, Milet et al. (2007) found an association between a common T/C SNP in the 3-prime region of the BMP2 gene (112261), rs235756, and hemochromatosis penetrance. Mean ferritin level, adjusted for age and sex, was 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. The subjects studied were all homozygous for the common C282Y mutation. The results further suggested an interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV (608374), with a small additive effect of a SNP in BMP4 (112262). Le Gac et al. (2008) reported a 47-year-old woman of Sardinian descent who presented with mild hemochromatosis. Genetic analysis showed that she was homozygous for a deletion involving the entire HFE gene; however, her phenotype was relatively mild and similar to that of women homozygous for the common lower-penetrance C282Y mutation. The report indicated that additional genetic and environmental factors must play a role in the pathogenesis of the disease. Genotype/Phenotype Correlations Dadone et al. (1982) found saturation of transferrin above 62% to be the best simply measured indicator of genotype: homozygosity was accurately predicted in 92% of cases. The logarithmic scale of serum ferritin concentration was only 71% accurate. The frequency of the hemochromatosis gene was estimated at 0.069 +/- 0.020, corresponding to a heterozygote frequency of 0.13 and a homozygote frequency of 0.005. Barton et al. (1999) studied the phenotype-genotype correlation in 150 family members (72 males and 78 females) of 61 Caucasian American probands. Thirty-four of the family members had an HFE phenotype. Genotyping was limited to the 2 major alleles, C282Y and H63D. Among the family members, 92% of C282Y homozygotes, 34.5% of C282Y/H63D compound heterozygotes, and none of the H63D homozygotes had the HFE phenotype. In contrast, a few individuals heterozygous for one or the other allele had iron overload. Pseudodominant patterns of inheritance were not infrequently observed. Hence, phenotyping and genotyping are complementary in screening for hemochromatosis among family members of probands. Mura et al. (2001) studied 545 probands who were homozygous for the C282Y mutation (613609.0001), showed various signs of clinical hemochromatosis, and had been referred for treatment by phlebotomy. Iron loading was found to be significantly lower in females than in males and to be correlated with increasing age in both males and females. A study of 18 same-sex sib pairs showed no correlation of iron marker status between HH sibs and other sibs, indicating a variable phenotypic expression of iron loading independent of the HFE genotype. Mura et al. (2001) also found that transferrin saturation percentage was the best indicator of the hereditary hemochromatosis phenotype in young subjects, and serum ferritin concentration was the best marker of iron overload in these patients. The superoxide dismutase-2 (SOD2; 147460) val16 allele (147460.0001) has 30 to 40% lower enzyme activity and increases susceptibility to oxidative stress. Valenti et al. (2004) found a significantly increased frequency of the val16 allele among 217 unrelated patients with hereditary hemochromatosis who developed dilated or nondilated cardiomyopathy compared to HH patients without cardiomyopathy and controls (frequencies of 0.67, 0.45, and 0.52, respectively). The val/val genotype conferred a 10.1-fold increased risk for cardiomyopathy in the HH patients. The association was independent of cirrhosis, diabetes, arthropathy, and hypogonadism, and did not apply to ischemic heart disease. Valenti et al. (2004) concluded that the val16 allele increased the risk of cardiomyopathy due to iron overload toxicity and oxidation in HH patients as a result of decreased activity of the SOD2 enzyme. To test whether common HFE mutations that associate with this condition and predispose to increases in serum iron indices are overrepresented in diabetic populations, Halsall et al. (2003) determined the allele frequencies of the C282Y (613609.0001) and H63D (613609.0002) HFE mutations among a cohort of 552 patients with typical type 2 diabetes mellitus. There was no evidence for overrepresentation of iron-loading HFE alleles in type 2 diabetes mellitus, suggesting that screening for HFE mutations in this population is of no value. Diagnosis Early diagnosis of hemochromatosis by clinical features is difficult, but important because organ damage can be prevented by early therapy. Hepatic iron is the most sensitive index of preclinical disease; of noninvasive tests, serum ferritin is unreliable, whereas transferrin saturation correlates with hepatic iron content (Rowe et al., 1977; Edwards et al., 1977). Unexplained elevation of transferrin saturation should prompt study for hemochromatosis, and elevated serum iron is a diagnostically valuable finding which can be sought in relatives of full-blown cases. On the basis of data generated by an ongoing study of hemochromatosis in Brittany, France, Borecki et al. (1990) concluded that percent transferrin saturation is a reliable indicator of the homozygous state but that, contrary to previous studies, there is no evidence for partial expression of this value in heterozygotes. Phatak et al. (1998) reported that the prevalence of clinically proven and biopsy-proven hemochromatosis combined was 4.5 per 1,000 in a total sample of 16,031 primary care patients and 5.4 per 1,000 in white persons in the sample. The prevalence was higher in men than in women. Diagnosis was achieved by serum transferrin saturation, followed by the same test under fasting conditions and supplemented by serum ferritin levels. Patients with a fasting serum transferrin saturation of 55% or more and a serum ferritin level of 200 micro g/L or more with no other apparent cause were presumed to have hemochromatosis and were offered liver biopsy to confirm the diagnosis. Feder et al. (1996) viewed hemochromatosis as a model disorder for genetic testing since it is a frequent disorder and effective intervention, namely therapeutic phlebotomy, is available. Cox (1996) discussed the importance of their simple PCR-based test to detect homozygosity for the mutant hemochromatosis gene. Powell et al. (1998) pointed out that a DNA-based test for the HFE gene was commercially available, but its place in the diagnosis of hemochromatosis was still being evaluated. ### Screening for Hemochromatosis From a screening of 1,968 employees of 2 large corporations, Leggett et al. (1990) concluded that the prevalence of significant iron overload due to homozygous hemochromatosis warranting treatment is approximately 1 in 300 among Australians (predominantly Caucasians). They suggested that transferrin saturation should be included in adult health screening programs. Worwood et al. (1991) urged that a regular program be instituted for identifying homozygotes for hemochromatosis on the basis of ferritin concentrations and inviting these individuals to donate frequently to keep the ferritin concentration toward the lower end of the normal range. Such a program would be beneficial both to persons with this common disease and to the blood supply. In a discussion of the research priorities in hereditary hemochromatosis, Brittenham et al. (1998) commented on anticipating impediments for implementation of a screening program for the disorder: the risk that the genetic information resulting from screening might be used by insurers, employers, or others to deny health care coverage or services to persons identified as being at risk for iron overload; and concern that the diagnosis of hereditary hemochromatosis would lead to changes in self perception, family interactions, and risk-taking behaviors. Because of these considerations, education, counseling, and obtaining informed consent are all important. Looker and Johnson (1998) did a study to determine the prevalence of an initially elevated serum transferrin saturation and the prevalence of concurrently elevated serum transferrin saturation and serum ferritin levels in the adult population of the United States. They examined 15,839 men and nonpregnant women 20 years of age or older. Depending on the cut-off values used to determine serum transferrin saturation, the prevalence of initially elevated values ranged from 1 to 6%. Approximately 11 to 22% of those with elevated serum transferrin saturation had concurrently elevated serum ferritin levels. Looker and Johnson (1998) concluded that a hemochromatosis screening program that used a cut-off value of greater than 60% to define elevated serum transferrin saturation would identify 1.4 to 2.5 million U.S. adults for further testing. Hickman et al. (2000) noted that the measurement of transferrin saturation was not suitable for large-scale, automated population screening for HH. The authors developed an automated measurement of unsaturated iron binding capacity and screened 5,182 consecutive blood samples received by a hospital chemical pathology department over 28 consecutive days. Six hundred ninety-seven samples had a value of less than 30 micromoles/liter, the cutoff value for this study. In these samples, measurement of transferrin saturation identified 294 samples for further analysis. HFE C282Y genotyping was possible in 227 of these and identified 9 C282Y homozygotes and 44 C282Y heterozygotes. A clinical diagnosis of HH had been made independently in 2 of the 9 homozygotes. Hickman et al. (2000) concluded that this technique provided a cost-effective screening tool. Bulaj et al. (2000) examined the usefulness of genetic screening of relatives of probands with hemochromatosis. They studied 291 probands homozygous for mutations in the HFE gene who had presented to a clinic with signs or symptoms of hemochromatosis or who had elevated transferrin-saturation values. They identified 214 homozygous relatives of these 291 homozygous probands. Of the 113 male homozygous relatives (mean age, 41 years), 96 (85%) had iron overload, and 43 (38%) had at least 1 disease-related condition. Of the 52 men over 40 years of age, 27 (52%) had at least 1 disease-related condition. Of the 101 female homozygous relatives (mean age, 44 years), 69 (68%) had iron overload, and 10 (10%) had at least 1 disease-related condition. Of the 43 women over 50 years of age, 7 (16%) had at least 1 disease-related condition. If the proband had a disease-related condition, male relatives were more likely to have morbidity than if the proband had no disease-related condition. Bulaj et al. (2000) concluded that a 'substantial number' of homozygous relatives of patients with hemochromatosis, more commonly men than women, have conditions related to hemochromatosis that had not previously been detected clinically. Clinical Management Niederau et al. (1985) concluded that HH patients diagnosed in the precirrhotic stage and treated with therapeutic phlebotomy have a normal life expectancy, whereas cirrhotic patients have a shortened life expectancy and a high risk of liver cancer even when complete iron depletion has been achieved. Siemons and Mahler (1987) found that phlebotomy conducted over a 16-month period restored fertility and normal endocrinologic findings in a 37-year-old man with severe hypogonadotropic hypogonadism due to hemochromatosis. Barton et al. (1998) recommended that therapeutic phlebotomy to remove excess iron be initiated in men with serum ferritin levels of 300 micrograms/L or more and in women with serum ferritin levels of 200 micrograms/L or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of removal of 450 to 500 mL of blood weekly until the serum ferritin level is 10 to 20 micrograms/L, and maintenance of the serum ferritin level at 50 micrograms/L or less thereafter by periodic removal of blood. Treatment before the development of complications can prevent them; in patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoods. This can reduce the rate of iron reaccumulation, reduce retention of nonferrous metals, and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection. Population Genetics The frequency of the hemochromatosis gene in Utah was placed at 5.6% (Cartwright et al., 1979). Homozygotes had a frequency of 0.3% and heterozygotes a frequency of 10.6%. A similar gene frequency was estimated for Brittany (Beaumont et al., 1979). Krikker (1982) described the newly established Hemochromatosis Research Foundation, Inc. As justification for its existence, Krikker wrote as follows: 'The incidence of heterozygosity for the hemochromatosis allele in the white population is approximately 10%. The expected incidence of homozygosity is about 2 to 3 per 1000, an estimate supported by the finding of homozygosity in 1 in 333 residents of Utah (Cartwright et al., 1979), 1 in 400 Bretons (Beaumont et al., 1979), and in an autopsy study 1 in 500 Scots (MacSween and Scott, 1973).' In an extensive study of hemochromatosis in Brittany, Lalouel et al. (1985) confirmed the Salt Lake City data (Cartwright et al., 1979; Kravitz et al., 1979). In the county of Jamtland in central Sweden, an area known in the past for a high prevalence of iron deficiency, Olsson et al. (1983, 1984) screened for iron overload by a laboratory routine that automatically included determination of serum iron and transferrin saturation. They found a prevalence of 0.5% for genetic iron overload, which suggested that 12.8% of the population are gene carriers. Meyer et al. (1987) used serum ferritin concentration as a screening test for iron overload in 599 Afrikaners living in the South Western Cape, South Africa. Sixteen subjects, all males from different families, had concentrations greater than 400 micrograms/L. Reevaluations 3 and 5 years later included remeasurement of serum ferritin, assessment of alcohol intake, measurements of serum gamma-glutamyltransferase, percentage saturation of transferrin, and HLA typing. The serum ferritin concentration is significantly raised after excessive alcohol consumption; however, the measurement of serum gamma-glutamyltransferase helps resolve the confusion because a serum ferritin concentration above 300 micrograms/L is very unlikely to be the result of alcohol-induced hepatic damage if the gamma-glutamyltransferase is less than 50 units per liter. Of the 16 index persons, 4 were diagnosed as homozygous for the HLA-linked iron-loading gene. Six appeared to be heterozygotes, 3 were heterozygotes who were also abusing alcohol, and 2 did not fit into any of the diagnostic groups. The calculated gene frequency was 0.082, with an expected heterozygote frequency of 0.148. The fact that no females were identified in the study suggested to the authors that their criteria for homozygosity were set too high. When the data were recalculated for the 300 males, the gene frequency became 0.115 and the heterozygote frequency became 0.204. Simon et al. (1987) presented findings they interpreted as fitting well with the hypothesis that 'the hemochromatosis mutation was a rare if not unique event that produced an ancestral HLA marking that was subsequently modified by recombinations and geographical scattering due to migrations.' Among 11,065 presumably healthy blood donors (5,840 men and 5,225 women), Edwards et al. (1988) found that transferrin saturation of 62% or more after an overnight fast had a frequency of 0.008 in men and 0.003 in women. Detailed studies were performed in 38 persons with values higher than 62%; 35 underwent liver biopsy. Liver iron stores ranged from normal to markedly increased. Twelve sibs with an identical HLA match to a proband underwent liver biopsy, and 11 had increased liver iron stores. Analysis of pedigrees led to the conclusion that 26 of the 38 probands were homozygotes and 12 were heterozygotes. Basing the estimate of the frequency of homozygosity on the data in men, Edwards et al. (1988) arrived at an estimate of 0.0045, corresponding to a gene frequency of 0.067. By means of a screening using transferrin saturation followed by repeat transferrin saturation and serum ferritin, clinical examination, and laparoscopy, Karlsson et al. (1988) concluded that the prevalence of hemochromatosis in Finland is about 5 per 10,000. Milman et al. (1990) studied 1 Faroese and 4 Danish kindreds with hemochromatosis. Milman (1991) analyzed 179 patients ascertained in Denmark between 1950 and 1985, as well as 13 preclinical subjects ascertained through family studies or high serum transferrin-saturation values. The high frequency of the HFE gene may account, through the mechanism of pseudodominance, for the simulation of dominant inheritance and the consequent debates in the past as to the mode of inheritance of hemochromatosis. Dokal et al. (1991) reported on a family with affected members in 2 generations in a pseudodominant pedigree pattern. The affected father was deceased. The heterozygous mother and all 6 children (3 homozygotes, 3 heterozygotes) were HLA identical (A1B8/A3B14). Affected sibs were recognized in the precirrhotic stage of hemochromatosis by analysis of serum parameters of iron status in combination with magnetic resonance imaging. In the Saguenay-Lac-Saint-Jean region of northeastern Quebec, De Braekeleer (1993) estimated the prevalence of hereditary hemochromatosis to be 0.014, giving a heterozygote frequency of 0.21. These were among the highest frequencies found in white populations. Fertility studies showed that carriers of the gene tended to have more children than noncarriers. However, since the differences were not statistically significant, genetic drift could not be excluded. In an analysis of 82 unrelated HFE patients and 82 unrelated healthy controls, Jazwinska et al. (1993) found that allele 8 at the D6S105 locus was present in 93% of patients and only 21% of controls, giving an approximate relative risk for this allele of 48.4. HLA-A3 was present in 62% of patients and 26% of controls, giving an approximate relative risk for A3 of 4.8. They concluded that the microsatellite marker D6105 was the closest marker to HFE reported to that date. Jazwinska et al. (1995) found that hemochromatosis shows a very strong founder effect in Australia, with the majority of patients being of Celtic (Scottish/Irish) origin. By analyzing chromosomes from 26 multiply affected hemochromatosis pedigrees for linkage disequilibrium and genetic heterogeneity, they were able to assign hemochromatosis status unambiguously to 107 chromosomes: 64 as affected and 43 as unaffected. With the serologic marker HLA-A and 4 microsatellite markers, highly significant allelic association with hemochromatosis was found. One predominant ancestral haplotype was present in 33% of 64 affected chromosomes and was associated exclusively with hemochromatosis (haplotype relative risk 903). No other common haplotype was significantly associated with hemochromatosis. Thus, the common mutation probably underlies hemochromatosis in Australian patients, having been introduced into this population on an ancestral haplotype. Furthermore, the candidate HFE region extends between and includes D6S248 and D6S105. Pozzato et al. (2001) found a high prevalence of HFE gene mutations in the Cimbri population of the Asiago plateau, situated in the Italian region of Veneto. The Cimbri population descends from an ancient tribe of Celtic ancestry who settled on the plateau around the 2nd century B.C. and who preserved their independence and ethnic integrity. In 103 unrelated blood donors with parents and grandparents born in the Asiago plateau, the allele frequencies of the C282Y and H63D mutations were 0.048 and 0.174, respectively. The study confirmed the high prevalence of HFE gene mutations in Celtic populations, and the authors speculated that these mutations gave them selective advantages because of their iron-poor diet. They theorized that a larger amount of iron can be transferred from the mother through the placenta, reducing perinatal mortality and morbidity. Using a relative risk of 1.0 for the C282Y homozygote, Risch (1997) calculated the risk of the C282Y/H63D compound heterozygote to be 0.00525 and the relative risk of other genotypes to be 0.00015. There appeared to be a modestly increased risk (about 4-fold) associated with homozygosity for H63D. Great haplotype diversity on non-C282Y chromosomes had been observed in patients. This was not surprising, as the disequilibrium on H63D chromosomes spans a much shorter distance (700 kb) than on C828Y chromosomes (more than 7 Mb), consistent with the higher frequency and likely older origin for H63D. Indeed, the disequilibrium analysis of H63D chromosomes provided compelling evidence both for the implication of H63D in hemochromatosis and that HFE is the hemochromatosis gene. Beckman et al. (1997) found that the C282Y mutation is rare or absent in Asiatic (Indian, Chinese) populations. The highest allele frequency they found was in Swedes (7.5%). Parkkila et al. (1997) suggested a selective advantage of the C282Y mutation on the basis of improved survival during infancy, childhood, and pregnancy in times past, by leading to increased iron absorption and accumulation of larger body iron stores. Although this selection could operate at the level of increased dietary iron absorption, such mutations might also lead to enhanced maternal/fetal iron transport. Such an effect might confer a selective advantage on the fetus under conditions of maternal iron deprivation. Burt et al. (1998) determined the frequency of the C282Y and H63D HFE mutations in randomly selected adults from Christchurch, New Zealand. Heterozygote frequencies were 13.2% for C282Y and 24.3% for H63D. Heterozygotes for both alleles had significantly higher serum iron concentrations and transferrin saturations; only C282Y heterozygotes had significantly higher serum ferritin concentrations. Five individuals were homozygous for the C282Y mutation; 3 (2 females aged 38, and 1 male aged 71) had persistently elevated serum ferritin levels and liver biopsy findings consistent with hemochromatosis. The remaining 2 C282Y homozygotes (2 females aged 20 and 31) did not have elevated ferritin levels and were not biopsied. The authors commented that the population frequency of C282Y homozygosity was approximately 1 in 200 and that population screening programs should restrict genotyping to individuals with an elevated transferrin saturation. Steinberg et al. (2001) estimated the prevalence of the C282Y and H63D mutations in the U.S. population as 5.4% and 13.5%, respectively. The prevalence estimates of homozygosity for the C282Y and H63D mutations were 0.26% and 1.89%, respectively, and 1.97% for compound heterozygosity for these 2 alleles. The prevalence estimate for C282Y heterozygosity was 9.54% among non-Hispanic whites, 2.33% among non-Hispanic blacks, and 2.75% among Mexican Americans. The prevalence estimates for HFE mutations were within the expected range for non-Hispanic whites and blacks, but were less than expected for the C282Y mutation among Mexican Americans. Merryweather-Clarke et al. (1999) retrospectively analyzed 837 random dried blood spot samples from neonatal screening programs in Scandinavia for mutations in the HFE gene. They found that the C282Y allele had a frequency of 2.3% in Greenland, 4.5% in Iceland, 5.1% in the Faroe Islands, and 8.2% in Denmark. The high prevalence of HFE mutations in Denmark suggested that population screening for C282Y could be highly advantageous in terms of preventive health care. Furthermore, long-term follow-up evaluation of C282Y homozygotes and H63D/C282Y compound heterozygotes would provide an indication of the penetrance of the mutations. Rochette et al. (1999) stated that over 80% of hemochromatosis patients are homozygous for the C282Y mutation in the unprocessed protein. In a proportion of these patients, compound heterozygosity is found for C282Y and H63D. The clinical significance of the second mutation is such that it appears to predispose 1 to 2% of compound heterozygotes to expression of the disease. The distribution of the 2 mutations differs, C282Y being limited to those of northwestern European ancestry, and H63D being found at allele frequencies of more than 5% in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends 6 Mb or less, suggesting that this mutation arose during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending 700 kb or less. Rochette et al. (1999) found the H63D and C282Y mutations on new haplotypes. In Sri Lanka, they found H63D on 3 new haplotypes and found C282Y on 1 new haplotype, demonstrating that these mutations have arisen independently on this island. The results suggested that the HFE gene has been subject to selection pressure. In a population of white adults of northern European ancestry in Busselton, Australia, Olynyk et al. (1999) found that 0.5% were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one-quarter had serum ferritin levels that remained normal over a 4-year period. Brown et al. (2001) used National Hospital Discharge Survey and census data to estimate hemochromatosis-associated hospitalization rates for persons 18 years of age and over. From 1979 to 1997, the rate of hemochromatosis-associated hospitalizations was 2.3 per 100,000 persons in the U.S. The rate among persons 60 years of age and over increased more than 60% during this time. Barton and Acton (2001) screened 1,373 African American controls in 5 regions of the U.S. for the C282Y and H63D mutations in the HFE gene. The frequency of the C282Y/C282Y genotype was 0.00011; that of C282Y/H63D, 0.00067; and that of H63D/H63D, 0.0101. Penetrance-adjusted estimates indicated that approximately 9 per 100,000 African Americans have a hemochromatosis phenotype and 2 common HFE mutations. Hemochromatosis-associated genotype frequencies varied 11.7-fold across regions. De Juan et al. (2001) analyzed the frequency of the C282Y, H63D, and S65C (613609.0003) HFE gene mutations in 35 unrelated HH patients from the Basque population. Only 20 (57.1%) of the patients were homozygous for the C282Y mutation, while 5 patients were compound heterozygous for C282Y/H63D or H63D/S65C. Eight patients were heterozygous for 1 of the 3 mutations, and 2 patients lacked any of the mutations studied. In a control group of 116 healthy blood donors of Basque origin, de Juan et al. (2001) found allele frequencies of 29.7%, 5.2%, and 3.0% for the H63D, C282Y, and S65C mutations, respectively. The authors suggested that the peculiar genetic characteristics of the Basques could explain the heterogeneity of HH genotypes found in this study, and the presence of other genetic and external factors could explain the severe iron overload and HH in some of the H63D heterozygotes and no mutated genotypes. The C282Y mutation probably occurred on a single chromosome carrying the ancestral hemochromatosis haplotype, which subsequently was spread by emigration and founder effect. The C282Y mutation is thought to have appeared 60 to 70 generations ago. Milman and Pedersen (2003) hypothesized that the distribution of the C282Y mutation in Europe is consistent with an origin among the Germanic Iron Age population in southern Scandinavia. From this area, the mutation could later be spread by the migratory activities of the Vikings. Milman and Pedersen (2003) found several arguments in favor of the 'Viking hypothesis': first, the highest frequencies (5.1 to 9.7%) of the C282Y mutation are observed in populations in the northern part of Europe, i.e., Denmark, Norway, Sweden, Faroe Islands, Iceland, eastern part of England and the Dublin area, all Viking homelands and settlements. Second, the highest allele frequencies are reported among populations living along the coastlines. Third, the frequencies of the C282Y mutation decline from northern to southern Europe. Intermediate allele frequencies (3.1 to 4.8%) are seen in populations in central Europe. Low allele frequencies (0 to 3.1%) are recognized in populations in southern Europe and the Mediterranean. Distante et al. (2004) reviewed the evidence on C282Y frequencies, extended haplotypes involving HLA-A and HLA-B alleles, calculations of mutation age, selective advantage, and the relative importance of population migration and cultural change in the neolithic transition in Europe. They concluded that the C282Y mutation occurred in mainland Europe before 4000 B.C. In a study of 645 Native Americans compared with 43,453 white participants in a hemochromatosis and iron overload screening study, Barton et al. (2006) found that the allele frequencies of HFE C282Y and H63D were significantly lower in Native Americans than in whites. Matas et al. (2006) studied the prevalence of the C282Y and H63D mutations in 255 non-Ashkenazi Jewish individuals. Analysis of 24 patients who were H63D homozygotes revealed that 12 had secondary causes of iron overload; of those who did not, 2 had symptomatic hemochromatosis, whereas the remaining 10 had only altered iron metabolism, particularly elevated ferritin, without clinical symptoms. Matas et al. (2006) concluded that homozygosity for the H63D mutation confers an increased risk of iron overload and therefore genetic susceptibility to developing hereditary hemochromatosis. ### HLA Association In 50 unselected and unrelated patients with hemochromatosis, Ritter et al. (1984) found a high association with the HLA haplotype A3B14 (relative risk 23.4). One family with this haplotype was traced back to the end of the seventeenth century. Ritter et al. (1984) suggested that the high frequency of the hemochromatosis gene might be the result of a selective advantage of increased iron sequestration under conditions of iron deficiency: homozygous males would not lose reproductive capacity from effects of iron deficiency on testicular function, and females, homozygous and perhaps heterozygous as well, would be better prepared to meet the increased iron demands of pregnancy. Simon et al. (1988) suggested that a single ancient mutation of a gene involved in iron homeostasis resulted in the present-day hemochromatosis allele. This mutation was thought to have occurred on a chromosome 6 carrying HLA-A3 and HLA-B7. Over the years recombination events between the HLA-A and HLA-B loci presumably led to the observed association with other HLA-B alleles on haplotypes carrying HLA-A3, and recombinations between HLA-A and the hemochromatosis locus produced associations with other HLA-A alleles and haplotypes. The original mutation should be progressing toward equilibrium with the HLA alleles, with the residual association resulting either because there has been insufficient time to reach equilibrium or because the association confers a selective advantage (Kushner et al., 1988). A recent recombination event or perhaps a new mutation has placed a hemochromatosis allele on an HLA-A2,B12 chromosome in a population that made a major contribution to the present-day Australian gene pool. Because of the predominant origin of the present-day Australian population, Summers et al. (1989) suggested that this chromosome originated in England or perhaps, in view of the family names of many of the patients, Ireland. Jouanolle et al. (1990) studied RFLPs from the HLA-A region and identified a significantly high frequency of a particular EcoRI fragment among the hemochromatosis patients who were HLA-A3 in tissue type. In Denmark, Milman et al. (1988) found the pattern of HLA antigens associated with hemochromatosis to be similar to those reported both in Germany, where HLA-A3,B7 dominated, and in Brittany, Great Britain, and central Sweden, where HLA-A3,B14 dominated. In 74 Danish patients with hemochromatosis and 21 homozygous relatives, Milman et al. (1992) found atypical frequencies of HLA type: A3 was present in 53.6% as compared to 15.1% in the general population. B7 was present in 33.1% as compared with 15.6% in the general population. The 2 most frequent haplotypes were A3,B5 (10.3% vs 0.3%) and A3,B7 (25.6% vs 6.6%). In South Wales, Cragg et al. (1988) found that 80% of 15 unrelated patients had HLA-A3 compared with 24% of 600 unrelated and unaffected persons. The most common haplotype was HLA-A3,B7. They found no evidence in support of the possibility that either the ferritin heavy chain gene (134770) or HLA class I genes are candidates for the gene mutant in hemochromatosis. In studies of 24 Australian families, Summers et al. (1989) found linkage to HLA in at least 23. The evidence was interpreted as indicating the involvement of a single genetic locus in most (probably all) cases of familial hemochromatosis in Australia. As in all other populations reported, an association of HLA-A3 and HLA-B7 with the disease was found in the Australian cases. In addition, HLA-A2 and HLA-B12 were in significant linkage disequilibrium in patients but not in controls, which might indicate a new mutation or recent recombination between HLA-A and hemochromatosis either in the Australian patient population or in the founding population. In a review of 57 families with hereditary hemochromatosis, Adams (1992) found 3 pairs of HLA-identical, sex-matched sibs in which the younger sib demonstrated considerably more iron loading than the older sib. In 19 pairs of HLA-identical, sex-matched sibs homozygous for hemochromatosis, the iron loading was more marked in the older sib. There was no evidence of blood loss, difference in alcohol consumption, or dietary iron loading to explain the increased iron loading in the younger sibs. Yaouanq et al. (1992) used 5 biallelic polymorphisms located in the HLA class I region to test 198 HLA-typed subjects from the families of 22 hemochromatosis patients. The 5 polymorphisms provided sufficient information to identify unequivocally extended restriction haplotypes in all families. The restriction haplotypes cosegregated with the HFE allele and enabled identification of genotypically identical sibs in all families studied. The method avoids the disadvantages of HLA serologic typing and should be useful for genetic counseling in HFE families. Pathogenesis By immunocytochemistry and Western blot analysis, Waheed et al. (1999) showed that the HFE protein colocalizes with and is physically associated with the transferrin receptor (TFRC; 190010) and beta-2-microglobulin (BM2; 109700) in human duodenal crypt enterocytes. Crypt enterocytes exhibited dramatically higher transferrin (TF; 190000)-bound iron uptake than villus cells, but villus cells showed 2 to 3 times higher uptake of ionic iron than crypt cells. Waheed et al. (1999) proposed that the HFE protein modulates the uptake of transferrin-bound iron from plasma by crypt enterocytes and participates in the mechanism by which the crypt enterocytes sense the level of body iron stores. Impairment of this function caused by HFE gene mutations in hereditary hemochromatosis could provide a paradoxical signal in crypt enterocytes that programs the differentiating enterocytes to absorb more dietary iron when they mature into villus enterocytes. The hypothesis put forward by Waheed et al. (1999) was tested by Fleming et al. (1999), who demonstrated that in homozygous Hfe-deficient mice an increased duodenal expression of the divalent metal transporter (DMT1; 600523) occurred. Using Northern blot analyses, they quantitated duodenal expression of both classes of DMT1 transcripts: 1 containing an iron-responsive element (IRE), called DMT1(IRE), and 1 containing no IRE, called DMT1(non-IRE). Hfe homozygous deficient mice demonstrated an increase in duodenal DMT1(IRE) mRNA (average, 7.7-fold), despite their elevated transferrin saturation and hepatic iron content. Duodenal expression of DMT1(non-IRE) was not increased, nor was hepatic expression of DMT1 increased. These data supported the model for hemochromatosis in which HFE mutations lead to inappropriately low crypt cell iron, with resultant stabilization of DMT1(IRE) mRNA, upregulation of DMT1, and increased absorption of dietary iron. At the cell surface, HFE complexes with TFRC, increasing the dissociation constant of transferrin (TF) for its receptor 10-fold. HFE does not remain at the cell surface, but traffics with TFRC to transferrin-positive internal compartments. Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, Roy et al. (1999) showed that the expression of HFE reduced uptake of radioactive iron from TF by 33%, but did not affect the endocytic or exocytic rates of TFRC cycling. Therefore, HFE appears to reduce cellular acquisition of iron from TF within endocytic compartments. HFE specifically reduces iron uptake from TF, as non-TF-mediated iron uptake from Fe-nitrilotriacetic acid was not altered. These results explained the decreased ferritin levels seen in the HeLa cell system, and demonstrated the specific control of HFE over the TF-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in persons with hereditary hemochromatosis lacking functional HFE. By Northern blot and competitive RT-PCR analyses, Zoller et al. (1999) detected enhanced expression of the duodenal metal transporter NRAMP2 (SLC11A2; 600523) in the duodenum of HFE patients compared to controls. Sequence analysis failed to detect mutations in NRAMP2 in the 7 patients or 2 controls. The authors proposed that patients with a defective HFE gene and iron-depleted duodenal cells have a compensatory increase in the expression of NRAMP2 and that its blockade may be a key to successful therapy of HFE. Townsend and Drakesmith (2002) proposed a molecular model for the function of HFE protein and the mechanism by which mutations in HFE lead to hereditary hemochromatosis. They proposed that HFE has 2 mutually exclusive activities in cells: inhibition of uptake or inhibition of release of iron. The balance between serum transferrin saturation and serum transferrin-receptor concentrations determines which of these functions predominates. With this input, HFE enables the intestinal crypt cells and reticuloendothelial system to interpret the body's iron requirements and regulate iron absorption and distribution. Townsend and Drakesmith (2002) suggested that mutations in the HFE gene result in the overabsorption of dietary iron with iron deposition in tissues. The patterns of tissue iron deposition, e.g., in the liver, are consistent with clinical observations of organ dysfunction in hereditary hemochromatosis. Zoller et al. (2003) studied the mRNA and protein expression and activity of cytochrome b reductase-1 (CYBRD1; 605745) in duodenal biopsies of patients with iron deficiency anemia, hereditary hemochromatosis, and controls. They found that CYBRD1 activity in iron deficiency is stimulated via enhanced protein expression, whereas in hemochromatosis due to mutations in the HFE gene it is upregulated posttranslationally. Hemochromatosis patients with no mutations in HFE did not have increased CYBRD1 activity. Zoller et al. (2003) concluded that there are different kinetics of intestinal iron uptake between iron deficiency and hemochromatosis due to mutations in HFE, and that duodenal iron accumulation in hereditary hemochromatosis due to mutations in HFE and hereditary hemochromatosis due to mutations in other genes is pathophysiologically different. Drakesmith et al. (2005) found that the Nef protein of human immunodeficiency virus-1 (HIV-1) downregulated macrophage-expressed HFE. Iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wildtype HFE. The effect was lost with Nef-deleted HIV-1 or with infected macrophages from hemochromatosis patients expressing mutant HFE. Iron accumulation in HIV-1-infected wildtype macrophages was paralleled by increased cellular HIV-1 Gag protein expression. Animal Model De Sousa et al. (1994) reported a comparative histologic and quantitative analysis of iron distribution in the tissues of mice homozygous and heterozygous for knockout of the beta-2-microglobulin gene, which is complexed with HLA class I molecules. Progressive hepatic iron overload, indistinguishable from that observed in human hemochromatosis, was found only in mice homozygous for the mutated B2M gene. Rothenberg and Voland (1996) identified a multigene system in the murine major histocompatibility complex that contains excellent candidates for the murine equivalent of the human HFE locus and implicates nonclassic class I genes in the control of iron absorption. This gene system is characterized by multiple copies of 2 head-to-head genes encoded on opposite strands and driven by a common regulatory motif. This regulatory motif has striking homology to the promoter region of the beta-globin gene (141900), a gene obviously involved in iron metabolism, and hence termed beta-globin analogous promoter, beta-GAP or BGAP. Upstream of the BGAP sequence are nonclassic class I genes. At least 1 of these nonclassic class I genes, Q2, is expressed in the gastrointestinal tract, the primary site of iron absorption. Also expressed in the gastrointestinal tract and downstream of the BGAP motif is a second set of putative genes, termed Hephaestus (HEPH). Based on these observations, Rothenberg and Voland (1996) hypothesized that the genes that seemed to be controlled by BGAP regulatory motifs would be responsible for the control of iron absorption. As a test of this hypothesis, they predicted that mice with altered expression of class I gene products, the beta-2-microglobulin knockout mice, would develop iron overload. This prediction was confirmed, and these results indicated to the authors that B2M-associated proteins are involved in the control of intestinal iron absorption and are strong candidates for the site of the mutation in hemochromatosis. The most frequent mutation in the HFE gene responsible for hemochromatosis, C282Y (613609.0001), interferes with the binding of beta-2-microglobulin to the HFE gene product. Many individuals homozygous for the defective allele of the HFE gene do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the hereditary hemochromatosis phenotype. Mice deficient in the product of the B2M class I light chain fail to express HFE and other class I MHC family proteins, and they have been found to manifest many characteristics of the hereditary hemochromatosis phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, Sproule et al. (2001) performed classic genetic analysis of the iron-loading phenotype in B2M-deficient mice in the context of different genetic backgrounds. They found that strain background was a major determinant in iron loading. Sex played a smaller but still significant role. Resistance and susceptibility to iron overload segregated as complex genetic traits in F1 and backcross progeny. These results suggested the existence of naturally variant autosomal and Y chromosome-linked modifier loci that, in the context of mice genetically predisposed by virtue of B2M deficiency, can profoundly influence the severity of iron loading. These results thus provided a genetic explanation for some of the variability of the hereditary hemochromatosis phenotype in humans. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, Zhou et al. (1998) studied the effects of a targeted disruption of the murine homolog of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates, and hepatic iron concentration was 8-fold higher than that of wildtype littermates. Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different from that in littermates. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. The study showed that HFE protein is involved in the regulation of iron homeostasis and that mutations in the gene are responsible for hereditary hemochromatosis. Beutler (1998) emphasized the pathologic and clinical importance of the knockout mouse model for hemochromatosis. The puzzling linkage between genetic hemochromatosis and the histocompatibility loci became even more puzzling when the gene involved, HFE, was identified. Indeed, within the well-defined, mainly peptide-binding, MHC-class I family of molecules, HFE seems to perform an unusual but essential function. Understanding of HFE function in iron homeostasis was only partial; an even more open question was its possible role in the immune system. To advance knowledge in both of these areas, Bahram et al. (1999) studied deletion of the HFE alpha-1 and alpha-2 putative ligand-binding domains in vivo. HFE-deficient mice were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion developed iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allowed a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. However, extensive phenotyping of primary and secondary lymphoid organs including the gut provided no compelling evidence for an obvious immune-linked function for HFE. Clinical studies have demonstrated that the severity of iron loading is highly variable among individuals with identical HFE genotypes. To determine whether genetic factors other than Hfe genotype influence the severity of iron loading in the murine model of hereditary hemochromatosis, Fleming et al. (2001) bred the disrupted murine Hfe allele onto 3 different genetically defined mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron status and sensitivity to dietary iron loading. Although the Hfe -/- mice from all 3 strains demonstrated increased transferrin saturations and liver iron concentrations compared with Hfe +/+ mice, strain differences in severity of iron accumulation were striking. Targeted disruption of the Hfe gene led to hepatic iron levels in Hfe -/- AKR mice that were 2.5 or 3.6 times higher than those of Hfe -/- C3H or Hfe -/- C57BL/6 mice, respectively. The Hfe -/- mice also demonstrated strain-dependent differences in transferrin saturation, with the highest values in AKR mice and the lowest values in C3H mice. These observations demonstrated that heritable factors markedly influence iron homeostasis in response to Hfe disruption. The authors suggested that analysis of mice from crosses between C57BL/6 and AKR mice should allow the mapping and subsequent identification of genes modifying the severity of iron loading in this murine model of hereditary hemochromatosis. Both in humans and in mouse models, hereditary hemochromatosis is associated with a paucity of iron in reticuloendothelial cells. It has been suggested that HFE modulates uptake of transferrin-bound iron by undifferentiated intestinal crypt cells, thereby programming the absorptive capacity of enterocytes derived from these cells (Trinder et al., 2002). Although the expression of mouse hepcidin (HAMP; 606464), a hepatic regulator of iron transport, is normally greater during iron overload, Hfe -/- mice have inappropriately low expression of Hamp. Nicolas et al. (2003) crossed Hfe -/- mice with transgenic mice overexpressing Hamp and found that Hamp inhibited the iron accumulation normally observed in the Hfe -/- mice. They suggested that the findings argued against the crypt programming model and suggested that failure of Hamp induction contributes to the pathogenesis of hemochromatosis, providing a rationale for the use of HAMP in the treatment of this disease. Muckenthaler et al. (2003) performed microarray assays to study the changes in duodenal and hepatic gene expression in Hfe-deficient mice. They found alterations in the expression of Hamp as well as unexpected alterations in the expression of Slc39a1 (the mouse ortholog of SLC40A1; 604653) and duodenal cytochrome b (CYBRD1), which encode key iron transport proteins. They proposed that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1. Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (HAMP; 606464) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. HAMP is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD. Roy et al. (2004) reported that mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggested a previously unidentified role for Hfe in innate immunity and ACD. Ludwiczek et al. (2007) found that the L-type calcium channel blocker nifedipine increased Dmt1 (600523)-mediated cellular iron transport in vitro. In Hfe-null mice and mice with secondary iron overload, nifedipine mobilized iron from the liver and enhanced urinary iron excretion. Mechanistically, the effect resulted from prolonging the iron-transporting activity of Dmt1 and delaying current inactivation. History The first description of hemochromatosis is attributed to Trousseau (1865). His first patient was a 28-year-old man with severe diabetes. Trousseau wrote: 'From the time this man came into the hospital, I was struck by the almost bronzed appearance of his countenance, and the blackish color of his penis.' At autopsy the liver was found to be very large. 'The entire surface of the organ was granular; it was of a uniform grayish-yellow color; it was very dense, resisting pressure so much as to prevent penetration by the finger. It creaked under the scalpel, and the surface of the cut was granular in place of being smooth.' The hereditary nature of hemochromatosis was emphasized particularly by Sheldon (1935). In his classic monograph entitled 'Haemochromatosis,' Sheldon (1935) reviewed references to a familial or hereditary basis of the disease made by 14 authors and stated: 'Further evidence is greatly desirable on this aspect of the disease, since the fact of an occasional familial incidence must obviously be taken into account in any theory regarding the origin of the disease.' The pedigree of Nussbaumer et al. (1952) was reproduced by Sorsby (1953). The ferritin heavy chain gene (FTH; 134770) was mapped to chromosome 11 by somatic cell hybridization (Hentze et al., 1986). Early in situ hybridization studies suggested that another FTH gene lies in the region 6p21.3-p12 (Cragg et al., 1985; McGill et al., 1987). David et al. (1989) noted that 2 H-type ferritin subunits had been identified in porcine spleen, tadpoles, and HeLa cells. suggesting that there may be a second functional FTH locus on chromosome 6. However, in 83 hemochromatosis patients and 84 controls as well as in 19 nuclear families, David et al. (1989) found no significant difference in the FTH gene using 10 restriction enzymes. The authors concluded that the genomic abnormality responsible for HH is not a major deletion of the FTH gene. Dugast et al. (1990) found that 2 human ferritin heavy chain genes lie near the hemochromatosis locus on 6p. One of these was shown to be a processed pseudogene. Comparison of its sequence with those of other FTH pseudogenes indicated that these pseudogenes may have derived from a functional FTH gene other than that on chromosome 11, raising the possibility that the other gene on 6p may be functional and may be the site of the mutation in hemochromatosis. Zappone et al. (1991) found no major deletions or alterations in the region of 6p containing these 2 ferritin H genes in patients with hemochromatosis. They also described a polymorphism in one of the genes that they had previously shown to be a processed pseudogene. The PIC value of the polymorphism was calculated as 0.49 and it did not correlated with HH. Using a somatic cell hybrid regional mapping panel for the short arm of chromosome 6, as well as linkage analysis in hemochromatosis families and a population study of hemochromatosis patients and normal individuals, Summers et al. (1991) concluded that the FTH pseudogene sequence on chromosome 6, described by Dugast et al. (1990), maps to 6p, centromeric to the glyoxalase (138750) locus and distant from the hemochromatosis locus. Thus, it was excluded as a candidate gene for hemochromatosis. Robson et al. (1997) reviewed the identification of the probable gene mutant in hemochromatosis. They pointed out that Simon et al. (1976) first reported the association between specific HLA antigens and hemochromatosis and that it took 20 years to identify the strongest candidate gene to that time. They emphasized that formal proof from functional studies was still required to prove that mutations in this gene cause hemochromatosis. They also discussed why the gene has proved so elusive. Lonjou et al. (1998) contrasted the general concepts of linkage and allelic association. Recombination acts on the genetic map, not on the physical map. On the other hand, the physical map is usually more accurate. Choice of the genetic or physical map for positional cloning by allelic association depends on the goodness of fit of data to each map under an established model. Huntington disease illustrates the usual case in which the greater reliability of physical data outweighs recombinational heterogeneity. Hemochromatosis represents an exceptional case in which unrecognized recombinational heterogeneity retarded positional cloning for a decade. In hemochromatosis, recombinational heterogeneity was demonstrated by the fact that the ratio of physical to genetic distance was 0.97 distally and 6.14 proximally. The power of allelic association was limited by scarcity of markers until microsatellites were introduced and subsequently by failure to recognize that 1 cM corresponds to several Mb in the region telomeric to HLA-A. Finally, HFE was shown to lie more distally than earlier assumed, but the preferred marker D6S105 was still nearly 2 Mb from HFE. Lonjou et al. (1998) suggested that allowance for nonuniform recombination would have saved a decade of fruitless search near HLA-A, 4.6 Mb from HFE. The reasons for preferring 'allelic association' to 'linkage disequilibrium' were spelled out by Edwards (1980). INHERITANCE \- Autosomal recessive CARDIOVASCULAR Heart \- Cardiomyopathy \- Congestive heart failure \- Arrhythmia \- Cardiomegaly RESPIRATORY Lung \- Pleural effusion ABDOMEN \- Abdominal pain \- Ascites Liver \- Cirrhosis \- Hepatomegaly \- Hepatocellular carcinoma Spleen \- Splenomegaly GENITOURINARY External Genitalia (Male) \- Impotence \- Testicular atrophy \- Azoospermia Internal Genitalia (Female) \- Amenorrhea SKELETAL \- Arthropathy \- Osteoporosis SKIN, NAILS, & HAIR Skin \- Hyperpigmentation \- Telangiectases Hair \- Alopecia ENDOCRINE FEATURES \- Diabetes mellitus \- Hypogonadotropic hypogonadism \- Abnormal glucose tolerance LABORATORY ABNORMALITIES \- Increased transaminases \- Increased serum iron \- Increased transferrin saturation (>60%) \- Increased serum ferritin \- Increased hepatic parenchymal cell stainable iron MISCELLANEOUS \- Affects between 1 in 200 to 1 in 400 individuals of northern European descent MOLECULAR BASIS \- Caused by mutation in the hereditary hemochromatosis gene (HFE, 613609.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	HEMOCHROMATOSIS, TYPE 1	c3469186	1,919	omim	https://www.omim.org/entry/235200	2019-09-22T16:27:12	{"doid": ["0111029"], "omim": ["235200"], "icd-9": ["275.01"], "icd-10": ["E83.110"], "orphanet": ["465508"], "synonyms": ["HEMOCHROMATOSIS", "Symptomatic form of classic hemochromatosis", "HEMOCHROMATOSIS, HEREDITARY", "Symptomatic form of HFE-related hereditary hemochromatosis", "Alternative titles"], "genereviews": ["NBK1440"]}
A number sign (#) is used with this entry because of evidence that familial cold autoinflammatory syndrome-4 (FCAS4) is caused by heterozygous mutation in the NLRC4 gene (606831) on chromosome 2p22. One such family has been reported. For a phenotypic description and a discussion of genetic heterogeneity of familial cold autoinflammatory syndrome, see FCAS1 (120100). Clinical Features Kitamura et al. (2014) reported a 3-generation Japanese family in which multiple individuals had an autoinflammatory disorder characterized by onset of episodic high fevers, urticaria-like rash, and arthralgias beginning at 2 to 3 months of age. The symptoms were often induced by exposure to cold stimuli. The rash was not accompanied by itching, and the patients did not have splenomegaly or bone erosions. The symptoms resolved without treatment in most cases, although some patients took nonsteroidal antiinflammatory drugs to reduce joint pain. Inheritance The transmission pattern of FCAS4 in the family reported by Kitamura et al. (2014) was consistent with autosomal dominant inheritance. Molecular Genetics In affected members of a Japanese family with FCAS4, Kitamura et al. (2014) identified a heterozygous missense mutation in the NLRC4 gene (H443P; 606831.0003). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro cellular functional expression studies showed that the H443P mutation increased oligomerization of NLRC4 and resulted in hyperactivation of caspase-1 (CASP1; 147678) with an increase in secretion of IL1B (147720). Animal Model Kitamura et al. (2014) found that expression of the murine equivalent of the human NLRC4 H443P mutation in mouse spleen caused dermatitis and swollen joints beginning at 3 weeks of age. Mutant mice developed splenomegaly with inflammatory cell infiltration and bone erosion. Splenocytes derived from mutant mice showed increased Il1b secretion, and serum levels of Il1b, Il17a (603149), and Gcsf (CSF3; 138970) were increased in mutant mice compared to controls. Most of the cells that produced Il17a in mutant mice were neutrophils, not T cells, and depletion of these cells and/or antibodies against Il1b and Il17a decreased footpad swelling. Exposure to cold stimuli increased the autoinflammation in mutant mice, similar to that observed in affected members of a Japanese family with the mutation. INHERITANCE \- Autosomal dominant SKELETAL \- Arthralgia, episodic SKIN, NAILS, & HAIR Skin \- Rash, urticarial, episodic \- Non pruritic METABOLIC FEATURES \- Fever, intermittent IMMUNOLOGY \- Autoinflammatory disorder MISCELLANEOUS \- Onset in early infancy (2 to 3 months of age) \- Episodic \- Symptoms usually resolve without treatment \- One Japanese family has been reported (last curated December 2014) MOLECULAR BASIS \- Caused by mutation in the NLR family, caspase recruitment domain-containing 4 gene (NLRC4, 606831.0003 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 4	c0343068	1,920	omim	https://www.omim.org/entry/616115	2019-09-22T15:49:57	{"doid": ["0090065"], "mesh": ["D056587"], "omim": ["616115"], "orphanet": ["47045"]}
Pulmonary sequestration Other namesBronchopulmonary sequestration or cystic lung lesion SpecialtyPulmonology A pulmonary sequestration is a medical condition wherein a piece of tissue that ultimately develops into lung tissue is not attached to the pulmonary arterial blood supply, as is the case in normally developing lung. This sequestered tissue is therefore not connected to the normal bronchial airway architecture, and fails to function in, and contribute to, respiration of the organism. This condition is usually diagnosed in children and is generally thought to be congenital in nature. More and more, these lesions are diagnosed in utero by prenatal ultrasound. ## Contents * 1 Presentation * 1.1 Complications * 2 Cause * 3 Diagnosis * 3.1 Types * 3.1.1 Intralobar sequestration * 3.1.2 Extralobar sequestration * 3.2 Imaging * 3.2.1 Chest radiograph * 3.2.2 Ultrasound * 3.2.3 CT * 3.2.4 MRI * 4 Treatment * 5 References * 6 Sources * 7 External links ## Presentation[edit] Symptoms can vary greatly, but they include a persistent dry cough. ### Complications[edit] Failure to have a pulmonary sequestration removed can lead to a number of complications. These include: * Potentially fatal hemorrhage * The creation of a left-right shunt, where blood flows in a shortcut through the feed off the aorta * Chronic infection with diseases such as * Bronchiectasis * Tuberculosis * Aspergillosis * Bronchial carcinoid * Bronchogenic squamous cell carcinoma ## Cause[edit] There is still much debate to whether pulmonary sequestration is a congenital problem or acquired through recurrent pulmonary infection. It is widely believed that extralobar pulmonary sequestrations are a result of prenatal pulmonary malformation while intralobar pulmonary sequestrations can develop due to recurrent pulmonary infections in adolescents and young adults. The most frequently supported theory of sequestration formation involves an accessory lung bud that develops from the ventral aspect of the primitive foregut. The pluripotential tissue from this additional lung bud migrates in a caudal direction with the normally developing lung. It receives its blood supply from vessels that connect to the aorta and cover the primitive foregut. These attachments to the aorta remain to form the systemic arterial supply of the sequestration. Early embryologic development of the accessory lung bud results in formation of the sequestration within normal lung tissue. The sequestration is encased within the same pleural covering. This is the intrapulmonary variant. In contrast, later development of the accessory lung bud results in the extrapulmonary type that may give rise to communication with the GI tract. Both types of sequestration usually have arterial supply from the thoracic or abdominal aorta. Rarely, the celiac axis, internal mammary, subclavian, or renal artery may be involved. Intrapulmonary sequestration occurs within the visceral pleura of normal lung tissue. Usually, no communication with the tracheobronchial tree occurs. The most common location is in the posterior basal segment, and nearly two thirds of pulmonary sequestrations appear in the left lung. Venous drainage is usually via the pulmonary veins. Foregut communication is very rare, and associated anomalies are uncommon. Extrapulmonary sequestration is completely enclosed in its own pleural sac. It may occur above, within, or below the diaphragm, and nearly all appear on the left side. No communication with the tracheobronchial tree occurs. Venous drainage is usually via the systemic venous system. Foregut communication and associated anomalies, such as diaphragmatic hernia, are more common.[citation needed] ## Diagnosis[edit] Bronchopulmonary sequestration (BPS) is a rare congenital malformation of the lower respiratory tract.It consists of a nonfunctioning mass of normal lung tissue that lacks normal communication with the tracheobronchial tree, and that receives its arterial blood supply from the systemic circulation.[citation needed] BPS is estimated to comprise one to six percent of all congenital pulmonary malformations, making it an extremely rare disorder.[1] Sequestrations are classified anatomically.Intralobar sequestration (ILS) in which the lesion is located within a normal lobe and lacks its own visceral pleura.Extralobar sequestration (ELS) in which the mass is located outside the normal lung and has its own visceral pleuraThe blood supply of 75% of pulmonary sequestrations is derived from the thoracic or abdominal aorta.The remaining 25% of sequestrations receive their blood flow from the subclavian, intercostal, pulmonary, pericardiophrenic, innominate, internal mammary, celiac, splenic, or renal arteries.[citation needed] ### Types[edit] #### Intralobar sequestration[edit] * The intralobar variety accounts for 75 percent of all sequestrations.[1] * Usually presents in adolescence or adulthood as recurrent pneumonias.[1] * The lung tissue lies within the same visceral pleura as the lobe in which it occurs.[1] * Males and females are equally affected with ILS.[1] * In ILS, the arterial supply is usually derived from the lower thoracic or upper abdominal aorta. * Venous drainage is usually to the left atrium via pulmonary veins establishing a left to left shunt. * Abnormal connections to the vena cava, azygous vein, or right atrium may occur. * Two thirds of the time, the sequestration is located in the paravertebral gutter in the posterior segment of the left lower lobe. * Unlike extralobar sequestration, it is rarely associated with other developmental abnormalities. * Patients present with signs and symptoms of pulmonary infection of a lower lobe mass. * It is believed that sequestrations become infected when bacteria migrate through the Pores of Kohn or if the sequestration is incomplete. #### Extralobar sequestration[edit] * The extralobar variety accounts for 25 percent of all sequestrations.[1] * ELS usually presents in infancy with respiratory compromise.[1] * Develops as an accessory lung contained within its own pleura.[1] * ELS has a male to female predominance of 3:1 to 4:1.[1] * Related to the left hemidiaphragm in 90% of cases. * ELS may present as a subdiaphragmatic or retroperitoneal mass. * In general, the arterial supply of ELS comes from an aberrant vessel from thoracic aorta. * It usually drains via the systemic venous system to the right atrium, vena cava, or azygous systems. * Congenital anomalies occur more frequently in patients with ELS than ILS. * Associated anomalies include Congenital cystic adenomatoid malformation (CCAM), congenital diaphragmatic hernia, vertebral anomalies, congenital heart disease, pulmonary hypoplasia, and colonic duplication * Since it is enveloped in its own pleural sac, it rarely gets infected so almost always presents as a homogeneous soft tissue mass. * The mass may be closely associated with the esophagus, and fistulae may develop. ### Imaging[edit] * An arteriogram has been considered vital in documenting the systemic blood supply, allowing definitive diagnosis as well as preoperative planning. * The advent of new noninvasive imaging techniques has changed this thinking. #### Chest radiograph[edit] * Sequestrations typically appear as a uniformly dense mass within the thoracic cavity or pulmonary parenchyma. * Recurrent infection can lead to the development of cystic areas within the mass. * Air-fluid levels due to bronchial communication can be seen. #### Ultrasound[edit] * The typical sonographic appearance of BPS is an echogenic homogeneous mass that may be well defined or irregular. * Some lesions have a cystic or more complex appearance. * Doppler studies are helpful to identify the characteristic aberrant systemic artery that arises from the aorta and to delineate venous drainage. #### CT[edit] Chest CT showing pulmonary sequestration * CT scans have 90% accuracy in the diagnosis of pulmonary sequestration. * The most common appearance is a solid mass that may be homogeneous or heterogeneous, sometimes with cystic changes. * Less frequent findings include a large cavitary lesion with an air-fluid level, a collection of many small cystic lesions containing air or fluid, or a well-defined cystic mass. * Emphysematous changes at the margin of the lesion are characteristic and may not be visible on the chest radiograph. * CT technique for optimal depiction of lesions by using state-of-the-art volumetric scanning requires a fast intravenous (IV) contrast injection rate and appropriate volume and delay based upon size. * Multiplanar and 3D reconstructions are helpful. #### MRI[edit] * Contrast-enhanced MRA or even conventional T1-weighted spin-echo (SE) images may help in the diagnosis of pulmonary sequestration by demonstrating a systemic blood supply, particularly from the aorta, to a basal lung mass. * In addition, MRA may demonstrate venous drainage of the mass and may obviate more invasive investigations. * However, CT allows sharper delineation of thin-walled cysts and emphysematous changes than MRI. ## Treatment[edit] Usually the sequestration is removed after birth via surgery. In most cases this surgery is safe and effective; the child will grow up to have normal lung function.[citation needed] In a few instances, fetuses with sequestrations develop problematic fluid collections in the chest cavity. In these situations a Harrison catheter shunt can be used to drain the chest fluid into the amniotic fluid. In rare instances where the fetus has a very large lesion, resuscitation after delivery can be dangerous. In these situations a specialized delivery for management of the airway compression can be planned called the EXIT procedure, or a fetal laser ablation procedure can be performed. During this minimally invasive fetal intervention, a small needle is inserted into the sequestration, and a laser fiber is targeted at the abnormal blood vessel going to the sequestration. The goal of the operation is to use laser energy to stop the blood flow to the sequestration, causing it to stop growing. Ideally, after the surgery, the sequestration steals less blood flow from the fetus, and the heart and lungs start growing more normally as the sequestration shrinks in size and the pleural effusion goes away. The treatment for this is a wedge resection, segmentectomy, or lobectomy via a VATS procedure or thoracotomy. Pulmonary sequestrations usually get their blood supply from the thoracic aorta. (intrapulmonary sequestration drains via pulmonary veins, extra pulmonary sequestration drains to the IVC) ## References[edit] 1. ^ a b c d e f g h i Walker, Christopher M.; Wu, Carol C.; Gilman, Matthew D.; Godwin, J. David; Shepard, Jo-Anne O.; Abbott, Gerald F. (May 2014). "The Imaging Spectrum of Bronchopulmonary Sequestration". Current Problems in Diagnostic Radiology. 43 (3): 100–114. doi:10.1067/j.cpradiol.2014.01.005. ## Sources[edit] * Truitt AK; Carr SR; Cassese J; Kurkchubasche AG; Tracy TF Jr; Luks FI. (2006). "Perinatal management of congenital cystic lung lesions in the age of minimally invasive surgery". J Pediatr Surg: 41:893–896. * Savic B; Birtel FJ; Tholen W; Funke HD; Knoche R. (1979). "Lung sequestration: report of seven cases and review of 540 published cases". Thorax. 34 (1): 34:96–101. doi:10.1136/thx.34.1.96. PMC 471015. PMID 442005. * Fabre O; Porte H; Godart F; Rey C; Wurtz A. (1998). "Long-Term Cardiovascular Consequences of Undiagnosed Intralobar Pulmonary Sequestration". Annals of Thoracic Surgery. 65 (4): 65, 1144–6. doi:10.1016/S0003-4975(98)00032-0. PMID 9564949. * Borrelli EP (2017). "Maybe it is More than Pneumonia: Case Report of an intralobar sequestration in a 20-year-old male". Respiratory Case Reports. 6 (2): 6, 96–98. doi:10.5505/respircase.2017.92499. * Ferguson (1983). "Congenital lesion of the lungs and emphysema". Gibbons surgery of the Chest (4th ? ed.). WB Saunders. pp. 668–709. ISBN Unknown. * Rubin E; Garcia H; Horowitz M; Guerra J. (1994). "Fatal Massive Hemoptysia Secondary to Intralobar Sequestration". Chest. 106 (3): 954–955. doi:10.1378/chest.106.3.954. PMID 8082388. * Sabiston D, Spencer F. Surgery of the Chest (6th ed.). pp. 853–862. ## External links[edit] Classification D * ICD-10: Q33.2 * ICD-9-CM: 748.5 * MeSH: D001998 * DiseasesDB: 32120 * SNOMED CT: 18620009 External resources * eMedicine: ped/2628 radio/585 * Emedicine on pulmonary sequestrations * v * t * e Congenital malformations and deformations of respiratory system Upper RT Nose * Choanal atresia * Arrhinia Larynx * Laryngeal cyst * Laryngocele * Laryngomalacia Lower RT Trachea and bronchus * Tracheomalacia * Tracheal stenosis * Bronchomalacia * Tracheobronchomegaly Lung * Bronchiectasis * Pulmonary hypoplasia * Pulmonary sequestration * Congenital cystic adenomatoid malformation [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Pulmonary sequestration	c0006288	1,921	wikipedia	https://en.wikipedia.org/wiki/Pulmonary_sequestration	2021-01-18T18:35:51	{"gard": ["4593"], "mesh": ["D001998"], "umls": ["C0006288"], "icd-9": ["748.5"], "icd-10": ["Q33.2"], "orphanet": ["3161"], "wikidata": ["Q688890"]}
Group of inherited metabolic disorders This article is about the medical condition. For other uses, see Porphyry (disambiguation). Not to be confused with Porphyra. Porphyria Left figure is urine on the first day while the right figure is urine after three days of sun exposures showing the classic change in color to purple. Pronunciation * /pɔːrˈfɪriə/ or /pɔːrˈfaɪriə/ SpecialtyHematology, dermatology, neurology SymptomsDepending on subtype—abdominal pain, chest pain, vomiting, confusion, constipation, fever, seizures, blisters with sunlight[1][2] Usual onsetRecurrent attacks that last days to weeks[2] CausesUsually genetic[2] Diagnostic methodBlood, urine, and stool tests, genetic testing[2] Differential diagnosisLead poisoning, alcoholic liver disease[3] TreatmentDepends on type and symptoms[2] Frequency1 to 100 in 50,000 people[1] Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system.[1] The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration.[1] Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate.[1][2][4] The attacks usually last for days to weeks.[2] Complications may include paralysis, low blood sodium levels, and seizures.[4] Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications.[2][4] If the skin is affected, blisters or itching may occur with sunlight exposure.[2] Most types of porphyria are inherited from one or both of a person's parents and are due to a mutation in one of the genes that make heme.[2] They may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner.[1] One type, porphyria cutanea tarda, may also be due to increased iron in the liver, hepatitis C, alcohol, or HIV/AIDS.[1] The underlying mechanism results in a decrease in the amount of heme produced and a build-up of substances involved in making heme.[1] Porphyrias may also be classified by whether the liver or bone marrow is affected.[1] Diagnosis is typically made by blood, urine, and stool tests.[2] Genetic testing may be done to determine the specific mutation.[2] Treatment depends on the type of porphyria and the person's symptoms.[2] Treatment of porphyria of the skin generally involves the avoidance of sunlight, while treatment for acute porphyria may involve giving intravenous heme or a glucose solution.[2] Rarely, a liver transplant may be carried out.[2] The precise prevalence of porphyria is unclear, but it is estimated to affect between 1 and 100 per 50,000 people.[1] Rates are different around the world.[2] Porphyria cutanea tarda is believed to be the most common type.[1] The disease was described as early as 370 BC by Hippocrates.[5] The underlying mechanism was first described by German physiologist and chemist Felix Hoppe-Seyler in 1871.[5] The name porphyria is from the Greek πορφύρα, porphyra, meaning "purple", a reference to the color of the urine that may be present during an attack.[5] ## Contents * 1 Signs and symptoms * 1.1 Acute porphyrias * 1.2 Chronic porphyrias * 2 Cause * 2.1 Genetics * 2.2 Triggers * 3 Pathogenesis * 4 Diagnosis * 4.1 Porphyrin studies * 4.2 Additional tests * 5 Management * 5.1 Acute porphyria * 5.1.1 Carbohydrate administration * 5.1.2 Heme analogs * 5.1.3 Cimetidine * 5.1.4 Symptom control * 5.1.5 Early identification * 5.1.6 Neurologic and psychiatric disorders * 5.1.7 Underlying liver disease * 5.1.8 Hormone treatment * 5.2 Erythropoietic porphyria * 6 Epidemiology * 7 History * 7.1 Vampires and werewolves * 7.2 Notable cases * 8 References * 9 External links ## Signs and symptoms[edit] This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (January 2016) (Learn how and when to remove this template message) A skin rash in a person with porphyria ### Acute porphyrias[edit] The acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP), aminolevulinic acid dehydratase deficiency porphyria (ALAD) and hereditary coproporphyria (HCP). These diseases primarily affect the nervous system, resulting in episodic crises known as acute attacks. The major symptom of an acute attack is abdominal pain, often accompanied by vomiting, hypertension (elevated blood pressure), and tachycardia (an abnormally rapid heart rate).[4] The most severe episodes may involve neurological complications: typically motor neuropathy (severe dysfunction of the peripheral nerves that innervate muscle), which leads to muscle weakness and potentially to quadriplegia (paralysis of all four limbs) and central nervous system symptoms such as seizures and coma. Occasionally, there may be short-lived psychiatric symptoms such as anxiety, confusion, hallucinations, and, very rarely, overt psychosis. All these symptoms resolve once the acute attack passes. Given the many presentations and the relatively low occurrence of porphyria, patients may initially be suspected to have other, unrelated conditions. For instance, the polyneuropathy of acute porphyria may be mistaken for Guillain–Barré syndrome, and porphyria testing is commonly recommended in those situations.[6] ### Chronic porphyrias[edit] The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP). None of these are associated with acute attacks; their primary manifestation is with skin disease. For this reason, these four porphyrias—along with two acute porphyrias, VP and HCP, that may also involve skin manifestations—are sometimes called cutaneous porphyrias. Skin disease is encountered where excess porphyrins accumulate in the skin. Porphyrins are photoactive molecules, and exposure to light results in promotion of electrons to higher energy levels. When these return to the resting energy level or ground state, energy is released. This accounts for the property of fluorescence typical of the porphyrins. This causes local skin damage. Two distinct patterns of skin disease are seen in porphyria: * Immediate photosensitivity. This is typical of XLDPP and EPP. Following a variable period of sun exposure—typically about 30 minutes—patients complain of severe pain, burning, and discomfort in exposed areas. Typically, the effects are not visible, though occasionally there may be some redness and swelling of the skin. * Vesiculo-erosive skin disease. This—a reference to the characteristic blistering (vesicles) and open sores (erosions) noted in patients—is the pattern seen in CEP, PCT, VP, and HCP. The changes are noted only in sun-exposed areas such as the face and back of the hands. Milder skin disease, such as that seen in VP and HCP, consists of increased skin fragility in exposed areas with a tendency to form blisters and erosions, particularly after minor knocks or scrapes. These heal slowly, often leaving small scars that may be lighter or darker than normal skin. More severe skin disease is sometimes seen in PCT, with prominent lesions, darkening of exposed skin such as the face, and hypertrichosis: abnormal hair growth on the face, particularly the cheeks. The most severe disease is seen in CEP and a rare variant of PCT known as hepatoerythropoietic porphyria (HEP); symptoms include severe shortening of digits, loss of skin appendages such as hair and nails, and severe scarring of the skin with progressive disappearance of ears, lips, and nose. Patients may also show deformed, discolored teeth or gum and eye abnormalities. ## Cause[edit] The porphyrias are generally considered genetic in nature.[citation needed] ### Genetics[edit] Subtypes of porphyrias depend on which enzyme is deficient. Porphyria type Deficient enzyme Type of porphyria Inheritance Symptoms Prevalence X-linked dominant protoporphyria (XLDPP) 5-aminolevulinate (ALA) synthase (ALAS) Erythropoietic X-linked dominant Photosensitivity, cirrhosis[7] Rare; about 50 cases reported[8] Aminolevulinate dehydratase deficiency porphyria (ALADP) 5-aminolevulinate dehydratase (ALAD) Hepatic Autosomal recessive[9] Abdominal pain, neuropathy[9] Extremely rare; fewer than 10 cases ever reported.[10] Acute intermittent porphyria (AIP) Hydroxymethylbilane synthase (HMBS) formerly porphobilinogen deaminase (PBGD) Hepatic Autosomal dominant[9] Periodic abdominal pain, peripheral neuropathy, psychiatric disorders, tachycardia[9] 1 in 10,000[11]–20,000[11] Congenital erythropoietic porphyria (CEP) uroporphyrinogen synthase (UROS) Erythropoietic Autosomal recessive[9] Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia, splenomegaly[9] 1 in 1,000,000 or less.[12] Porphyria cutanea tarda (PCT) uroporphyrinogen decarboxylase (UROD) Hepatic Approximately 80% sporadic,[13] 20% Autosomal dominant[9] Photosensitivity with vesicles and bullae[9] 1 in 10,000[14] Hereditary coproporphyria (HCP) coproporphyrinogen oxidase (CPOX) Hepatic Autosomal dominant[9] Photosensitivity, neurologic symptoms, colic[9] 1 in 500,000[14] Harderoporphyria coproporphyrinogen oxidase (CPOX) Erythropoietic Autosomal recessive[9] Jaundice, anemia, enlarged liver and spleen, often neonatal. Photosensitivity later. Extremely rare; fewer than 10 cases ever reported. Variegate porphyria (VP) protoporphyrinogen oxidase (PPOX) Hepatic Autosomal dominant[15] Photosensitivity, neurologic symptoms, developmental delay 1 in 300 in South Africa[14] 1 in 75,000 in Finland[16] Erythropoietic protoporphyria (EPP) ferrochelatase (FECH) Erythropoietic Autosomal dominant[9] Photosensitivity with skin lesions. Gallstones, mild liver dysfunction[9] 1 in 75,000[14]–200,000[14] In the autosomal recessive types, if a person inherits a single gene they may become a carriers. Generally they do not have symptoms, but may pass the gene onto offspring.[17] ### Triggers[edit] Acute porphyria can be triggered by a number of drugs, most of which are believed to trigger it by interacting with enzymes in the liver which are made with heme. Such drugs include:[18][19][20] * Sulfonamides, including sulfadiazine, sulfasalazine and trimethoprim/sulfamethoxazole. * Sulfonylureas like glibenclamide, gliclazide and glimepiride, although glipizide is thought to be safe. * Barbiturates including thiopental, phenobarbital, primidone, etc. * Systemic treatment with antifungals including fluconazole, griseofulvin, ketoconazole and voriconazole. (Topical use of these agents is thought to be safe due to minimal systemic absorption.) * Certain antibiotics like rifapentine, rifampicin, rifabutine, isoniazid, nitrofurantoin and, possibly, metronidazole. * Ergot derivatives including dihydroergotamine, ergometrine, ergotamine, methysergide, etc. * Certain antiretroviral medications (e.g. indinavir, nevirapine, ritonavir, saquinavir, etc.) * Progestogens * Some anticonvulsants including: carbamazepine, ethosuximide, phenytoin, topiramate, valproate. * Some painkillers like dextropropoxyphene, ketorolac, metamizole, pentazocine * Some cancer treatments like bexarotene, busulfan, chlorambucil, estramustine, etoposide, flutamide, idarubicin, ifosfamide, irinotecan, ixabepilone, letrozole, lomustine, megestrol, mitomycin, mitoxantrone, paclitaxel, procarbazine, tamoxifen, topotecan * Some antidepressants like imipramine, phenelzine, trazodone * Some antipsychotics like risperidone, ziprasidone * Some retinoids used for skin conditions like acitretin and isotretinoin * Miscellaneous others including: cocaine, methyldopa, fenfluramine, disulfiram, orphenadrine, pentoxifylline, and sodium aurothiomalate. ## Pathogenesis[edit] Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow) In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes.[citation needed] The body requires porphyrins to produce heme, which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or in the bone marrow and red blood cells.[21] Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. Heme function plays a central role in cellular metabolism. This is not the main problem in the porphyrias; most heme synthesis enzymes—even dysfunctional enzymes—have enough residual activity to assist in heme biosynthesis. The principal problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted (in the urine or feces). There are eight enzymes in the heme biosynthetic pathway, four of which—the first one and the last three—are in the mitochondria, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria.The hepatic porphyrias are characterized by acute neurological attacks (seizures, psychosis, extreme back and abdominal pain, and an acute polyneuropathy), while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth.Variegate porphyria (also porphyria variegata or mixed porphyria), which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. Hereditary coproporphyria, which is characterized by a deficiency in coproporphyrinogen oxidase, coded for by the CPOX gene, may also present with both acute neurologic attacks and cutaneous lesions. All other porphyrias are either skin- or nerve-predominant.[citation needed] ## Diagnosis[edit] ### Porphyrin studies[edit] Porphyria is diagnosed through biochemical analysis of blood, urine, and stool.[12][22] In general, urine estimation of porphobilinogen (PBG) is the first step if acute porphyria is suspected. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway.[23] In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to hereditary tyrosinemia type I.[24] In cases of mercury\- or arsenic poisoning-induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins I & III, coproporphyrins I & III, and pre-coproporphyrin.[25] Repeat testing during an attack and subsequent attacks may be necessary in order to detect a porphyria, as levels may be normal or near-normal between attacks. The urine screening test has been known to fail in the initial stages of a severe, life-threatening attack of acute intermittent porphyria.[citation needed] Up to 90% of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been noted in DNA tests to be latent for classic symptoms and may require DNA or enzyme testing. The exception to this may be latent post-puberty genetic carriers of hereditary coproporphyria.[citation needed] As most porphyrias are rare conditions, general hospital labs typically do not have the expertise, technology, or staff time to perform porphyria testing. In general, testing involves sending samples of blood, stool, and urine to a reference laboratory.[12] All samples to detect porphyrins must be handled properly. Samples should be taken during an acute attack; otherwise a false negative result may occur. Samples must be protected from light and either refrigerated or preserved.[12] If all the porphyrin studies are negative, one must consider pseudoporphyria. A careful medication review often will find the cause of pseudoporphyria. ### Additional tests[edit] Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver. Basic biochemical tests may assist in identifying liver disease, hepatocellular carcinoma, and other organ problems.[citation needed] ## Management[edit] ### Acute porphyria[edit] #### Carbohydrate administration[edit] Often, empirical treatment is required if the diagnostic suspicion of a porphyria is high since acute attacks can be fatal. A high-carbohydrate diet is typically recommended; in severe attacks, a dextrose 10% infusion is commenced, which may aid in recovery by suppressing heme synthesis, which in turn reduces the rate of porphyrin accumulation. However, this can worsen hyponatraemia and should be done with extreme caution as it can prove fatal.[26] #### Heme analogs[edit] Hematin (trade name Panhematin) and heme arginate (trade name NormoSang) are the drugs of choice in acute porphyria, in the United States and the United Kingdom, respectively. These drugs need to be given very early in an attack to be effective; effectiveness varies amongst individuals. They are not curative drugs but can shorten attacks and reduce the intensity of an attack. Side effects are rare but can be serious. These heme-like substances theoretically inhibit ALA synthase and hence the accumulation of toxic precursors. In the United Kingdom, supplies of NormoSang are kept at two national centers; emergency supply is available from St Thomas's Hospital, London.[27] In the United States, Lundbeck manufactures and supplies Panhematin for infusion.[28] Heme arginate (NormoSang) is used during crises but also in preventive treatment to avoid crises, one treatment every 10 days.[citation needed] Any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin, heme arginate, or even tin mesoporphyrin, as these are signs of impending syndrome of inappropriate antidiuretic hormone (SIADH) or peripheral nervous system involvement that may be localized or severe, progressing to bulbar paresis and respiratory paralysis.[citation needed] #### Cimetidine[edit] Cimetidine has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis.[29] #### Symptom control[edit] Pain is severe, frequently out of proportion to physical signs, and often requires the use of opiates to reduce it to tolerable levels. Pain should be treated as early as medically possible. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot baths and showers may lessen nausea temporarily, though caution should be used to avoid burns or falls.[citation needed] #### Early identification[edit] It is recommended that patients with a history of acute porphyria, and even genetic carriers, wear an alert bracelet or other identification at all times. This is in case they develop severe symptoms, or in case of accidents where there is a potential for drug exposure, and as a result they are unable to explain their condition to healthcare professionals. Some drugs are absolutely contraindicated for patients with any form of porphyria.[30] #### Neurologic and psychiatric disorders[edit] Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the abdomen.[31] Intestinal pseudo-obstruction, ileus, intussusception, hypoganglionosis, and encopresis in children have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction. Pain treatment with long-acting opioids, such as morphine, is often indicated, and, in cases where seizure or neuropathy is present, gabapentin is known to improve outcome.[32] Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturates especially must be avoided. Some benzodiazepines are safe and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control. Gabapentin has the additional feature of aiding in the treatment of some kinds of neuropathic pain.[32] Magnesium sulfate and bromides have also been used in porphyria seizures; however, development of status epilepticus in porphyria may not respond to magnesium alone. The addition of hematin or heme arginate has been used during status epilepticus.[33] Depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of antidepressants. Some psychotropic drugs are porphyrinogenic, limiting the therapeutic scope. Other psychiatric symptoms such as anxiety, restlessness, insomnia, depression, mania, hallucinations, delusions, confusion, catatonia, and psychosis may occur.[34] #### Underlying liver disease[edit] Some liver diseases may cause porphyria even in the absence of genetic predisposition. These include hemochromatosis and hepatitis C. Treatment of iron overload may be required.[2] Patients with the acute porphyrias (AIP, HCP, VP) are at increased risk over their life for hepatocellular carcinoma (primary liver cancer) and may require monitoring. Other typical risk factors for liver cancer need not be present.[2] #### Hormone treatment[edit] Hormonal fluctuations that contribute to cyclical attacks in women have been treated with oral contraceptives and luteinizing hormones to shut down menstrual cycles. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks. Androgens and fertility hormones have also triggered attacks.[citation needed] In 2019, givosiran was approved in the United States for the treatment of acute hepatic porphyria.[35][36] ### Erythropoietic porphyria[edit] These are associated with accumulation of porphyrins in erythrocytes and are rare. The pain, burning, swelling, and itching that occur in erythropoietic porphyrias generally require avoidance of bright sunlight. Most kinds of sunscreen are not effective, but SPF-rated long-sleeve shirts, hats, bandanas, and gloves can help. Chloroquine may be used to increase porphyrin secretion in some EPs.[12] Blood transfusion is occasionally used to suppress innate heme production. The rarest is congenital erythropoietic porphyria (CEP), otherwise known as Gunther's disease. The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of Type 1 porphyrins, and later hypertrichosis. Hemolytic anemia usually develops. Pharmaceutical-grade beta carotene may be used in its treatment.[37] A bone marrow transplant has also been successful in curing CEP in a few cases, although long-term results are not yet available.[38] In December 2014, afamelanotide received authorization from the European Commission as a treatment for the prevention of phototoxicity in adult patients with EPP.[39] ## Epidemiology[edit] Rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in the United States.[40] The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people.[41] Porphyrias have been detected in all races and in multiple ethnic groups on every continent. There are high incidence reports of AIP in areas of India and Scandinavia. More than 200 genetic variants of AIP are known, some of which are specific to families, although some strains have proven to be repeated mutations. ## History[edit] The underlying mechanism was first described by Felix Hoppe-Seyler in 1871,[42] and acute porphyrias were described by the Dutch physician Barend Stokvis in 1889.[43][44] The links between porphyrias and mental illness have been noted for decades. In the early 1950s, patients with porphyrias (occasionally referred to as "porphyric hemophilia"[45]) and severe symptoms of depression or catatonia were treated with electroshock therapy. ### Vampires and werewolves[edit] Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon certain perceived similarities between the condition and the folklore. In January 1964, L. Illis's 1963 paper, "On Porphyria and the Aetiology of Werewolves," was published in Proceedings of the Royal Society of Medicine. Later, Nancy Garden argued for a connection between porphyria and the vampire belief in her 1973 book, Vampires. In 1985, biochemist David Dolphin's paper for the American Association for the Advancement of Science, "Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends," gained widespread media coverage, popularizing the idea.[citation needed] The theory has been rejected by a few folklorists and researchers as not accurately describing the characteristics of the original werewolf and vampire legends or the disease, and as potentially stigmatizing people with porphyria.[46][47] A 1995 article from the Postgraduate Medical Journal (via NIH) explains: > As it was believed that the folkloric vampire could move about freely in daylight hours, as opposed to the 20th century variant, congenital erythropoietic porphyria cannot readily explain the folkloric vampire but may be an explanation of the vampire as we know it in the 20th century. In addition, the folkloric vampire, when unearthed, was always described as looking quite healthy ("as they were in life"), while due to disfiguring aspects of the disease, sufferers would not have passed the exhumation test. Individuals with congenital erythropoietic porphyria do not crave blood. The enzyme (hematin) necessary to alleviate symptoms is not absorbed intact on oral ingestion, and drinking blood would have no beneficial effect on the sufferer. Finally, and most important, the fact that vampire reports were literally rampant in the 18th century, and that congenital erythropoietic porphyria is an extremely rare manifestation of a rare disease, makes it an unlikely explanation of the folkloric vampire.[48] ### Notable cases[edit] George III in his coronation robes Mary, Queen of Scots c. 1578. * King George III. The mental illness exhibited by George III in the regency crisis of 1788 has inspired several attempts at retrospective diagnosis. The first, written in 1855, thirty-five years after his death, concluded that he had acute mania. M. Guttmacher, in 1941, suggested manic-depressive psychosis as a more likely diagnosis. The first suggestion that a physical illness was the cause of King George's mental derangement came in 1966, in a paper called "The Insanity of King George III: A Classic Case of Porphyria",[49] with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia".[50] The papers, by a mother/son psychiatrist team, were written as though the case for porphyria had been proven, but the response demonstrated that many experts, including those more intimately familiar with the manifestations of porphyria, were unconvinced. Many psychiatrists disagreed with the diagnosis, suggesting bipolar disorder as far more probable. The theory is treated in Purple Secret,[51] which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to have had it.[52] In 2005, it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria.[53] This study found high levels of arsenic in King George's hair. In 2010, one analysis of historical records argued that the porphyria claim was based on spurious and selective interpretation of contemporary medical and historical sources.[54] The mental illness of George III is the basis of the plot in The Madness of King George, a 1994 British film based upon the 1991 Alan Bennett play, The Madness of George III. The closing credits of the film include the comment that the King's symptoms suggest that he had porphyria and notes that the disease is "periodic, unpredictable, and hereditary". * Descendants of George III. Among other descendants of George III theorized by the authors of Purple Secret to have had porphyria (based on analysis of their extensive and detailed medical correspondence) were his great-great-granddaughter Princess Charlotte of Prussia (Emperor William II's eldest sister) and her daughter Princess Feodora of Saxe-Meiningen. They uncovered better evidence that George III's great-great-great-grandson Prince William of Gloucester was reliably diagnosed with variegate porphyria.[55] * Mary, Queen of Scots. It is believed that Mary, Queen of Scots, King George III's ancestor, also had acute intermittent porphyria,[56] although this is subject to much debate. It is assumed she inherited the disorder, if indeed she had it, from her father, James V of Scotland. Both father and daughter endured well-documented attacks that could fall within the constellation of symptoms of porphyria. Maria I of Portugal in a c. 1790s portrait attributed to Giuseppe Troni or Thomas Hickey. * Maria I of Portugal. Maria I—known as "Maria the Pious" or "Maria the Mad" because of both her religious fervor and her acute mental illness, which made her incapable of handling state affairs after 1792 – is also thought to have had porphyria. Francis Willis, the same physician who treated George III, was even summoned by the Portuguese court but returned to England after the court limited the treatments he could oversee. Contemporary sources, such as Secretary of State for Foreign Affairs Luís Pinto de Sousa Coutinho, noted that the queen had ever-worsening stomach pains and abdominal spasms: hallmarks of porphyria.[57] * Vlad III. Vlad III was also said to have had acute porphyria, which may have started the notion that vampires were allergic to sunlight.[58] * Vincent van Gogh. Other commentators have suggested that Vincent van Gogh may have had acute intermittent porphyria.[59] * King Nebuchadnezzar of Babylon. The description of this king in Daniel 4 suggests to some that he had porphyria.[60] * Physician Archie Cochrane. He was born with porphyria, which caused health problems throughout his life.[61] * Paula Frías Allende. The daughter of the Chilean novelist Isabel Allende, she fell into a porphyria-induced coma in 1991,[62] which inspired Isabel to write the memoir Paula, dedicated to her. ## References[edit] 1. ^ a b c d e f g h i j k "porphyria". GHR. July 2009. Archived from the original on 26 October 2016. Retrieved 26 October 2016. 2. ^ a b c d e f g h i j k l m n o p q r "Porphyria \| NIDDK". National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved 6 December 2018. 3. ^ Dancygier, Henryk (2009). Clinical Hepatology: Principles and Practice of Hepatobiliary Diseases. Springer Science & Business Media. p. 1088. ISBN 9783642045196. Archived from the original on 8 September 2017. 4. ^ a b c d Stein, PE; Badminton, MN; Rees, DC (February 2017). "Update review of the acute porphyrias". British Journal of Haematology. 176 (4): 527–538. doi:10.1111/bjh.14459. PMID 27982422. 5. ^ a b c McManus, Linda (2014). Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms. Elsevier. p. 1488. ISBN 9780123864574. Archived from the original on 8 September 2017. 6. ^ Albers JW, Fink JK (2004). "Porphyric neuropathy" (PDF). Muscle Nerve. 30 (4): 410–422. doi:10.1002/mus.20137. hdl:2027.42/34640. PMID 15372536. 7. ^ grh.nlm.nih.gov/condition/x-linked sideroblastic anemia 8. ^ http://www.orpha.net/consor/cgi-bin/OC[permanent dead link] 9. ^ a b c d e f g h i j k l m Table 18-1 in: Marks, Dawn B.; Swanson, Todd; Sandra I Kim; Marc Glucksman (2007). Biochemistry and molecular biology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 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GeneReviews. Seattle, USA: University of Washington. PMID 23409300. Archived from the original on 18 January 2017. Retrieved 18 April 2015. 16. ^ Mustajoki P (1980). "Variegate porphyria. Twelve years' experience in Finland". The Quarterly Journal of Medicine. 49 (194): 191–203. PMID 7433635. 17. ^ "Porphyria - Symptoms and causes". Mayo Clinic. Retrieved 5 March 2020. 18. ^ Tishler, PV. "About Porphyria: Safety database". Porphyria Drug Safety Database. American Porphyria Foundation. Archived from the original on 12 July 2017. Retrieved 27 August 2017. 19. ^ Brun, A. "napos". The Drug Database for Acute Porphyria. European Porphyria Network. Archived from the original on 23 August 2017. Retrieved 27 August 2017. 20. ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. p. 663. ISBN 978-0-85711-084-8. 21. ^ Lourenço, Charles Marquez; Lee, Chul; Anderson, Karl E. (2012). "Disorders of Haem Biosynthesis". 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Berlin: Springer. pp. 19–52, Chapter 2. 26. ^ patient.co.uk. "Porphyrias - immediate management". Archived from the original on 20 October 2016. Retrieved 19 October 2016. 27. ^ British Medical Association, Royal Pharmaceutical Society of Great Britain (March 2009). "9.8.2: Acute porphyrias". British National Formulary (BNF 57). United Kingdom: BMJ Group and RPS Publishing. p. 549. ISBN 978-0-85369-845-6. 28. ^ American Porphyria Foundation (2010). "Panhematin for Acute Porphyria". Archived from the original on 25 August 2010. Retrieved 5 August 2010. 29. ^ Cherem JH, Malagon J, Nellen H (2005). "Cimetidine and acute intermittent porphyria". Ann. Intern. Med. 143 (9): 694–5. doi:10.7326/0003-4819-143-9-200511010-00023. PMID 16263899. 30. ^ "Porphyria - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Retrieved 6 December 2018. 31. ^ Birgisdottir BT, Asgeirsson H, Arnardottir S, Jonsson JJ, Vidarsson B (2010). "[Acute abdominal pain caused by acute intermittent porphyria - case report and review of the literature]". Laeknabladid (in Icelandic). 96 (6): 413–18. PMID 20519771. 32. ^ a b Tsao YC, Niu DM, Chen JT, Lin CY, Lin YY, Liao KK (2010). "Gabapentin reduces neurovisceral pain of porphyria". Acta Neurol Taiwan. 19 (2): 112–5. PMID 20714961. 33. ^ Cherian A, Thomas SV (2009). "Status epilepticus". Ann Indian Acad Neurol. 12 (3): 140–53. doi:10.4103/0972-2327.56312. PMC 2824929. PMID 20174493. 34. ^ Murray ED, Buttner N, Price BH. (2012) Depression and Psychosis in Neurological Practice. In: Neurology in Clinical Practice, 6th Edition. Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds.) Butterworth Heinemann. 12 April 2012. ISBN 978-1437704341 35. ^ "FDA approves first treatment for inherited rare disease". U.S. Food and Drug Administration (FDA) (Press release). 20 November 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain. 36. ^ "FDA approves givosiran for acute hepatic porphyria". U.S. Food and Drug Administration (FDA) (Press release). 20 November 2019. Archived from the original on 21 November 2019. Retrieved 20 November 2019. This article incorporates text from this source, which is in the public domain. 37. ^ Martin A Crook.2006. Clinical chemistry and Metabolic Medicine. seventh edition. Hodder Arnold. ISBN 0-340-90616-2 38. ^ Faraci M, Morreale G, Boeri E, Lanino E, Dallorso S, Dini G, Scuderi F, Cohen A, Cappelli B (2008). "Unrelated HSCT in an adolescent affected by congenital erythropoietic porphyria". Pediatr Transplant. 12 (1): 117–120. doi:10.1111/j.1399-3046.2007.00842.x. PMID 18186900. 39. ^ "Community register of medicinal products for human use". ec.europa.eu. European Commission. Archived from the original on 24 December 2014. Retrieved 24 December 2014. 40. ^ eMedicine > Porphyria, Cutaneous Archived 5 December 2010 at the Wayback Machine Authors: Vikramjit S Kanwar, Thomas G DeLoughery, Richard E Frye and Darius J Adams. Updated: 27 July 2010. 41. ^ Genetics Home Reference > Porphyria Archived 5 August 2010 at the Wayback Machine Reviewed July 2009 42. ^ Hoppe-Seyler F (1871). "Das Hämatin". Tubinger Med-Chem Untersuch. 4: 523–33. 43. ^ Nick Lane (16 December 2002). "Born to the purple: the story of porphyria". Scientific American. Archived from the original on 11 October 2007. Retrieved 5 August 2008. 44. ^ Stokvis BJ. "Over twee zeldzame kleurstoffen in urine van zieken". Nederl Tijdschr Geneeskd (in Dutch). 2: 409–417. Reprinted in Stokvis BJ (December 1989). "Over twee zeldzame kleurstoffen in urine van zieken". Ned Tijdschr Geneeskd (in Dutch). 133 (51): 2562–70. PMID 2689889. 45. ^ Denver, Joness. "An Encyclopaedia of Obscure Medicine". Published by University Books, Inc., 1959. 46. ^ American Vampires: Fans, Victims, Practitioners, Norine Dresser, W. W. Norton & Company, 1989. 47. ^ "Did vampires suffer from the disease porphyria — or not?" Archived 5 February 2013 at the Wayback Machine The Straight Dope, 7 May 1999. 48. ^ Cox, Ann M. (1995). "Porphyria and vampirism: another myth in the making". Postgraduate Medical Journal. 71 (841): 643–644. doi:10.1136/pgmj.71.841.643-a. PMC 2398345. PMID 7494765. 49. ^ Macalpine I, Hunter R (January 1966). "The "insanity" of King George 3d: a classic case of porphyria". Br Med J. 1 (5479): 65–71. doi:10.1136/bmj.1.5479.65. PMC 1843211. PMID 5323262. 50. ^ Macalpine I, Hunter R, Rimington C (January 1968). "Porphyria in the royal houses of Stuart, Hanover, and Prussia. A follow-up study of George 3d's illness". Br Med J. 1 (5583): 7–18. doi:10.1136/bmj.1.5583.7. PMC 1984936. PMID 4866084. 51. ^ Warren, Martin; Rh̲l, John C. G.; Hunt, David C. (1998). Purple secret: genes, "madness" and the Royal houses of Europe. London: Bantam Books. ISBN 978-0-593-04148-2. 52. ^ The authors demonstrated a single point mutation in the PPOX gene but not one that has been associated with disease. 53. ^ Cox TM, Jack N, Lofthouse S, Watling J, Haines J, Warren MJ (2005). "King George III and porphyria: an elemental hypothesis and investigation". The Lancet. 366 (9482): 332–335. doi:10.1016/S0140-6736(05)66991-7. PMID 16039338. S2CID 13109527. 54. ^ Peters TJ, Wilkinson D (2010). "King George III and porphyria: a clinical re-examination of the historical evidence". History of Psychiatry. 21 (81 Pt 1): 3–19. doi:10.1177/0957154X09102616. PMID 21877427. S2CID 22391207. 55. ^ Smith, Martin; Smith, Alison (21 December 2009). Tetrapyrroles: Birth, Life and Death. ISBN 9780387785189. Archived from the original on 4 July 2014. Retrieved 9 April 2014. 56. ^ "bulletin: The University of Sussex NewsletterThe Royal Family's Toxic Time-Bomb Friday 25th June 1999". Archived from the original on 15 September 2013. Retrieved 18 August 2013. 57. ^ Roberts, Jenifer (2009). The Madness of Queen Maria [The Remarkable Life of Maria I of Portugal]. Templeton Press. ISBN 978-0954558918. 58. ^ "BBC News - UK - Charles visits 'relative' Dracula's home". Archived from the original on 24 August 2013. 59. ^ Loftus LS, Arnold WN (1991). "Vincent van Gogh's illness: acute intermittent porphyria?". BMJ. 303 (6817): 1589–1591. doi:10.1136/bmj.303.6817.1589. PMC 1676250. PMID 1773180. 60. ^ Beveridge A (2003). "The madness of politics". J R Soc Med. 96 (12): 602–604. doi:10.1258/jrsm.96.12.602. PMC 539664. PMID 14645615. 61. ^ Cochrane, Archibald L; Blythe, Max (2009) [1989]. One Man's Medicine: An Autobiography of Professor Archie Cochrane. Cardiff: Cardiff University. ISBN 978-0-9540884-3-9. 62. ^ Allende, Isabel (1995). Paula. New York, NY: HarperCollins. ISBN 978-0-06-017253-4. ## External links[edit] * Porphyria at Curlie * The Drug Database for Acute Porphyria - comprehensive database on drug porphyrinogenicity * Orphanet's disease page on Porphyria Classification D * ICD-10: E80.0-E80.2 * ICD-9-CM: 277.1 * MeSH: D011164 External resources * MedlinePlus: 001208 * Patient UK: Porphyria * Orphanet: 738 * v * t * e Heme metabolism disorders Porphyria, hepatic and erythropoietic (porphyrin) early mitochondrial: * ALAD porphyria * Acute intermittent porphyria cytoplasmic: * Gunther disease/congenital erythropoietic porphyria * Porphyria cutanea tarda/Hepatoerythropoietic porphyria late mitochondrial: * Hereditary coproporphyria * Harderoporphyria * Variegate porphyria * Erythropoietic protoporphyria Hereditary hyperbilirubinemia (bilirubin) unconjugated: * Gilbert's syndrome * Crigler–Najjar syndrome * Lucey–Driscoll syndrome conjugated: * Dubin–Johnson syndrome nd sheet * Rotor syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Porphyria	c0235387	1,922	wikipedia	https://en.wikipedia.org/wiki/Porphyria	2021-01-18T18:43:36	{"gard": ["10353"], "mesh": ["D011164"], "umls": ["C0235387"], "orphanet": ["738"], "wikidata": ["Q271759"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (April 2015) An atrioventricular fistula is a fistula between an atrium and a ventricle of the heart. Formation of an AVF is a potential complication of catheter ablation.[1] ## References[edit] 1. ^ Catheter Ablation of Cardiac Arrhythmias (4 ed.). Elsevier. 2020. pp. 636–647. 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 [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Atrioventricular fistula	c0340330	1,923	wikipedia	https://en.wikipedia.org/wiki/Atrioventricular_fistula	2021-01-18T19:04:00	{"umls": ["C0340330"], "icd-10": ["Q21.2"], "wikidata": ["Q4817566"]}
Duodenal cancer Endoscopic image of adenocarcinoma of duodenum seen in the post-bulbar duodenum SpecialtyGastroenterology, general surgery, oncology Symptomsvomiting blood, blood in the stool Duodenal cancer is a cancer in the first section of the small intestine known as the duodenum. Cancer of the duodenum is relatively rare compared to stomach cancer and colorectal cancer. Its histology is usually adenocarcinoma. Familial adenomatous polyposis (FAP), Gardner syndrome, Lynch syndrome, Muir–Torre syndrome, celiac disease, Peutz–Jeghers syndrome, Crohn's disease and juvenile polyposis syndrome are risk factors for developing this cancer.[1] The duodenum is the first part of the small intestine. It is located between the stomach and the jejunum. After foods combine with stomach acid, they descend into the duodenum where they mix with bile from the gallbladder and digestive fluid from the pancreas. ## Contents * 1 Signs and symptoms * 2 Treatment * 3 References * 4 External links ## Signs and symptoms[edit] The cancerous mass tends to block food from getting to the small intestine. If food cannot get to the intestines, it will cause pain, acid reflux, and weight loss because the food cannot get to where it is supposed to be processed and absorbed by the body. Patients with duodenal cancer may experience abdominal pain, weight loss, nausea, vomiting, and chronic gastrointestinal bleeding. ## Treatment[edit] Resection is sometimes a part of a treatment plan,[2] but duodenal cancer is difficult to remove surgically because of the area that it resides in—there are many blood vessels supplying the lower body. Chemotherapy is sometimes used to try to shrink the cancerous mass. Other times intestinal bypass surgery is tried to reroute the stomach to intestine connection around the blockage. A 'Whipple' procedure is a type of surgery that is sometimes possible with this cancer. In this procedure, the duodenum, a portion of the Pancreas (the head), and the gall bladder are usually removed, the small intestine is brought up to the Pylorus (the valve at the bottom of the stomach) and the liver and pancreatic digestive enzymes and bile are connected to the small intestine below the pylorus. The removal of part of the Pancreas often requires taking pancreatic enzyme supplements to aid digestion. These are available in the form of capsules by prescription. It is not unusual for a people having received a Whipple procedure to feel well, and to lead a normal life. Some patients need to be fitted with tubes to either add nutrients (feeding tubes) or drainage tubes to remove excess processed food that can not pass the blockage. ## References[edit] 1. ^ Kalogerinis PT, Poulos JE, Morfesis A, et al. (2010). "Duodenal carcinoma at the ligament of Treitz. A molecular and clinical perspective". BMC Gastroenterol. 10: 109. doi:10.1186/1471-230X-10-109. PMC 2949773. PMID 20849628. 2. ^ Gold JS, Tang LH, Gönen M, Coit DG, Brennan MF, Allen PJ (November 2007). "Utility of a prognostic nomogram designed for gastric cancer in predicting outcome of patients with R0 resected duodenal adenocarcinoma". Annals of Surgical Oncology. 14 (11): 3159–67. doi:10.1245/s10434-007-9542-1. PMID 17680313. ## External links[edit] Classification D * ICD-10: C17.0 * ICD-9-CM: 152.0 * MeSH: D004379 * SNOMED CT: 363403002 * v * t * e Digestive system neoplasia GI tract Upper Esophagus * Squamous cell carcinoma * Adenocarcinoma Stomach * Gastric carcinoma * Signet ring cell carcinoma * Gastric lymphoma * MALT lymphoma * Linitis plastica Lower Small intestine * Duodenal cancer * Adenocarcinoma Appendix * Carcinoid * Pseudomyxoma peritonei Colon/rectum * Colorectal polyp: adenoma, hyperplastic, juvenile, sessile serrated adenoma, traditional serrated adenoma, Peutz–Jeghers Cronkhite–Canada * Polyposis syndromes: Juvenile * MUTYH-associated * Familial adenomatous/Gardner's * Polymerase proofreading-associated * Serrated polyposis * Neoplasm: Adenocarcinoma * Familial adenomatous polyposis * Hereditary nonpolyposis colorectal cancer Anus * Squamous cell carcinoma Upper and/or lower * Gastrointestinal stromal tumor * Krukenberg tumor (metastatic) Accessory Liver * malignant: Hepatocellular carcinoma * Fibrolamellar * Hepatoblastoma * benign: Hepatocellular adenoma * Cavernous hemangioma * hyperplasia: Focal nodular hyperplasia * Nodular regenerative hyperplasia Biliary tract * bile duct: Cholangiocarcinoma * Klatskin tumor * gallbladder: Gallbladder cancer Pancreas * exocrine pancreas: Adenocarcinoma * Pancreatic ductal carcinoma * cystic neoplasms: Serous microcystic adenoma * Intraductal papillary mucinous neoplasm * Mucinous cystic neoplasm * Solid pseudopapillary neoplasm * Pancreatoblastoma Peritoneum * Primary peritoneal carcinoma * Peritoneal mesothelioma * Desmoplastic small round cell tumor [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Duodenal cancer	c0541912	1,924	wikipedia	https://en.wikipedia.org/wiki/Duodenal_cancer	2021-01-18T18:43:59	{"mesh": ["D004379"], "umls": ["C0541912", "C0153426"], "wikidata": ["Q1266395"]}
A rare genetic endocrine disease characterized by early onset of severe intractable diarrhea and intestinal malabsorption, followed by obesity and hormonal deficiencies due to insufficient activation of several prohormones, resulting in hypocortisolism, hypothyroidism, diabetes insipidus, hypogonadism, growth deficiency, and diabetes mellitus. Extent and age of onset of hormone deficiencies are variable between patients. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Obesity due to prohormone convertase I deficiency	c1833053	1,925	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=71528	2021-01-23T18:28:14	{"mesh": ["C563423"], "omim": ["600955"], "icd-10": ["E66.8"], "synonyms": ["PCI deficiency"]}
Cerebellar hypoplasia with endosteal sclerosis appears to have been described first by Stoll et al. (1986). The parents in this case were consanguineous. Charrow et al. (1991) described a brother and sister and an unrelated boy with congenital cerebellar hypoplasia and endosteal sclerosis. All 3 children presented with ataxia and developmental delay and were found to have microcephaly, short stature, oligodontia, strabismus, nystagmus, and congenital hip dislocation. Ozgen et al. (2005) described the disorder in a girl who they had followed for 11 years. The major clinical symptoms were cerebellar hypoplasia causing ataxia, hypotonia, mild to moderate developmental delay, growth retardation, endosteal sclerosis, tooth eruption disturbances, and hip dislocations. The endosteal sclerosis remained stationary over time, as did the clinical neurologic symptoms, but neuroradiologic manifestations slowly progressed. Ozgen et al. (2005) concluded that the disorder is probably autosomal recessive. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly Eyes \- Strabismus \- Nystagmus Teeth \- Oligodontia SKELETAL \- Endosteal sclerosis Pelvis \- Congenital hip dislocation NEUROLOGIC Central Nervous System \- Congenital cerebellar hypoplasia \- Ataxia \- Developmental delay ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	CEREBELLAR HYPOPLASIA WITH ENDOSTEAL SCLEROSIS	c1859301	1,926	omim	https://www.omim.org/entry/213002	2019-09-22T16:29:52	{"mesh": ["C535353"], "omim": ["213002"], "orphanet": ["85186"]}
Non-distal monosomy 10q is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 10, with a highly variable phenotype principally characterized by developmental delays (usually of language and speech), variable cognitive impairment and neurobehavioral abnormalities such as autism spectrum disorders and attention deficit disorder. Macrocephaly and mild dysmorphic features may by associated. Overlap with other syndromes, such as Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and juvenile polyposis syndrome has been reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Non-distal monosomy 10q	None	1,927	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1581	2021-01-23T17:48:47	{"icd-10": ["Q93.5"], "synonyms": ["Non-distal deletion 10q", "Non-telomeric monosomy 10q"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article does not cite any sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Conjunctival concretion" – news · newspapers · books · scholar · JSTOR (November 2011) (Learn how and when to remove this template message) This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (November 2011) (Learn how and when to remove this template message) This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (December 2011) (Learn how and when to remove this template message) Concretion in the palpebral conjunctiva, is called conjunctival concretion, that is a (or a cluster of) small, hard, yellowish-white calcified matter, superficially buried beneath the palpebral conjunctiva. Most of concretions in the eye form in the palpebral conjunctiva, which is a clear membrane to surround the inside of the eyelid; fewer can be located in the cornea and retina. ## Contents * 1 Symptoms * 2 Cause * 2.1 Clinical Statistics * 3 Treatment * 4 References ## Symptoms[edit] Conjunctival concretions are generally asymptomatic. Common symptoms include eye discomfort, eye irritation, and foreign body sensation. Sometimes, the larger, harder or multiple concretions make the rubbing off of the superficial layers of the conjunctiva or eyelids to cause conjunctival abrasion, especially prominent when upon blinking. In severe cases, dysfunction or inflammation of the Meibomian (Meibomianitis, an inflammation of the tarsal glands) glands may occur. ## Cause[edit] Chronic conjunctivitis (e.g. trachoma) and aging factor are two causes of conjunctival concretion, which will make the conjunctiva cellular degeneration to produce an epithelial inclusion cyst, filled with epithelial cells and keratin debris. After calcification, the conjunctival cyst hardens and forms a conjunctival concretion. Congenital conjunctival concretion condition is also more common. ### Clinical Statistics[edit] Conjunctival concretions can be single, also multiple, less confluent. There is no difference between the site of the occurrence on the upper and lower eyelid, nor right or left eye. The vast majority of concretions are in the conjunctival surface rather than deep. There is no difference in age for predilection or incidence of concretions, due to the causes of conjunctivitis, aging, and even congenital factor. ## Treatment[edit] Conjunctival concretions can be seen easily by everting the eyelid. The projecting concretions can be removed if they are causing concerning symptoms. Removal can be performed by an eye doctor. Sometimes just a needle or a scalpel is used to remove the concretion under local light anesthesia of the conjunctiva in adults. ## References[edit] [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Conjunctival concretion	c0155162	1,928	wikipedia	https://en.wikipedia.org/wiki/Conjunctival_concretion	2021-01-18T18:31:03	{"umls": ["C0155162"], "wikidata": ["Q1410676"]}
Combined oxidative phosphorylation defect type 15 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by onset in infancy or early childhood of muscular hypotonia, gait ataxia, mild bilateral pyramidal tract signs, developmental delay (affecting mostly speech and coordination) and subsequent intellectual disability. Short stature, obesity, microcephaly, strabismus, nystagmus, reduced visual acuity, lactic acidosis, and a brain neuropathology consistent with Leigh syndrome are also reported. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Combined oxidative phosphorylation defect type 15	c3554182	1,929	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=319524	2021-01-23T17:16:36	{"omim": ["614947"], "icd-10": ["E88.8"], "synonyms": ["COXPD15"]}
PFIC1, a type of progressive familial intrahepathic cholestasis (PFIC, see this term), is an infantile hereditary disorder in bile formation that is hepatocellular in origin and associated with extrahepatic features. ## Epidemiology Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000 births. PFIC1 is the less frequent type of PFIC. ## Clinical description Its onset occurs mostly during infancy. Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. Patients usually develop fibrosis and end-stage liver disease before adulthood. Extrahepatic features have been reported including persistent short stature, watery diarrhea, pancreatitis and sensorineural deafness. ## Etiology PFIC1 is due to mutations in the ATP8B1 gene (18q21-22) encoding the FIC1 protein expressed at the canalicular membrane of hepatocytes as well as in other epithelia. In hepatocytes, abnormal protein might indirectly disrupt biliary bile acid secretion, explaining the low biliary bile acid concentration found in PFIC1 patients. Extrahepatic features of the disease are probably related to the extrahepatic expression of FIC1. ## Diagnostic methods PFIC1 should be suspected in children with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis presenting with normal serum gamma-GT activity and high serum bile acid concentration. Usually, serum alpha-fetoprotein level is normal and alanine aminotransferase values are below five times the upper limit of normal. Liver ultrasonography is usually normal but may reveal a huge gallbladder. Liver histology reveals canalicular cholestasis and the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes. When performed, cholangiography shows a normal biliary tree and allows bile collection. Biliary lipid analysis reveals mildly decreased biliary bile salt concentration. Genotyping confirms the diagnosis. ## Differential diagnosis In the scope of cholestasis with normal gamma-GT, differential diagnosis includes mainly primary bile acid synthesis defects and PFIC2 (see these terms). ## Antenatal diagnosis Prenatal diagnosis can be proposed if a mutation has been identified in each parent. ## Genetic counseling Transmission is autosomal recessive. ## Management and treatment Ursodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage but is not fully effective. Rifampicin is helpful to control pruritus. Nasobiliary drainage may help to select potential responders to biliary diversion. However, because of severe cholestasis, half of patients are ultimately candidates for liver transplantation (LT). Diarrhea often worsens after LT and might be favorably managed by bile adsorptive resin treatment. LT does not prevent extrahepatic progression of the disease, and does not lead to catch-up growth. Furthermore, severe steatohepatitis of the liver graft has been reported. Specialized follow-up is mandatory lifelong. FIC1 defect predisposes to development of intrahepatic cholestasis of pregnancy (see this term). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Progressive familial intrahepatic cholestasis type 1	c4551898	1,930	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79306	2021-01-23T18:27:32	{"gard": ["9802"], "mesh": ["C535933"], "omim": ["211600"], "icd-10": ["K76.8"], "synonyms": ["Byler disease", "FIC1 deficiency", "PFIC1"]}
This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (April 2014) Coronal Image of a TOFI and a Normal Control TOFI[1][2] (thin-outside-fat-inside) is used to describe lean individuals with a disproportionate amount of fat (adipose tissue) stored in their abdomen. The figure to illustrate this shows two men, both 35 years old, with a BMI of 25 kg/m2. Despite their similar size, the TOFI had 5.86 litres of internal fat, whilst the healthy control had only 1.65 litres. Subjects defined as TOFI with body mass index (BMI) <25 kg/m2 have increased levels of many of the risk factors associated with the metabolic syndrome. This phenotype is a further refinement of “metabolically-obese normal-weight"[3][4][5] (MONW). Subjects defined as TOFI have been described as being at higher risk of developing insulin resistance and type II diabetes due to the fact that they have reduced physical activity/VO2max, reduced insulin sensitivity, higher abdominal adiposity, and a more atherogenic lipid profile. Another important characteristic observed in this cohort is elevated levels of liver fat. It is shown that overconsumption of fructose can lead to TOFI by inducing inflammation associated cortisol release.[6] ## Contents * 1 Measurement * 2 Epidemiology * 3 Society and culture * 4 See also * 5 References ## Measurement[edit] To classify an individual as TOFI, it is essential to measure their internal fat content. This is done by using magnetic resonance Imaging (MRI) or CT scanning. The parameters of the MRI scanner are manipulated to show fat as bright (white) and lean tissue as dark. Indirect methods such as waist circumference are not suitable as individuals with an identical waist circumference can have vastly different levels of internal fat. Variation in visceral fat in men with the same waist circumference The figure clearly shows that despite having an identical waist circumference (in this example all men had a waist of 84 cm), there is considerable variation in the amount of visceral fat (volumes shown on the image in litres) present. ## Epidemiology[edit] This is difficult to establish in the general population since the necessary imaging examinations are time consuming and expensive; however, in a 2012 research study it was estimated that 14% of the men and 12% of the women scanned with a BMI 20–25 kg/m2 were classified as TOFI[1]. ## Society and culture[edit] Since the first scientific observations that some lean subjects could have as much, if not more, body fat internally than overweight or obese individuals,[7] there has been considerable media and press interest in this area of research. The first article in the popular press appeared in 2006 in The Guardian,[8] followed by many other newspapers[9][10] and television documentaries.[11][12] ## See also[edit] * Normal weight obesity * Metabolically healthy obesity ## References[edit] 1. ^ Thomas, E. Louise; Frost, Gary; Taylor-Robinson, Simon D.; Bell, Jimmy D. (2012). "Excess body fat in obese and normal-weight subjects". Nutrition Research Reviews. 25 (1): 150–161. doi:10.1017/S0954422412000054. PMID 22625426. 2. ^ Thomas, E. Louise; Parkinson, James R.; Frost, Gary S.; Goldstone, Anthony P.; Doré, Caroline J.; McCarthy, John P.; Collins, Adam L.; Fitzpatrick, Julie A.; Durighel, Giuliana; Taylor-Robinson, Simon D.; Bell, Jimmy D. (2011). "The Missing Risk: MRI and MRS Phenotyping of Abdominal Adiposity and Ectopic Fat". Obesity. 20 (1): 76–87. doi:10.1038/oby.2011.142. PMID 21660078. 3. ^ Ruderman Neil B.; Schneider, S. H.; Berchtold, P. (August 1981). "The "metabolically-obese," normal-weight individual". American Journal of Clinical Nutrition. 34 (8): 1617–1621. 4. ^ Conus, Florence; Rabasa-Lhoret, Rémi; Péronnet, François (2007). "Characteristics of metabolically obese normal-weight (MONW) subjects". Applied Physiology, Nutrition, and Metabolism. 32 (6): 4–12. doi:10.1139/H07-926. PMID 17332780. 5. ^ De Lorenzo, A.; Martinoli, R.; Vaia, F.; Di Renzo, L. (December 2006). "Normal weight obese (NWO) women: an evaluation of a candidate new syndrome". Nutrition, Metabolism & Cardiovascular Diseases. 16 (8): 513–523. doi:10.1016/j.numecd.2005.10.010. PMID 17126766. 6. ^ DiNicolantonio, James J.; Mehta, Varshil; Onkaramurthy, Neema; O'Keefe, James H. (2017-12-07). "Fructose-induced Inflammation and Increased Cortisol: A New Mechanism for How Sugar Induces Visceral Adiposity". Progress in Cardiovascular Diseases. doi:10.1016/j.pcad.2017.12.001. ISSN 1873-1740. PMID 29225114. 7. ^ Thomas, E. Louise; Saeed, Nadeem; Hajnal, Joseph V.; Brynes, Audrey; Goldstone, Anthony P.; Frost, Gary; Bell, Jimmy D. (November 1998). "Magnetic resonance imaging of total body fat". Journal of Applied Physiology. 85 (5): 1778–1785. PMID 9804581. 8. ^ Revill, Jo (10 December 2006). "Are you a Tofi? (That's thin on the outside, fat inside)". Science. The Observer. Guardian. Retrieved 2013-04-23. 9. ^ Derbyshire, David (2006-12-11). "Get in touch with your inner fat". Telegraph. Retrieved 2013-04-23. 10. ^ Cheng, Maria (2007-05-10). "DIET: Thin people may be fat inside". Usatoday.Com. Retrieved 2013-04-23. 11. ^ "Jacques's MRI scan". The Men Who Made Us Fat. Episode 1. 2012-06-14. BBC. BBC Two. Retrieved 2013-04-23. 12. ^ "BBC News - Health Explained: What is fat?". BBC. 2010-09-01. Retrieved 2013-04-23. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	TOFI	None	1,931	wikipedia	https://en.wikipedia.org/wiki/TOFI	2021-01-18T18:35:50	{"wikidata": ["Q7670962"]}
International Convention against Doping in SportTypeDoping in sport Drafted19 October 2005 Signed19 October 2005 LocationParis, France Effective1 February 2007 Condition30 ratifications Parties189[1] DepositaryDirector-General of UNESCO LanguagesArabic, English, French, Russian, and Spanish The International Convention against Doping in Sport is a multilateral UNESCO treaty by which states agree to adopt national measures to prevent and eliminate drug doping in sport. ## Contents * 1 Content * 2 Creation and state parties * 3 Notes * 4 External links ## Content[edit] States that agree to the Convention align their domestic rules with the World Anti-Doping Code, which is promulgated by the World Anti-Doping Agency. This includes facilitating doping controls and supporting national testing programmes; encouraging the establishment of "best practice" in the labelling, marketing, and distribution of products that might contain prohibited substances; withholding financial support from those who engage in or support doping; taking measures against manufacturing and trafficking; encouraging the establishment of codes of conduct for professions relating to sport and anti-doping; and funding education and research on drugs in sport. ## Creation and state parties[edit] The Convention was adopted at the General Conference of UNESCO in Paris on 19 October 2005. It entered into force on 1 February 2007 after it had been ratified by 30 state parties. As of February 2018, the Convention has been ratified by 187 states, which includes 185 UN member states plus the Cook Islands and State of Palestine.[1] The following eight UN members are states that are not parties to the Convention: * Afghanistan * East Timor * Guinea-Bissau * Lebanon * Liechtenstein * Mauritania * São Tomé and Príncipe * South Sudan ## Notes[edit] 1. ^ a b Ratifications. ## External links[edit] * Text. * Ratifications (alphabetical) * Ratifications (by date). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	International Convention against Doping in Sport	None	1,932	wikipedia	https://en.wikipedia.org/wiki/International_Convention_against_Doping_in_Sport	2021-01-18T18:40:49	{"wikidata": ["Q15991223"]}
Tachyphylaxis (Greek ταχύς, tachys, "rapid", and φύλαξις, phylaxis, "protection") is a medical term describing an acute, sudden decrease in response to a drug after its administration;[1] i.e. a rapid and short-term onset of drug tolerance. It can occur after an initial dose or after a series of small doses. Increasing the dose of the drug may be able to restore the original response.[2] ## Contents * 1 Characteristics * 1.1 Molecular interaction * 2 Examples * 2.1 Psychedelics * 2.2 Opioids * 2.3 Beta-2 agonists * 2.4 Nicotine * 2.5 Other examples * 3 Intervention and reversal * 3.1 Intranasal decongestants * 4 See also * 5 References * 6 External links ## Characteristics[edit] Tachyphylaxis is characterized by the rate sensitivity: the response of the system depends on the rate with which a stimulus is presented. To be specific, a high-intensity prolonged stimulus or often-repeated stimulus may bring about a diminished response also known as desensitization. ### Molecular interaction[edit] In biological sciences, molecular interactions are the physical bases of the operation of the system. The control of the operation, in general, involves interaction of a stimulus molecule with a receptor/enzyme subsystem by, typically, binding to the macromolecule A and causing an activation or an inhibition of the subsystem by forming an activated form of the macromolecule B. The following schematic represents the activity: A → p B {\displaystyle A{\xrightarrow {\ \ p\ \ }}B} where p is the activation rate coefficient. It is customary that p is called a rate constant, but, since the p stands for measure of the intensity of the stimulus causing the activation, p may be variable (non-constant). More complete is an open system, namely, in its simplest form, R → A → p ( S ) B → q , {\displaystyle R{\xrightarrow {}}A{\xrightarrow {\ \ p(S)\ \ }}B{\xrightarrow {\ \ q\ \ }},} where R stands for the rate of production of A, p(S) is the activation rate coefficient explicitly expressing its dependence on the stimulus intensity S and q represents the rate coefficient of removal from the state B. In this elementally open system the steady state of B always equal to R/q. The above scheme is only the necessary condition for the rate sensitivity phenomenon, and other pathways of deactivation of B may be considered, with the subsequent return to the inactive form of the receptor/enzyme A. Examples[3][4][5] offer particular use of such (mathematical) models in endocrinology, physiology and pharmacology. ## Examples[edit] ### Psychedelics[edit] Psychedelics such as LSD-25 and psilocybin-containing mushrooms demonstrate very rapid tachyphylaxis. In other words, one may be unable to 'trip' two days in a row. Some people are able to 'trip' by taking up to three times the dosage, yet some users may not be able to negate tachyphylaxis at all until a period of days has gone by. ### Opioids[edit] In a patient fully withdrawn from opioids, going back to an intermittent schedule or maintenance dosing protocol, a fraction of the old tolerance level will rapidly develop, usually starting two days after therapy is resumed and, in general, leveling off after day 7. Whether this is caused directly by opioid receptors modified in the past or affecting a change in some metabolic set-point is unclear. Increasing the dose will usually restore efficacy; relatively rapid opioid rotation may also be of use if the increase in tolerance continues. ### Beta-2 agonists[edit] Inhalation of an agonist for the beta-2 adrenergic receptor, such as Salbutamol, Albuterol (US), is the most common treatment for asthma. Polymorphisms of the beta-2 receptor play a role in tachyphylaxis. Expression of the Gly-16 allele (glycine at position 16) results in greater receptor downregulation by endogenous catecholamines at baseline compared to Arg-16. This results in a greater single-use bronchodilator response in individuals homozygous for Arg-16 compared to Gly-16 homozygotes.[6] However, with regular beta-2 agonist use, asthmatic Arg-16 individuals experience a significant decline in bronchodilator response. This decline does not occur in Gly-16 individuals. It has been proposed that the tachyphylactic effect of regular exposure to exogenous beta-2 agonists is more apparent in Arg-16 individuals because their receptors have not been downregulated prior to agonist administration.[7] ### Nicotine[edit] Nicotine may also show tachyphylaxis over the course of a day, although the mechanism of this action is unclear.[8] ### Other examples[edit] * Nitroglycerine (or Glyceryl Trinitrate) and other nitrovasodilators of the nitrate type demonstrates tachyphylaxis, requiring drug-free intervals when administered transdermally[medical citation needed] * Hydralazine displays tachyphylaxis if given as a monotherapy for antihypertensive treatment. It is administered with a beta-blocker with or without a diuretic.[medical citation needed] * Metoclopramide[medical citation needed] * Dobutamine, a direct-acting beta agonist used in congestive heart failure, also demonstrates tachyphylaxis.[medical citation needed] * Desmopressin used in the treatment of type 1 von Willebrand disease is, in general, given every 12–24 hours in limited numbers due to its tachyphylactic properties.[9] * Ranitidine, used for acid reflux treatment, can display rapid tachyphylaxis within six weeks of treatment initiation, limiting its long-term use potential.[medical citation needed] * Hormone replacement, when used in menopausal women in the form of estrogen and progesterone implants, is cited as having potential to lead to tachyphylaxis, but that citation is based on a single study done in 1990[10] and no follow-up research is available to support this interpretation. ## Intervention and reversal[edit] ### Intranasal decongestants[edit] Use of intranasal decongestants (such as oxymetazoline) for more than three days leads to tachyphylaxis of response and rebound congestion, caused by alpha-adrenoceptor mediated down-regulation and drug desensitization of response.The mechanism may include receptor internalisation and resistance to endogenous vasoconstrictors causing worsening in symptoms post use of medication. Oxymetazoline-induced tachyphylaxis and rebound congestion are reversed by intranasal fluticasone. [11] ## See also[edit] * Desensitization (medicine) * Habituation * Mithridatism * Physical dependence * Physiological tolerance * Downregulation and upregulation ## References[edit] 1. ^ Bunnel, Craig A. Intensive Review of Internal Medicine, Harvard Medical School 2009.[page needed] 2. ^ Lehne, Richard A. (2013). "Tachyphylaxis". Pharmacology for Nursing Care. Philadelphia: Saunders. p. 81. ISBN 978-1-4377-3582-6. 3. ^ Ekblad EB, Ličko V (January 1984). "A model eliciting transient responses". The American Journal of Physiology. 246 (1 Pt 2): R114–21. doi:10.1152/ajpregu.1984.246.1.R114. PMID 6320668. 4. ^ Ličko V, Raff H (February 1985). "Rate sensitivity of blood pressure to hypoxia". Journal of Theoretical Biology. 112 (4): 839–845. doi:10.1016/S0022-5193(85)80065-5. PMID 3999765. 5. ^ Ličko V (1985). "Drugs, Receptors and Tolerance". Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs. pp. 311–322. ISBN 0-931890-20-9. 6. ^ Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R (December 1997). "Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing". The Journal of Clinical Investigation. 100 (12): 3184–8. doi:10.1172/JCI119874. PMC 508532. PMID 9399966. 7. ^ Israel E, Drazen JM, Liggett SB, et al. (July 2000). "The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma" (PDF). American Journal of Respiratory and Critical Care Medicine. 162 (1): 75–80. doi:10.1164/ajrccm.162.1.9907092. PMID 10903223. 8. ^ Zuo Y, Lu H, Vaupel DB, et al. (November 2011). "Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system". Neuropsychopharmacology. 36 (12): 2498–512. doi:10.1038/npp.2011.139. PMC 3194077. PMID 21796109. 9. ^ Benjamin, Ivor (2016-01-01). Andreoli and Carpenter's Cecil Essentials of Medicine. Elsevier Health Sciences. p. 558. ISBN 9781437718997. 10. ^ "nal.usda.gov". Archived from the original on 2008-08-07. 11. ^ Vaidyanathan S, Williamson P, Clearie K, Khan F, Lipworth B (July 2010). "Fluticasone reverses oxymetazoline-induced tachyphylaxis of response and rebound congestion". American Journal of Respiratory and Critical Care Medicine. 182 (1): 19–24. doi:10.1164/rccm.200911-1701OC. PMID 20203244. ## External links[edit] * Tachyphylaxis and Tolerance: Biomathematics of Rate Sensitivity * Tachyphylaxis at the US National Library of Medicine Medical Subject Headings (MeSH) * v * t * e Pharmacology Ligand (biochemistry) Excitatory * Agonist * Endogenous agonist * Irreversible agonist * Partial agonist * Superagonist * Physiological agonist Inhibitory * Antagonist * Competitive antagonist * Irreversible antagonist * Physiological antagonist * Inverse agonist * Enzyme inhibitor * Drug * Neurotransmitter * Agonist-antagonist * Pharmacophore Pharmacodynamics Activity at receptor * Mechanism of action * Mode of action * Binding * Receptor (biochemistry) * Desensitization (pharmacology) Other effects of ligand * Selectivity (Binding, Functional) * Pleiotropy (drugs) * Non-specific effect of vaccines * Adverse effects * Toxicity (Neurotoxicity) Analysis * Dose–response relationship * Hill equation (biochemistry) * Schild plot * Del Castillo Katz model * Cheng-Prussoff Equation * Methods (Organ bath, Ligand binding assay, Patch-clamp) Metrics * Efficacy * Intrinsic activity * Potency (EC50, IC50, ED50, LD50, TD50) * Therapeutic index * Affinity Pharmacokinetics Metrics * Loading dose * Volume of distribution (Initial) * Rate of infusion * Onset of action * Biological half-life * Plasma protein binding * Bioavailability LADME * (L)ADME: (Liberation) * Absorption * Distribution * Metabolism * Excretion (Clearance) * Compartment * Bioequivalence Related fields Neuroscience and psychology * Neuropsychopharmacology * Neuropharmacology * Psychopharmacology * Electrophysiology Medicine * Clinical pharmacology * Pharmacy * Medicinal chemistry * Pharmacoepidemiology Biochemistry and genetics * Pharmacoinformatics * Pharmacogenetics * Pharmacogenomics Toxicology * Pharmacotoxicology * Neurotoxicology Drug discovery * Classical pharmacology * Reverse pharmacology * Photopharmacology * Immunopharmacology * Cell biology * Physiology Other * Coinduction (anaesthetics) * Combination therapy * Functional analog (chemistry) * Polypharmacology * Chemotherapy * List of drugs * WHO list of essential medicines Tolerance and resistance * Drug tolerance * Tachyphylaxis * Drug resistance * Antibiotic resistance * Multiple drug resistance Antimicrobial pharmacology * Antimicrobial pharmacodynamics * Minimum inhibitory concentration * Bacteriostatic * Minimum bactericidal concentration * Bactericide [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Tachyphylaxis	None	1,933	wikipedia	https://en.wikipedia.org/wiki/Tachyphylaxis	2021-01-18T18:48:39	{"mesh": ["D013618"], "wikidata": ["Q2464757"]}
Severe combined immunodeficiency (SCID) T-B+ due to JAK3 deficiency is a form of SCID (see this term) characterized by severe and recurrent infections, associated with diarrhea and failure to thrive. ## Epidemiology Annual incidence is between 1/100,000 and 1/1,000,000 live births depending on the population. ## Clinical description The disease shares the same clinical picture as SCID due to gamma chain deficiency (see this term). Patients present in the first few months of life with the classical clinical features of SCID, i.e. chronic diarrhea, failure to thrive, recurrent respiratory infections and/or generalized infections due to opportunistic pathogens. Patients may present with skin rash, abnormalities of liver function, and pancytopenia. Materno-fetal transfusion-associated graft versus host disease is also associated with the disease. The disease is characterized by a lack of circulating T and NK (Natural Killer) cells and normal number of B lymphocytes. ## Etiology SCID due to JAK3 deficiency results from a defect in the JAK3 gene encoding an intracellular tyrosine kinase, the Janus activating kinase 3 required for cytokine-mediated signaling. ## Genetic counseling Transmission is autosomal recessive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	T-B+ severe combined immunodeficiency due to JAK3 deficiency	c1833275	1,934	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=35078	2021-01-23T17:54:35	{"mesh": ["C563440"], "omim": ["600802"], "icd-10": ["D81.2"], "synonyms": ["T-B+ SCID due to JAK3 deficiency"]}
Genetic recurrent myoglobinuria is an inborn error of metabolism characterized by abnormal urinary excretion of myoglobin due to acute destruction of skeletal muscle fibers. ## Epidemiology The exact prevalence remains unknown. ## Clinical description In the majority of cases, the disease manifests in childhood and is often triggered by exertion or infection (febrile illness). Hypertonia, muscle stiffness and muscle pain, impaired kidney function and elevated levels of serum creatine kinase are common clinical features. ## Etiology Mutations in the mitochondrial DNA-encoded cytochrome C oxidase genes (MT-CO1 and MT-CO2) should be considered in patients with recurrent myoglobinuria. Recently, mutations in the LPIN1 gene (chromosome 2p21) have been reported to have a causative role in three patients with recurrent episodes of myoglobinuria, originating from consanguineous families. ## Genetic counseling The disorder may occur sporadically, or be inherited in either a recessive or dominant manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Genetic recurrent myoglobinuria	c1849386	1,935	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99845	2021-01-23T18:44:56	{"mesh": ["C564832"], "omim": ["268200", "550500"], "icd-10": ["R82.1"]}
Myiasis is a parasitic infestation caused by larvae of several fly species. Diagnosis and treatment are generally quite simple. This infestation is, however, rarely seen in the vulvar area. Infestation of vulvar area with larvae and maggots is called vulvar myiasis. Very few cases have been described in literature.[1] ## References[edit] 1. ^ Passos MR, Carvalho AV, Dutra AL, et al. (1998). "Vulvar myiasis". Infect Dis Obstet Gynecol. 6 (2): 69–71. doi:10.1002/(SICI)1098-0997(1998)6:2<69::AID-IDOG8>3.0.CO;2-2. PMC 1784782. PMID 9702589. ## Further reading[edit] * Yazar S, Ozcan H, Dinçer S, Sahin I (2002). "Vulvar Myiasis" (PDF). Yonsei Med. J. 43 (4): 553–5. PMID 12205748. says "BACKGROUND: To report a rare case of vulvar myiasis caused by Wohlfartia magnifica, including clinical and microscopic observations. CASE: A vulvar lesion was found in a 31-year-old married female villager with the history of dropping fly larvae from vulva, vulvar pain and itching sensation. The larvae were identified as the species of Wohlfartia magnifica. The lesion was washed with batticon over a period of five days and the patient was discharged. CONCLUSION: Vulvar myiasis should be considered in the differential diagnosis of genital lesions. The diagnosis can be easily established based on microscopic features of the maggots, especially those relating to stigma structures." ## External links[edit] * Diptera.info [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Vulvar myiasis	None	1,936	wikipedia	https://en.wikipedia.org/wiki/Vulvar_myiasis	2021-01-18T18:32:00	{"wikidata": ["Q7943638"]}
A rare, genetic syndromic intellectual disability characterized by developmental delay, mild to severe intellectual disability, facial features (bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance) and a wide spectrum of other nonspecific variable clinical features. ## Epidemiology To date, more than 70 cases have been reported. ## Clinical description Patients have a variable degree of intellectual disability, global developmental delay (notably with severe speech and language impairment), muscular hypotonia, and facial features (including broad forehead, bitemporal narrowing, upslanting palpebral fissures, low-set ears, flat nasal bridge, bulbous nose, thin vermillion border and open mouth with tongue protrusion). Highly variable additional features include cardiac defects (persistent foramen ovale, ventricular septal defects or tetralogy of Fallot), cerebellar ataxia, seizures, growth difficulties, microcephaly, ventriculomegaly or myelination defects. ## Etiology The disorder is sporadic caused by either a sequence variation in the mediator complex subunit 13-like gene (MED13L), an intragenic microdeletion within the gene, or by a larger microdeletion encompassing the entire gene. Rare intragenic microduplications within MED13L are also reported. ## Diagnostic methods The syndrome could be suspected on the association of developmental delay, speech impairment, motor delay, and facial features (notably, an open mouth with a protruding tongue, a thin vermillion border, upslanting palpebral fissures and a bulbous nasal tip). Molecular genetic testing approaches include array-comparative genomic hybridization for microdeletion identification, and sequencing of the entire MED13L coding region for sequence variants (gene panel, exome sequencing). ## Differential diagnosis Some patients share some clinical features observed in Kleefstra syndome, Mowat-Wilson syndrome, Kabuki syndrome and 1p36 microdeletion. ## Antenatal diagnosis Pathogenic variations are de novo. However, very rare cases of parental mosaicism are described and prenatal genetic testing may be possible in such families with a proband. No specific prenatal signs are reported. ## Genetic counseling Most cases arise de novo and thus the sibling recurrence risk is low. The disorder is autosomal dominant with 50% risk of transmission from affect individuals to their offspring; however, transmission of the condition has never been reported. ## Management and treatment Management is mainly supportive and symptomatic. Affected patients should benefit from speech therapy. Development, walking evolution, hearing and vision should be monitored closely. ## Prognosis The prognosis and function consequences are variable and dependent on the associated anomalies and intellectual disability. * European Reference Network [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Developmental delay-facial dysmorphism syndrome due to MED13L deficiency	c4225208	1,937	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=369891	2021-01-23T18:44:30	{"omim": ["616789"], "icd-10": ["Q87.8"], "synonyms": ["MED13L-related intellectual disability syndrome"]}
A number sign (#) is used with this entry because susceptibility to this platelet-type bleeding disorder (BDPLT13) is conferred by heterozygous mutation in the gene encoding the thromboxane A2 receptor (TBXA2R; 188070) on chromosome 19p13. Description Susceptibility to platelet-type bleeding disorder-13 is due to a defective thromboxane A2 receptor on platelets. The susceptibility is inherited in an autosomal dominant pattern, but clinical features, including mild mucocutaneous bleeding, occur only in the presence of a 'second hit' affecting platelet function; this second hit may be either in the TBXA2R gene or in another gene affecting the coagulation cascade (summary by Mumford et al., 2010). Clinical Features Weiss and Lages (1977) reported a 10-year-old boy with easy bruising and excessive bleeding after a tooth extraction at age 2 years. Laboratory studies showed normal platelet counts, but defective second phase platelet aggregation in response to epinephrine or ADP. Addition of platelet-rich plasma from a normal person who had ingested aspirin resulted in platelet aggregation, indicating that the defect was not in cyclooxygenase (PTGS1; 176805). Addition of prostaglandin G2 did not result in patient platelet aggregation, suggesting a defect in the production of or response to thromboxane A2. Weiss and Lages (1977) postulated a defect in thromboxane synthesis (TBXAS1; 274180). However, in a follow-up study, Lages et al. (1981) found that the patient's platelets did not aggregate in response to TBXAS1 generated from arachidonic acid in normal platelets, but were capable of synthesizing thromboxane from both arachidonic acid and prostaglandin G2. Patient platelets also showed a defect in mobilization of intracellular calcium. Overall, the findings indicated that the defect in this patient did not result from a thromboxane synthetase deficiency, but may be due to impaired platelet response to thromboxane A2 and impaired mobilization of platelet calcium, consistent with the possibility that thromboxane A2 may act as a calcium ionophore. Ushikubi et al. (1987) and Fuse et al. (1993) reported 2 unrelated patients with a mild bleeding disorder caused by impaired platelet aggregation responses to TBXA2 and its analogs, despite a normal response to thrombin. Although the patients' platelets exhibited normal binding activities to TXA2 analogs, they showed decreased GTPase activity and second messenger formation when stimulated by a stable TXA2 agonist. Platelets also showed defective intracellular calcium mobilization in response to these stimuli. This led to the proposal that the defect in the patients was due to impaired coupling of TBXA2R to the G protein. Hirata et al. (1994) provided follow-up of the patient reported by Ushikubi et al. (1987). The patient's son, daughter, and brother had a similar, but milder, defect in platelet aggregation in response to a TXA2 agonist. Mumford et al. (2010) reported a 14-year-old white boy with a history of easy bruising and prolonged epistaxis since infancy. Laboratory studies showed lack of platelet aggregation in response to low doses of arachidonic acid and impaired aggregation in response to a TBXA2 agonist. Platelets from the father showed a similar pattern, although he had no bleeding symptoms. Inheritance Susceptibility to this bleeding disorder due to defective thromboxane A2 receptor is an autosomal dominant trait (Hirata et al., 1994). Molecular Genetics In affected members of 2 unrelated families with a bleeding disorder (Ushikubi et al., 1987 and Fuse et al., 1993), Hirata et al. (1994) identified a heterozygous mutation in the TBXA2 gene (R60L; 188070.0001). The mutant receptor expressed in Chinese hamster ovary cells showed normal ligand binding affinities, but decreased agonist-induced second messenger formation. Dominant inheritance of the disorder suggested that the mutation produces a dominant-negative effect. In a 14-year-old white boy with a mild mucocutaneous bleeding disorder characterized by defective platelet response to TBXA2, Mumford et al. (2010) identified a heterozygous mutation in the TBXA2R gene (D304N; 188070.0002). The patient's father, who also carried the mutation, had no bleeding symptoms. In vitro studies of platelets from both the boy and his father showed impaired aggregation and ATP secretion responses to arachidonic acid and a TBXA2R agonist. In vitro functional expression studies in CHO cells showed normal surface membrane expression of the mutant protein, but there was significantly decreased binding and a significant reduction (more than 85%) in intracellular calcium levels in response to a TBXA2R agonist compared to wildtype, consistent with a loss of function. Noting the phenotypic differences between the boy and his father, Mumford et al. (2010) speculated that the clinical bleeding phenotype demonstrated by the boy represented the effect of the heterozygous D304N mutation combined with an additional unidentified hemostatic defect. Mumford et al. (2010) concluded that heterozygosity for mutations in the TBXA2R gene is sufficient to cause abnormal platelet functional responses in vitro, but is insufficient to cause clinically significant dysfunction in vivo. In an individual whose platelets showed defective response to TBXA2 in vitro, Flamm et al. (2012) identified a heterozygous mutation in the TBXA2R gene (V241G; 188070.0003). In vitro functional expression studies showed normal expression of the mutant receptor, but impaired calcium mobilization and aggregation in response to a TBXA2 agonist. Because G protein signaling through ADP was normal, Flamm et al. (2012) concluded that the mutation caused abnormal coupling of TBXA2R to Gq, resulting in impaired calcium mobilization. The individual's platelets also showed impaired response to the anticoagulants aspirin and indomethacin, which inhibit the production of thromboxane A2. The individual had no self-reported bleeding tendencies. INHERITANCE \- Autosomal dominant HEAD & NECK Nose \- Epistaxis SKIN, NAILS, & HAIR Skin \- Ecchymoses \- Easy bruising HEMATOLOGY \- Bleeding tendency, mild \- Defective platelet aggregation in response to arachidonic acid \- Defective platelet calcium mobilization \- Normal platelet count \- Normal serum thromboxane B2 MOLECULAR BASIS \- Susceptibility conferred by mutation in the platelet thromboxane A2 receptor gene (TBXA2R, 188070.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	BLEEDING DISORDER, PLATELET-TYPE, 13, SUSCEPTIBILITY TO	c3279614	1,938	omim	https://www.omim.org/entry/614009	2019-09-22T15:56:46	{"omim": ["614009"], "orphanet": ["220443"], "synonyms": ["Alternative titles", "BLEEDING DISORDER, SUSCEPTIBILITY TO, DUE TO DEFECTIVE PLATELET THROMBOXANE A2 RECEPTOR"]}
An astrogliopathy and the most severe and common form of Alexander disease (AxD), presenting before the age of 4 and characterized by seizures, megalencephaly and developmental delay with progressive deterioration. ## Epidemiology The prevalence is unknown. This form accounts for approximately 60% of AxD cases. ## Clinical description AxD type I typically presents between birth and the age of 4. Those with a neonatal onset (within the first 30 days) usually have a more severe disease course presenting with symptoms of generalized, frequent, and often intractable seizures, aqueductal stenosis (leading to hydrocephalus with raised intracranial pressure) and severe motor and intellectual disability. In infantile-onset cases, ataxia, hyperreflexia and pyramidal signs are seen along with seizures. Megalencephaly and frontal bossing are further manifestations of the disease. In all infants there is a loss of developmental milestones with progressive psychomotor retardation. The disease course is severe with death usually, but not always, occurring in the first two decades after diagnosis. In the neonatal form the disease progresses even faster with severe disability or death occurring within the first years of life. ## Etiology AxD is caused by gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene (17q21). This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the CNS. It is currently unknown how Rosenthal fibers are involved in disease pathogenesis. ## Diagnostic methods MRI shows characteristic leukodystrophy with frontal, basal ganglia signal abnormality, brainstem signal abnormality and contrast enhancement. Molecular genetic testing for a mutation in the GFAP gene confirms diagnosis. The presence of Rosenthal fibers in astrocytes can also be seen in other diseases and is therefore not diagnostic. ## Differential diagnosis Differential diagnoses include: peroxisomal biogenesis disorders, Zellweger syndrome spectrum, glutaric aciduria type I, Aicardi-Goutières syndrome, the frontal variant of adrenoleukodystrophy and megalencephalic leukoencephalopathy with subcortical cysts (see these terms). ## Antenatal diagnosis Although most cases of AxD type I are sporadic, antenatal diagnosis is possible if a disease causing mutation has been identified in an affected family member. ## Genetic counseling AxD type I typically occurs sporadically and is associated with the occurrence of de novo mutations. Most patients do not reproduce. Gonadal mosaicism should be considered in advising families of the risk of recurrence when a de novo mutation is identified. Genetic counseling can be proposed to families with a history of the disease and family members can be tested for the disease-causing mutation. Penetrance is complete. ## Management and treatment There is no cure for AxD type I. Treatment is symptomatic and focuses on seizure control, maintenance of pulmonary function and nutrition. Those with severe feeding difficulties and recurrent vomiting may require a percutaneous gastrostomy tube or the placement of a nasogastric tube. Antibiotics can be given to treat intercurrent infections and antiepileptic drugs are given to control seizures. Orthopedic complications should be prevented, in particular scoliosis, and the management of spasticity by a multidisciplinary team is an important component of care. Psychological counseling can also be proposed to families of infants with the disease. ## Prognosis The prognosis is poor but with supportive therapies some patients have lived into adolescence and adulthood. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Alexander disease type I	c0270726	1,939	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=363717	2021-01-23T17:56:02	{"mesh": ["D038261"], "omim": ["203450"], "icd-10": ["E75.2"], "synonyms": ["AxD type I"]}
For a phenotypic description and a discussion of genetic heterogeneity of abdominal aortic aneurysm, see AAA1 (100070). Mapping Bown et al. (2011) performed a genomewide association study in 1,866 patients with abdominal aortic aneurysm (AAA) and 5,435 controls, and performed replication analysis of 9 promising signals (p less than 10(-5)) in 2,871 additional AAA cases and 32,687 controls, with further follow-up in 1,491 AAA cases and 11,060 controls. The lead SNP at 1 of the 9 loci, rs1466535, located within intron 1 of the LRP1 gene (107770) on chromosome 12q13.3, demonstrated significant association in the replication sample (p = 0.0042), with confirmation in the follow-up study (p = 0.035). In a combined analysis, rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10); odds ratio, 1.15). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease (see 607339), blood pressure (see 145500), diabetes (see 125853), or hyperlipidemia (see 144250), suggesting that this locus is specific to AAA. Gene expression studies showed a trend towards increased LRP1 expression for the CC genotype in arterial tissues, with a significant increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia (1.19-fold; p = 0.029). Electrophoretic mobility-shift assay indicated that the rs1466535 T allele might disrupt a binding site for SREBP1 (184756). [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	AORTIC ANEURYSM, FAMILIAL ABDOMINAL, 4	c0162871	1,940	omim	https://www.omim.org/entry/614375	2019-09-22T15:55:27	{"doid": ["7693"], "mesh": ["D017544"], "omim": ["100070", "614375"], "orphanet": ["86"], "synonyms": []}
Codependency is a concept that attempts to characterize imbalanced relationships where one person enables another person's addiction, poor mental health, immaturity, irresponsibility, or under-achievement.[1] Definitions of codependency vary, but typically include high self-sacrifice, a focus on others' needs, suppression of one's own emotions, and attempts to control or fix other people's problems.[2] People who self-identify as codependents exhibit low self-esteem, but it is unclear whether this is a cause or an effect of characteristics associated with codependency.[3] Codependency is generally defined as a subclinical, situational, and/or episodic behavioral condition similar to that of dependent personality disorder. ## Contents * 1 History * 2 Definition * 2.1 Codependency * 2.2 Dependent personality disorder * 3 Behaviors and characteristics * 3.1 Individual dynamics * 3.2 Romantic relationship dynamics * 3.3 Family dynamics * 4 Recovery and prognosis * 5 Controversy * 6 See also * 7 References * 8 Further reading * 9 External links ## History[edit] The idea of codependency may have its roots in the theories of German psychoanalyst Karen Horney. In 1941, she proposed that some people adopt what she termed a "Moving Toward" personality style to overcome their basic anxiety. Essentially, these people move toward others by gaining their approval and affection, and subconsciously control them through their dependent style. They are unselfish, virtuous, martyr-like, faithful, and turn the other cheek despite personal humiliation. Approval from others is more important than respecting themselves.[4] The term codependency is most often identified with Alcoholics Anonymous and the realization that the Alcoholism was not solely about the addict but also about the family and friends who constitute a network for the alcoholic."[5] The term “codependent” is used to describe how family members and friends might actually interfere with recovery by overhelping."[6] The application of this term was very much driven by the self-help community.[7] Janet G. Woititz's Adult Children of Alcoholics had come out in 1983 and sold two million copies while being on the New York Times bestseller list for 48 weeks.[7] Robin Norwood's Women Who Love Too Much, 1985, sold two and a half million copies and spawned Twelve Step groups across the country for women "addicted" to men.[7] Melody Beattie popularized the concept of codependency in 1986 with the book Codependent No More which sold eight million copies.[8] In 1986, Timmen Cermak, M.D. wrote Diagnosing and Treating Co-Dependence: A Guide for Professionals. In the book and an article published in the Journal of Psychoactive Drugs (Volume 18, Issue 1, 1986), Cermak argued (unsuccessfully) for the inclusion of codependency as a separate personality disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R; American Psychiatric Association, 1987).[9] Cermak's book paved the way for a Twelve-step take-off program, called Co-Dependents Anonymous.[10] The first Co-Dependents Anonymous meeting was held October 22, 1986.[10] ## Definition[edit] "Dependency" is well-established in psychological literature.[citation needed] Early psychoanalytic theory emphasized the oral character and structural basis of dependency, social learning theory considers a tendency to be acquired by learning and experience, and ethological attachment theory posits that attachment or affectional bonding is the basis for positive dependency, which should be distinguished from the negatively-valanced definition posited by codependence theorists.[citation needed] ### Codependency[edit] Timmen Cermak, M.D., proposed that co-dependency be listed as a personality disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R; American Psychiatric Association, 1987). Cermak reasoned that when specific personality traits become excessive and maladaptive and cause significant impairment in functioning or cause significant distress, it warrants a personality disorder diagnosis. Cermak's definition was published in the Journal of Psychoactive Drugs in 1986.[11] Cermak proposed the following criteria for this disorder:[11] 1. Continued investment of self-esteem in the ability to control both oneself and others in the face of serious adverse consequences. 2. Assumption of responsibility for meeting others' needs to the exclusion of acknowledging one's own. 3. Anxiety and boundary distortions relative to intimacy and separation. 4. Enmeshment in relationships with personality disordered, chemically dependent, other co‐dependent, or impulse‐disordered individuals. 5. Three or more of the following: 1. Excessive reliance on denial 2. Constriction of emotions (with or without dramatic outbursts) 3. Depression 4. Hypervigilance 5. Compulsions 6. Anxiety 7. Substance abuse 8. Has been (or is) the victim of recurrent physical or sexual abuse 9. Stress related medical illnesses 10. Has remained in a primary relationship with an active substance abuser for at least two years without seeking outside help. Codependency has not been included in the Diagnostic and Statistical Manual of Mental Disorders; DSM-III-R or later versions. ### Dependent personality disorder[edit] Dependent personality disorder is included in the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric Association. The definition and criteria have changed in the different versions of the DSM. In the DSM-I, passive dependency personality was characterized by helplessness, denial, and indecisiveness, and was considered a subtype of passive-aggressive personality. By DSM-IV, there were nine criteria with an essential feature of a pervasive or lifetime pattern of dependent and submissive behavior. The DSM-IV definition emphasized the excessive need to be taken care of, leading to submissive and clinging behavior and fear of separation.[12] ## Behaviors and characteristics[edit] ### Individual dynamics[edit] A codependent is someone who cannot function on their own and whose thinking and behavior is instead organized around another person, process, or substance.[13] Many codependents place a lower priority on their own needs, while being excessively preoccupied with the needs of others. Codependency can occur in any type of relationship, including family, work, friendship, and also romantic, peer or community relationships.[14] ### Romantic relationship dynamics[edit] Some codependents often find themselves in relationships where their primary role is that of rescuer, supporter, and confidante. These helper types are often dependent on the other person's poor functioning to satisfy their own emotional needs.[1] Codependent relationships are marked by intimacy problems, dependency, control (including caretaking), denial, dysfunctional communication and boundaries, and high reactivity. Often, there is imbalance, so one person is abusive or in control or supports or enables another person's addiction, poor mental health, immaturity, irresponsibility, or under-achievement.[15] Commonly observable characteristics of codependency are:[1][16] * intense and unstable interpersonal relationships * inability to tolerate being alone, accompanied by frantic efforts to avoid being alone * autophobia * chronic feelings of boredom and emptiness * subordinating one's own needs to those of the person with whom one is involved * overwhelming desire for acceptance and affection * perfectionism * over-controlling * external referencing * dishonesty and denial * manipulation * lack of trust * low self-worth * victim mentality In a codependent relationship, the codependent person's sense of purpose is based on making extreme sacrifices to satisfy their partner's needs. Codependent relationships signify a degree of unhealthy "clinginess" and needy behavior, where one person does not have self-sufficiency or autonomy. One or both parties depend on their loved one for fulfillment.[17] The mood and emotions of the codependent are often determined by how they think other individuals perceive them (especially loved ones). This perception is self-inflicted and often leads to clingy, needy behavior which can hurt the health of the relationship.[18] Particularly problematic pairings include: Personality disorder and codependent pairing * Borderline personality disorder – there is a tendency for loved ones of people with borderline personality disorder (BPD) to slip into "caretaker" roles, giving priority and focus to problems in the life of the person with BPD rather than to issues in their own lives. Further, the codependent may gain a sense of worth by being "the sane one" or "the responsible one".[19] * Narcissistic personality disorder – codependents of narcissists are sometimes called co-narcissists.[20] Narcissists, with their ability to get others to "buy into their vision" and help them make it a reality, seek and attract partners who will put others' needs before their own.[21] Codependents can provide the narcissist with an obedient and attentive audience.[22] Among the reciprocally interlocking interactions of the pair are the narcissist's overpowering need to feel important and special and the codependent person's strong need to help others feel that way. Codependent or impulse-disordered individuals and codependent pairing[11] * Attention-deficit hyperactivity disorder (ADHD). * Obsessive-compulsive disorder (OCD) * Bipolar disorder * Substance use disorder (SUD) * Autism spectrum disorder (ASD) * Personality disorder (PD) * Traumatic brain injury (TBI) * Psychosis * Dementia ### Family dynamics[edit] In the dysfunctional family the child learns to become attuned to the parent's needs and feelings instead of the other way around.[15] Parenting is a role that requires a certain amount of self-sacrifice and giving a child's needs a high priority. A parent can, nevertheless, be codependent towards their own children if the caretaking or parental sacrifice reaches unhealthy or destructive levels.[14] Generally, a parent who takes care of their own needs (emotional and physical) in a healthy way will be a better caretaker, whereas a codependent parent may be less effective, or may even do harm to a child.[14] Codependent relationships often manifest through enabling behaviors, especially between parents and their children.[23] Another way to look at it is that the needs of an infant are necessary but temporary, whereas the needs of the codependent are constant. Children of codependent parents who ignore or negate their own feelings may become codependent. ## Recovery and prognosis[edit] Not all mental health professionals agree about standard methods of treatment.[24] Caring for an individual with a physical addiction is not necessarily treating a pathology. The caregiver may only require assertiveness skills and the ability to place responsibility for the addiction on the other.[25][26] There are various recovery paths for individuals who struggle with codependency. For example, some may choose cognitive-behavioral psychotherapy, sometimes accompanied by chemical therapy for accompanying depression. There also exist support groups for codependency, such as Co-Dependents Anonymous (CoDA), Al-Anon/Alateen, Nar-Anon, and Adult Children of Alcoholics (ACoA), which are based on the twelve-step program model of Alcoholics Anonymous and Celebrate Recovery, a Christian, Bible-based group.[27] Many self-help guides have been written on the subject of codependency. Sometimes an individual can, in attempts to recover from codependency, go from being overly passive or overly giving to being overly aggressive or excessively selfish.[25] Many therapists maintain that finding a balance through healthy assertiveness (which leaves room for being a caring person and also engaging in healthy caring behavior) is true recovery from codependency and that becoming extremely selfish, a bully, or an otherwise conflict-addicted person is not.[25][26] Developing a permanent stance of being a victim (having a victim mentality) would also not constitute true recovery from codependency and could be another example of going from one extreme to another.[25] A victim mentality could also be seen as a part of one's original state of codependency (lack of empowerment causing one to feel like the "subject" of events rather than being an empowered actor).[25] Someone truly recovered from codependency would feel empowered and like an author of their life and actions rather than being at the mercy of outside forces.[25] A victim mentality may also occur in combination with passive–aggressive control issues.[25] From the perspective of moving beyond victim-hood, the capacity to forgive and let go (with exception of cases of very severe abuse) could also be signs of real recovery from codependency, but the willingness to endure further abuse would not.[25] Unresolved patterns of codependency can lead to more serious problems like alcoholism, drug addiction, eating disorders, sex addiction, psychosomatic illnesses, and other self-destructive or self-defeating behaviors.[28] People with codependency are also more likely to attract further abuse from aggressive individuals (such as those with BPD or NPD), more likely to stay in stressful jobs or relationships, less likely to seek medical attention when needed and are also less likely to get promotions and tend to earn less money than those without codependency patterns.[28] For some people, the social insecurity caused by codependency can progress into full-blown social anxiety disorders like social phobia, avoidant personality disorder or painful shyness.[28] Other stress-related disorders like panic disorder, depression or PTSD may also be present.[28] ## Controversy[edit] While Timmen Cermak, M.D., proposed that co-dependency be listed as a personality disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R; American Psychiatric Association, 1987), it was not accepted by the committee and, as such, no medical consensus exists on the definition of codependency.[1] With no definition, the term is easily applicable to many behaviors and has been overused by some self-help authors and support communities.[29] Some clinicians think that the term codependency has been overused by the general populace and labeling a patient as codependent can be confusing and may even shame them rather than help them focus on how their traumas shape their current relationships.[30] Codependency is a theory. There is no evidence that codependence is caused by a disease process.[31] Attachment theory may be a more helpful model for understanding and dealing with attachment in adults.[32] Codependency does not refer to all caring behavior or feelings, but only those that are excessive to an unhealthy degree.[25] Some scholars and treatment providers think that codependency is an overresponsibility and that overresponsibility needs to be understood as a positive impulse gone awry. Responsibility for relationships with others needs to coexist with responsibility to self.[33] ## See also[edit] * Alcoholism in family systems * Adult Children of Alcoholics * Attachment theory * Anxious-preoccupied attachment style * Dependent personality disorder * Misplaced loyalty * Parentification ## References[edit] 1. ^ a b c d Johnson, R. Skip (13 July 2014). "Codependency and Codependent Relationships". BPDFamily.com. Retrieved 9 September 2014. 2. ^ Dear, G.E.; Roberts, C.M.; Lange, L. (2004). "Defining codependency: An analysis of published definitions". In S. Shohov (Ed.), Advances in psychology research. 34: 63–79 – via Huntington, NY: Nova Science Publishers. 3. ^ Marks, A.; Blore, R.; Hine, D.; Dear, G. (2012). "Development and Validation of a Revised Measure of Codependency". Australian Journal of Psychology. 64: 119–127. 4. ^ Rotunda, Ph.D, Robert J. "Codependency". University of West Florida. 5. ^ Davis, Lennard J. (2008). Obsession: A History. London: University of Chicago Press. p. 178. ISBN 978-0-226-13782-7. 6. ^ Hendriksen, Ellen. "Is Your Relationship Codependent? And What Exactly Does That Mean?". Scientific American. Scientific American. Retrieved 12 January 2017. 7. ^ a b c Travis, Trish (2009). The Language of the Heart, A Cultural History of the Recovery Movement from Alcoholics Anonymous to Oprah Winfrey. Chapel Hill, N.C.: University of North Carolina Press. p. 168. ISBN 978-0-8078-3319-3. 8. ^ J. S. Rice, A Disease of One's Own (1998) p. 2 9. ^ Morgan Jr., JP (1991). "What is codependency?". J Clin Psychol. 47 (5): 720–9. doi:10.1002/1097-4679(199109)47:5<720::aid-jclp2270470515>3.0.co;2-5. PMID 1939721. 10. ^ a b Irving, Leslie (1999). Codependent Forevermore, The Invention of Self in a Twelve Step Group. Chicago: University of Chicago Press. p. 30. ISBN 978-0-226-38471-9. 11. ^ a b c Cermak M.D., Timmen L. (1986). "Diagnostic Criteria for Codependency". Journal of Psychoactive Drugs. 18 (1): 15–20. doi:10.1080/02791072.1986.10524475. PMID 3701499. 12. ^ Sperry, M.D., Ph.D., Len (13 May 2013). Handbook of Diagnosis and Treatment of DSM-IV Personality Disorders. Kentucky: Routledge. p. 108. ISBN 9780415935692.CS1 maint: multiple names: authors list (link) 13. ^ Lancer, Darlene (2012). Codependency for Dummies (1st ed.). New Jersey: John Wiley & Sons, Inc. p. 30. ISBN 978-1118095225. 14. ^ a b c Codependents Anonymous: Patterns and Characteristics Archived 2013-08-24 at the Wayback Machine 15. ^ a b Lancer, Darlene (2014). Conquering Shame and Codependency: 8 Steps to Freeing the True You. Minnesota: Hazelden. pp. 63–65. ISBN 978-1-61649-533-6. 16. ^ Winning Teams: Definitions in Psychology, Dr. David Thomas PhD 17. ^ Wetzler, PhD, Scott. "Psychology division chief at Albert Einstein College of Medicine". WebMD. Retrieved 5 December 2014. 18. ^ Reynolds, Rick (2014-08-19). "Why Is Codependency A Serious Problem For Relationships?". 19. ^ Danielle, Alicia. "Codependency and Borderline Personality Disorder: How to Spot It". Clearview Women's Center. Archived from the original on 7 December 2014. Retrieved 5 December 2014. 20. ^ Rappoport, Alan, PhD. Co-Narcissism: How We Adapt to Narcissistic Parents. The Therapist, 2005. 21. ^ Simon Crompton, All About Me: Loving a Narcissist (London 2007) p. 157 and p. 235 22. ^ Crompton, p. 31 23. ^ "Are You Enabling?". Ambrosia Treatment Center. 2016-02-11. Retrieved 14 August 2017. 24. ^ Gomberg, Edith S Lisansky (1989). Gomberg, Edith S (ed.). On Terms Used and Abused: The Concept of 'Codependency'. Drugs & Society. 3. pp. 113–32. doi:10.1300/J023v03n03_05. ISBN 978-0-86656-965-1. 25. ^ a b c d e f g h i Moos, R.H.; Finney, J.W.; Cronkite, R.C. (1990). Alcoholism Treatment: Context, Process and Outcome. New York: Oxford University Press. ISBN 978-0-19-504362-4.[page needed] 26. ^ a b Affleck, Glenn; Tennen, Howard; Croog, Sydney; Levine, Sol (1987). "Causal attribution, perceived benefits, and morbidity after a heart attack: An 8-year study". Journal of Consulting and Clinical Psychology. 55 (1): 29–35. doi:10.1037/0022-006X.55.1.29. PMID 3571655. 27. ^ Collet, L (1990). "After the anger, what then? ACOA: Self-help or self-pity?". Family Therapy Networker. 14 (1): 22–31. 28. ^ a b c d "Codependence", in: Benjamin J. Sadock & Virginia A. Sadock (eds), Kaplan & Sadock's Comprehensive Textbook of Psychiatry on CD, Philadelphia: Lippincott Williams & Wilkins, 7th ed. 2000, ISBN 0-7817-2141-5, ISBN 2-07-032070-7. 29. ^ Kaminer, Wendy (1990). "Chances Are You're Codependent Too". 30. ^ Pikiewicz, Kristi. ""Codependent" No More?". 31. ^ Chiauzzi; Liljegren (1993). "Taboo topics in addiction treatment. An empirical review of clinical folklore". Journal of Substance Abuse Treatment. 10 (3): 303–16. doi:10.1016/0740-5472(93)90079-H. PMID 8315704. 32. ^ Levine, Amir; Heller, Rachael S. F. (2010). Attached. New York, New York: Tarcher/Penguin. pp. 56–61. ISBN 9781101475164. 33. ^ Anderson, S.C. (1994). "A critical analysis of the concept of codependency". Social Work. 39 (6): 677–685. PMID 7992137. ## Further reading[edit] * Cermak M.D, Timmen L., Diagnosing and Treating Co-Dependence: A Guide for Professionals Who Work with Chemical Dependents, Their Spouses, and Children (Professional Series), 1998, Hazelden Publishing, Minnesota, ISBN 978-0935908329 * CoDA, Co-Dependents Anonymous, 1997, CoDA Resource Publishing, Phoenix, ISBN 978-0964710504 * Beattie, Melody Codependent No More: How to Stop Controlling Others and Start Caring for Yourself, 1986, Hazelden, Minnesota, ISBN 978-0894864025 * Whitfield M.D., Charles L.,Healing The Child Within: Discovery and Recovery for Adult Children of Dysfunctional Families, 1987, Health Communications, Inc., Florida, ISBN 978-0932194404 * Lancer, Darlene, Conquering Shame and Codependency: 8 Steps to Freeing the True You, 2014, Hazelden, Minnesota, ISBN 1616495332 ## External links[edit] Look up codependency in Wiktionary, the free dictionary. * Codependency support: general at Curlie * Codependency support: co-alcoholic at Curlie * Codependency support: borderline personality disorder at Curlie * v * t * e Borderline personality disorder General * Dimensional models of personality disorders * Impulse control disorders * Trauma model of mental disorders * Misdiagnosis of borderline personality disorder Symptoms and behaviors * Dissociation * Eating disorders * Emotional dysregulation * Feelings of emptiness * Hypersexuality * Idealization and devaluation * Impulsivity * Mood swings * Projection * Self-harm * Splitting * Suicidal ideation Management * Dialectical behavior therapy * Dynamic deconstructive psychotherapy * McLean Hospital * Mentalization-based treatment * Schema therapy * Social psychiatry * Transference focused psychotherapy Family challenges * BPDFamily (support group) * Codependency * Complex PTSD * Emotional blackmail * Family estrangement * Personal boundaries * v * t * e Narcissism Types * Collective * Egomania * Flying monkeys * Healthy * Malignant * Narcissistic personality disorder * Spiritual * Workplace Characteristics * Betrayal * Boasting * Egocentrism * Egotism * Empathy (lack of) * Envy * Entitlement (exaggerated sense of) * Fantasy * Grandiosity * Hubris * Magical thinking * Manipulative * Narcissistic abuse * Narcissistic elation * Narcissistic rage and narcissistic injury * Narcissistic mortification * Narcissistic supply * Narcissistic withdrawal * Perfectionism * Self-esteem * Self-righteousness * Shamelessness * Superficial charm * Superiority complex * True self and false self * Vanity Defences * Denial * Idealization and devaluation * Distortion * Projection * Splitting Cultural phenomena * Control freak * Don Juanism * Dorian Gray syndrome * My way or the highway * Selfie Related articles * Codependency * Counterdependency * Dark triad * Ego ideal * "Egomania" (film) * Egotheism * Empire-building * God complex * History of narcissism * Messiah complex * Micromanagement * Narcissism of small differences * Narcissistic leadership * Narcissistic parent * Narcissistic Personality Inventory * Narcissus (mythology) * On Narcissism * Sam Vaknin * Self-love * Self-serving bias * Spoiled child * The Culture of Narcissism * Workplace bullying [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Codependency	c0086025	1,941	wikipedia	https://en.wikipedia.org/wiki/Codependency	2021-01-18T18:51:26	{"mesh": ["D017004"], "wikidata": ["Q21109"]}
Epidermolysis bullosa simplex due to exophilin 5 deficiency is a rare, hereditary, basal epidermolysis bullosa simplex characterized by mild, generalized trauma-induced scale crusts and intermittent blistering, sometimes combined with erosions and bleeding, recovering with slight scarring and post-inflammatory hyperpigmentation. Clinical symptoms improve with age. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Epidermolysis bullosa simplex due to exophilin 5 deficiency	c3554367	1,942	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=412189	2021-01-23T19:02:35	{"omim": ["615028"], "icd-10": ["Q81.0"], "synonyms": ["EBS-AR exophilin 5"]}
Phytophotodermatitis Phytophotodermatitis caused by lime SpecialtyDermatology Phytophotodermatitis, also known as berloque dermatitis[1][2][3] or margarita photodermatitis,[4][5] is a cutaneous phototoxic inflammatory reaction resulting from contact with a light-sensitizing botanical agent followed by exposure to ultraviolet light (from the sun, for instance). Symptoms include erythema, edema, blisters (vesicles and/or bullae), and delayed hyperpigmentation. Heat and moisture tend to exacerbate the reaction. A reaction may be elicited in any person who has been exposed to adequate amounts of both a photosensitizing agent and ultraviolet light. Phytophotodermatitis is not an immunologic response; no prior exposure to the photosensitizing agent is required. The photosensitizing substances found in phototoxic plants belong to a class of chemical compounds called the furanocoumarins, which are activated by long-wavelength ultraviolet (UVA) light. The most toxic of these organic compounds are the linear furanocoumarins, so called since they exhibit a linear chemical structure. Bergapten and xanthotoxin (also known as methoxsalen), two linear furanocoumarins derived from psoralen, are invariably found in plants associated with phytophotodermatitis.[2] ## Contents * 1 Symptoms * 2 Phototoxic species * 2.1 Apiaceae * 2.2 Rutaceae * 2.3 Moraceae * 3 Prevention * 4 Treatment * 5 History * 6 See also * 7 References * 8 External links ## Symptoms[edit] A severe case of phytophotodermatitis in an 11-year-old boy. A reaction typically begins within 24 hours of exposure and peaks at 48–72 hours after exposure.[6] Initially, the skin turns red and starts to itch and burn. Large blisters (or bullae) form within 48 hours.[7] The blisters may leave black, brown, or purplish scars that can last for several years. This hyperpigmentation of the skin is caused by the production of melanin triggered by the furanocoumarins. Although media reports have suggested that eye exposure to the agent can lead to temporary or permanent blindness, the risk of permanent blindness is not supported by existing research.[8] Phytophotodermatitis can affect people of any age. In children, it has been mistaken for child abuse.[9] ## Phototoxic species[edit] Plants associated with phytophotodermatitis mainly come from four plant families:[2][10] the carrot family (Apiaceae), the citrus family (Rutaceae), the mulberry family (Moraceae), and the legume family (Fabaceae). ### Apiaceae[edit] The carrot family Apiaceae (or Umbelliferae) is the main family of plants associated with phytophotodermatitis. Of all the plant species that have been reported to induce phytophotodermatitis, approximately half belong to the family Apiaceae.[11] False bishop's weed (Ammi majus), the world's major source of the linear furanocoumarin xanthotoxin, has been used since antiquity to treat vitiligo[2] but accidental or inappropriate use of this plant can lead to phytophotodermatitis.[12] Despite this danger, A. majus continues to be cultivated for its furanocoumarins,[13] which are still used for the treatment of skin disease. Numerous species in the family Apiaceae are cultivated as food products, some of which exhibit phototoxic effects. In particular, celery, parsnip, and parsley have been reported to cause phytophotodermatitis among agricultural workers, grocery workers, and other occupational food handlers.[14][15][16][17][18][19][2] A number of phototoxic plant species in the carrot family have become invasive species, including wild parsnip (Pastinaca sativa)[20][21] and the tall hogweeds of the genus Heracleum,[22][23] namely, Persian hogweed (Heracleum persicum), Sosnowsky's hogweed (Heracleum sosnowskyi), and giant hogweed (Heracleum mantegazzianum). In particular, the public health risks of giant hogweed are well known.[24] Other plant species in the family Apiaceae that are associated with phytophotodermatitis include blister bush (Notobubon galbanum), cow parsley (Anthriscus sylvestris), wild carrot (Daucus carota), various species of the genus Angelica (e.g., Korean angelica Angelica gigas), and most (if not all) species of the genus Heracleum (esp. the tall invasive hogweeds and the cow parsnips, Heracleum sphondylium and Heracleum maximum). ### Rutaceae[edit] The citrus family Rutaceae is the second most widely distributed family of plants associated with phytophotodermatitis. Effect of common rue on skin Numerous citrus fruits in the family Rutaceae exhibit phototoxic effects. Of these, perhaps the best known is lime.[25][26][27][28] Phytophotodermatitis associated with limes is sometimes colloquially referred to as "lime disease,"[29][30] not to be confused with Lyme disease. In the family Rutaceae, the most severe reactions are caused by the essential oil of the bergamot orange (Citrus bergamia).[2][31] Bergamot essential oil has a higher concentration of bergapten (3000–3600 mg/kg) than any other citrus-based essential oil, even lime oil, which contains 1700–3300 mg/kg of bergapten.[32] Other plant species in the family Rutaceae that are associated with phytophotodermatitis include burning bush (Dictamnus albus),[33] common rue (Ruta graveolens),[34][35][36][37] and other plants in the genus Ruta. ### Moraceae[edit] The mulberry family Moraceae is often associated with phytophotodermatitis. Multiple species in the genus Ficus are known to exhibit phototoxic effects. Of these, the common fig (Ficus carica) is well known and thoroughly documented. Like Ammi majus in the family Apiaceae, the common fig has been used since antiquity to treat vitiligo[38] but the milky sap of fig leaves can cause phytophotodermatitis if used accidentally or inappropriately.[39][40][41][42][43][44] A literature search revealed 19 cases of fig leaf-induced phytophotodermatitis reported between 1984 and 2012.[44] In Brazil, several hospitals reported more than 50 cases of fig leaf-induced burn in one summer.[43] In most cases, patients reportedly used the leaves of the fig plant for folk remedies, tanning, or gardening. Other plant species in the family Moraceae that are associated with phytophotodermatitis include Ficus pumila[45][46] and Brosimum gaudichaudii.[47] Like Ficus carica, the South American species Brosimum gaudichaudii has been shown to contain both psoralen and bergapten. ## Prevention[edit] The first and best line of defense against phytophotodermatitis is to avoid contact with phototoxic substances in the first place: * Avoid contact with the plant family Apiaceae, citrus fruits, and other biological agents known to have phototoxic effects. Do not incinerate phototoxic plants and agents since this will serve to disperse the phototoxic substances more widely.[48] * In outdoor situations where contact with phototoxic plants is likely, wear long pants and a long-sleeve shirt. Wear gloves and protective eyewear before handling such plants. * If protective clothing is not available, apply sunscreen to exposed areas. This will provide some measure of protection if contact is made. * After an outdoor activity, take a shower or a bath as soon as possible. Wash your clothing and then wash your hands after handling the dirty clothes. A second line of defense is to avoid sunlight, so as not to activate a phototoxic substance: * If you come in contact with a phototoxic substance, immediately wash the affected area with soap and cold water, and avoid any further exposure to sunlight for at least 48 hours. Heat and moisture can worsen the skin reaction,[24] which is why it’s important to wash the affected area with soap and cold water. * Stay indoors, if possible. Be sure to avoid light shining through windows. * If staying indoors is not an option, cover the affected area with sun protective clothing. * In lieu of sun-protective clothing, apply sunscreen[49] to the affected areas after washing. Phytophotodermatitis is triggered by long wavelength ultraviolet light (called UVA) in the range of 320–380 nanometers,[6] so the best sun-protective clothing and sunscreen products will block these wavelengths of UVA radiation. In 2011, the U.S. Food and Drug Administration (FDA) established a "broad spectrum" test for determining a sunscreen product's UVA protection.[50] Sunscreen products that pass the test are allowed to be labeled as "Broad Spectrum" sunscreens, which protect against both UVA and UVB rays. There is no equivalent test or FDA-approved labeling for sun-protective clothing. Some clothing is labeled with an Ultraviolet Protection Factor (UPF) but test results from Consumer Reports[51] suggest that UPF is an unreliable indicator of UV protection. ## Treatment[edit] Many different topical and oral medications may be used to treat the inflammatory reaction of phytophotodermatitis. A dermatologist may also prescribe a bleaching cream to help treat the hyperpigmentation and return the skin pigmentation back to normal. If the patient does not receive treatment, the affected sites may develop permanent hyperpigmentation or hypopigmentation.[6] ## History[edit] The photosensitizing effects of plants have been known since antiquity. In Egypt around 2000 B.C., the juice of Ammi majus "was rubbed on patches of vitiligo after which patients were encouraged to lie in the sun."[2] In A.D. 50, the Greek physician Dioscorides observed that pigment would return to patches of vitiligo if "cataplasmed with ye leaves or ye boughes of ye Black Figge,"[38] an apparent reference to Ficus carica, the common fig. These ancient practices acknowledged the hyperpigmentation effects now known to accompany phytophotodermatitis. One of the earliest reports of plant-based dermatitis was given by Chaumton in 1815, who noted that the outer rind and root of cow parsnip (a common name for any Heracleum species of plant) contained an acrid sap sufficiently strong to inflame and ulcerate the skin.[52] Similarly in 1887 Sornevin reported that Heracleum sphondylium caused dermatitis. However, neither of these early reports recognized the crucial role of ultraviolet radiation. "Berloque dermatitis"[3] (from the French word "berloque" meaning trinket or charm) is a term coined by Rosenthal in 1925 to describe the pendant-like streaks of pigmentation observed on the neck, face, and arms of patients.[53][2] He was unaware that, in 1916, Freund had correctly observed that these pigmentation effects were due to sun exposure after the use of Eau de Cologne, a perfume infused with bergamot oil.[54] It is now known that bergamot oil contains a significant amount of bergapten,[2] a linear furanocoumarin that gets its name from the bergamot orange. In 1937, dermatitis from Heracleum mantegazzianum was reported by Miescher and Burckhardt who suspected the possibility of light sensitization.[55] A few years later, Kuske confirmed this hypothesis.[56][57] In 1942, Klaber introduced the term "phytophotodermatitis" to emphasize that both plants and light were required to affect a reaction.[58][28] Darrell Wilkinson, a British dermatologist, gave an accurate description of the disease in the 1950s.[59] In 1961, Efremov reported 357 cases of phytophotodermatitis from Heracleum dulce (sweet cow parsnip). He "noted the requirement for sunlight in evoking the dermatitis since inunction of the juice of the plant without exposure to sunlight was harmless."[60] Between 1962 and 1976, numerous reports of phytophotodermatitis from giant hogweed (Heracleum mantegazzianum) were reported. By 1980, the photosensitizing effects of various plant species had become well known (as evidenced by the comprehensive work of Mitchell and Rook[61]). ## See also[edit] * List of cutaneous conditions * Photodermatitis * Psoralen * Photosensitivity in humans * Stinging plant, plants with hairs that inject poisons ## References[edit] 1. ^ James WD, Berger TG, Elston DM, eds. (2006). Andrews' Diseases of the Skin: Clinical Dermatology. Saunders Elsevier. p. 32. ISBN 978-0-7216-2921-6. 2. ^ a b c d e f g h i McGovern TW, Barkley TM (2000). "Botanical Dermatology". The Electronic Textbook of Dermatology. Internet Dermatology Society. 37 (5). Section Phytophotodermatitis. doi:10.1046/j.1365-4362.1998.00385.x. PMID 9620476. Retrieved November 29, 2018. 3. ^ a b Alikhan A (March 4, 2016). "Berloque Dermatitis". Medscape. Retrieved August 9, 2018. 4. ^ Riahi RR, Cohen PR, Robinson FW, Gray JM (June 2009). "What Caused The Rash On This Man's Wrist And Hand?". The Dermatologist. 11 (6). 5. ^ Abramowitz AI, Resnik KS, Cohen KR (March 1993). "Margarita photodermatitis". The New England Journal of Medicine. 328 (12): 891. doi:10.1056/NEJM199303253281220. PMID 8441448. 6. ^ a b c Baugh WP (September 8, 2016). "Phytophotodermatitis". Medscape. Retrieved August 9, 2018. 7. ^ Solis RR, Dotson DA, Trizna Z (2000). "Phytophotodermatitis: a sometimes difficult diagnosis". Archives of Family Medicine. 9 (10): 1195–6. doi:10.1001/archfami.9.10.1195. PMID 11115230. 8. ^ "Giant Hogweed" (PDF). Peterborough, Ont.: Ministry of Natural Resources and Forestry, Government of Ontario. p. 2. Retrieved July 15, 2018. 9. ^ Barradell R, Addo A, McDonagh AJ, Cork MJ, Wales JK (April 1993). "Phytophotodermatitis mimicking child abuse". European Journal of Pediatrics. 152 (4): 291–2. doi:10.1007/BF01956735. PMID 8482273. S2CID 11778627. 10. ^ Kavli G, Volden G (April 1984). "Phytophotodermatitis". Photo-Dermatology. 1 (2): 65–75. PMID 6397734. 11. ^ Pathak MA, Daniels Jr F, Fitzpatrick TB (September 1962). "The Presently Known Distribution of Furocoumarins (Psoralens) in Plants". Journal of Investigative Dermatology. 39 (3): 225–239. doi:10.1038/jid.1962.106. PMID 13941836. 12. ^ Alouani I, Fihmi N, Zizi N, Dikhaye S (2018). "Phytophotodermatitis following the use of Ammi Majus Linn (Bishop's weed) for vitiligo". Our Dermatol. Online. 9 (1): 93–94. doi:10.7241/ourd.20181.29. 13. ^ "Plants For A Future: Ammi majus". 14. ^ Birmingham DJ, Key MM, Tublich GE, Perone VB (1961). "Phototoxic bullae among celery harvesters". Arch Dermatol. 83 (1): 73–87. doi:10.1001/archderm.1961.01580070079008. Cited in McGovern and Barkley 2000, section Phytophotodermatitis. 15. ^ Centers for Disease Control (CDC) (January 1985). "Phytophotodermatitis among grocery workers--Ohio". MMWR. Morbidity and Mortality Weekly Report. 34 (1): 11–3. PMID 3155560. 16. ^ Berkley SF, Hightower AW, Beier RC, Fleming DW, Brokopp CD, Ivie GW, Broome CV (September 1986). "Dermatitis in grocery workers associated with high natural concentrations of furanocoumarins in celery". Annals of Internal Medicine. 105 (3): 351–5. doi:10.7326/0003-4819-105-3-351. PMID 2943201. 17. ^ Aberer W (January 1992). "Occupational dermatitis from organically grown parsnip (Pastinaca sativa L.)". Contact Dermatitis. 26 (1): 62. doi:10.1111/j.1600-0536.1992.tb00880.x. PMID 1534739. 18. ^ Lovell CR (1993). Plants and the skin (1st ed.). Oxford: Blackwell Scientific Publications. Cited in McGovern and Barkley 2000, section Phytophotodermatitis. 19. ^ Lutchman L, Inyang V, Hodgkinson D (November 1999). "Phytophotodermatitis associated with parsnip picking". Journal of Accident & Emergency Medicine. 16 (6): 453–4. doi:10.1136/emj.16.6.453. PMC 1343418. PMID 10572825. 20. ^ Averill KM, Di'Tommaso A (2007). "Wild parsnip (Pastinaca sativa): A troublesome species of increasing concern" (PDF). Weed Technology. 21: 279–287. doi:10.1614/WT-05-186.1. S2CID 86774319. 21. ^ Cain N, Darbyshire SJ, Francis A, Nurse RE, Simard M (2010). "The Biology of Canadian weeds. 144. Pastinaca sativa L." Can. J. Plant Sci. 90 (2): 217–240. doi:10.4141/CJPS09110. 22. ^ Booy O, Cock M, Eckstein L, Hansen SO, Hattendorf J, Hüls J, Jahodová S, Krinke L, Marovoková L, Müllerová J, Nentwig W, Nielsen C, Otte A, Pergl J, Perglová I, Priekule I, Pusek P, Ravn HP, Thiele J, Trybush S, Wittenberg R (2005). The giant hogweed best practice manual: guidelines for the management and control of invasive weeds in Europe (PDF). Hørsholm: Center for Skov, Landskab og Planlægning/Københavns Universitet. ISBN 87-7903-209-5. Retrieved September 1, 2018. 23. ^ MacDonald F, Anderson H (May 2012). "Giant Hogweed (Heracleum mantegazzianum): Best Management Practices in Ontario" (PDF). 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PMID 25317269. 28. ^ a b de Almeida Junior HL, Sartori DS, Jorge VM, Rocha NM, de Castro LA (2016). "Phytophotodermatitis: A Review of Its Clinical and Pathogenic Aspects". Journal of Dermatological Research. 1 (3): 51–56. doi:10.17554/j.issn.2413-8223.2016.01.15. 29. ^ "Lime Disease: How a Fruity Drink Can Give You a Rash". SciShow. July 24, 2017. Retrieved November 5, 2018. 30. ^ Weber IC, Davis CP, Greeson DM (1999). "Phytophotodermatitis: the other "lime" disease". The Journal of Emergency Medicine. 17 (2): 235–7. doi:10.1016/S0736-4679(98)00159-0. PMID 10195477. 31. ^ Kaddu S, Kerl H, Wolf P (2001). "Accidental bullous phototoxic reactions to bergamot aromatherapy oil". J Am Acad Dermatol. 45 (3): 458–461. doi:10.1067/mjd.2001.116226. PMID 11511848. Cited in CIR 2013. 32. ^ "Toxicological Assessment of Furocoumarins in Foodstuffs" (PDF). The German Research Foundation (DFG). DFG Senate Commission on Food Safety (SKLM). 2004. Retrieved November 1, 2018. 33. ^ Schempp CM, Sonntag M, Schöpf E, Simon JC (September 1996). "Dermatitis bullosa striata pratensis caused by Dictamnus albus L. (burning bush)". Hautarzt (in German). 47 (9): 708–710. doi:10.1007/s001050050494. PMID 8999028. S2CID 23601334. 34. ^ Wessner D, Hofmann H, Ring J (October 1999). "Phytophotodermatitis due to Ruta graveolens applied as protection against evil spells". Contact Dermatitis. 41 (4): 232. doi:10.1111/j.1600-0536.1999.tb06145.x. PMID 10515113. 35. ^ Furniss D, Adams T (2007). "Herb of grace: an unusual cause of phytophotodermatitis mimicking burn injury". Journal of Burn Care & Research. 28 (5): 767–9. doi:10.1097/BCR.0B013E318148CB82. PMID 17667834. 36. ^ Eickhorst K, Deleo V, Csaposs J (March 2007). "Rue the herb: Ruta graveolens--associated phytophototoxicity". Dermatitis. 18 (1): 52–5. doi:10.2310/6620.2007.06033. PMID 17303046. 37. ^ Arias-Santiago SA, Fernández-Pugnaire MA, Almazán-Fernández FM, Serrano-Falcón C, Serrano-Ortega S (November 2009). "Phytophotodermatitis due to Ruta graveolens prescribed for fibromyalgia". Rheumatology. 48 (11): 1401. doi:10.1093/rheumatology/kep234. PMID 19671699. 38. ^ a b Mitchell J, Rook A (1979). Botanical Dermatology: Plants and Plant Products Injurious to the Skin. Vancouver: Greengrass. Cited in McGovern and Barkley 2000, section Phytophotodermatitis. 39. ^ Bollero D, Stella M, Rivolin A, Cassano P, Risso D, Vanzetti M (November 2001). "Fig leaf tanning lotion and sun-related burns: case reports". Burns. 27 (7): 777–779. doi:10.1016/S0305-4179(01)00033-X. PMID 11600261. 40. ^ Derraik JG, Rademaker M (2007). "Phytophotodermatitis caused by contact with a fig tree (Ficus carica)". N Z Med J. 120 (1261): U2720. PMID 17867224. 41. ^ Polat M, Öztaş P, Dikilitaş MC, Allı N (December 2008). "Phytophotodermatitis due to Ficus carica". Dermatol Online J. 14 (12): 9. PMID 19265622. 42. ^ Zhang R, Zhu W (2011). "Phytophotodermatitis due to Chinese herbal medicine decoction". Indian J Dermatol. 56 (3): 329–331. doi:10.4103/0019-5154.82498. PMC 3132918. PMID 21772602. 43. ^ a b Sforza M, Andjelkov K, Zaccheddu R (July 2013). "Severe burn on 81% of body surface after sun tanning". Turkish Journal of Trauma and Emergency Surgery. 19 (4): 383–384. doi:10.5505/tjtes.2013.44522. PMID 23884685. 44. ^ a b Son JH, Jin H, You HS, Shim WH, Kim JM, Kim GW, Kim HS, Ko HC, Kim MB, Kim BS (February 2017). "Five Cases of Phytophotodermatitis Caused by Fig Leaves and Relevant Literature Review". Annals of Dermatology. 29 (1): 86–90. doi:10.5021/ad.2017.29.1.86. PMC 5318534. PMID 28223753. 45. ^ English PB, Grey LP (June 1943). "Sap dermatitis and conjunctivitis caused by the wild fig (Ficus pumila)". Medical Journal of Australia. 1 (26): 578–579. doi:10.5694/j.1326-5377.1943.tb44690.x. Cited in Mitchell and Rook 1979. 46. ^ Rademaker M, Derraik JG (July 2012). "Phytophotodermatitis caused by Ficus pumila". Contact Dermatitis. 67 (1): 53–56. doi:10.1111/j.1600-0536.2012.02026.x. PMID 22681467. 47. ^ Martins JE, Pozetti GL, Sodré M (1974). "Effects of psoralen and bergapten on irradiated skin". Int J Dermatol. 13 (3): 124–128. doi:10.1111/j.1365-4362.1974.tb01781.x. PMID 4836605. 48. ^ Davis D (August 12, 2011). "Sun-related Skin Condition Triggered by Chemicals in Certain Plants, Fruits". Dermatology, Mayo Clinic. Retrieved August 8, 2018. 49. ^ Leonard J (August 19, 2017). "Phytophotodermatitis: When plants and light affect the skin". Medical News Today. Retrieved August 8, 2018. 50. ^ "FDA announces new requirements for over-the-counter (OTC) sunscreen products marketed in the U.S." U.S. Food and Drug Administration. June 11, 2011. Retrieved August 9, 2018. 51. ^ "Testing sun protective clothing". Consumer Reports. August 11, 2015. Retrieved August 9, 2018. 52. ^ Chaumton, FP (1815). Flore Med Paris. 2: 32. Cited by Mitchell and Rook (1979), p. 692. 53. ^ Rosenthal O (1925). "Berloque dermatitis: Berliner Dermatologische". Dermatologische Zeitschrift. 42: 295. doi:10.1159/000250611. Cited in Alikhan 2016. 54. ^ Freund E (1916). "Uber bisher noch nicht beschriebene kunstliche Hautverfarbungen". Dermatol Wochenschrift. 63: 931–933. Cited in McGovern and Barkley 2000, section Phytophotodermatitis. 55. ^ Miescher G, Burckhardt W (1937). "Herakleum Dermatitis: Case Presentation". Schweizer Medizinische Wochenschriff. 67: 82. Cited by Mitchell and Rook (1979), p. 696. 56. ^ Kuske H. "Experimental investigations on photodermatitis caused by plant juices". Archiv für Dermatologie und Syphilis. 178: 273. Cited by Mitchell and Rook (1979), p. 696. 57. ^ Kuske H (1940). "Perkutane Photosensibilisierung durch pflanzliche Wirkstoffe". Dermatology. 82 (5–6): 273. doi:10.1159/000253838. Cited by Mitchell and Rook (1979), p. 696. 58. ^ Klaber R (1942). "Phytophotodermatitis". Br. J. Dermatol. 54 (7): 193–211. doi:10.1111/j.1365-2133.1942.tb10682.x. Cited by McGovern and Barkley, section Phytophotodermatitis. 59. ^ "Munks Roll Details for Peter Edward Darrell Sheldon Wilkinson". munksroll.rcplondon.ac.uk. Retrieved 2017-11-10. 60. ^ Efremov AI. "The Photodermatitis caused by Sweet Cow Parsnip (Heracleum dulce)". Vestn. Derm. Vener. (in Russian). 4: 64. Cited by Mitchell and Rook (1979), p. 693. 61. ^ Mitchell J, Rook A (1979). Botanical Dermatology: Plants and Plant Products Injurious to the Skin. Vancouver: Greengrass. ## External links[edit] Classification D * ICD-10: L56.2 * DiseasesDB: 31395 Wikimedia Commons has media related to Phytophotodermatitis. * v * t * e Radiation-related disorders / Photodermatoses Ultraviolet/ionizing * Sunburn * Phytophotodermatitis * Solar urticaria * Polymorphous light eruption * Benign summer light eruption * Juvenile spring eruption * Acne aestivalis * Hydroa vacciniforme * Solar erythema Non-ionizing Actinic rays * Actinic keratosis * Atrophic actinic keratosis * Hyperkeratotic actinic keratosis * Lichenoid actinic keratosis * Pigmented actinic keratosis * Actinic cheilitis * Actinic granuloma * Actinic prurigo * Chronic actinic dermatitis Infrared/heat * Erythema ab igne (Kangri ulcer * Kairo cancer * Kang cancer * Peat fire cancer) * Cutis rhomboidalis nuchae * Poikiloderma of Civatte Other * Radiation dermatitis * Acute * Chronic radiodermatitis) * Favre–Racouchot syndrome * Photoaging * Photosensitivity with HIV infection * Phototoxic tar dermatitis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Phytophotodermatitis	c0521480	1,943	wikipedia	https://en.wikipedia.org/wiki/Phytophotodermatitis	2021-01-18T18:35:42	{"umls": ["CL505184"], "icd-10": ["L56.2"], "wikidata": ["Q1660485"]}
Feline cognitive dysfunction (FCD) is a cognitive disease prevalent in cats, directly related to the brain aging, leading to changes in awareness, deficits in learning and memory, and decreased responsiveness to stimuli. It is also known as cognitive dysfunction syndrome (CDS). Alzheimer's disease and dementia in humans are diseases with comparable symptoms and pathology.[1][2][3] ## Contents * 1 Causes * 2 Symptoms * 3 Other conditions with similar symptoms * 4 Prevention * 5 Treatment * 6 See also * 7 References * 8 Further reading ## Causes[edit] The exact cause of FCD is currently unknown. Genetic factors may predispose an animal to the condition.[4] Signs of cognitive dysfunction may be connected with a prosencephalon or cerebrum problem.[5] ## Symptoms[edit] Older cats display more symptoms of the disease than younger cats.[6][7] Behavioural symptoms usually become apparent in cats older than 10 years.[3] Main signs of FCD can be summarized with the acronym DISH: * Disorientation, * reduced social Interactions, * Changes in Sleep patterns, * loss of Housetraining skills.[8] Affected cats may wander aimlessly and look lost in space, seem restless and anxious, fail to recognize familiar faces such as their owners, caretakers or other cats in the clowder, display decreased interest in social interactions or increased aggression, experience insomnia, sometimes along with increased nocturnal vocalizations[2][7][9] with no apparent reason. ## Other conditions with similar symptoms[edit] Signs of FCD can be found in a number of other pathologies such as brain tumors[7][10] or non brain-related diseases, which makes it important to exclude the possibility of other causes. For example, excessive urination may signify a kidney disease,[11] and the look of numbness and detachment may be caused by a large variety of conditions, from pain to affected vision.[12] Arthritis may hinder a cat's ability to get into the litter box in time. Night-time vocalizing is relatively common in hyperthyroid cats or cats with hypertension, which can also cause retinal detachment and blindness, leading to anxiety and confusion. Progressively painful periodontal disease can discourage the cat from visiting its food bowl with the same enthusiasm it showed at a younger age. If all other possible diseases are excluded, and MRI and analysis of cerebrospinal fluid fail to reveal a physical problem in the brain, then the problem may be treated by an animal behaviorist or veterinary psychiatrist.[5] ## Prevention[edit] As the cause of the disease is unknown, there is no way to be certain in prevention of the condition. However, the following measures are considered effective:[5] * absence of other animals in the house whose presence may be stressful to the cat, * vitamin E-rich diet, * conveniently accessible litter boxes, * ramps for the stairs if the cat experiences difficulties going up and down, * routine checkups with a veterinarian to detect a disease on early stage. ## Treatment[edit] The disease is little-researched and thus considered incurable at the moment, but its symptoms can be managed with treatment.[7] Cognitive dysfunction syndrome in dogs is an established diagnosis, but there has been limited research for cats and treatment options are limited.[13] Drugs used for treatment of the disease have been approved for use in dogs. However, they are used off-label in treatment of cats.[1] Early diagnosis improves results of long-term treatment.[6] Improving home environment may help in managing the disease.[2][8] The treatment must always be arranged with a veterinarian for each particular animal, but the suggested measures include the following (veterinarian's advice is needed for right dosage of any supplements): * species-appropriate diet rich in omega-3, * physical and mental exercise, such as treat-release toys, * S-adenosylmethionine supplement, * medium-chain triglycerides (can improve brain energy metabolism and decrease the amyloid protein buildup that results in brain lesions in older pets),[14] * antioxidants, such as resveratrol (Japanese knotweed), which protects against free radical damage and beta-amyloid deposits, N-acetyl cysteine (NAC), phosphatidylserine and apoaequorin, * vitamins E, C and B complex, * melatonin as a sedation for nocturnal vocalizations and insomnia, As the disease progresses, it gradually gets more difficult to ease, which increases the importance of detecting the diseases on the earliest possible stage. Recommendations include limiting the access to the parts of the house that may present danger to the animal, set a consistent schedule for feeding, playing and interacting with the cat, "talking" with the animal and calling it by the name so that the familiar voice soothes it, and adding more litterboxes in case the cat experiences excessive urination or defecation. ## See also[edit] * Cats portal * Canine cognitive dysfunction * Cerebellar hypoplasia (non-human) * Feline spongiform encephalopathy ## References[edit] 1. ^ a b Ilona Rodan; Sarah Heath (24 August 2015). Feline Behavioral Health and Welfare. Elsevier Health Sciences. p. 351. ISBN 978-1-4557-7401-2. 2. ^ a b c "Feline Cognitive Dysfunction - Cat Behavior Associates". Retrieved 10 January 2017. 3. ^ a b "Cognitive Dysfunction in Cats". Retrieved 10 January 2017. 4. ^ "Dementia (Geriatric) in Cats \| petMD". www.petmd.com. Retrieved 2018-12-16. 5. ^ a b c "Cognitive Dysfunction". Cornell University College of Veterinary Medicine. 2017-10-09. Retrieved 2018-12-16. 6. ^ a b Irene Rochlitz (17 April 2007). The Welfare of Cats. Springer Science & Business Media. pp. 113–114. ISBN 978-1-4020-3227-1. 7. ^ a b c d Susan Little (1 September 2015). August's Consultations in Feline Internal Medicine. Elsevier Health Sciences. pp. 977–978. ISBN 978-0-323-22652-3. 8. ^ a b "Is Your Kitty Confused? 4 Signs of Cognitive Dysfunction Syndrome". www.vetstreet.com. pp. 1–2. Retrieved 10 January 2017. 9. ^ "Older Cats with Behavior Problems". Retrieved 10 January 2017. 10. ^ "Cognitive Dysfunction in Cats". PetPlace.com. Retrieved 10 January 2017. 11. ^ "Why is My Cat Peeing so Much?". Pet Health Network. Retrieved 2018-12-16. 12. ^ "Sudden Onset Blindness in Cats". Pet Health Network. Retrieved 2018-12-16. 13. ^ Issues in Veterinary Research and Medicine: 2011 Edition. ScholarlyEditions. 9 January 2012. p. 936. ISBN 978-1-4649-6435-0. 14. ^ "Cats and Dietary Medium-Chain Triglycerides". Retrieved 2018-12-16. ## Further reading[edit] * Curtis W. Dewey; Ronaldo C. da Costa (8 September 2015). Practical Guide to Canine and Feline Neurology. Wiley. ISBN 978-1-119-06204-2. * Karen Overall (4 June 2013). Manual of Clinical Behavioral Medicine for Dogs and Cats. Elsevier Health Sciences. pp. 432–439. ISBN 978-0-323-24065-9. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Feline cognitive dysfunction	None	1,944	wikipedia	https://en.wikipedia.org/wiki/Feline_cognitive_dysfunction	2021-01-18T18:49:44	{"wikidata": ["Q28456883"]}
Anesthesia dolorosa or anaesthesia dolorosa or deafferentation pain is pain felt in an area (usually of the face) which is completely numb to touch. The pain is described as constant, burning, aching or severe. It can be a side effect of surgery involving any part of the trigeminal system, and occurs after 1–4% of peripheral surgery for trigeminal neuralgia. No effective medical therapy has yet been found. Several surgical techniques have been tried, with modest or mixed results. The value of surgical interventions is difficult to assess because published studies involve small numbers of mixed patient types and little long term follow-up.[1] * Gasserian ganglion stimulation is stimulation of the gasserian ganglion with electric pulses from a small generator implanted beneath the skin. There are mixed reports, including some reports of marked, some of moderate and some of no improvement. Further studies of more patients with longer follow-up are required to determine the efficacy of this treatment. * Deep brain stimulation was found in one review to produce good results in forty-five percent of 106 cases. Though relief may not be permanent, several years of relief may be achieved with this technique. * Mesencephalotomy is the damaging of the junction of the trigeminal tract and the periaqueductal gray in the brain, and has produced pain relief in a group of patients with cancer pain; but when applied to six anesthesia dolorosa patients, no pain relief was achieved, and the unpleasant sensation was in fact increased. * Dorsal root entry zone lesioning, damaging the point where sensory nerve fibers meet spinal cord fibers, produced favorable results in some patients and poor results in others, with incidence of ataxia at 40%. Patient numbers were small, follow-up was short and existing evidence does not indicate long term efficacy. * One surgeon treated thirty-five patients using trigeminal nucleotomy, damaging the nucleus caudalis, and reported 66% "abolition of allodynia and a marked reduction in or (less frequently) complete abolition of deep background pain."[1] ## References[edit] 1. ^ a b Giller C. Atypical facial pain and anesthesia dolorosa. In: Burchiel KJ. Surgical management of pain. New York: Thieme; 2002. ISBN 0-86577-912-0. p. 311–6. * v * t * e Diseases relating to the peripheral nervous system Mononeuropathy Arm median nerve * Carpal tunnel syndrome * Ape hand deformity ulnar nerve * Ulnar nerve entrapment * Froment's sign * Ulnar tunnel syndrome * Ulnar claw radial nerve * Radial neuropathy * Wrist drop * Cheiralgia paresthetica long thoracic nerve * Winged scapula * Backpack palsy Leg lateral cutaneous nerve of thigh * Meralgia paraesthetica tibial nerve * Tarsal tunnel syndrome plantar nerve * Morton's neuroma superior gluteal nerve * Trendelenburg's sign sciatic nerve * Piriformis syndrome Cranial nerves * See Template:Cranial nerve disease Polyneuropathy and Polyradiculoneuropathy HMSN * Charcot–Marie–Tooth disease * Dejerine–Sottas disease * Refsum's disease * Hereditary spastic paraplegia * Hereditary neuropathy with liability to pressure palsy * Familial amyloid neuropathy Autoimmune and demyelinating disease * Guillain–Barré syndrome * Chronic inflammatory demyelinating polyneuropathy Radiculopathy and plexopathy * Brachial plexus injury * Thoracic outlet syndrome * Phantom limb Other * Alcoholic polyneuropathy Other General * Complex regional pain syndrome * Mononeuritis multiplex * Peripheral neuropathy * Neuralgia * Nerve compression syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Anesthesia dolorosa	c0474367	1,945	wikipedia	https://en.wikipedia.org/wiki/Anesthesia_dolorosa	2021-01-18T18:59:15	{"mesh": ["D061221"], "umls": ["C0474367"], "wikidata": ["Q483872"]}
Isosporiasis (also known as cystoisosporiasis) is an exclusively human parasitosis occurring mainly in the tropics and subtropics, due to infection with Isospora belli (through ingestion of contaminated food), that is frequently asymptomatic or that can cause fever and diarrhea, but that is usually a self-limiting condition in the immunocompetent. HIV-positive individuals are particularly at risk of suffering from symptomatic isosporiasis and can manifest with a more severe clinical course of chronic diarrhea and severe weight loss. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Isosporiasis	c0311386	1,946	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=472	2021-01-23T17:17:18	{"gard": ["3033"], "mesh": ["D021865"], "umls": ["C0311386"], "icd-10": ["A07.3"], "synonyms": ["Cystoisosporiasis"]}
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: "Botryomycosis" – news · newspapers · books · scholar · JSTOR (October 2008) (Learn how and when to remove this template message) Botryomycosis Other namesBacterial pseudomycosis SpecialtyInfectious disease Botryomycosis; is a rare chronic granulomatous bacterial infection that affects the skin, and sometimes the viscera.[1]:255 Botryomycosis has been known to affect humans, horses, cattle, swine, dogs and cats. ## Contents * 1 Presentation * 1.1 Associated conditions * 2 Causes * 3 Diagnosis * 4 History * 5 Notes * 6 External links ## Presentation[edit] ### Associated conditions[edit] There are only a handful of documented cases of botryomycosis in humans, and its pathogenesis is not completely understood. However, it is usually described in individuals with impaired immunity, or with an underlying disease such as diabetes mellitus, cystic fibrosis or HIV infection. ## Causes[edit] Staphylococcus aureus is usually the organism that causes the infection,[2] however it can also be caused by Pseudomonas aeruginosa or several other species of bacteria. The anatomic structure of its lesion is similar to that of actinomycosis and eumycetoma, and its granules resemble the sulfur granules of actinomycosis. ## Diagnosis[edit] This section is empty. You can help by adding to it. (July 2019) ## History[edit] The disease was originally discovered by Otto Bollinger (1843–1909) in 1870, and its name was coined by Sebastiano Rivolta (1832–1893) in 1884. The name refers to its grape-like granules (Gr. botryo = grapes) and the mistakenly implied fungal etiology (Gr. mykes = fungus).[3] In 1919 the bacterial origin of the infection was discovered. ## Notes[edit] 1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 2. ^ "botryomycosis" at Dorland's Medical Dictionary 3. ^ Medscape Today Primary Pulmonary Botryomycosis Concise Review of Veterinary Microbiology - Quinn and Markey 2003 ## External links[edit] * Essay on Pulmonary Botryomycosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Botryomycosis	c2937266	1,947	wikipedia	https://en.wikipedia.org/wiki/Botryomycosis	2021-01-18T19:00:36	{"umls": ["C2937266"], "wikidata": ["Q4948827"]}
Saddle sore SpecialtySports medicine SymptomsSkin abrasion CausesHorse riding or cycling PreventionReducing friction This article needs additional citations for verification. Relevant discussion may be found on the talk page. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Saddle sore" – news · newspapers · books · scholar · JSTOR (April 2019) (Learn how and when to remove this template message) A saddle sore in humans is a skin ailment on the buttocks due to, or exacerbated by, horse riding or cycling on a bicycle saddle. It often develops in three stages: skin abrasion, folliculitis (which looks like a small, reddish acne), and finally abscess. Because it most commonly starts with skin abrasion, it is desirable to reduce the factors which lead to skin abrasion. Some of these factors include: * Reducing the friction. In equestrian activities, friction is reduced with a proper riding position and using properly fitting clothing and equipment. In cycling, friction from bobbing or swinging motion while pedaling is reduced by setting the appropriate saddle height. Angle and fore/aft position can also play a role, and different cyclists have different needs and preferences in relation to this. * Selecting an appropriate size and design of horse riding saddle or bicycle saddle. * Wearing proper clothing. In bicycling, this includes cycling shorts, with chamois padding. For equestrian activity, long, closely fitted pants such as equestrian breeches or jodhpurs minimize chafing. For western riding, closely fitted jeans with no heavy inner seam, sometimes combined with chaps, are preferred. Padded cycling shorts worn under riding pants helps some equestrians, and extra padding, particularly sheepskin, on the seat of the saddle may help in more difficult situations such as long-distance endurance riding. * Using petroleum jelly, chamois cream or lubricating gel to further reduce friction. If left untreated over an extended period of time, saddle sores may need to be drained by a physician. In animals such as horses and other working animals, saddle sores often form on either side of the withers, which is the area where the front of a saddle rests, and also in the girth area behind the animal's elbow, where they are known as a girth gall. Saddle sores can occur over the loin, and occasionally in other locations. These sores are usually caused by ill-fitting gear, dirty gear, lack of proper padding, or unbalanced loads.[1] Reducing friction is also of great help in preventing equine saddle sores. Where there is swelling but not yet open sores, the incidence of sore backs may be reduced by loosening the girth without immediately removing the saddle after a long ride, thus allowing normal circulation to return slowly. ## See also[edit] * Bicycling * Pack saddle ## References[edit] 1. ^ Hayes, Capt. M. Horace, Veterinary Notes for Horse Owners, Stanley Paul, London, 1977 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Saddle sore	c0263557	1,948	wikipedia	https://en.wikipedia.org/wiki/Saddle_sore	2021-01-18T19:04:52	{"umls": ["C0263557"], "wikidata": ["Q2612029"]}
Psychological disorder proposed by professor Makoto Natsume A waitress at a restaurant is expected to exhibit positivity, such as smiling and expressing positive emotion towards customers Smile mask syndrome (Japanese: スマイル仮面症候群, Hepburn: sumairu kamen shōkōgun), abbreviated SMS, is a psychological disorder proposed by professor Makoto Natsume of Osaka Shoin Women's University, in which subjects develop depression and physical illness as a result of prolonged, unnatural smiling.[1] Natsume proposed the disorder after counselling students from the university in his practice and noticing that a number of students had spent so much time faking their smiles that they were unaware that they were smiling even while relating stressful or upsetting experiences to him. Natsume attributes this to the great importance placed on smiling in the Japanese service industry, particularly for young women.[2] Smiling is an important skill for Japanese women working in the service industry. Almost all service industry companies in Japan require their female staff to smile for long periods of time.[3] Natsume says that his female patients often talk about the importance of smiling when the topic of the conversation is on their workplace. He relates examples of patients saying that they felt their smile had a large effect on whether they were hired or not, and that their superiors had stressed the effect that good smiles had on customers.[2] According to Natsume, this atmosphere sometimes causes women to smile unnaturally for so long that they start to suppress their real emotions and become depressed.[3] Japanese author Tomomi Fujiwara notes that the demand for a common smile in the workplace emerged in Japan around the 1980s, and blames the cultural changes wrought by the Tokyo Disneyland, opened in 1983, for popularizing the demand for an obligatory smile in the workplace.[3] The smile mask syndrome has also been identified in Korea.[4] Korean writer Bae Woo-ri noted that smiling gives one a competitive advantage over the others, and has become a necessary attribute of many employees, just like a "neat uniform".[4] Yoon-Do-rahm, a psychology counselor, compared the current society, which is full of smile-masks, to a clown show; both are characterized by plentiful, yet empty and fake, smiles.[4] Smile mask syndrome can cause physical problems as well as mental ones. Natsume relates that many of his patients developed muscle aches and headaches as a result of prolonged smiling, and says that these are similar to the symptoms of repetitive strain injury.[3] ## See also[edit] * Honne and tatemae * Emotional labor ## References[edit] 1. ^ Belkin, Lisa. "Putting Some Fun Back Into 9 to 5", New York Times, March 6, 2008 2. ^ a b Natsume, Makoto (2006). Smile Kamen Shōkōgun: Hontō no Warai no Torimodoshi-kata. NHK. Previewed at "Seikatsunin Shinsho". NHK. Retrieved March 4, 2013. 3. ^ a b c d Leo Lewis, Smiling can seriously damage your health, The Times, February 9, 2008 4. ^ a b c Lee, Sun-you (December 2012). "The Depressing Truth Behind a Smile". The Hanyang Journal. 316: 8–9. Retrieved March 21, 2013. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Smile mask syndrome	None	1,949	wikipedia	https://en.wikipedia.org/wiki/Smile_mask_syndrome	2021-01-18T18:38:46	{"wikidata": ["Q7544659"]}
Ischial bursitis (also known as weaver's bottom) is inflammation of the synovial bursa located between gluteus maximus muscle and ischial tuberosity.[1] It is usually caused by prolonged sitting on a hard surface. ## References[edit] 1. ^ Fauci, Anthony (2010). Harrison's Rheumatology, Second Edition. McGraw-Hill Professional Publishing; Digital Edition. p. 271. ISBN 9780071741460. * v * t * e Soft tissue disorders Capsular joint Synoviopathy * Synovitis/Tenosynovitis * Calcific tendinitis * Stenosing tenosynovitis * Trigger finger * De Quervain syndrome * Transient synovitis * Ganglion cyst * osteochondromatosis * Synovial osteochondromatosis * Plica syndrome * villonodular synovitis * Giant-cell tumor of the tendon sheath Bursopathy * Bursitis * Olecranon * Prepatellar * Trochanteric * Subacromial * Achilles * Retrocalcaneal * Ischial * Iliopsoas * Synovial cyst * Baker's cyst * Calcific bursitis Noncapsular joint Symptoms * Ligamentous laxity * Hypermobility Enthesopathy/Enthesitis/Tendinopathy upper limb * Adhesive capsulitis of shoulder * Impingement syndrome * Rotator cuff tear * Golfer's elbow * Tennis elbow lower limb * Iliotibial band syndrome * Patellar tendinitis * Achilles tendinitis * Calcaneal spur * Metatarsalgia * Bone spur other/general: * Tendinitis/Tendinosis Nonjoint Fasciopathy * Fasciitis: Plantar * Nodular * Necrotizing * Eosinophilic Fibromatosis/contracture * Dupuytren's contracture * Plantar fibromatosis * Aggressive fibromatosis * Knuckle pads [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Ischial bursitis	c0410076	1,950	wikipedia	https://en.wikipedia.org/wiki/Ischial_bursitis	2021-01-18T18:45:30	{"wikidata": ["Q6079234"]}
Phakomatosis pigmentokeratotica (PPK) is a very rare epidermal nevus disorder characterized by the association of speckled lentiginous nevi with epidermal sebaceous nevi, and extracutaneous anomalies. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Phakomatosis pigmentokeratotica	c2931658	1,951	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2874	2021-01-23T17:11:27	{"gard": ["4311"], "mesh": ["C537893"], "umls": ["C2931658"], "icd-10": ["Q85.8"]}
Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare condition which causes joint abnormalities that begin at birth or during early childhood. The name comes from the main symptoms, including permanent bending of the fingers (camptodactyly), joint disease (arthropathy), and changes in the hip joint resulting in shortened legs and a possible limp (coxa vara). Some people with CACP also have too many cells between their joints (synovial hyperplasia) and too much fluid around the heart (pericardial effusion) or lungs (pleural effusion). Camptodactyly-arthyropathy-coxa vara-pericarditis syndrome is caused by a mutation in the PRG4 gene. This gene is responsible for making a protein that lubricates the joints.The condition is inherited in an autosomal recessive manner. CACP may be at first confused with juvenile idiopathic arthritis because the two diseases have similar symptoms. Diagnosis is based on clinical findings (symptoms which the doctor notices on a physical exma) and a biopsy of the fluid between the joints (synovial fluid). Genetic testing can confirm the diagnosis. Treatment options such as physical therapy and pain medication focus on relieving symptoms of the disease. The medication for juvenile idiopathic arthritis is not helpful for those with CACP. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Camptodactyly arthropathy coxa vara pericarditis syndrome	c1859690	1,952	gard	https://rarediseases.info.nih.gov/diseases/306/camptodactyly-arthropathy-coxa-vara-pericarditis-syndrome	2021-01-18T18:01:39	{"mesh": ["C537560"], "omim": ["208250"], "umls": ["C1859690"], "orphanet": ["2848"], "synonyms": ["Arthropathy camptodactyly syndrome", "Pericarditis arthropathy camptodactyly syndrome", "PAC syndrome", "Fibrosing serositis, familial", "Camptodactyly arthropathy pericarditis syndrome", "Congenital familial hypertrophic synovitis", "Camptodactyly-arthropathy-coxa vara-pericarditis syndrome", "Arthropathy-camptodactyly syndrome", "CACP syndrome", "Camptodactyly-arthropathy-coxa-vara-pericarditis syndrome", "Jacobs syndrome", "Pericarditis-arthropathy-camptodactyly syndrome"]}
Congenital lip pit SpecialtyOral & Maxillofacial Surgery Usual onsetAt birth TreatmentFistulectomy PrognosisExcellent A congenital lip pit or lip sinus is a congenital disorder characterized by the presence of pits and possibly associated fistulas in the lips. They are often hereditary, and may occur alone or in association with cleft lip and palate, termed Van der Woude syndrome.[1] ## Contents * 1 Diagnosis * 1.1 Classification * 2 Treatment * 3 See also * 4 References * 5 External links ## Diagnosis[edit] ### Classification[edit] They are divided into three types based on their location:[2] * commissural pits, which are small pits near the labial commissure of the mouth,[3] * a pit in the upper lip, in which case it may be called a midline sinus of the upper lip,[2] and * pits in the lower lip, in which case it may be called a congenital sinus of the lower lip.[2] In some cases commissural pits have been reported in combination with preauricaluar pits, which are near the ear.[1] ## Treatment[edit] Lip pits are harmless and do not usually require any treatment, although in some reported cases surgical excision has been used or if associated with a draining sinus tract.[1] ## See also[edit] * Skin dimple ## References[edit] 1. ^ a b c Rajendran A; Sundaram S (10 February 2014). Shafer's Textbook of Oral Pathology (7th ed.). Elsevier Health Sciences APAC. pp. 16–17. ISBN 978-81-312-3800-4. 2. ^ a b c Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 3. ^ McKusick, Victor A. (27 May 2009). "Commissural Lip Pits". Online Mendelian Inheritance in Man. Retrieved 2017-05-22. ## External links[edit] Classification D * OMIM: 120500 * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus Oral mucosa – Lining of mouth * Amalgam tattoo * Angina bullosa haemorrhagica * Behçet's disease * Bohn's nodules * Burning mouth syndrome * Candidiasis * Condyloma acuminatum * Darier's disease * Epulis fissuratum * Erythema multiforme * Erythroplakia * Fibroma * Giant-cell * Focal epithelial hyperplasia * Fordyce spots * Hairy leukoplakia * Hand, foot and mouth disease * Hereditary benign intraepithelial dyskeratosis * Herpangina * Herpes zoster * Intraoral dental sinus * Leukoedema * Leukoplakia * Lichen planus * Linea alba * Lupus erythematosus * Melanocytic nevus * Melanocytic oral lesion * Molluscum contagiosum * Morsicatio buccarum * Oral cancer * Benign: Squamous cell papilloma * Keratoacanthoma * Malignant: Adenosquamous carcinoma * Basaloid squamous carcinoma * Mucosal melanoma * Spindle cell carcinoma * Squamous cell carcinoma * Verrucous carcinoma * Oral florid papillomatosis * Oral melanosis * Smoker's melanosis * Pemphigoid * Benign mucous membrane * Pemphigus * Plasmoacanthoma * Stomatitis * Aphthous * Denture-related * Herpetic * Smokeless tobacco keratosis * Submucous fibrosis * Ulceration * Riga–Fede disease * Verruca vulgaris * Verruciform xanthoma * White sponge nevus Teeth (pulp, dentin, enamel) * Amelogenesis imperfecta * Ankylosis * Anodontia * Caries * Early childhood caries * Concrescence * Failure of eruption of teeth * Dens evaginatus * Talon cusp * Dentin dysplasia * Dentin hypersensitivity * Dentinogenesis imperfecta * Dilaceration * Discoloration * Ectopic enamel * Enamel hypocalcification * Enamel hypoplasia * Turner's hypoplasia * Enamel pearl * Fluorosis * Fusion * Gemination * Hyperdontia * Hypodontia * Maxillary lateral incisor agenesis * Impaction * Wisdom tooth impaction * Macrodontia * Meth mouth * Microdontia * Odontogenic tumors * Keratocystic odontogenic tumour * Odontoma * Dens in dente * Open contact * Premature eruption * Neonatal teeth * Pulp calcification * Pulp stone * Pulp canal obliteration * Pulp necrosis * Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * Perio-endo lesion * Teething Periapical, mandibular and maxillary hard tissues – Bones of jaws * Agnathia * Alveolar osteitis * Buccal exostosis * Cherubism * Idiopathic osteosclerosis * Mandibular fracture * Microgenia * Micrognathia * Intraosseous cysts * Odontogenic: periapical * Dentigerous * Buccal bifurcation * Lateral periodontal * Globulomaxillary * Calcifying odontogenic * Glandular odontogenic * Non-odontogenic: Nasopalatine duct * Median mandibular * Median palatal * Traumatic bone * Osteoma * Osteomyelitis * Osteonecrosis * Bisphosphonate-associated * Neuralgia-inducing cavitational osteonecrosis * Osteoradionecrosis * Osteoporotic bone marrow defect * Paget's disease of bone * Periapical abscess * Phoenix abscess * Periapical periodontitis * Stafne defect * Torus mandibularis Temporomandibular joints, muscles of mastication and malocclusions – Jaw joints, chewing muscles and bite abnormalities * Bruxism * Condylar resorption * Mandibular dislocation * Malocclusion * Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease This dermatology article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Congenital lip pit	c0158670	1,953	wikipedia	https://en.wikipedia.org/wiki/Congenital_lip_pit	2021-01-18T18:43:20	{"umls": ["C0158670", "C0341059"], "wikidata": ["Q5160444"]}
Phimosis An erect penis with a case of phimosis Pronunciation * /fɪˈmoʊsɪs/ or /faɪˈmoʊsɪs/[1][2] SpecialtyUrology SymptomsUnable to pull the foreskin back past the glans[3] ComplicationsBalanitis,[3] penile cancer, urinary retention Usual onsetNormal at birth[3] DurationTypically resolves by 3 years old[4] CausesNormal, balanitis, balanitis xerotica obliterans[5] Risk factorsDiaper rash, poor cleaning, diabetes[6] Differential diagnosisHair tourniquet, lymphedema of the penis[6] PreventionSteroid cream, stretching exercises, circumcision[4] Frequency0.5%–13% (in uncircumcised males 18 years or older)[7] Phimosis is a condition in which the foreskin of the penis cannot stretch to allow it to be pulled back past the glans.[3] A balloon-like swelling under the foreskin may occur with urination.[3] In teenagers and adults, it may result in pain during an erection, but is otherwise not painful.[3] Those affected are at greater risk of inflammation of the glans, known as balanitis, and other complications.[3] In young children, it is normal not to be able to pull back the foreskin at all.[4] Over 90% of cases resolve by the age of seven, although full retraction is still prevented by preputial adhesions in over half at this age.[4][5] 99% of cases resolve by age 16.[5] Occasionally, phimosis may be caused by an underlying condition such as scarring due to balanitis or balanitis xerotica obliterans.[5] This can typically be diagnosed by seeing scarring of the opening of the foreskin.[5] Typically, it resolves without treatment by the age of three.[4] Efforts to pull back the foreskin during the early years of a young male's life should not be attempted.[4] For those in whom the condition does not improve further, time can be given or a steroid cream may be used to attempt to loosen the tight skin.[4] If this method, combined with stretching exercises, is not effective, then other treatments such as circumcision may be recommended.[4] A potential complication of phimosis is paraphimosis, where the tight foreskin becomes trapped behind the glans.[5] The word is from the Greek φίμωσις phimōsis meaning "muzzling".[8][9][10] ## Contents * 1 Signs and symptoms * 1.1 Severity * 2 Cause * 3 Treatment * 3.1 Nonsurgical * 3.2 Surgical * 4 Prognosis * 5 Epidemiology * 6 History * 7 References * 8 External links ## Signs and symptoms[edit] At birth, the inner layer of the foreskin is sealed to the glans penis. The foreskin is usually non-retractable in early childhood, and some males may reach the age of 18 before their foreskin can be fully retracted.[11] Medical associations advise not to retract the foreskin of an infant, in order to prevent scarring.[12][13] Some argue that non-retractability may "be considered normal for males up to and including adolescence."[14][15] Hill states that full retractability of the foreskin may not be achieved until late childhood or early adulthood.[16] A Danish survey found that the mean age of first foreskin retraction is 10.4 years.[17] Rickwood, as well as other authors, has suggested that true phimosis is over-diagnosed due to failure to distinguish between normal developmental non-retractability and a pathological condition.[18][19][20] Some authors use the terms "physiologic" and "pathologic" to distinguish between these types of phimosis; [21] others use the term "non-retractile foreskin" to distinguish this developmental condition from pathologic phimosis.[18] In some cases a cause may not be clear, or it may be difficult to distinguish physiological phimosis from pathological phimosis if an infant appears to have discomfort while urinating or demonstrates obvious ballooning of the foreskin. However, ballooning does not indicate urinary obstruction.[22] In women, a comparable condition is known as "clitoral phimosis", whereby the clitoral hood cannot be retracted, limiting exposure of the glans clitoridis.[23] ### Severity[edit] Score 5 phimosis: Severe with no retraction. * Score 1: full retraction of foreskin, tight behind the glans. * Score 2: partial exposure of glans, prepuce (not congenital adhesions) limiting factor. * Score 3: partial retraction, meatus just visible. * Score 4: slight retraction, but some distance between tip and glans, i.e. neither meatus nor glans can be exposed. * Score 5: absolutely no retraction of the foreskin.[24] ## Cause[edit] There are three mechanical conditions that prevent foreskin retraction: * The tip of the foreskin is too narrow to pass over the glans penis. This is normal in children and adolescents.[25][26] * The inner surface of the foreskin is fused with the glans penis. This is normal in children and adolescents, but abnormal in adults.[26] * The frenulum is too short to allow complete retraction of the foreskin (a condition called frenulum breve).[26] Pathological phimosis (as opposed to the natural non-retractability of the foreskin in childhood) is rare and the causes are varied. Some cases may arise from balanitis (inflammation of the glans penis).[27] Lichen sclerosus et atrophicus (thought to be the same condition as balanitis xerotica obliterans) is regarded as a common (or even the main)[28] cause of pathological phimosis.[29] This is a skin condition of unknown origin that causes a whitish ring of indurated tissue (a cicatrix) to form near the tip of the prepuce. This inelastic tissue prevents retraction. Phimosis may occur after other types of chronic inflammation (such as balanoposthitis), repeated catheterization, or forcible foreskin retraction.[30] Phimosis may also arise in untreated diabetics due to the presence of glucose in their urine giving rise to infection in the foreskin.[31] Phimosis in older children and adults can vary in severity, with some able to retract their foreskin partially (relative phimosis), while others are completely unable to retract their foreskin, even when the penis is in a flaccid state (full phimosis). ## Treatment[edit] Physiologic phimosis, common in males 10 years of age and younger, is normal, and does not require intervention.[25][32][33] Non-retractile foreskin usually becomes retractable during the course of puberty.[33] If phimosis in older children or adults is not causing acute and severe problems, nonsurgical measures may be effective. Choice of treatment is often determined by whether circumcision is viewed as an option of last resort to be avoided or as the preferred course.[citation needed] ### Nonsurgical[edit] * Topical steroid creams such as betamethasone, mometasone furoate and cortisone are effective in treating phimosis and should be considered before circumcision.[32][34][35] It is theorized that the steroids work by reducing the body's inflammatory and immune responses, and also by thinning the skin.[32] * Gently stretching of the foreskin can be accomplished manually. Skin that is under tension expands by growing additional cells. There are different ways to stretch the phimosis. If the opening of the foreskin is already large enough, the foreskin is rolled over two fingers and these are carefully pulled apart. If the opening is still too small, flesh tunnels can be used. These are inserted into the foreskin opening and should preferably be made of silicone so that they can be folded when inserted and so that they do not interfere when worn. The diameter is gradually increased until the foreskin can be retracted without difficulty. Even phimosis with a diameter of less than a millimetre can be stretched with these rings. Rings in different sizes are also available as stretching sets. * Stretching the foreskin opening with two fingers * Stretching the foreskin opening with flesh tunnel of different diameters ### Surgical[edit] Preputioplasty: Fig 1. Penis with tight phimotic ring making it difficult to retract the foreskin. Fig 2. Foreskin retracted under anaesthetic with the phimotic ring or stenosis constricting the shaft of the penis and creating a "waist". Fig 3. Incision closed laterally. Fig 4. Penis with the loosened foreskin replaced over the glans. Surgical methods range from the complete removal of the foreskin to more minor operations to relieve foreskin tightness: * Dorsal slit (superincision) is a single incision along the upper length of the foreskin from the tip to the corona, exposing the glans without removing any tissue. * Ventral slit (subincision) is an incision along the lower length of the foreskin from the tip of the frenulum to the base of the glans, removing the frenulum in the process. Often used when frenulum breve occurs alongside the phimosis. * Preputioplasty, in which a limited dorsal slit with transverse closure is made along the constricting band of skin,[36] can be an effective alternative to circumcision.[20] It has the advantage of only limited pain and a short healing duration relative to circumcision, while also avoiding cosmetic effects.[36] * Circumcision is sometimes performed for phimosis, and is an effective treatment; however, this method has become less common as of 2012.[11] While circumcision prevents phimosis, studies of the incidence of healthy infants circumcised for each prevented case of phimosis are inconsistent.[19][30] ## Prognosis[edit] The most acute complication is paraphimosis. In this condition, the glans is swollen and painful, and the foreskin is immobilized by the swelling in a partially retracted position. The proximal penis is flaccid. Some studies found phimosis to be a risk factor for urinary retention[37] and carcinoma of the penis.[38] ## Epidemiology[edit] A number of medical reports of phimosis incidence have been published over the years. They vary widely because of the difficulties of distinguishing physiological phimosis (developmental nonretractility) from pathological phimosis, definitional differences, ascertainment problems, and the multiple additional influences on post-neonatal circumcision rates in cultures where most newborn males are circumcised. A commonly cited incidence statistic for pathological phimosis is 1% of uncircumcised males.[19][30][39] When phimosis is simply equated with nonretractility of the foreskin after age 3 years, considerably higher incidence rates have been reported.[33][40] Others have described incidences in adolescents and adults as high as 50%, though it is likely that many cases of physiological phimosis or partial nonretractility were included.[41] ## History[edit] According to some accounts, phimosis prevented Louis XVI of France from impregnating his wife for the first seven years of their marriage. She was 14 and he was 15 when they married in 1770. However, the presence and nature of his genital anomaly is not considered certain, and some scholars (such as Vincent Cronin and Simone Bertiere) assert that surgical repair would have been mentioned in the records of his medical treatments if this had indeed occurred.[citation needed] Non-retractile prepuce in adolescence is normal, common, and usually resolves with increasing maturity.[33] US president James Garfield was assassinated by Charles Guiteau in 1881. Guiteau's autopsy report indicated that he had phimosis. At the time, this led to the speculation that Guiteau's murderous behavior was due to phimosis-induced insanity.[42] ## References[edit] 1. ^ OED 2nd edition, 1989 as /faɪˈməʊsɪs/. 2. ^ Entry "phimosis" in Merriam-Webster Online Dictionary Archived 2017-09-22 at the Wayback Machine. 3. ^ a b c d e f g "Phimosis". PubMed Health. Archived from the original on 5 November 2017. Retrieved 28 October 2016. 4. ^ a b c d e f g h "What are the treatment options for phimosis?". PubMed Health. Institute for Quality and Efficiency in Health Care. 7 October 2015. Archived from the original on 5 November 2017. Retrieved 28 October 2016. 5. ^ a b c d e f McGregor, TB; Pike, JG; Leonard, MP (March 2007). "Pathologic and physiologic phimosis: approach to the phimotic foreskin". Canadian Family Physician. 53 (3): 445–8. PMC 1949079. PMID 17872680. 6. ^ a b Domino, Frank J.; Baldor, Robert A.; Golding, Jeremy (2013). The 5-Minute Clinical Consult 2014. Lippincott Williams & Wilkins. p. 138. ISBN 9781451188509. 7. ^ Morris, Brian J.; Matthews, Jim G.; Krieger, John N. (2020). "Prevalence of Phimosis in Males of All Ages: Systematic Review". Urology. Elsevier BV. 135: 124–132. doi:10.1016/j.urology.2019.10.003. ISSN 0090-4295. 8. ^ φίμωσις, φιμός. Liddell, Henry George; Scott, Robert; A Greek–English Lexicon at the Perseus Project. 9. ^ Harper, Douglas. "phimosis". Online Etymology Dictionary. 10. ^ Kirk, Raymond Maurice; Winslet, Marc C. (2007). Essential General Surgical Operations. Elsevier Health Sciences. p. 365. ISBN 978-0443103148. Archived from the original on 2017-11-05. 11. ^ a b Sukhbir Kaur Shahid (5 March 2012). "Phimosis in Children". ISRN Urology. 2012: 707329. doi:10.5402/2012/707329. PMC 3329654. PMID 23002427. 12. ^ "Care of the Uncircumcised Penis". Guide for parents. American Academy of Pediatrics. September 2007. Archived from the original on 2012-08-30. 13. ^ "Caring for an uncircumcised penis". Information for parents. Canadian Paediatric Society. July 2012. Archived from the original on 2012-07-16. 14. ^ Huntley JS, Bourne MC, Munro FD, Wilson-Storey D (September 2003). "Troubles with the foreskin: one hundred consecutive referrals to paediatric surgeons". J R Soc Med. 96 (9): 449–451. doi:10.1258/jrsm.96.9.449. PMC 539600. PMID 12949201. 15. ^ Denniston; Hill (October 2010). "Gairdner was wrong". Can Fam Physician. 56 (10): 986–987. PMC 2954072. PMID 20944034. Archived from the original on 2015-09-23. Retrieved 2014-04-05. 16. ^ George Hill (2003). "Circumcision for phimosis and other medical indications in Western Australian boys". The Medical Journal of Australia. 178 (11): 587, author reply 589–90. doi:10.5694/j.1326-5377.2003.tb05368.x. PMID 12765511. Archived from the original on 2008-08-30. 17. ^ Thorvaldsen MA, Meyhoff H.. Patologisk eller fysiologisk fimose?. Ugeskrift for Læger. 2005 [archived 2016-02-07];167(16):1852–62. PMID 15929334. 18. ^ a b Rickwood AM, Walker J (1989). "Is phimosis overdiagnosed in boys and are too many circumcisions performed in consequence?". Ann R Coll Surg Engl. 71 (5): 275–7. PMC 2499015. PMID 2802472. "Authors review English referral statistics and suggest phimosis is overdiagnosed, especially in boys under 5 years, because of confusion with developmentally nonretractile foreskin." 19. ^ a b c Spilsbury K, Semmens JB, Wisniewski ZS, Holman CD (2003). "Circumcision for phimosis and other medical indications in Western Australian boys". Med. J. Aust. 178 (4): 155–8. doi:10.5694/j.1326-5377.2003.tb05130.x. PMID 12580740. Archived from the original on 2004-11-09.. Recent Australian statistics with good discussion of ascertainment problems arising from surgical statistics. 20. ^ a b Van Howe RS (1998). "Cost-effective treatment of phimosis". Pediatrics. 102 (4): e43. doi:10.1542/peds.102.4.e43. PMID 9755280. Archived from the original on 2009-08-19. A review of estimated costs and complications of 3 phimosis treatments (topical steroids, praeputioplasty, and surgical circumcision). The review concludes that topical steroids should be tried first, and praeputioplasty has advantages over surgical circumcision. This article also provides a good discussion of the difficulty distinguishing pathological from physiological phimosis in young children and alleges inflation of phimosis statistics for purposes of securing insurance coverage for post-neonatal circumcision in the United States. 21. ^ McGregor TB, Pike JG, Leonard MP (March 2007). "Pathologic and physiologic phimosis: approach to the phimotic foreskin". Can Fam Physician. 53 (3): 445–8. PMC 1949079. PMID 17872680. 22. ^ Babu R, Harrison SK, Hutton KA (2004). "Ballooning of the foreskin and physiological phimosis: is there any objective evidence of obstructed voiding?". BJU Int. 94 (3): 384–387. doi:10.1111/j.1464-410X.2004.04935.x. PMID 15291873. 23. ^ Munarriz R, Talakoub L, Kuohung W, et al. (2002). "The prevalence of phimosis of the clitoris in women presenting to the sexual dysfunction clinic: lack of correlation to disorders of desire, arousal and orgasm". J Sex Marital Ther. 28 (Suppl 1): 181–5. doi:10.1080/00926230252851302. PMID 11898701. 24. ^ Kikiros, C. S.; Beasley, S. W.; Woodward, A. A. (1993-05-01). "The response of phimosis to local steroid application" (PDF). Pediatric Surgery International. 8 (4): 329–332. doi:10.1007/BF00173357. ISSN 0179-0358. Archived (PDF) from the original on 2016-03-04. 25. ^ a b Kayaba H, Tamura H, Kitajima S, et al.. Analysis of shape and retractability of the prepuce in 603 Japanese boys. J Urol. 1996;156(5):1813–5.. doi:10.1016/S0022-5347(01)65544-7. PMID 8863623. 26. ^ a b c Øster J. Further fate of the foreskin: incidence of preputial adhesions, phimosis, and smegma among Danish schoolboys. Arch Dis Child. 1968;43(228):200–3. doi:10.1136/adc.43.228.200. PMID 5689532. 27. ^ Edwards S (June 1996). "Balanitis and balanoposthitis: a review". Genitourin Med. 72 (3): 155–9. doi:10.1136/sti.72.3.155. PMC 1195642. PMID 8707315. 28. ^ Bolla G, Sartore G, Longo L, Rossi C (2005). "[The sclero-atrophic lichen as principal cause of acquired phimosis in pediatric age]". Pediatr Med Chir (in Italian). 27 (3–4): 91–3. PMID 16910457. 29. ^ Buechner SA (September 2002). "Common skin disorders of the penis". BJU Int. 90 (5): 498–506. doi:10.1046/j.1464-410X.2002.02962.x. PMID 12175386. 30. ^ a b c Cantu Jr. S. Phimosis and paraphimosis at eMedicine 31. ^ Bromage, Stephen J.; Anne Crump; Ian Pearce (2008). "Phimosis as a presenting feature of diabetes". BJU International. 101 (3): 338–340. doi:10.1111/j.1464-410X.2007.07274.x. PMID 18005214. Archived from the original on 2013-01-05. 32. ^ a b c Hayashi, Y.; Kojima, Y.; Mizuno, K.; Kohri, K. (2011). "Prepuce: phimosis, paraphimosis, and circumcision". ScientificWorldJournal. 11: 289–301. doi:10.1100/tsw.2011.31. PMC 5719994. PMID 21298220. 33. ^ a b c d Øster J (1968). "Further fate of the foreskin. Incidence of preputial adhesions, phimosis, and smegma among Danish schoolboys". Arch. Dis. Child. 43 (228): 200–203. doi:10.1136/adc.43.228.200. PMC 2019851. PMID 5689532. 34. ^ Zampieri N, Corroppolo M, Giacomello L, et al.. Phimosis: Stretching methods with or without application of topical steroids?. J Pediatr. 2005;147(5):705–6. doi:10.1016/j.jpeds.2005.07.017. PMID 16291369. 35. ^ Moreno, G; Corbalán, J; Peñaloza, B; Pantoja, T (Sep 2, 2014). "Topical corticosteroids for treating phimosis in boys". The Cochrane Database of Systematic Reviews. 9 (9): CD008973. doi:10.1002/14651858.CD008973.pub2. PMID 25180668. 36. ^ a b Cuckow PM, Rix G, Mouriquand PD (1994). "Preputial plasty: a good alternative to circumcision". J. Pediatr. Surg. 29 (4): 561–563. doi:10.1016/0022-3468(94)90092-2. PMID 8014816. 37. ^ Minagawa T, Murata Y (June 2008). "[A case of urinary retention caused by true phimosis]". Hinyokika Kiyo (in Japanese). 54 (6): 427–9. PMID 18634440. 38. ^ Daling JR, Madeleine MM, Johnson LG, et al. (September 2005). "Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease". Int. J. Cancer. 116 (4): 606–616. doi:10.1002/ijc.21009. PMID 15825185. 39. ^ Shankar KR, Rickwood AM (1999). "The incidence of phimosis in boys" (PDF). BJU Int. 84 (1): 101–102. doi:10.1046/j.1464-410x.1999.00147.x. PMID 10444134. This study gives a low incidence of pathological phimosis (0.6% of uncircumcised boys by age 15 years) by asserting that balanitis xerotica obliterans is the only indisputable type of pathological phimosis and anything else should be assumed "physiological". Restrictiveness of definition and circularity of reasoning have been criticized. 40. ^ Imamura E (1997). "Phimosis of infants and young children in Japan". Acta Paediatr Jpn. 39 (4): 403–5. doi:10.1111/j.1442-200x.1997.tb03605.x. PMID 9316279. A study of phimosis prevalence in over 4,500 Japanese children reporting that over a third of uncircumcised had a nonretractile foreskin by age 3 years. 41. ^ Ohjimi T, Ohjimi H (1981). "Special surgical techniques for relief of phimosis". J Dermatol Surg Oncol. 7 (4): 326–30. doi:10.1111/j.1524-4725.1981.tb00650.x. PMID 7240535. 42. ^ Hodges FM (1999). "The history of phimosis from antiquity to the present". In Milos, Marilyn Fayre; Denniston, George C.; Hodges, Frederick Mansfield (eds.). Male and Female Circumcision: Medical, Legal and Ethical Considerations in Pediatric Practice. New York: Kluwer Academic/Plenum Publishers. pp. 37–62. doi:10.1007/978-0-585-39937-9_5. ISBN 978-0-306-46131-6. ## External links[edit] Classification D * ICD-10: N47 * ICD-10-CM: N47.1 * ICD-9-CM: 605 * MeSH: D010688 * DiseasesDB: 10019 * SNOMED CT: 253854008 External resources * eMedicine: emerg/423 * Phimosis, by the University of California, San Francisco Urology department * v * t * e Male diseases of the pelvis and genitals Internal Testicular * Orchitis * Hydrocele testis * Testicular cancer * Testicular torsion * Male infertility * Aspermia * Asthenozoospermia * Azoospermia * Hyperspermia * Hypospermia * Oligospermia * Necrospermia * Teratospermia Epididymis * Epididymitis * Spermatocele * Hematocele Prostate * Prostatitis * Acute prostatitis * Chronic bacterial prostatitis * Chronic prostatitis/chronic pelvic pain syndrome * Asymptomatic inflammatory prostatitis * Benign prostatic hyperplasia * Prostate cancer Seminal vesicle * Seminal vesiculitis External Penis * Balanoposthitis / Balanitis * Balanitis plasmacellularis * Pseudoepitheliomatous keratotic and micaceous balanitis * Phimosis * Paraphimosis * Priapism * Sexual dysfunction * Erectile dysfunction * Peyronie's disease * Penile cancer * Penile fracture * Balanitis xerotica obliterans Other * Hematospermia * Retrograde ejaculation * Postorgasmic illness syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Phimosis	c0031538	1,954	wikipedia	https://en.wikipedia.org/wiki/Phimosis	2021-01-18T18:58:33	{"mesh": ["D010688"], "umls": ["C0031538"], "wikidata": ["Q382641"]}
Diastrophic dysplasia is a disorder of cartilage and bone development. Diastrophic dysplasia is characterized by shortened arms and legs, spinal deformities, hitchhiker thumbs, joint contractures, and joint pain (osteoarthritis). Joint contractures and spinal deformity tend to worsen with age. Mental development and intelligence are usually normal. Occasionally, children with diastrophic dysplasia die in infancy due to respiratory complications such as pneumonia. Management consists of maintaining joint position and mobility through physical therapy and casting. Surgical correction of clubfoot may be necessary. Arthroplasty of the hips and knees to decrease pain and increase motility may also be indicated. Indications for surgical correction of scoliosis have not yet been established. Diastrophic dysplasia is caused by mutations in the SLC26A2 gene and is inherited in an autosomal recessive manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Diastrophic dysplasia	c0220726	1,955	gard	https://rarediseases.info.nih.gov/diseases/6275/diastrophic-dysplasia	2021-01-18T18:00:53	{"mesh": ["C536170"], "omim": ["222600"], "orphanet": ["628"], "synonyms": ["DTD", "DD", "Diastrophic dwarfism"]}
Proteus syndrome is a rare condition characterized by overgrowth of the bones, skin, and other tissues. Organs and tissues affected by the disease grow out of proportion to the rest of the body. The overgrowth is usually asymmetric, which means it affects the right and left sides of the body differently. Newborns with Proteus syndrome have few or no signs of the condition. Overgrowth becomes apparent between the ages of 6 and 18 months and gets more severe with age. In people with Proteus syndrome, the pattern of overgrowth varies greatly but can affect almost any part of the body. Bones in the limbs, skull, and spine are often affected. The condition can also cause a variety of skin growths, particularly a thick, raised, and deeply grooved lesion known as a cerebriform connective tissue nevus. This type of skin growth usually occurs on the soles of the feet and is hardly ever seen in conditions other than Proteus syndrome. Blood vessels (vascular tissue) and fat (adipose tissue) can also grow abnormally in Proteus syndrome. Some people with Proteus syndrome have neurological abnormalities, including intellectual disability, seizures, and vision loss. Affected individuals may also have distinctive facial features such as a long face, outside corners of the eyes that point downward (down-slanting palpebral fissures), a low nasal bridge with wide nostrils, and an open-mouth expression. For reasons that are unclear, affected people with neurological symptoms are more likely to have distinctive facial features than those without neurological symptoms. It is unclear how these signs and symptoms are related to abnormal growth. Other potential complications of Proteus syndrome include an increased risk of developing various types of noncancerous (benign) tumors and a type of blood clot called a deep venous thrombosis (DVT). DVTs occur most often in the deep veins of the legs or arms. If these clots travel through the bloodstream, they can lodge in the lungs and cause a life-threatening complication called a pulmonary embolism. Pulmonary embolism is a common cause of death in people with Proteus syndrome. ## Frequency Proteus syndrome is a rare condition with an incidence of less than 1 in 1 million people worldwide. Only a few hundred affected individuals have been reported in the medical literature. Researchers believe that Proteus syndrome may be overdiagnosed, as some individuals with other conditions featuring asymmetric overgrowth have been mistakenly diagnosed with Proteus syndrome. To make an accurate diagnosis, most doctors and researchers now follow a set of strict guidelines that define the signs and symptoms of Proteus syndrome. ## Causes Proteus syndrome results from a mutation in the AKT1 gene. This genetic change is not inherited from a parent; it arises randomly in one cell during the early stages of development before birth. As cells continue to grow and divide, some cells will have the mutation and other cells will not. This mixture of cells with and without a genetic mutation is known as mosaicism. The AKT1 gene helps regulate cell growth and division (proliferation) and cell death. A mutation in this gene disrupts a cell's ability to regulate its own growth, allowing it to grow and divide abnormally. Increased cell proliferation in various tissues and organs leads to the abnormal growth characteristic of Proteus syndrome. Studies suggest that an AKT1 gene mutation is more common in groups of cells that experience overgrowth than in the parts of the body that grow normally. In some published case reports, mutations in a gene called PTEN have been associated with Proteus syndrome. However, many researchers now believe that individuals with PTEN gene mutations and asymmetric overgrowth do not meet the strict guidelines for a diagnosis of Proteus syndrome. Instead, these individuals actually have condition that is considered part of a larger group of disorders called PTEN hamartoma tumor syndrome. One name that has been proposed for the condition is segmental overgrowth, lipomatosis, arteriovenous malformations, and epidermal nevus (SOLAMEN) syndrome; another is type 2 segmental Cowden syndrome. However, some scientific articles still refer to PTEN-related Proteus syndrome. ### Learn more about the gene associated with Proteus syndrome * AKT1 ## Inheritance Pattern Because Proteus syndrome is caused by AKT1 gene mutations that occur during early development, the disorder is not inherited and does not run in families. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Proteus syndrome	c0085261	1,956	medlineplus	https://medlineplus.gov/genetics/condition/proteus-syndrome/	2021-01-27T08:24:35	{"gard": ["7475"], "mesh": ["D016715"], "omim": ["176920"], "synonyms": []}
Autoimmune gastrointestinal dysmotility (AGID) is a type of dysautonomia that may be idiopathic (cause unknown) or associated with cancer elsewhere in the body, most commonly small cell lung cancer. Signs and symptoms may include early satiety (feeling full quickly), nausea, vomiting, bloating, diarrhea, constipation and involuntary weight loss. Management options for AGID include treating specific symptoms, treatment of any underlying cancer if necessary, and/or immunotherapy. Nutrition and hydration therapy are important supportive treatment measures. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Autoimmune gastrointestinal dysmotility	None	1,957	gard	https://rarediseases.info.nih.gov/diseases/12063/autoimmune-gastrointestinal-dysmotility	2021-01-18T18:01:59	{"synonyms": ["AGID"]}
A number sign (#) is used with this entry because of evidence that susceptibility to epidermodysplasia verruciformis-1 (EV1) is conferred by homozygous or compound heterozygous mutation in the TMC6 gene (605828) on chromosome 17q25. Description Epidermodysplasia verruciformis (EV) is a rare genodermatosis associated with a high risk of skin cancer. EV results from an abnormal susceptibility to specific related human papillomavirus (HPV) genotypes and to the oncogenic potential of some of them, mainly HPV5. Infection with EV-associated HPV leads to the early development of disseminated flat wart-like and pityriasis versicolor-like lesions. Patients are unable to reject their lesions, and cutaneous Bowen carcinomas in situ and invasive squamous cell carcinomas develop in about half of them, mainly on sun-exposed areas (summary by Ramoz et al., 2000). ### Genetic Heterogeneity of Susceptibility to Epidermodysplasia Verruciformis Susceptibility to EV2 (618231) is conferred by mutation in the TMC8 gene (605829) on chromosome 17q25; EV3 (618267) by mutation in the CIB1 gene (602293) on chromosome 15q26; EV4 (618307) by mutation in the RHOH gene (602037) on chromosome 4p13; and EV5 (618309) by mutation in the IL7 gene (146660) on chromosome 8q12. Clinical Features The lesions in epidermodysplasia verruciformis often resemble verrucae planae (Sullivan and Ellis, 1939). The mucous membranes, hair, and nails are not affected. Malignant degeneration, usually of the superficial basal cell type, is frequent. Characteristic changes in the epidermal cells with peculiar vacuolization are observed. Ellis (1953) stated that this disorder occurs most frequently in Orientals. Ramoz et al. (2002) described 5 families with epidermodysplasia verruciformis. Patients had early onset of the disease, a disseminated infection by EV-specific HPV genotypes, including at least one of the potentially oncogenic genotypes (HPV types 5, 8, 14, 17, or 20), and lesions of the skin showing the cytopathic effect pathognomonic of EV. Significant variations were observed, however, in the HPV genotypes detected, the extension of the lesions and the development of skin carcinomas. HPV5, the genotype most frequently associated with EV cancers, was detected only in families A1, A2, and C1, whereas the less oncogenic HPV20, an HPV5-related genotype, was found in all 5 families. Tate et al. (2004) reported a 65-year-old Japanese woman with EV. The patient had suffered from warts beginning when she was a teenager. Excision of Bowen disease from the skin of the hand was carried out 3 times at the ages of 51, 52, and 64 years, and gastrectomy was performed for gastric cancer when she was 53 years of age. Multiple skin cancers of the face showed squamous cell carcinoma and Bowen disease. The parents were unaffected and were not related. Three of 6 sibs were also affected. Inheritance Sullivan and Ellis (1939) found that of the 16 previously reported families, 4 had consanguineous parents. Familial aggregation was described by Midana (1949) and by Jablonska et al. (1966). Hermann (1955) found parental consanguinity. Lutzner (1977) considered this an autosomal recessive disorder. The family reported by Jablonska et al. (1979) suggested autosomal dominant inheritance. The fact that spouses and some family members stayed free of the disease speaks against intrafamilial infection as the cause. Feuerman et al. (1979) reported the cases of 2 Arab brothers. The parents and 7 sibs were unaffected. Mapping In Algerian and Colombian consanguineous families segregating EV, Ramoz et al. (2000) mapped the disorder to a 1-cM interval on chromosome 17q25. Pathogenesis The view that epidermodysplasia verruciformis is an extensive form of viral verrucae planae is supported by successful autoinoculation and heteroinoculation experiments. Lutz (1957) was one of the first to describe the condition; he accepted that it is not an entity but suggested that genetic predisposition may account for the extensiveness of the eruption of warts. By electron microscopy, Baker (1968) and others demonstrated particles suggesting papovavirus. The common wart virus can be demonstrated in the warts by both electron and fluorescent microscopy (Yabe and Sadakane, 1975). Warts appear to progress to squamous cell carcinoma in about 10% of cases (Lutzner, 1977). As in Shope papilloma, virus is no longer demonstrable in the cancers. Jablonska et al. (1979) observed papillomaviruses (HPVs), either HPV3 or HPV4 and sometimes both, in cases and found that the clinical picture differed depending on which virus was involved. Malignancies developed only in family members infected with HPV4. Orth et al. (1979) pointed to papillomavirus type 5 as the determinant of malignant evolution of the warts. Individuals with epidermodysplasia verruciformis are not prone to bacterial, fungal, or viral infections, and are not abnormally susceptible to genital papillomaviral infections. Molecular Genetics In affected members of consanguineous Colombian and Algerian families with EV mapped to chromosome 17q25, Ramoz et al. (2002) identified 2 homozygous nonsense mutations in the EVER1 gene (TMC6; 605828.0001-605828.0002) in EV1 and 2 homozygous mutations in the EVER2 gene (TMC8; 605829.0001-605829.0002) in EV2 (618231). In a Japanese woman with EV1, Tate et al. (2004) found compound heterozygosity for mutations in the TMC6 gene (605828.0003-605828.0004). The parents were unaffected and were not related. INHERITANCE \- Autosomal recessive SKIN, NAILS, & HAIR Skin \- Epidermodysplasia verruciformis \- Verrucae planae \- Pityriasis versicolor-like lesions, disseminated \- Basal cell carcinoma \- Cutaneous Bowen carcinomas IMMUNOLOGY \- Susceptibility to human papillomavirus (HPV) genotypes NEOPLASIA \- Basal cell carcinoma \- Cutaneous Bowen carcinomas LABORATORY ABNORMALITIES \- Epidermal cell vacuolization MOLECULAR BASIS \- Caused by mutation in the transmembrane channel-like 6 gene (TMC6, 605828.0001 ): Caused by mutation in the transmembrane channel-like 8 gene (TMC8, 605829.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	EPIDERMODYSPLASIA VERRUCIFORMIS, SUSCEPTIBILITY TO, 1	c0014522	1,958	omim	https://www.omim.org/entry/226400	2019-09-22T16:28:12	{"mesh": ["D004819"], "omim": ["226400"], "orphanet": ["302"], "synonyms": ["Alternative titles", "EPIDERMODYSPLASIA VERRUCIFORMIS"]}
Combined immunodeficiency (CID) due to STIM1 deficiency is a form of CID due to Calcium release activated Ca2+(CRAC) channel dysfunction (see this term) characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia. ## Epidemiology To date, it has been reported in 4 patients from two families. ## Clinical description CID due to STIM1 deficiency is characterized by recurrent viral, bacterial, mycobacterial and fungal infections from birth, chronic diarrhea, pneumonia, meningitis, enteritis, gastrointestinal candidiasis, sepsis and otitis media. In addition, patients present at birth with congenital myopathy (see this term), characterized by non-progressive generalized muscular dysplasia. This presents as global muscular hypotonia and partial iris hypoplasia. All patients present with ectodermal dysplasia that is characterized by hypocalcified amelogenesis imperfecta (see this term) and leads to the loss of soft dental enamel. Patients also show signs of lymphoproliferative and autoimmune disease including lymphadenopathy, hepatosplenomegaly, autoimmune thrombocytopenia and autoimmune hemolytic anemia (see these terms). ## Etiology The disease is caused by mutations in the STIM1 gene (11p15.5) which codes for stromal interaction molecule 1. ## Genetic counseling Transmission is autosomal recessive. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Combined immunodeficiency due to STIM1 deficiency	c2748557	1,959	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=317430	2021-01-23T17:43:59	{"mesh": ["C557827"], "omim": ["612783"], "icd-10": ["D81.8"], "synonyms": ["CID due to STIM1 deficiency"]}
Progressive pseudorheumatoid disyplasia (PPD) is a disorder of bone and cartilage that affects many joints. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Major signs and symptoms include stiff joints (contractures), short stature, and widening of the ends of the finger and toe bones as well as other tubular bones. Bony widening at the fingers' joints progresses leading to permanent bending of the fingers (camptodactyly). Spine involvement results in short trunk and hunching of the back (kyphosis). It may initially be mistaken for juvenile rheumatoid arthritis, however people with this condition do not have the laboratory test results of juvenile rheumatoid arthritis. PPD is caused by a mutation in the WISP3 gene and is inherited in an autosomal recessive pattern. There is still no cure. Treatment may include pain medication and hip and knee joint replacement surgery at an early age. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Progressive pseudorheumatoid dysplasia	c0432215	1,960	gard	https://rarediseases.info.nih.gov/diseases/9184/progressive-pseudorheumatoid-dysplasia	2021-01-18T17:58:08	{"mesh": ["C535387"], "omim": ["208230"], "orphanet": ["1159"], "synonyms": ["Spondyloepiphyseal dysplasia tarda-progressive arthropathy syndrome", "Progressive pseudorheumatoid arthropathy of childhood", "PPAC", "Spondyloepiphyseal dysplasia tarda - progressive arthropathy", "PPD", "SEDT-PA", "Arthropathy, progressive pseudorheumatoid, of childhood", "Spondyloepiphyseal dysplasia tarda with progressive arthropathy", "Progressive pseudorheumatoid chondrodysplasia"]}
Excessive internet use that causes psychological disorders. 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: "Internet addiction disorder" – news · newspapers · books · scholar · JSTOR (June 2019) Internet addiction disorder An old flyer for an internet addiction support group in New York City. Specialty * Psychiatry * psychology Internet addiction disorder (IAD) also known as problematic internet use or pathological internet use is generally defined as problematic, compulsive use of the internet, that results in significant impairment in an individual's function in various life domains over a prolonged period of time. Young people are at particular risk of developing Internet Addiction Disorder or Problematic Internet Use.[1] This and other relationships between digital media use and mental health have been under considerable research, debate and discussion amongst experts in several disciplines, and have generated controversy from the medical, scientific and technological communities. Such disorders can be diagnosed when an individual engages in online activities at the cost of fulfilling daily responsibilities or pursuing other interests, and without regard for the negative consequences. The Internet can foster various addictions including addiction to pornography, game-playing, auction sites, social networking sites, and surfing of the Web.[2] Excessive Internet use has not been recognised as a disorder by the World Health Organization, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or the International Classification of Diseases (ICD-11). The diagnosis of gaming disorder has been included in the International Classification of Diseases (ICD-11). Controversy around the diagnosis includes whether the disorder is a separate clinical entity, or a manifestation of underlying psychiatric disorders. Research has approached the question from a variety of viewpoints, with no universally standardised or agreed definitions, leading to difficulties in developing evidence based recommendations. As adolescents (12–19 years) and emerging adults (20–29 years) access the Internet more than any other age groups and undertake a higher risk of overuse of the Internet, the problem of Internet addiction disorder is most relevant to young people.[3] ## Contents * 1 Consequences * 1.1 Mental health consequences * 1.2 Social consequences * 2 Signs and symptoms * 2.1 Physical symptoms * 3 Related disorders * 3.1 Online gambling addiction * 3.2 Online gaming addiction (Internet gaming disorder) * 3.3 Communication addiction disorder (compulsive talking) * 3.4 Virtual reality addiction * 3.5 Video streaming addiction * 4 Risk factors * 4.1 Interpersonal difficulties * 4.2 Social support * 4.3 Psychological factors * 4.4 Other factors * 5 Diagnosis * 5.1 Difficulties * 5.2 Screening instruments * 5.3 Classification * 6 Treatment * 6.1 Psychosocial treatment * 6.2 Medication * 7 Prevalence * 8 Terminology * 9 Society * 9.1 Internet and Technology Addicts Anonymous * 9.2 NoSurf * 10 Public concern * 10.1 China * 10.2 South Korea * 10.3 Japan * 11 See also * 12 References * 13 Further reading ## Consequences[edit] ### Mental health consequences[edit] A longitudinal study of Chinese high school students (2010) suggests that individuals with moderate to severe risk of Internet addiction are 2.5 times more likely to develop depressive symptoms than their IAD-free counterparts.[4] ### Social consequences[edit] The best-documented evidence of Internet addiction so far is time-disruption, which subsequently results in interference with regular social life, including academic, professional performance and daily routines.[5] Some studies also reveal that IAD can lead to disruption of social relationships in Europe and Taiwan.[6][7] It is, however, also noted by others that IAD is beneficial for peer relations in Taiwan.[8] Dr. Keith W. Beard (2005) states that "an individual is addicted when an individual’s psychological state, which includes both mental and emotional states, as well as their scholastic, occupational and social interactions, is impaired by the overuse of [Internet]".[9] As a result of its complex nature, some scholars do not provide a definition of Internet addiction disorder and throughout time, different terms are used to describe the same phenomenon of excessive Internet use.[10] Internet addiction disorder is used interchangeably with problematic Internet use, pathological Internet use, and Internet addictive disorder. In some cases, this behavior is also referred to as Internet overuse, problematic computer use, compulsive Internet use, Internet abuse, harmful use of the Internet, and Internet dependency. ## Signs and symptoms[edit] ### Physical symptoms[edit] Physical symptoms include a weakened immune system due to lack of sleep, loss of exercise, and increased the risk for carpel tunnel syndrome and eye and back strain.[11] Symptoms of withdrawal might include agitation, depression, anger and anxiety when the person is away from technology. These psychological symptoms might even turn into physical symptoms such as rapid heartbeat, tense shoulders and shortness of breath.[11] ## Related disorders[edit] People using their smartphones. ### Online gambling addiction[edit] According to David Hodgins, a professor of psychology at the University of Calgary, online gambling is considered to be as serious as pathological gambling. It is known as an "isolated disorder" which means that those who have a gambling problem prefer to separate themselves from interruptions and distractions. Because gambling is available online, it increases the opportunity for problem gamblers to indulge in gambling without social influences swaying their decisions. This is why this disorder has become more a problem at this date in time and is why it is so difficult to overcome. The opportunity to gamble online is almost always available in this century opposed to only having the opportunity in a public forum at casinos for example. Online gambling has become quite popular especially with today's adolescents. Today's youth has a greater knowledge of modern software and search engines along with a greater need for extra money. So not only is it easier for them to find opportunities to gamble over any subject, but the incentive to be granted this money is desperately desired. ### Online gaming addiction (Internet gaming disorder)[edit] Main article: Video game addiction Video game addiction is a known issue around the world. Incidence and severity grew in the 2000s, with the advent of broadband technology, games allowing for the creation of avatars, 'second life' games, and MMORPGs (massive multiplayer online role playing games). World of Warcraft has the largest MMORPG community online and there have been a number of studies about the addictive qualities of the game. Addicts of the game range from children to mature adults. A well-known example is Ryan van Cleave, a university professor whose life declined as he became involved in online gaming.[12] Andrew Doan, MD, PhD, a physician with a research background in neuroscience, battled his own addictions with video games, investing over 20,000 hours of playing games over a period of nine years.[13] Online gaming addiction may be considered in terms of B.F. Skinner's theory of operant conditioning, which claims that the frequency of a given behavior is directly linked to rewarding and punishment of that behavior. If a behavior is rewarded, it is more likely to be repeated. If it is punished, it becomes suppressed.[14] Orzack, a clinical psychologist at McLean Hospital in Massachusetts claims that 40 percent of World of Warcraft (WoW) players are addicted. Orzack says that the best way to optimize the desired behavior in the subject is to provide rewards for correct behavior, and then adjust the number of times the subject is required to exhibit that behavior before a reward is provided. For instance, if a rat must press a bar to receive food, then it will press faster and more often if it does not know how many times it needs to press the bar. An equivalent in World of Warcraft would be purple (epic) loot drops.[15] Players in World of Warcraft will often spend weeks hunting for a special item which is based on a chance system, sometimes with only a 0.01% chance of it being dropped by a slain monster. The rarity of the item and difficulty of acquiring the item gives the player a status amongst their peers once they obtain the item. Jim Rossignol, a finance journalist who reports on Internet gaming has described how he overcame his own addiction and channeled his compulsion into a desirable direction as a reporter of Internet gaming and gaming culture.[16] ### Communication addiction disorder (compulsive talking)[edit] Main article: Communication addiction disorder Communication addiction disorder (CAD) is a supposed behavioral disorder related to the necessity of being in constant communication with other people, even when there is no practical necessity for such communication. CAD has been linked to Internet addiction.[17] Users become addicted to the social elements of the Internet, such as Facebook and YouTube. Users become addicted to one-on-one or group communication in the form of social support, relationships, and entertainment. However, interference with these activities can result in conflict and guilt. This kind of addiction is called problematic social media use. Social network addiction is a dependence of people by connection, updating, and control of their and their friend's social network page.[18] For some people, in fact, the only important thing is to have a lot of friends in the network regardless if they are offline or only virtual; this is particularly true for teenagers as a reinforcement of egos.[19][20] Sometimes teenagers use social networks to show their idealized image to the others.[21] However, other studies claim that people are using social networks to communicate their real personality and not to promote their idealized identity.[22] ### Virtual reality addiction[edit] Main article: Virtual reality addiction Virtual-reality addiction is an addiction to the use of virtual reality or virtual, immersive environments. Currently, interactive virtual media (such as social networks) are referred to as virtual reality,[23] whereas future virtual reality refers to computer-simulated, immersive environments or worlds. Experts warn about the dangers of virtual reality, and compare the use of virtual reality (both in its current and future form) to the use of drugs, bringing with these comparisons the concern that, like drugs, users could possibly become addicted to virtual reality.[citation needed] ### Video streaming addiction[edit] Main article: Television addiction Video streaming addiction is an addiction to watching video content online. This can include TV shows, movies, short video clips and other content. Each person's experience is unique but may people who have this addiction also display addictive relationship with offline video content too (such as television, DVDs, VHS tapes, etc.) Addicts often display binge behaviour. ## Risk factors[edit] ### Interpersonal difficulties[edit] It is argued that interpersonal difficulties such as introversion, social problems,[24] and poor face-to-face communication skills,[25] often lead to internet addiction. Internet-based relationships offer a safe alternative for people with aforementioned difficulties to escape from the potential rejections and anxieties of interpersonal real-life contact.[26] ### Social support[edit] Individuals who lack sufficient social connection and social support are found to run a higher risk of Internet addiction. They resort to virtual relationships and support to alleviate their loneliness.[27][28] As a matter of fact, the most prevalent applications among Internet addicts are chat rooms, interactive games, instant messaging, or social media.[26] Some empirical studies reveal that conflict between parents and children and not living with mother significantly associated with IA after one year.[29] Protective factors such as quality communication between parents and children[30] and positive youth development[31] are demonstrated, in turn, to reduce the risk of IA. ### Psychological factors[edit] Prior addictive or psychiatric history are found to influence the likelihood of being addicted to the Internet.[29][32] Some individuals with prior psychiatric problems such as depression and anxiety turn to compulsive behaviors to avoid the unpleasant emotions and situation of their psychiatric problems and regard being addicted to the Internet a safer alternative to substance addictive tendency. But it is generally unclear from existing research which is the cause and which is the effect partially due to the fact that comorbidity is common among Internet addicts. The most common co-morbidities that have been linked to IAD are major depression and attention deficit hyperactivity disorder (ADHD). The rate of ADHD and IAD associating is as high as 51.6%.[33] Internet addicts with no previous significant addictive or psychiatric history are argued to develop an addiction to some of the features of Internet use: anonymity, easy accessibility, and its interactive nature.[26] ### Other factors[edit] Parental educational level, age at first use of the Internet, and the frequency of using social networking sites and gaming sites are found to be positively associated with excessive Internet use among adolescents in some European countries, as well as in the USA.[6][34] ## Diagnosis[edit] Diagnosis of Internet addiction disorder is empirically difficult. Various screening instruments have been employed to detect Internet addiction disorder. Current diagnoses are faced with multiple obstacles. ### Difficulties[edit] Given the newness of the Internet and the inconsistent definition of Internet addiction disorder, practical diagnosis is far from clear-cut. With the first research initiated by Kimberly S. Young in 1996, the scientific study of Internet addiction has merely existed for more than 20 years.[35] A few obstacles are present in creating an applicable diagnostic method for Internet addiction disorder. * Wide and extensive use of the Internet: Diagnosing Internet addiction is often more complex than substance addiction as internet use has largely evolved into be an integral or necessary part of human lives. The addictive or problematic use of the internet is thus easily masked or justified.[26] Also, the Internet is largely a pro-social, interactive, and information-driven medium, while other established addiction behaviors such as gambling are often seen as a single, antisocial behavior that has very little socially redeeming value. Many so-called Internet addicts do not suffer from the same damage to health and relationships that are common to established addictions.[36] * High comorbidity: Internet addiction is often accompanied by other psychiatric disorders such as personality disorder and intellectual disability.[26][37][38][39][40] It is found that Internet addiction is accompanied by other DSM-IV diagnosis 86% of the time.[41] In one study conducted in South Korea, 30% of the identified Internet addicts have accompanying symptoms such as anxiety or depression and another 30% have a second disorder such as attention deficit hyperactivity disorder (ADHD).[42] Another study in South Korea found an average of 1.5 other diagnoses among adolescent internet addicts.[41] Further, it is noted in the United States that many patients only resort to medical help when experiencing difficulties they attribute to other disorders.[26][41] For many individuals, overuse or inappropriate use of the Internet is a manifestation of their depression, social anxiety disorders, impulse control disorders, or pathological gambling.[43] It generally remains unclear from existing literature whether other psychiatric disorders is the cause or manifest of Internet addiction. Despite the advocacy of categorizing Internet addiction as an established illness,[41][44] neither DSM-IV (1995) nor DSM-5 (2013) considers Internet addiction as a mental disorder.[45] A subcategory of IAD, Internet gaming disorder is listed in DSM-5 as a condition that requires more research in order to be considered as a full disorder in May 2013.[45][46][47] The WHO's draft 11th Revision of the International Classification of Diseases (ICD-11) scheduled for publication in 2018 also include gaming disorder.[48] There is still considerable controversy over whether IAD should be included in the DSM-5 and recognized as a mental disease in general.[49] ### Screening instruments[edit] DSM-based instruments Most of the criteria utilized by research are adaptations of listed mental disorders (e.g., pathological gambling) in the Diagnostic and Statistical Manual of Mental Disorders (DSM) handbook.[10] Dr. Ivan K. Goldberg, who first broached the concept of Internet addiction, adopted a few criteria for IAD on the basis of DSM-IV, including “hoping to increase time on the network” and “dreaming about the network.”[10] By adapting the DSM-IV criteria for pathological gambling, Dr. Kimberly S. Young (1998) proposed one of the first integrated sets of criteria, Diagnostic Questionnaire (YDQ), to detect Internet addiction. A person who fulfills any five of the eight adapted criteria would be regarded as Internet addicted:[50][51][52] 1. Preoccupation with the Internet; 2. A need for increased time spent online to achieve the same amount of satisfaction; 3. Repeated efforts to curtail Internet use; 4. Irritability, depression, or mood lability when Internet use is limited; 5. Staying online longer than anticipated; 6. Putting a job or relationship in jeopardy to use the Internet; 7. Lying to others about how much time is spent online; and 8. Using the Internet as a means of regulating mood. While Young's YDQ assessment for IA has the advantage of simplicity and ease of use, Keith W. Beard and Eve M. Wolf (2001) further asserted that all of the first five (in the order above) and at least one of the final three criteria (in the order above) be met to delineate Internet addiction in order for a more appropriate and objective assessment.[53] Young further extended her eight-question YDQ assessment to the now most widely used Internet Addiction Test (IAT),[50][54][55] which consists of 20 items with each on a five-point Likert scale. Questions included on the IAT expand upon Young's earlier eight-question assessment in greater detail and include questions such as "Do you become defensive or secretive when anyone asks you what you do online?" and "Do you find yourself anticipating when you go online again?". A complete list of questions can be found in Dr. Kimberly S. Young's 1998 book Caught in the Net: How to Recognize the Signs of Internet Addiction and A Winning Strategy for Recovery and Drs. Laura Widyanto and Mary McMurran's 2004 article titled The Psychometric Properties of the Internet Addiction Test. The Test score ranges from 20 to 100 and a higher value indicates a more problematic use of the Internet: * 20–39 = average Internet users, * 40–69 = potentially problematic Internet users, and * 70–100 = problematic Internet users. Over time, a considerable number of screening instruments have been developed to diagnose Internet addiction, including the Internet Addiction Test (IAT),[50] the Internet-Related Addictive Behavior Inventory (IRABI),[56] the Chinese Internet Addiction Inventory (CIAI),[57] the Korean Internet Addiction Self-Assessment Scale (KS Scale),[58] the Compulsive Internet Use Scale (CIUS),[59] the Generalized Problematic Internet Use Scale (GPIUS),[60] the Internet Consequences Scale (ICONS),[61] and the Problematic Internet Use Scale (PIUS).[62] Among others, the Internet Addiction Test (IAT) by Young (1998) exhibits good internal reliability and validity and has been used and validated worldwide as a screening instrument.[63][64][55] Although the various screening methods are developed from diverse contexts, four dimensions manifest themselves across all instruments:[41][65] * Excessive use: compulsive Internet use and excessive online time-use; * Withdrawal symptoms: withdrawal symptoms including feelings such as depression and anger, given restricted Internet use; * Tolerance: the need for better equipment, increased internet use, and more applications/software; * Negative repercussions: Internet use caused negative consequences in various aspects, including problematic performance in social, academic, or work domains. More recently, researchers Mark D. Griffiths (2000) and Dr. Jason C. Northrup and colleagues (2015) claim that Internet per se is simply the medium and that the people are in effect addicted to processes facilitated by the Internet.[65][66] Based on Young's Internet Addiction Test (IAT),[50] Northrup and associates further decompose the internet addiction measure into four addictive processes: Online video game playing, online social networking, online sexual activity, and web surfing.[65] The Internet Process Addiction Test (IPAT)[65] is created to measure the processes to which individuals are addicted. Screening methods that heavily rely on DSM criteria have been accused of lacking consensus by some studies, finding that screening results generated from prior measures rooted in DSM criteria are inconsistent with each other.[7] As a consequence of studies being conducted in divergent contexts, studies constantly modify scales for their own purposes, thereby imposing a further challenge to the standardization in assessing Internet addiction disorder.[10] Single-question instruments Some scholars and practitioners also attempt to define Internet addiction by a single question, typically the time-use of the Internet.[42][67] The extent to which Internet use can cause negative health consequences is, however, not clear from such a measure.[10] The latter of which is critical to whether IAD should be defined as a mental disorder. ### Classification[edit] As many scholars have pointed out, the Internet serves merely as a medium through which tasks of divergent nature can be accomplished.[65][66] Treating disparate addictive behaviors under the same umbrella term is highly problematic.[68] Dr. Kimberly S. Young (1999) asserts that Internet addiction is a broad term which can be decomposed into several subtypes of behavior and impulse control problems, namely,[69] * Cybersexual addiction: compulsive use of adult websites for cybersex and cyberporn (see Internet sex addiction) * Cyber-relationship addiction: Over-involvement in online relationships * Net compulsions: Obsessive online gambling, shopping or day-trading * Information overload: Compulsive web surfing or database searches * Computer addiction: Obsessive computer game playing (see Video game addiction) For a more detailed description of related disorders please refer to the related disorders section above. ## Treatment[edit] Current interventions and strategies used as treatments for Internet addiction stem from those practiced in substance abuse disorder. In the absence of "methodologically adequate research", treatment programs are not well corroborated.[70] Psychosocial treatment is the approach most often applied.[49] In practice, rehab centers usually devise a combination of multiple therapies.[57] ### Psychosocial treatment[edit] Cognitive behavioral therapy The cognitive behavioral therapy with Internet addicts (CBT-IA) is developed in analogy to therapies for impulse control disorder.[26][71] Several key aspects are embedded in this therapy:[72][73] * Learning time management strategies; * Recognizing the benefits and potential harms of the Internet; * Increasing self-awareness and awareness of others and one's surroundings; * Identifying "triggers" of Internet "binge behavior", such as particular Internet applications, emotional states, maladaptive cognitions, and life events; * Learning to manage emotions and control impulses related to accessing the Internet, such as muscles or breathing relaxation training; * Improving interpersonal communication and interaction skills; * Improving coping styles; * Cultivating interests in alternative activities. Three phases are implemented in the CBT-IA therapy:[26][71] 1. Behavior modification to control Internet use: Examine both computer behavior and non-computer behavior and manage Internet addicts' time online and offline; 2. Cognitive restructuring to challenge and modify cognitive distortions: Identify, challenge, and modify the rationalizations that justify excessive Internet use; 3. Harm reduction therapy to address co-morbid issues: Address any co-morbid factors associated with Internet addiction, sustain recovery, and prevent relapse. Symptom management of CBT-IA treatment has been found to sustain six months post-treatment.[26] Motivational interviewing The motivational interviewing approach is developed based on therapies for alcohol abusers.[26][73] This therapy is a directive, patient-centered counseling style for eliciting behavior change through helping patients explore and resolve ambivalence with a respectful therapeutic manner. It does not, however, provide patients with solutions or problem solving until patients' decision to change behaviors.[72] Several key elements are embedded in this therapy:[26] * Asking open-ended questions; * Giving affirmations; * Reflective listening Other psychosocial treatment therapies include reality therapy, Naikan cognitive psychotherapy, group therapy, family therapy, and multimodal psychotherapy.[72] ### Medication[edit] IAD may be associated with a co-morbidity, so treating a related disorder may also help in the treatment of IAD. When addicts were treated with certain anti-depressants it reduced time online by 65% and also reduced cravings of being online. The anti-depressants that have been most successful are selective serotonin reuptake inhibitors such as escitalopram and a heterocyclic atypical anti-depressant called bupropion. A psychostimulant, methylphenidate has also shown beneficial effects.[33] ## Prevalence[edit] Research-based prevalence rate of Internet addiction Country or region Rate or population Sample Year Instrument Global 6%[54] A meta-analysis-based estimate 1994–2012 YDQ & IAT Asia Asia 20%[74] Pakistan 9%[75] 231 Medical students 2020 IAT China 10.4%[76] 10,158 adolescents 2016 IAT Hong Kong 17–26.7%[77] Over 3000 high school students 2009–2015 IAT Taiwan 13.8%[78] 1708 high school students n.a. YDQ South Korea 2.1%[41] An estimate based on Korean population aged 6–19 years 2006 Japan 2.0%[79] 853 adolescents aged 12–15 years 2014 IAT Europe Europe 4.4%[80] 11,956 adolescents in 11 European countries 2009–2010 YDQ Germany 1.5 million[81] An estimate based on German population n.a. Spain 16.3%[82] 40,955 school adolescents aged 12–17 years 2016 PIUS-a Norway 0.7%[83] 3399 individuals aged 16–74 years 2007 YDQ UK 18.3%[84] 371 college students n.a. PIUS North America USA 0.3–0.7%[85] 2513 adults 2004 Non-standard Different samples, methodologies, and screening instruments are employed across studies. ## Terminology[edit] The notion of "Internet addictive disorder" was initially conjured up by Ivan K. Goldberg in 1995 as a joke to parody the complexity and rigidity of the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM). In his first narration, Internet addictive disorder was described as having the symptoms of "important social or occupational activities that are given up or reduced because of Internet use", "fantasies or dreams about the Internet," and "voluntary or involuntary typing movements of the fingers."[86] The definition of Internet addiction disorder has troubled researchers ever since its inception. In general, no standardized definition has been provided despite that the phenomenon has received extensive public and scholar recognition.[5][10] Below are some of the commonly used definitions. In 1998, Jonathan J. Kandell defined Internet addiction as "a psychological dependence on the Internet, regardless of the type of activity once logged on."[87] English psychologist Mark D. Griffiths (1998) conceived Internet addiction as a subtype of broader technology addiction, and also a subtype of behavioral addictions.[88] ## Society[edit] ### Internet and Technology Addicts Anonymous[edit] Internet and Technology Addicts Anonymous (ITAA), founded in 2009, is a 12-step program supporting users coping with the problems resulting from compulsive internet and technology use.[89] Some common sub-addictions include smartphone addiction, binge watching addiction, and social media addiction. There are face to face meetings in some cities. Telephone / online meetings take place every day of the week, at various times (and in various languages) that allow people worldwide to attend. Similar to 12-step fellowships such as Overeaters Anonymous, Workaholics Anonymous, or Sex and Love Addicts Anonymous, most members do not define sobriety as avoiding all technology use altogether. Instead, most ITAA members come up with their own definitions of abstinence or problem behaviors, such as not using the computer or internet at certain hours or locations or not going to certain websites or categories of websites that have proven problematic in the past. Meetings provide a source of live support for people, to share struggles and victories, and to learn to better function in life once less of it is spent on problematic technology use. ### NoSurf[edit] The NoSurf Reddit community [90] maintains a list of resources and strategies helpful for people trying to decrease their internet usage. This includes lists of software programs that people use to control which sites they visit and when, as well as a discussion group that takes place on Discord. ## Public concern[edit] Internet addiction has raised great public concern in Asia and some countries consider Internet addiction as one of the major issues that threatens public health, in particular among adolescents.[41][72] ### China[edit] Internet addiction is commonly referred to as "electronic opium"[91] or "electronic heroin" in China.[92] The government of the People's Republic of China is the first country to formally classify Internet addiction a clinical disorder by recognizing Clinical Diagnostic Criteria for Internet Addiction in 2008.[93][94] The government has enacted several policies to regulate adolescents' Internet use, including limiting daily gaming time to 3 hours and requiring users' identification in online video games.[95] Mistreatment in China In the absence of guidance from China's Health Ministry and a clear definition of Internet addiction, dubious treatment clinics have sprouted up in the country.[42] As part of the treatment, some clinics and camps impose corporal punishment upon patients of Internet addiction and some conducted electroconvulsive therapy (ECT) against patients, the latter of which has caused wide public concern and controversy.[42][96] A few salient mistreatment practices have been well-documented by news reports: One of the most commonly resorted treatments for Internet-addicted adolescents in China is inpatient care, either in a legal or illegal camp. It is reported that children were sent to "correction" against their will. Some are seized and tied by staff of the camp, some are drugged by their parents, and some are tricked into treatment.[94][97][98][99] In many camps and clinics, corporal punishment is frequently used to "correct" Internet addiction disorder. The types of corporal punishment practiced include, but not limited to, kilometers-long hikes, intense squats, standing, starving, and confinement.[42][100][101][102] After a physical-abuse-caused death case of an adolescent Internet-addict was reported in 2009, the Chinese government has officially inhibited physical violence to "wean" teens from the Internet.[103] But multiple abuse and death cases of Internet addicts have been reported after the ban. Among Internet addiction rehab centers that use corporal punishment in treatment, Yuzhang Academy in Nanchang, Jiangxi Province, is the most heavily discussed. In 2017, the Academy was accused of using severe corporal punishment against students, the majority of which are Internet addicts. Former students claimed that the Academy hit problematic students with iron rulers, "whip them with finger-thick steel cables", and lock students in small cells week long.[104] Several suicidal cases emerged under the great pressure.[105] In November 2017, the Academy stopped operating after extensive media exposure and police intervention.[106] Electroconvulsive therapy In China, electroconvulsive therapy (ECT) is legally used for schizophrenia and mood disorders. Its off-label practices in treating adolescent Internet addicts has raised great public concern and stigmatized the legal use of ECT.[107] The most reported and controversial clinic treating Internet addiction disorder is perhaps the Linyi Psychiatric Hospital in Shandong Province.[42] Its center for Internet addiction treatment was established in 2006 by Yang Yongxin.[108] Various interviews of Yongxin Yang confirm that Yang has created a special therapy, xingnao ("brain-waking") therapy, to treat Internet addiction. As part of the therapy, electroconvulsive therapy is implemented with currents of 1–5 milliampere.[109] As Yang put it, the electroconvulsive therapy only involves sending a small current through the brain and will not harm the recipient.[110] As a psychiatric hospital, patients are deprived of personal liberty and are subject to electroconvulsive treatment at the will of hospital staffs.[96] And before admission, parents have to sign contracts in which they deliver their guardianship of kids partially to the hospital and acknowledge that their kids will receive ECT.[96] Frequently, ECT is employed as a punishment method upon patients who breaks any of the center's rules, including "eating chocolate, locking the bathroom door, taking pills before a meal and sitting on Yang's chair without permission".[96] It is reported in a CCTV-12 segment that a DX-IIA electroconvulsive therapy machine is utilized to correct Internet addiction. The machine was, later on, revealed to be illegal, inapplicable to minor[111][112] and can cause great pain and muscle spasm to recipients.[42] Many former patients in the hospital later on stood out and reported that the ECT they received in the hospital was extremely painful, tore up their head,[98] and even caused incontinence.[108][113] An Interview of the Internet addiction treatment center in Linyi Psychiatric Hospital is accessible via the following link. Since neither the safety nor the effectiveness of the method was clear, the Chinese Ministry of Health banned electroconvulsive therapy in treating Internet addiction disorder in 2009.[110][114] Drug In Yang's clinic, patients are forced to take psychiatric medication[97] in addition to Jiewangyin, a type of medication invented by himself. Neither the effectiveness nor applicability of the medication has been assessed, however. Physical abuse and death At clinics and rehab centers, at least 12 cases of physical abuse have been revealed by media in the recent years including seven deaths.[115][116] In 2009, a 15-year-old, Senshan Deng, was found dead eight hours after being sent to an Internet-addiction center in Nanning, Guangxi Province. It is reported that the teenager was beaten by his trainers during his stay in the center.[94] In 2009, another 14-year-old teenager, Liang Pu, was taken to hospital with water in the lungs and kidney failure after a similar attack in Sichuan Province.[103] In 2014, a 19-year-old, Lingling Guo, died in an Internet-addiction center with multiple injuries on head and neck in Zhengzhou, Henan Province.[94] In 2016, after escaping from an Internet addiction rehab center, a 16-year-old girl tied and starved her mother to death in revenge of the being sent to treatment in Heilongjiang Province.[94] In August 2017, an 18-year-old boy, Li Ao, was found dead with 20 external scars and bruises two days after his parents sent him to a military-style boot camp in Fuyang city, Anhui Province.[117] ### South Korea[edit] Being almost universally connected to the Internet and boasting online gaming as a professional sport, South Korea deems Internet addiction one of the most serious social issues[118] and describes it as a "national crisis".[119] Nearly 80% of the South Korean population have smartphones. According to government data, about two million of the country's population (less than 50 million) have Internet addiction problem, and approximately 68,000 10–19-year-old teenagers are addicted to the Internet, accounting for roughly 10% of the teenage population.[120] Even the very young generation are faced with the same problem: Approximately 40% of South Korean children between age three to five are using smartphones over three times per week. According to experts, if children are constantly stimulated by smartphones during infancy period, their brain will struggle to balance growth and the risk of Internet addiction.[121] It is believed that due to Internet addiction, many tragic events have happened in South Korea: A mother, tired of playing online games, killed her three-year-old son. A couple, obsessed with online child-raising games, left their young daughter die of malnutrition. A 15-year-old teenager killed his mother for not letting himself play online games and then committed suicide.[122] One Internet gaming addict stabbed his sister after playing violent games. Another addict killed one and injured seven others.[119] In response, the South Korea government has launched the first Internet prevention center in the world, the Jump Up Internet Rescue School, where the most severely addicted teens are treated with full governmental financial aid.[119] As of 2007, the government has built a network of 140 Internet-addiction counseling centers besides treatment programs at around 100 hospitals.[123] Typically, counselor- and instructor-led music therapy and equine therapy and other real-life group activities including military-style obstacle courses and therapeutic workshops on pottery and drumming are used to divert IAs' attention and interest from screens.[119][123] In 2011, the Korean government introduced the "Shutdown law", also known as the "Cinderella Act", to prevent children under 16 years old from playing online games from midnight (12:00) to 6 a.m.[120] ### Japan[edit] In Japan, internet addiction disorder has manifested into the citizens primarily affecting the youth and adolescent population. In the male youth the internet addiction shows a trend in increased time in gaming on their devices while the female youth shows trends in social media use. The smartphone and internet addiction in Japan has become detrimental to the society by affecting social interactions between people and their communication. They become used to interacting over the internet and their phones that it deteriorates some of their social skills over time.[124] Many cases of social withdrawal have been occurring in Japan since the late 1990's which inclines people to stay indoors most of the time. The term used for this is hikkomori, and it primarily affects the youth of Japan in that they are less inclined to leave their residences. Internet addiction can contribute to this effect because of how it diminishes social interactions and gives young people another reason to stay at home for longer. Many of the hikkomori people in Japan are reported to have friends in their online games, so they will experience a different kind of social interaction which happens in a virtual space.[125] ## See also[edit] Look up Internet addiction disorder in Wiktionary, the free dictionary. * Digital media use and mental health * Social media addiction * Addictive personality * Cyberslacking * Digital addict * Digital detox * Gaming disorder * List of repetitive strain injury software (i.e. break reminders) * Media multitasking * Pornography addiction * Procrastination * Psychological effects of Internet use * Social media addiction * Soft addiction * Underearners Anonymous * Workaholic ## References[edit] 1. ^ Tomczyk, Lukasz, Solecki, Roman. Problematic internet use and protective factors related to family and free time activities among young people. Kuram ve Uygulamada Egitim Bilimleri/Educational Sciences: Theory & Practice. 2019;19(3):1-13. 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"Hikikomori : Multidimensional understanding, assessment, and future international perspectives". Psychiatry and Clinical Neurosciences. 73 (8): 427–440. doi:10.1111/pcn.12895. ISSN 1440-1819. PMID 31148350. S2CID 171093449. ## Further reading[edit] * Kuss, D.; Lopez-Fernandez, O. (2016). "Internet-use related addiction: The state of the art of clinical research". European Psychiatry. 33: S366. doi:10.1016/j.eurpsy.2016.01.1038. * Starcevic, V.; Aboujaoude, E. (2017). "Internet addiction: Reappraisal of an increasingly inadequate concept". CNS Spectrums. 22 (1): 7–13. doi:10.1017/s1092852915000863. PMID 26831456. S2CID 30281599. * Montag, C.; Reuter, M. (2017). Internet addiction: Neuroscientific approaches and therapeutical implications including smartphone addiction. Springer. * Young, Kimberly S. "Internet Addiction: Symptoms, Evaluation, And Treatment" (PDF). Archived from the original (PDF) on 2015-04-21. * Dowling, Nicki A.; Quirk, Kelly L. (2009). "Screening for Internet Dependence: Do the Proposed Diagnostic Criteria Differentiate Normal from Dependent Internet Use?". CyberPsychology & Behavior. 12 (1): 21–27. doi:10.1089/cpb.2008.0162. hdl:10536/DRO/DU:30059269. PMID 19196045. * Dreier, M.; et al. (2012). "The development of adaptive and maladaptive patterns of Internet use among European adolescents at risk for internet addictive behaviours: A Grounded theory inquiry" (PDF). Eu Net Adb. * Anderson, E. L.; Steen, E.; Stavropoulos, V. (2017). "Internet use and Problematic Internet Use: A systematic review of longitudinal research trends in adolescence and emergent adulthood". International Journal of Adolescence and Youth. 22 (4): 430–454. doi:10.1080/02673843.2016.1227716. S2CID 152003110. * Beard, K. W. (2005). "Internet addiction: a review of current assessment techniques and potential assessment questions". CyberPsychology & Behavior. 8 (1): 7–14. doi:10.1007/s10648-005-8138-1. PMID 15738688. S2CID 7014879. * Douglas, A. C.; Mills, J. E.; Niang, M.; Stepchenkova, S.; Byun, S.; Ruffini, C.; Lee, S. K.; Loutfi, J.; Lee, J.; Atallah, M.; Blanton, M. (2008). "Internet addiction: Meta-synthesis of qualitative research for the decade 1996–2006". Computers in Human Behavior. 24 (6): 3027–3044. doi:10.1016/j.chb.2008.05.009. * Bax, T. (2013). Youth and internet addiction in China. Routledge. * Chou, C.; Condron, L.; Belland, J. C. (2005). "A review of the research on Internet addiction". Educational Psychology Review. 17 (4): 363–388. doi:10.1007/s10648-005-8138-1. S2CID 7014879. * Dreier, M.; Wölfling, K.; Müller, K.W. (2013). "Psychological Research and a Sociological Perspective on Problematic and Addictive Computer Game Use in Adolescents". Internet Addiction. A Public Health Concern in Adolescence. New York: Nova Science Publishers. pp. 87–110. * Dreier, M.; Wölfling, K.; Beutel, M.E. (2014). "Internetsucht bei Jugendlichen". Monatsschrift Kinderheilkunde. 162 (6): 496–502. doi:10.1007/s00112-013-3069-2. S2CID 30321570. * Grassani, E. (2014). L'assuefazione tecnologica. Metamorfosi del sistema uomo-macchina. Editoriale Delfino. Milan, Italy. * Grohol, J. M. (1999). "Internet Addiction Guide". Psych Central. * Hansen, S. (2002). "Excessive Internet usage or 'Internet Addiction'? The implications of diagnostic categories for student users". Journal of Computer Assisted Learning. 18 (2): 235–236. doi:10.1046/j.1365-2729.2002.t01-2-00230.x. * Padilla-Walker, Laura M.; Nelson, Larry J.; Carroll, Jason S.; Jensen, Alexander C. (2009). "More Than a Just a Game: Video Game and Internet Use During Emerging Adulthood". Journal of Youth and Adolescence. 39 (2): 103–13. doi:10.1007/s10964-008-9390-8. PMID 20084557. S2CID 207206263. * Potera C (Mar–Apr 1998). "Trapped in the Web?". Psychology Today. 31 (2): 66–70. * Surratt, Carla G (1999). Netaholics?: The creation of a pathology. Commack, NY: Nova Science Publishers. * Turel, Ofir; Serenko, Alexander; Bontis, Nick (2011). "Family and work-related consequences of addiction to organizational pervasive technologies" (PDF). Information & Management. 48 (2–3): 88–95. doi:10.1016/j.im.2011.01.004. INIST:24090862. * Tel Aviv University (August 18, 2007). "What exactly is internet addiction, and what is the treatment?". Science Daily. * Zur, O.; Zur, A. (2009). "On Digital Immigrants & Digital Natives". Zur Institute. * 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 Digital media use and mental health Proposed or recognised diagnostic categories * Gaming disorder (Video game addiction) * Problematic social media use * Internet addiction disorder * Problematic smartphone use * Nomophobia * Computer addiction * Television addiction * Internet sex addiction Disciplines involved * Digital sociology * Digital anthropology * Psychiatry * Psychology * Neuroscience Associated psychiatric conditions * Depression * Anxiety * Attention deficit hyperactivity disorder * Bipolar disorder Related concepts * Electronic media and sleep * Screen time * Digital detox * Smartphone zombie * Cyberbullying * Media multitasking * Online problem gambling * Technostress * Computer rage Authority control * GND: 7842524-4 * LCCN: sh97009080 * NDL: 01178140 * Internet portal * Psychology portal [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Internet addiction disorder	None	1,961	wikipedia	https://en.wikipedia.org/wiki/Internet_addiction_disorder	2021-01-18T18:35:19	{"wikidata": ["Q831735"]}
A number sign (#) is used with this entry because of evidence that chitotriosidase deficiency (CHITD) is caused by homozygous or compound heterozygous mutation in the CHIT1 gene (600031) on chromosome 1q32. Clinical Features Hollak et al. (1994) observed absent plasma chitotriosidase activity in 3 control subjects and 2 patients with Gaucher disease (see 230800). One of the parents of a Gaucher disease patient with almost complete absence of chitotriosidase activity also lacked enzyme activity, suggesting a familial nature of the deficiency. Boot et al. (1998) noted that a recessively inherited deficiency in chitotriosidase activity is frequently encountered, occurring in about 6% of Caucasians. In the Netherlands, about 1 in 20 individuals is completely deficient in enzymatically active chitotriosidase in all materials tested, including plasma, urine, cultured macrophages, leukocytes, and tissues (Guo et al., 1995). Molecular Genetics In individuals with chitotriosidase deficiency, Boot et al. (1998) identified a homozygous 24-bp duplication in the CHIT1 gene (600031.0001). The observed carrier frequency of about 35% indicated that the duplication is the predominant cause of chitotriosidase deficiency. The presence of the duplication in individuals from various ethnic backgrounds suggested that this mutation is relatively old. Grace et al. (2007) noted that the identification of CHIT1 gene mutations that alter plasma activity is important for the use of this biomarker to monitor disease activity and therapeutic response in Gaucher disease. They genotyped the CHIT1 gene in 320 unrelated patients with Gaucher disease, including 272 of Ashkenazi Jewish descent. Among all patients, 4% and 37.2% were homozygous and heterozygous, respectively, for the 24-bp duplication. In addition, Grace et al. (2007) identified 3 novel mutations in the CHIT1 gene (600031.0002-600031.0004) in individuals with Gaucher disease and chitotriosidase deficiency. INHERITANCE \- Autosomal recessive LABORATORY ABNORMALITIES \- No detectable chitotriosidase activity MISCELLANEOUS \- 'Nondisease' MOLECULAR BASIS \- Caused by mutation in the chitotriosidase gene (CHIT, 600031.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	CHITOTRIOSIDASE DEFICIENCY	c3279902	1,962	omim	https://www.omim.org/entry/614122	2019-09-22T15:56:27	{"omim": ["614122"]}
A rare, genetic, vitreoretinal degeneration characterized by a slowly progressive vitreoretinopathy with onset during the second or third decade of life. The disease initially presents as autoimmune uveitis with reduction in the b-wave on electroretinography, and progresses with development of photoreceptor degeneration, vitreous hemorrhage, cystoid macular edema, retinal neovascularization, intraocular fibrosis, secondary glaucoma, and retinal detachment leading to phthisis and complete blindness. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Autosomal dominant neovascular inflammatory vitreoretinopathy	c0242852	1,963	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=329211	2021-01-23T18:21:23	{"mesh": ["D018630"], "omim": ["193235"], "icd-10": ["H35.2"], "synonyms": ["ADNIV"]}
Eye disease involving splitting of the retina Retinoschisis This condition is usually inherited in an X-linked recessive manner. SpecialtyOphthalmology Retinoschisis is an eye disease characterized by the abnormal splitting of the retina's neurosensory layers, usually in the outer plexiform layer. Retinoschisis can be divided into degenerative forms which are very common and almost exclusively involve the peripheral retina and hereditary forms which are rare and involve the central retina as sometimes the peripheral retina. The degenerative forms are asymptomatic and involve the peripheral retina only and do not affect the visual acuity., Some rarer forms result in a loss of vision in the corresponding visual field.[1] Almost all cases are X-linked recessive and caused by a mutation in the retinoschisin gene (RS1).[2] ## Contents * 1 Classification * 1.1 Degenerative retinoschisis * 1.2 Hereditary retinoschisis * 1.3 Tractional retinoschisis * 1.4 Exudative retinoschisis * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Classification[edit] * Hereditary * X linked juvenile retinoschisis * Familial foveal retinoschisis * Tractional * Exudative * Secondary to Optic disc pit * Degenerative * Typical * Reticular ### Degenerative retinoschisis[edit] This type of retinoschisis is very common with a prevalence of up to 7 percent in normal persons. Its cause is unknown. It can easily be confused with retinal detachment by the non-expert observer and in difficult cases even the expert may have difficulty differentiating the two. Such differentiation is important since retinal detachment almost always requires treatment while retinoschisis never itself requires treatment and leads to retinal detachment (and hence to visual loss) only occasionally. Unfortunately one still sees cases of uncomplicated retinoschisis treated by laser retinopexy or cryopexy in an attempt to stop its progression towards the macula. Such treatments are not only ineffective but unnecessarily risk complications. There is no documented case in the literature of degenerative retinoschisis itself (as opposed to the occasional situation of retinal detachment complicating retinoschisis) in which the splitting of the retina has progressed through the fovea. There is no clinical utility in differentiating between typical and reticular retinoschisis. Degenerative retinoschisis is not known to be a genetically inherited condition. There is always vision loss in the region of the schisis as the sensory retina is separated from the ganglion layer. But as the loss is in the periphery, it goes unnoticed. It is the very rare schisis that encroaches on the macula where retinopexy is then properly used.[3] ### Hereditary retinoschisis[edit] Hereditary retinoschisis is derived from a defective retinoschisin protein, which is due to an X-linked genetic defect. The genetic form of this disease usually starts during childhood and is called X-linked Juvenile Retinoschisis (XLRS) or Congenital Retinoschisis. Affected males are usually identified in grade school, but occasionally are identified as young infants. It is estimated that this much less common form of retinoschisis affects one in 5,000 to 25,000 individuals, primarily young males. Schisis is derived from the Greek word meaning splitting, describing the splitting of the retinal layers from each other. However, schisis is a word fragment, and the term retinoschisis should be used, as should the term iridoschisis when describing splitting of the iris. If the retinoschisis involves the macula, then the high-resolution central area of vision used to view detail is lost, and this is one form of macular disease. Although it might be described by some as a "degeneration", the term macular degeneration should be reserved for the specific disease "age-related macular degeneration". Very few affected individuals go completely blind from retinoschisis, but some sufferers have very limited reading vision and are "legally blind". Visual acuity can be reduced to less than 20/200 in both eyes. Individuals affected by XLRS are at an increased risk for retinal detachment and eye hemorrhage, among other potential complications. Retinoschisis causes acuity loss in the center of the visual field through the formation of tiny cysts in the retina, often forming a "spoke-wheel" pattern that can be very subtle. The cysts are usually only detectable by a trained clinician. In some cases vision cannot be improved by glasses, as the nerve tissue itself is damaged by these cysts. The National Eye Institute (NEI) of the National Institutes of Health (NIH) is conducting clinical and genetic studies of X-Linked Juvenile Retinoschisis.[4] This study began in 2003 and as of 2018 is continuing to recruit patients. A better understanding of why and how XLRS develops might lead to improved treatments. Males diagnosed with X-linked juvenile retinoschisis and females who are suspected carriers may be eligible to participate. In addition to giving a medical history and submitting medical records, participants submit a blood sample and the NEI will perform a genetic analysis. There is no cost to participate in this study. ### Tractional retinoschisis[edit] This may be present in conditions causing traction on the retina especially at the macula.[5] This may occur in: a) The vitreomacular traction syndrome; b) Proliferative diabetic retinopathy with vitreoretinal traction; c) Atypical cases of impending macular hole. ### Exudative retinoschisis[edit] Retinoschisis involving the central part of the retina secondary to an optic disc pit was erroneously considered to be a serous retinal detachment until correctly described by Lincoff as retinoschisis. Significant visual loss may occur and following a period of observation for spontaneous resolution, treatment with temporal peripapillary laser photocoagulation followed by vitrectomy and gas injection followed by face-down positioning is very effective in treating this condition.[6] ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (September 2017) ## References[edit] 1. ^ Cassin, B. and Solomon, S. Dictionary of Eye Terminology. Gainesville, Florida: Triad Publishing Company, 1990. 2. ^ "OMIM Entry - # 312700 - RETINOSCHISIS 1, X-LINKED, JUVENILE; RS1". www.omim.org. Retrieved 2020-01-23. 3. ^ "Degenerative retinoschisis". Institut De La Vision. Retrieved 27 April 2015. 4. ^ "Clinical and Genetic Studies of X-Linked Juvenile Retinoschisis". ClinicalTrials.gov. Retrieved 2012-12-15. 5. ^ Faulborn, J; Ardjomand, N (January 2000). "Tractional retinoschisis in proliferative diabetic retinopathy: a histopathological study". Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht von Graefes Archiv für Klinische und Experimentelle Ophthalmologie. 238 (1): 40–44. doi:10.1007/s004170050007. PMID 10664051. 6. ^ Pollack, AL; McDonald, HR; Johnson, RN; Ai, E; Irvine, AR; Lahey, JM; Lewis, H; Rodriguez, A; Ryan EH, Jr; Shields, CL (December 2002). "Peripheral retinoschisis and exudative retinal detachment in pars planitis". Retina (Philadelphia, Pa.). 22 (6): 719–24. doi:10.1097/00006982-200212000-00006. PMID 12476097. ## External links[edit] Classification D * ICD-10: H33.1 * ICD-9-CM: 361.1 * OMIM: 312700 * MeSH: D041441 * DiseasesDB: 32603 External resources * eMedicine: article/1225857 * Orphanet: 792 * GeneReview/NCBI/NIH/UW entry on X-Linked Juvenile Retinoschisis * X-linked juvenile retinoschisis on Genetics Home Reference * NCBI Genetic Testing Registry * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Retinoschisis	c0152439	1,964	wikipedia	https://en.wikipedia.org/wiki/Retinoschisis	2021-01-18T18:38:55	{"mesh": ["D041441"], "umls": ["C0152439"], "wikidata": ["Q1049881"]}
Lipoid congenital adrenal hyperplasia Other namesCongenital lipoid adrenal hyperplasia due to StAR deficency[1] Lipoid congenital adrenal hyperplasia is inherited in an autosomal recessive manner Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). It arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones. Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. The adrenals are large and filled with lipid globules derived from cholesterol. ## Contents * 1 Presentation * 1.1 Mineralocorticoid deficiency * 1.2 Glucocorticoid deficiency * 1.3 Sex steroid deficiency and gonadal damage * 1.3.1 In development * 1.3.2 Female patients * 1.3.3 Male patients * 1.4 Late onset forms of the disease * 2 Genetics * 3 Pathophysiology * 4 Diagnosis * 5 Management * 5.1 Female patients * 5.2 Male patients * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Presentation[edit] Problems that emerge in persons with lipoid CAH can be divided into:[citation needed] 1. mineralocorticoid deficiency, 2. glucocorticoid deficiency, 3. sex steroid deficiency, and 4. damage to gonads caused by lipid accumulation. ### Mineralocorticoid deficiency[edit] Most infants born with lipoid CAH have had genitalia female enough that no disease was suspected at birth. Because the adrenal zona glomerulosa is undifferentiated and inactive before delivery, it is undamaged at birth and can make aldosterone for a while, so the eventual salt-wasting crisis develops more gradually and variably than with severe 21-hydroxylase-deficient CAH.[citation needed] Most come to medical attention between 2 weeks and 3 months of age, when after a period of poor weight gain and vomiting, they were found to be dehydrated, with severe hyponatremia, hyperkalemia, and metabolic acidosis ("Addisonian or adrenal crisis"). Renin but not aldosterone is elevated. Many infants born with this condition died before a method for diagnosis was recognized for proper treatment to begin. In some cases, the condition is more mild with signs and symptoms of mineralocorticoid and glucocorticoid deficiency appearing after months or even years (late onset).[citation needed] ### Glucocorticoid deficiency[edit] Insufficiency of cortisol synthesis has several consequences. Elevated ACTH is accompanied by and contributes to marked hyperpigmentation even in the newborn period. An inadequate cortisol response to stress undoubtedly hastens the deterioration as dehydration develops, can cause hypoglycemia, and contributes to the high mortality rate in infancy.[citation needed] ### Sex steroid deficiency and gonadal damage[edit] #### In development[edit] Prenatal production of DHEA by the fetal adrenal glands is impaired, resulting in abnormally low maternal estriol levels by the middle of pregnancy. The effects of impaired progesterone production from placental cells that originate from the affected baby (trophoblasts) in the case of lipoid CAH due to P450scc deficiency are still unclear, but are thought to result in miscarriage when the deficit in the enzyme's activity are severe enough.[citation needed]The results of reduced or absent testosterone output by fetal Leydig cells in the male is detailed below. #### Female patients[edit] Genetic XX females with lipoid CAH are born with normal external and internal pelvic anatomy. They come to medical attention when they develop a salt-wasting adrenal crisis or other signs of progressive adrenal insufficiency.[citation needed] With glucocorticoid and mineralocorticoid replacement, these girls will reach the age of puberty. Because the ovaries are relatively inactive in fetal life and childhood, they sustain little damage from lipid accumulation during childhood. In the case of lipoid CAH due to StAR deficiency, when rising gonadotropin levels initiate puberty, despite the inefficiency of sex steroid synthesis, the ovaries will usually make enough estradiol to produce breast development, and in some cases even menarche, with menses continuing for some years. Ovarian and adrenal androgen production is minimal and produces little pubic or other body hair.[citation needed] However insufficient estradiol and progesterone are produced to induce maturation of an egg and ovulation. Although prepubertal ovaries are inactive enough that no lipid accumulates to cause damage, once they have begun to produce estrogen, lipid damage begins to accrue and the ability to produce estrogen, as well as ovulate, is slowly degraded. Cysts also form in the ovaries. Women with lipoid CAH have been infertile presumably due to anovulation.[citation needed] #### Male patients[edit] The genitalia of XY fetuses with lipoid CAH are severely undervirilized due to impairment of steroid hormone synthesis. The fetal testes make AMH, which prevents a uterus and inner vagina from forming, but since the Leydig cells fail to make testosterone during development even in response to hCG, the testes are usually remain in the abdomen or lodge in the inguinal canals (undescended testes) and are nonfunctional. Consequently, XY patients do not undergo puberty and remain infertile.[citation needed] In addition to the testes remaining inside, formation of the penis, also dependent on testosterone, is compromised. Hence, the external genitalia in most of infants resemble that of normal females (though the vagina is a short, blind pouch), or is slightly ambiguous (more female than male). Nearly all reported XY cases have been assumed to be girls and raised as such.[citation needed] ### Late onset forms of the disease[edit] Milder cases of lipoid CAH have been described that arise from less severe mutations that compromise but do not eliminate the ability of StAR to instigate steroid production.[2] In these cases, mineralocorticoid deficiency emerges up to several years after birth. Sex steroid production may be sufficient to allow for normal sexual development as well and even fertility. These nonclassic forms of the disorder are sometimes diagnosed as familial glucocorticoid deficiency type 3.[3] ## Genetics[edit] This inherited disease is autosomal recessive. Understanding of the molecular basis for it has been advanced in the last decade by better understanding of adrenal steroidogenesis as well as genetic studies of affected patients.[4] It used to be assumed that lipoid CAH resulted from a defect of the enzyme that converted cholesterol to pregnenolone. The conversion reactions are mediated by a single enzyme, formerly referred to as 20,22-desmolase, but now identified as cytochrome P450scc (cholesterol side chain cleavage enzyme). However, few cases of lipoid CAH due to a mutation and defect of P450scc have been identified. Although the disorder is considered autosomal recessive, a single mutation in P450scc can be sufficient to cause the condition.[5] All other cases of lipoid adrenal hyperplasia that have been studied have been found to be due to mutations of the gene for the primary protein that transports cholesterol into the mitochondria, StAR, encoded by a gene on chromosome 8p11.2 in the human. Congenital adrenal hyperplasias are a family of autosomal recessive diseases resulting from defects in steps of the synthesis of steroid hormones from cholesterol. All forms of CAH involve excessive or defective production of sex steroids and can prevent or impair development of primary or secondary sex characteristics in affected infants, children, and adults. Many also involve excessive or defective production of mineralocorticoids, which can cause hypertension or salt-wasting.[citation needed] Lipoid CAH is one of the rarer forms of CAH and results from defects in the steps from cholesterol to pregnenolone.[4] This results in the catastrophic loss of most or all steroid hormones in the body. It is caused by mutations in either of two proteins: cytochrome P450scc and steroidogenic acute regulatory protein (StAR).[citation needed] ## Pathophysiology[edit] The deficiency results in impaired synthesis of all three categories of adrenal steroids (cortisol, mineralocorticoids, sex steroids) and high levels of adrenocorticotropic hormone (ACTH). A low level of steroid synthesis proceeds even without efficient transport, but is rarely enough to prevent the consequences of deficiency. While severe loss of steroid production results in manifestation of the disease within a few weeks of birth, milder forms (late onset) can present years after birth. Unlike in models of the disease in mice, patients with lipoid CAH do not always have enlarged adrenals due to lipid accumulation. This may in part be due to hormone replacement used to keep them alive preventing hyperstimulation of the gland by the pituitary.[citation needed] ACTH stimulates growth of the adrenal cells and increases LDL receptors to amplify transport of cholesterol into the cells of the adrenal cortex which make adrenal steroids, where it accumulates since little can enter the mitochondria for conversion to steroid. Normally, adrenal steroids then signal their presence to the brain to moderate ACTH levels (feedback inhibition). However, in the absence of this, ACTH levels are elevated and cholesterol uptake by the cortical cells continues unabated. The adrenals become markedly enlarged (hyperplastic) by the accumulated lipid. Lipid accumulation is thought to damage the cells further (“second hit hypothesis”).[citation needed] Because P450scc and StAR are also essential for sex steroid synthesis in the testis and ovary, the production of testosterone by Leydig cells in the testis and androgens (which leads to estrogen production by granulosa cells) and progesterone by ovarian theca cells and luteal cells, respectively, can also be impaired. Similar to the adrenal gland, cholesterol accumulation damages the Leydig cells of the testes. In the ovary, the damage begins after puberty, the time when the ovary starts making steroid with follicle development. The placenta also makes steroid to help maintain pregnancy. However, since StAR is not required for placental steroid production, pregnancy goes to term. When the mutation in P450scc that causes lipoid CAH is either heterozygous or its presence on both alleles does not completely destroy all function, affected babies can survive to birth as well. Also of note, enlargement of the adrenal gland is not always found in the patient, especially in cases where a mutation in the gene for P450scc is the cause.[6] The pathophysiology of lipoid CAH differs from other forms of CAH in certain aspects. First, the affected gene in most cases is that for a transport protein (StAR) rather than a steroidogenic enzyme. Second, because the defect compromises all steroid synthesis. Thus, there are no problems due to excessive mineralocorticoids or androgens. Third, lipid accumulation damages the testes and ovaries so that even with appropriate adrenal hormone replacement (and in the absence of other intervention), gonadal function and fertility cannot be preserved.[citation needed] ## Diagnosis[edit] In terms of diagnosis of this condition, gene sequencing can be done.[7] ## Management[edit] Management of salt-wasting crises and mineralocorticoid treatment are as for other forms of salt-wasting congenital adrenal hyperplasias: saline and fludrocortisone.Glucocorticoids can be provided at minimal replacement doses because there is no need for suppression of excessive adrenal androgens or mineralocorticoids. As with other forms of adrenal insufficiency, extra glucocorticoid is needed for stress coverage.[citation needed] ### Female patients[edit] XX females with lipoid CAH may need estrogen replacement at or after puberty. Active intervention has been used to preserve the possibility of fertility and conception in lipoid CAH females.[8] In a case report in 2009, a woman with late onset lipoid CAH due to StAR deficiency underwent hormone replacement therapy in combination with an assisted fertility technique, intracytoplasmic sperm injection.[9] This led to ovulation and with implantation of the in vitro fertilized egg, a successful birth. ### Male patients[edit] Most XY children are so undervirilized that they are raised as girls. The testes are uniformly nonfunctional and undescended; they are removed when the diagnosis is made due to the risk of cancer development in these tissues.[10] ## Epidemiology[edit] Lipoid CAH is quite rare in European and North American populations. Most cases occur in Japan and Korea (where the incidence is 1 in 300,000 births) and Palestinian Arabs. Despite autosomal inheritance, there has been an unexplained preponderance of genetic females in reported cases.[11] ## See also[edit] * Inborn errors of steroid metabolism * Congenital adrenal hyperplasia * Adrenal insufficiency * Disorders of sexual development * Intersexuality, pseudohermaphroditism, and ambiguous genitalia * Steroidogenic acute regulatory protein * Cholesterol side-chain cleavage enzyme * Cholesterol, sex hormone, and corticosteroid ## References[edit] 1. ^ "Congenital lipoid adrenal hyperplasia \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 14 April 2019. 2. ^ Baker BY, Lin L, Kim CJ, Raza J, Smith CP, Miller WL, Achermann JC (December 2006). "Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia". J. Clin. Endocrinol. Metab. 91 (12): 4781–5. doi:10.1210/jc.2006-1565. PMC 1865081. PMID 16968793. 3. ^ Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nürnberg G, Nürnberg P, Green J, Tomlinson JW, Krone NP, Lin L, Racine M, Berney DM, Achermann JC, Arlt W, Clark AJ (October 2009). "Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency". J. Clin. Endocrinol. Metab. 94 (10): 3865–3871. doi:10.1210/jc.2009-0467. PMC 2860769. PMID 19773404. 4. ^ a b Bhangoo A, Anhalt H, Ten S, King SR (March 2006). "Phenotypic variations in lipoid congenital adrenal hyperplasia". Pediatr Endocrinol Rev. 3 (3): 258–71. PMID 16639391. 5. ^ Tajima T, Fujieda K, Kouda N, Nakae J, Miller WL (August 2001). "Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency". J Clin Endocrinol Metab. 86 (8): 3820–5. doi:10.1210/jc.86.8.3820. PMID 11502818. 6. ^ Kim CJ, Lin L, Huang N, Quigley CA, AvRuskin TW, Achermann JC, Miller WL (March 2008). "Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc". J. Clin. Endocrinol. Metab. 93 (3): 696–702. doi:10.1210/jc.2007-2330. PMC 2266942. PMID 18182448. 7. ^ Kim, Chan Jong (December 2014). "Congenital lipoid adrenal hyperplasia". Annals of Pediatric Endocrinology & Metabolism. 19 (4): 179–183. doi:10.6065/apem.2014.19.4.179. ISSN 2287-1012. PMC 4316413. PMID 25654062. 8. ^ Bhangoo A, Buyuk E, Oktay K, Ten S (December 2007). "Phenotypic features of 46, XX females with StAR protein mutations". Pediatr Endocrinol Rev. 5 (2): 633–41. PMID 18084157. 9. ^ Sertedaki A, Pantos K, Vrettou C, Kokkali G, Christofidou C, Kanavakis E, Dacou-Voutetakis C (March 2009). "Conception and pregnancy outcome in a patient with 11-bp deletion of the steroidogenic acute regulatory protein gene". Fertil Steril. 91 (3): 934.e15–8. doi:10.1016/j.fertnstert.2008.07.1770. PMID 18829024. 10. ^ Abdulhadi-Atwan M, Jean A, Chung WK, Meir K, Ben Neriah Z, Stratigopoulos G, Oberfield SE, Fennoy I, Hirsch HJ, Bhangoo A, Ten S, Lerer I, Zangen DH (October 2007). "Role of a founder c.201_202delCT mutation and new phenotypic features of congenital lipoid adrenal hyperplasia in Palestinians". J Clin Endocrinol Metab. 92 (10): 4000–8. doi:10.1210/jc.2007-1306. PMID 17666473. 11. ^ Cantú-Reyna, Consuelo; Zepeda, Luis Manuel; Montemayor, René; Benavides, Santiago; González, Héctor Javier; Vázquez-Cantú, Mercedes; Cruz-Camino, Héctor (27 September 2016). "Incidence of Inborn Errors of Metabolism by Expanded Newborn Screening in a Mexican Hospital". Journal of Inborn Errors of Metabolism and Screening. 4: 232640981666902. doi:10.1177/2326409816669027. ## External links[edit] Classification D * ICD-10: E25.0 * OMIM: 201710 * MeSH: C537027 * DiseasesDB: 2565 External resources * Orphanet: 90790 * v * t * e Adrenal gland disorder Hyperfunction Aldosterone * Hyperaldosteronism * Primary aldosteronism * Conn syndrome * Bartter syndrome * Glucocorticoid remediable aldosteronism * AME * Liddle's syndrome * 17α CAH * Pseudohypoaldosteronism Cortisol * Cushing's syndrome * Pseudo-Cushing's syndrome * Steroid-induced osteoporosis Sex hormones * 21α CAH * 11β CAH Hypofunction Aldosterone * Hypoaldosteronism * 21α CAH * 11β CAH Cortisol * CAH * Lipoid * 3β * 11β * 17α * 21α Sex hormones * 17α CAH * Inborn errors of steroid metabolism Adrenal insufficiency * Adrenal crisis * Adrenalitis * Xanthogranulomatous * Addison's disease * Waterhouse–Friderichsen syndrome * v * t * e Inborn errors of steroid metabolism Mevalonate pathway * HMG-CoA lyase deficiency * Hyper-IgD syndrome * Mevalonate kinase deficiency To cholesterol * 7-Dehydrocholesterol path: Hydrops-ectopic calcification-moth-eaten skeletal dysplasia * CHILD syndrome * Conradi-Hünermann syndrome * Lathosterolosis * Smith–Lemli–Opitz syndrome * desmosterol path: Desmosterolosis Steroids Corticosteroid (including CAH) * aldosterone: Glucocorticoid remediable aldosteronism * cortisol/cortisone: CAH 17α-hydroxylase * CAH 11β-hydroxylase * both: CAH 3β-dehydrogenase * CAH 21-hydroxylase * Apparent mineralocorticoid excess syndrome/11β-dehydrogenase Sex steroid To androgens * 17α-Hydroxylase deficiency * 17,20-Lyase deficiency * Cytochrome b5 deficiency * 3β-Hydroxysteroid dehydrogenase deficiency * 17β-Hydroxysteroid dehydrogenase deficiency * 5α-Reductase deficiency * Pseudovaginal perineoscrotal hypospadias To estrogens * Aromatase deficiency * Aromatase excess syndrome Other * X-linked ichthyosis * Antley–Bixler syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Lipoid congenital adrenal hyperplasia	c0342474	1,965	wikipedia	https://en.wikipedia.org/wiki/Lipoid_congenital_adrenal_hyperplasia	2021-01-18T18:45:38	{"mesh": ["C537027"], "orphanet": ["90790"], "wikidata": ["Q4262866"]}
Copropraxia is a tic consisting of involuntarily performing obscene or forbidden gestures, or inappropriate touching.[1] Copropraxia comes from the Greek κόπρος (kópros), meaning "feces", and πρᾶξις (prâxis), meaning "action". Copropraxia is a rare characteristic of Tourette syndrome.[1] Related terms are coprolalia, referring to involuntary usage of profane words,[2] and coprographia, making vulgar writings or drawings. ## References[edit] 1. ^ a b Shimberg, Elaine Fantle (1995). Living with Tourette Syndrome. New York: Simon & Schuster. p. 31. ISBN 0-684-81160-X 2. ^ Coprolalia. Dictionary.com, Accessed 21 November 2006. * v * t * e Tourette syndrome Main * Causes and origins * History * Societal and cultural aspects * Management Terms * Coprolalia * Copropraxia * Echolalia * Echophenomenon * Echopraxia * Palilalia * Palipraxia * PANDAS * Premonitory urge * Sensory phenomena * Tic * Tic disorder * Tourettism People * Jean-Martin Charcot * Donald J. Cohen * Georges Gilles de la Tourette * Tim Howard * Jean Marc Gaspard Itard * Samuel Johnson * James F. Leckman * Arthur K. Shapiro Organizations * Tourette Association of America * Tourette Canada * Tourettes Action * Yale Child Study Center Media * Front of the Class * Hichki * I Have Tourette's but Tourette's Doesn't Have Me * John's Not Mad * "Le Petit Tourette" * Maze * Motherless Brooklyn * Quit It * The Secret Life of Lele Pons * The Tic Code * Tic Talk: Living with Tourette Syndrome This article about a medical condition affecting the nervous system is a stub. You can help Wikipedia by expanding it. * v * t * e This medical symptom article is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Copropraxia	None	1,966	wikipedia	https://en.wikipedia.org/wiki/Copropraxia	2021-01-18T18:40:37	{"wikidata": ["Q1428295"]}
Opsismodysplasia Other namesOPSMD [1] SpecialtyOrthopedic Opsismodysplasia is a type of skeletal dysplasia (a bone disease that interferes with bone development) first described by Zonana and associates in 1977, and designated under its current name by Maroteaux (1984). Derived from the Greek opsismos ("late"), the name "opsismodysplasia" describes a delay in bone maturation. In addition to this delay, the disorder is characterized by micromelia (short or undersized bones), particularly of the hands and feet, delay of ossification (bone cell formation), platyspondyly (flattened vertebrae), irregular metaphyses, an array of facial aberrations and respiratory distress related to chronic infection. Opsismodysplasia is congenital, being apparent at birth. It has a variable mortality, with some affected individuals living to adulthood. The disorder is rare, with an incidence of less than 1 per 1,000,000 worldwide. It is inherited in an autosomal recessive pattern, which means the defective (mutated) gene that causes the disorder is located on an autosome, and the disorder occurs when two copies of this defective gene are inherited. No specific gene has been found to be associated with the disorder. It is similar to spondylometaphyseal dysplasia, Sedaghatian type.[2][3][4][5][6] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Epidemiology * 5 History * 6 References * 7 External links ## Presentation[edit] Typical ossification center formation in a developing long bone of a fetal cat. Opsismodysplasia can be characterized by a delay in bone maturation, which refers to "bone aging", an expected sequence of developmental changes in the skeleton corresponding to the chronological age of a person. Factors such as gender and ethnicity also play a role in bone age assessment. The only indicator of physical development that can be applied from birth through mature adulthood is bone age. Specifically, the age and maturity of bone can be determined by its state of ossification, the age-related process whereby certain cartilaginous and soft tissue structures are transformed into bone. The condition of epiphyseal plates (growth plates) at the ends of the long bones (which includes those of the arms, hands, legs and feet) is another measurement of bone age. The evaluation of both ossification and the state of growth plates in children is often reached through radiography (X-rays) of the carpals (bones of the hand and wrist).[7][8][9][10][11] In opsismodysplasia, the process of ossification in long bones can be disrupted by a failure of ossification centers (a center of organization in long bones, where cartilage cells designated to await and undergo ossification gather and align in rows)[12] to form. This was observed in a 16-month-old boy with the disorder, who had no apparent ossification centers in the carpals (bones of the hand and wrist) or tarsals (bones of the foot). This was associated with an absence of ossification in these bones, as well as disfigurement of the hands and feet at age two. The boy also had no ossification occurring in the lower femur (thigh bone) and upper tibia (the shin bone).[13] ## Genetics[edit] Opsismodysplasia has an autosomal recessive pattern of inheritance. Opsismodysplasia is inherited in an autosomal recessive manner.[5] This means the defective gene(s) responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Currently, no specific mutation in any gene has been found to cause the disorder.[4][6] It appears that the gene inositol polyphosphate phosphatase-like 1 is the cause of this condition in at least some cases.[14] ## Diagnosis[edit] This section is empty. You can help by adding to it. (August 2017) ## Epidemiology[edit] Opsismodysplasia is a very rare disorder, and is estimated to occur in less than 1 in 1,000,000 people.[6] ## History[edit] The disorder was first described by Jonathan Zonana and associates in 1977.[2] Further observation of four cases of it was reported by Pierre Maroteaux and colleagues in 1982,[15] and Maroteaux was the first to call the disorder "opsismodysplasia", in a 1984 journal report of three affected individuals.[3] The name derives from the Greek opsismos, meaning "late",[4] while the term dysplasia refers to development.[6] ## References[edit] 1. ^ "OMIM Entry - # 258480 - OPSISMODYSPLASIA; OPSMD". omim.org. Retrieved 27 June 2019. 2. ^ a b Zonana, J.; Rimoin, D.; Lachman, R.; Cohen, A. (1977). "A unique chondrodysplasia secondary to a defect in chondroosseous transformation". Birth Defects Original Article Series. 13 (3D): 155–163. PMID 922134. 3. ^ a b Maroteaux, P.; Stanescu, V.; Stanescu, R.; Le Marec, B.; Moraine, C.; Lejarraga, H. (Sep 1984). "Opsismodysplasia: A new type of chondrodysplasia with predominant involvement of the bones of the hand and the vertebrae". American Journal of Medical Genetics. 19 (1): 171–182. doi:10.1002/ajmg.1320190117. PMID 6496568. 4. ^ a b c Cormier-Daire, V.; Delezoide, A.; Philip, N.; Marcorelles, P.; Casas, K.; Hillion, Y.; Faivre, L.; Rimoin, D.; Munnich, A.; Maroteaux, P.; Le Merrer, M. (Mar 2003). "Clinical, radiological, and chondro-osseous findings in opsismodysplasia: Survey of a series of 12 unreported cases". Journal of Medical Genetics. 40 (3): 195–200. doi:10.1136/jmg.40.3.195. PMC 1735387. PMID 12624139. 5. ^ a b Tyler, K.; Sarioglu, N.; Kunze, J. (Mar 1999). "Five familial cases of opsismodysplasia substantiate the hypothesis of autosomal recessive inheritance". American Journal of Medical Genetics. 83 (1): 47–52. doi:10.1002/(SICI)1096-8628(19990305)83:1<47::AID-AJMG9>3.0.CO;2-5. PMID 10076884. 6. ^ a b c d "::Opsismodysplasia". Orphanet. Retrieved April 15, 2011. 7. ^ Zerin, J.; Hernandez, R. (1991). "Approach to skeletal maturation". Hand Clinics. 7 (1): 53–62. PMID 2037639. 8. ^ Gilli, G. (1996). "The assessment of skeletal maturation". Hormone Research. 45 Suppl 2 (2): 49–52. doi:10.1159/000184847. PMID 8805044. 9. ^ Cox, L. (1997). "The biology of bone maturation and ageing". Acta Paediatrica. Supplement. 423: 107–108. doi:10.1111/j.1651-2227.1997.tb18386.x. PMID 9401555. S2CID 42513080. 10. ^ Zhang, A.; Gertych, A.; Liu, B. (Jun–Jul 2007). "Automatic bone age assessment for young children from newborn to 7-year-old using carpal bones". Computerized Medical Imaging and Graphics. 31 (4–5): 299–310. doi:10.1016/j.compmedimag.2007.02.008. PMC 2041862. PMID 17369018. 11. ^ Gertych, A.; Zhang, A.; Sayre, J.; Pospiechkurkowska, S.; Huang, H. (Jun–Jul 2007). "Bone age assessment of children using a digital hand atlas". Computerized Medical Imaging and Graphics. 31 (4–5): 322–331. doi:10.1016/j.compmedimag.2007.02.012. PMC 1978493. PMID 17387000. 12. ^ Gray, Henry; Spitzka, Edward Anthony (1910). Anatomy, descriptive and applied. the University of California: Lea & Febiger. p. 44. "ossification." 13. ^ Beemer, F. A.; Kozlowski, K. S. (Feb 1994). "Additional case of opsismodysplasia supporting autosomal recessive inheritance". American Journal of Medical Genetics. 49 (3): 344–347. doi:10.1002/ajmg.1320490321. PMID 8209898. 14. ^ Chai EC, Singaraja RR (2013) Opsismodysplasia: Implications of mutations in the developmental gene INPPL1. Clin Genet doi: 10.1111/cge.12136 15. ^ Maroteaux, P.; Stanescu, V.; Stanescu, R. (1982). "Four recently described osteochondrodysplasias". Progress in Clinical and Biological Research. 104: 345–350. PMID 7163279. ## External links[edit] Classification D * ICD-10: Q77.8 * OMIM: 258480 * MeSH: C537122 * DiseasesDB: 31936 External resources * Orphanet: 2746 * v * t * e Osteochondrodysplasia Osteodysplasia// osteodystrophy Diaphysis * Camurati–Engelmann disease Metaphysis * Metaphyseal dysplasia * Jansen's metaphyseal chondrodysplasia * Schmid metaphyseal chondrodysplasia Epiphysis * Spondyloepiphyseal dysplasia congenita * Multiple epiphyseal dysplasia * Otospondylomegaepiphyseal dysplasia Osteosclerosis * Raine syndrome * Osteopoikilosis * Osteopetrosis Other/ungrouped * FLNB * Boomerang dysplasia * Opsismodysplasia * Polyostotic fibrous dysplasia * McCune–Albright syndrome Chondrodysplasia/ chondrodystrophy (including dwarfism) Osteochondroma * osteochondromatosis * Hereditary multiple exostoses Chondroma/enchondroma * enchondromatosis * Ollier disease * Maffucci syndrome Growth factor receptor FGFR2: * Antley–Bixler syndrome FGFR3: * Achondroplasia * Hypochondroplasia * Thanatophoric dysplasia COL2A1 collagen disease * Achondrogenesis * type 2 * Hypochondrogenesis SLC26A2 sulfation defect * Achondrogenesis * type 1B * Autosomal recessive multiple epiphyseal dysplasia * Atelosteogenesis, type II * Diastrophic dysplasia Chondrodysplasia punctata * Rhizomelic chondrodysplasia punctata * Conradi–Hünermann syndrome Other dwarfism * Fibrochondrogenesis * Short rib – polydactyly syndrome * Majewski's polydactyly syndrome * Léri–Weill dyschondrosteosis [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Opsismodysplasia	c0432219	1,967	wikipedia	https://en.wikipedia.org/wiki/Opsismodysplasia	2021-01-18T19:00:57	{"gard": ["4098"], "mesh": ["C537122"], "umls": ["C0432219"], "icd-10": ["Q77.8"], "orphanet": ["2746"], "wikidata": ["Q7098730"]}
Hypophysitis Pituitary gland is located at the base of the human brain. SpecialtyEndocrinology Hypophysitis refers to an inflammation of the pituitary gland. Hypophysitis is rare and not fully understood. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 History * 7 See also * 8 References ## Signs and symptoms[edit] There are four categories of symptoms and signs. Most commonly, the initial symptoms are headaches and visual disturbances. Some symptoms are derived from the lesser functioning of the adenohypophyseal hormones. Of the adenohypophyseal hormones, the most frequently affected are corticotropes, lactotropes and gonadotropes, all which are found in the anterior pituitary. Polyuria is also a common symptom – which results in very dilute urine, as well as polydipsia which means having extreme thirst. Another symptom is hyperprolactinemia, which is when there are abnormally high prolactin levels in the blood. Usually, a mass will be found located on the sella turcica and loss of hormonal function.[1] ## Cause[edit] This section needs expansion. You can help by adding to it. (August 2018) Hypophysitis may have an underlying autoimmune aetiology, as in the case of autoimmune hypophysitis,[2] and lymphocytic hypophysitis.[3][4] ## Diagnosis[edit] Mainly, the diagnosis of hypophysitis is through exclusion – patients often undergo surgery because they are suspected of having a pituitary adenoma. But, the most accurate diagnosis is using Magnetic Resonance Imaging (MRI) to find any mass or lesions on the sella turcica.[5] It is a known side-effect of the new immune checkpoint inhibitors of the CTLA-4 inhibitor and PD-L1 inhibitor classes, used for the treatment of melanoma, and should be considered in patients on these drugs who present with endocrine dysfunction.[citation needed] ## Treatment[edit] It was shown through various testing that administration of bromocriptine can improve field of vision defects and lower prolactin levels. It was also found that when using corticosteroids, there was a decrease in size of the gland, and relieved compression on the dura mater. These corticosteroids were also found to have an immunosuppressive effect which helped with reducing the autoimmune reaction of the gland.[6] ## Prognosis[edit] The prognosis for hypophysitis was variable for each individual. The depending factors for hypophysitis included the advancement of the mass on the sella turcica, percentage of fibrosis, and the body's response to corticosteroids. Through the use of corticosteroids, the vision defects tend to recover when the gland size began to decrease. The prognoses of the limited number of reported cases were usually good.[7] ## History[edit] The first reported case was in 1962, with a 22-year-old who died of adrenal insufficiency 14 months after giving birth to her second child. Her symptoms began 3 months postpartum, with lassitude (weakness/lack of energy), goitre (iodine deficiency) and amenorrhea (absence of a menstrual period). This was originally reported by Goudie and Pinkerton in Glasgow, UK. There have only been approximately just over 100 cases reported. Majority of these cases were female, and usually began noticing symptoms late into their pregnancies and in early postpartum.[8] ## See also[edit] * Autoimmune hypophysitis[2] * Lymphocytic hypophysitis[3][4] * Pituitary disease * Hypopituitarism ## References[edit] 1. ^ "Autoimmune Hypophysitis Symptoms". Johns Hopkins University School of Medicine & Johns Hopkins Health System. 2002. Archived from the original on 2004-05-28. 2. ^ a b Caturegli P (June 2007). "Autoimmune hypophysitis: an underestimated disease in search of its autoantigen(s)". J. Clin. Endocrinol. Metab. 92 (6): 2038–40. doi:10.1210/jc.2007-0808. PMID 17554056. 3. ^ a b Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S (August 1995). "Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings". J. Clin. Endocrinol. Metab. 80 (8): 2302–11. doi:10.1210/jc.80.8.2302. PMID 7629223. 4. ^ a b "Lymphoid Hypophisitis". pituitaryadenomas.com. 5. ^ http://pathology2.jhu.edu/hypohysitis/theprognfollowup.cfm 6. ^ Carol C. Cheung; Shereen Ezzat; Harley S. Smyth; Sylvia L. Asa (1 March 2001). "The Spectrum and Significance of Primary Hypophysitis". The Journal of Clinical Endocrinology & Metabolism. 86 (3): 1048–1053. doi:10.1210/jcem.86.3.7265. PMID 11238484. 7. ^ http://pathology2.jhu.edu/hypophysitis/theprognfollowup.cfm 8. ^ http://pathology2.jhu.edu/hypophysitis/histricalnotes.cfm * v * t * e Pituitary disease Hyperpituitarism Anterior * Acromegaly * Hyperprolactinaemia * Pituitary ACTH hypersecretion Posterior * SIADH General * Nelson's syndrome * Hypophysitis Hypopituitarism Anterior * Kallmann syndrome * Growth hormone deficiency * Hypoprolactinemia * ACTH deficiency/Secondary adrenal insufficiency * GnRH insensitivity * FSH insensitivity * LH/hCG insensitivity Posterior Neurogenic diabetes insipidus General * Empty sella syndrome * Pituitary apoplexy * Sheehan's syndrome * Lymphocytic hypophysitis * Pituitary adenoma [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Hypophysitis	c0342409	1,968	wikipedia	https://en.wikipedia.org/wiki/Hypophysitis	2021-01-18T18:34:31	{"mesh": ["D000072659"], "umls": ["C0342409"], "wikidata": ["Q4120169"]}
## Clinical Features Kuang et al. (2001) identified a novel bleeding disorder inherited as an autosomal dominant trait in a family from East Texas. The disorder was characterized clinically by easy bruising, life-threatening bleeding with trauma or surgery, and menorrhagia in affected women. Laboratory studies demonstrated prolongation of the prothrombin time and activated partial thromboplastin time in affected individuals. Paradoxically, assays of known coagulation factors were all within normal limits. Inheritance The bleeding disorder in the family from East Texas was transmitted in an autosomal dominant manner (Kuang et al., 2001). Mapping By linkage analysis, Kuang et al. (2001) demonstrated that the bleeding disorder in the family from East Texas mapped to a 1.47-Mb region on chromosome 1q23 (maximum lod = 7.22 at theta = 0.0). No disease-causing mutations were found in the AT3 (107300) or F5 (612309) genes. Kuang et al. (2001) suggested that the bleeding disorder in this family may be caused by mutations in a novel protein involved in the coagulation cascade. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	BLEEDING DISORDER, EAST TEXAS TYPE	c1853831	1,969	omim	https://www.omim.org/entry/605913	2019-09-22T16:10:50	{"mesh": ["C565275"], "omim": ["605913"], "orphanet": ["391320"], "synonyms": ["Alternative titles", "BDET"]}
A number sign (#) is used with this entry because of evidence that atelosteogenesis type III (AO3) is caused by heterozygous mutation in the FLNB gene (603381), which encodes filamin B, on chromosome 3p14.3. For a discussion of genetic heterogeneity of atelosteogenesis, see AO1 (108720). Clinical Features Stern et al. (1990) described 5 examples of a short-limb dwarfism syndrome with manifestations overlapping those of atelosteogenesis and otopalatodigital syndrome type II (304120). They presented clinical, radiographic, genetic, and histologic data that demonstrated differences between these patients and previously reported cases of the other conditions. Like AO1, this new disorder, designated atelosteogenesis type III, has been observed only in isolated cases, suggesting fresh dominant mutation. In 1 of the 5 patients with AO3, there was advanced paternal age consistent with this possibility. On the other hand, Pyeritz (1993) reported a case of affected sibs. Schultz et al. (1999) reported a mother and son with atelosteogenesis type III. They stated that this was the first report of survival to adulthood, of prenatal diagnosis, and of dominant transmission. The authors reviewed 9 previously published cases to describe the syndrome more completely; they suggested that the physical and radiographic findings of AO3 and Larsen syndrome (150250) are quite similar, and that the disorders are probably allelic. Molecular Genetics In 2 unrelated individuals with sporadically occurring AO3, Krakow et al. (2004) identified heterozygosity for point mutations in the FLNB gene (603381) that predicted single-residue substitutions in the N-terminal actin-binding domain of filamin B (M202V, 603381.0007 and G751R, 603381.0008). They also identified the M202V mutation in a patient with AO1. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Frontal bossing \- Midface hypoplasia \- Micrognathia Nose \- Flat nasal bridge Mouth \- Cleft palate Neck \- Short neck SKELETAL Skull \- Hypoplastic maxilla \- Hypoplastic mandible \- Prominent occiput Spine \- Scoliosis \- Cervical spine segmentation defects \- Cervical kyphosis Pelvis \- Rounded iliac bones with shortened sacrosciatic notches \- Vertical, block-like ischia \- Flat acetabular roofs \- Horizontal sacrum Limbs \- Rhizomelic shortening \- Elbow dislocations \- Club-shaped humeri with early proximal epiphyseal ossification \- Club-shaped femora \- Knee dislocations \- Radial bowing \- Tibial bowing Hands \- Hitchhiker thumb \- Tombstone-shaped proximal phalanges \- Widened distal phalanges \- Bifid digits Feet \- Hitchhiker halluces \- Talipes equinovarus \- Widened gap first and second toe MOLECULAR BASIS \- Caused by mutation in the filamin B gene (FLNB, 603381.0006 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	ATELOSTEOGENESIS, TYPE III	c3668942	1,970	omim	https://www.omim.org/entry/108721	2019-09-22T16:44:42	{"doid": ["0050648"], "mesh": ["C579928"], "omim": ["108721"], "orphanet": ["56305"], "synonyms": ["Alternative titles", "AOIII"], "genereviews": ["NBK2534"]}
Chronic active EBV infection Other namesCAEBV Chronic active EBV infection or in its expanded form, chronic active Epstein–Barr virus infection is a very rare and often fatal complication of Epstein–Barr virus (EBV) infection that most often occurs in children or adolescents of Asian or South American lineage, although cases in Hispanics, Europeans and Africans have been reported.[1] It is classified as one of the Epstein-Barr virus-associated lymphoproliferative diseases (i.e. EBV+ LPD).[2] ## Contents * 1 Presentation * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 References ## Presentation[edit] The most common symptoms of CAEBV include:[1][3][4][5] * Fever * Hepatitis * Pancytopenia * Spleen enlargement * Hypersensitivity to mosquito bites Complications include:[1][3][5] * Interstitial pneumonia * Lymphoma, including B-cell, T-cell and NK-cell lymphomas[6] * Haemophagocytic syndrome * Coronary artery aneurysms * Liver failure * Nasopharyngeal carcinoma * Gastric adenocarcinoma * CNS * Intestinal perforation * Myocarditis * Peripheral neuropathy ## Pathophysiology[edit] It arises from the cells that constitute the immune system, most often the T-cells and NK cells in Asians/South Americans and the B-cells in the other racial groups.[1] Various cytokine anomalies have been reported in people with CAEBV, examples include:[5][7] * IL-1β ↑ (elevated) * IL-4 ↑ * IL-6 ↑ * IL-10 ↑ * IL-12 ↑ * IL-13 ↑ * IL-15 ↑ * TNF ↑ * IFN-γ ↑ There is also evidence supporting a role for TGF-β in the disease.[7] Those that develop the haemophagocytic syndrome often exhibit an abnormally high amount of IL-1β and IFN-γ.[8] ## Diagnosis[edit] This section is empty. You can help by adding to it. (February 2019) ## Treatment[edit] The only known cure for CAEBV is allogenic haematopoietic stem cell transplant (HSCT), with all other treatment options (rituximab, cytotoxic chemotherapy and immunosuppressive therapy) being nothing more than stopgaps.[1][3][5][7] ## Prognosis[edit] Without HSCT the condition is inevitably fatal and even HSCT is no guarantee, with a significant portion of patients dying from the disease progression.[8] Factors indicative of a poor prognosis include: thrombocytopenia, late onset of the disease (age ≥ 8 years) and T cell involvement.[9] ## References[edit] 1. ^ a b c d e Cohen, JI; Jaffe, ES; Dale, JK; Pittaluga, S; Heslop, HE; Rooney, CM; Gottschalk, S; Bollard, CM; Rao, VK; Marques, A; Burbelo, PD; Turk, SP; Fulton, R; Wayne, AS; Little, RF; Cairo, MS; El-Mallawany, NK; Fowler, D; Sportes, C; Bishop, MR; Wilson, W; Straus, SE (31 March 2011). "Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States". Blood. 117 (22): 5835–5849. doi:10.1182/blood-2010-11-316745. PMC 3112034. PMID 21454450. 2. ^ Rezk SA, Zhao X, Weiss LM (June 2018). "Epstein - Barr virus - associated lymphoid proliferations, a 2018 update". Human Pathology. 79: 18–41. doi:10.1016/j.humpath.2018.05.020. PMID 29885408. 3. ^ a b c Kimura, H; Hoshino, Y; Kanegane, H; Tsuge, I; Okamura, T; Kawa, K; Morishima, T (15 July 2001). "Clinical and virologic characteristics of chronic active Epstein-Barr virus infection" (PDF). Blood. 98 (2): 280–286. doi:10.1182/blood.V98.2.280. PMID 11435294. 4. ^ Gotoh, K; Ito, Y; Shibata-Watanabe, Y; Kawada, J; Takahashi, Y; Yagasaki, H; Kojima, S; Nishiyama, Y; Kimura, H (15 May 2008). "Clinical and virological characteristics of 15 patients with chronic active Epstein-Barr virus infection treated with hematopoietic stem cell transplantation" (PDF). Clinical Infectious Diseases. 46 (10): 1525–34. doi:10.1086/587671. PMID 18419486. 5. ^ a b c d Lu, G; Xie, ZD; Zhao, SY; Ye, LJ; Wu, RH; Liu, CY; Yang, S; Jin, YK; Shen, KL (5 February 2009). "Clinical analysis and follow-up study of chronic active Epstein-Barr virus infection in 53 pediatric cases" (PDF). Chinese Medical Journal. 122 (3): 262–6. doi:10.3760/cma.j.issn.0366-6999.2009.03.005 (inactive 2021-01-14). PMID 19236801.CS1 maint: DOI inactive as of January 2021 (link) 6. ^ Ohtsuka, R; Abe, Y; Sada, E; Kiyasu, J; Ashikari, A; Shiratsuchi, M; Nishimura, J; Takayanagi, R; Ohshima, K (2009). "Adult patient with Epstein-Barr virus (EBV)-associated lymphoproliferative disorder: chronic active EBV infection or de novo extranodal natural killer (NK)/T-cell lymphoma, nasal type?" (PDF). Internal Medicine. 48 (6): 471–4. doi:10.2169/internalmedicine.48.1346. PMID 19293549. 7. ^ a b c Cohen, JI (June 2009). "Optimal treatment for chronic active Epstein-Barr virus disease". Pediatric Transplantation. 13 (4): 393–396. doi:10.1111/j.1399-3046.2008.01095.x. PMC 2776035. PMID 19032417. 8. ^ a b Kimura, H; Hoshino, Y; Hara, S; Sugaya, N; Kawada, J; Shibata, Y; Kojima, S; Nagasaka, T; Kuzushima, K; Morishima, T (15 February 2005). "Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection" (PDF). The Journal of Infectious Diseases. 191 (4): 531–539. doi:10.1086/427239. PMID 15655776. 9. ^ Kimura, H; Morishima, T; Kanegane, H; Ohga, S; Hoshino, Y; Maeda, A; Imai, S; Okano, M; Morio, T; Yokota, S; Tsuchiya, S; Yachie, A; Imashuku, S; Kawa, K; Wakiguchi, H; Japanese Association for Research on Epstein-Barr Virus and Related Diseases (15 February 2003). "Prognostic factors for chronic active Epstein-Barr virus infection" (PDF). The Journal of Infectious Diseases. 187 (4): 527–533. doi:10.1086/367988. hdl:10126/4219. PMID 12599068. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Chronic active EBV infection	c4289792	1,971	wikipedia	https://en.wikipedia.org/wiki/Chronic_active_EBV_infection	2021-01-18T19:09:26	{"umls": ["CL504910"], "wikidata": ["Q17148477"]}
A saphena varix, or a saphenous varix is a dilation of the saphenous vein at its junction with the femoral vein in the groin. It is a common surgical problem, and patients may present with groin swelling. ## Clinical features[edit] It displays a cough impulse and may be mistaken for a femoral hernia. However it has a bluish tinge and disappears on lying down. On auscultation a venous hum may be heard. It is frequently associated with varicose veins.[1] Saphena varix can be easily diagnosed by ultrasound. Saphena varix shows flow on duplex ultrasonography. ## References[edit] 1. ^ Prince, Jim McMorran, Damian Crowther, Stew McMorran, Steve Youngmin, Ian Wacogne, Jon Pleat, Clive. "saphena varix - General Practice Notebook". www.gpnotebook.co.uk. * "Saphena varix - Health Facts Review". 5 April 2016. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Saphena varix	None	1,972	wikipedia	https://en.wikipedia.org/wiki/Saphena_varix	2021-01-18T18:49:26	{"wikidata": ["Q7420955"]}
A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the triad: congenital, bilateral, symmetrical, subtotal, external auditory canal atresia, bilateral vertical talus and increased interocular distance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	External auditory canal atresia-vertical talus-hypertelorism syndrome	c2930867	1,973	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3023	2021-01-23T18:33:33	{"gard": ["4638"], "mesh": ["C535290"], "omim": ["133705"], "umls": ["C2930867"], "icd-10": ["Q87.8"], "synonyms": ["Rasmussen-Johnsen-Thomsen syndrome"]}
Neutropenia-monocytopenia-deafness syndrome is characterised by neutropenia with myeloid marrow hypoplasia, monocytopenia, and congenital deafness. It has been described in three siblings who suffered recurrent bacterial infections. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Neutropenia-monocytopenia-deafness syndrome	None	1,974	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2690	2021-01-23T18:02:12	{"gard": ["3982"], "icd-10": ["D82.8"], "synonyms": ["Neutropenia-monocytopenia-hearing loss syndrome"]}
Eosinophilic granulomatosis with polyangiitis (EGPA) Other namesChurg–Strauss syndrome, allergic angiitis and granulomatosis.[1] Micrograph showing an eosinophilic vasculitis consistent with eosinophilic granulomatosis with polyangiitis. H&E stain. One of the American College of Rheumatology criteria for EGPA is extravascular eosinophil infiltration on biopsy.[2] SpecialtyImmunology, rheumatology SymptomsFatigue, fever, weight loss, night sweats, abdominal pain, cough, joint pain, muscle pain, bleeding into tissues under the skin, a rash with hives, small bumps, or a general feeling of ill.[1] Complicationshypereosinophilia, granulomatosis, vasculitis, inner ear infections with fluid build up, inflammation of the moist membrane lining the surface of the eyelids, or inflammation of peripheral nerves.[1] Risk factorsHistory of allergy, asthma and asthma-associated lung abnormalities (i.e., pulmonary infiltrates).[1] Diagnostic methodantineutrophil cytoplasmic antibodies (ANCA); cluster of asthma, eosinophilia, mono- or polyneuropathy, nonfixed pulmonary infiltrates, abnormality of the paranasal sinuses, and extravascular eosinophilia.[1] TreatmentSuppress the activity of the immune system to alleviate inflammation.[1] MedicationCorticosteroid medications such as prednisone or methylprednisolone, and mepolizumab.[1] Proliferation inhibitor for those with the presence of kidney or neurological disease.[1] Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as allergic granulomatosis,[3][4] is an extremely rare autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy).[5] It usually manifests in three stages. The early (prodromal) stage is marked by airway inflammation; almost all patients experience asthma and/or allergic rhinitis. The second stage is characterized by abnormally high numbers of eosinophils (hypereosinophilia), which causes tissue damage, most commonly to the lungs and the digestive tract.[5] The third stage consists of vasculitis, which can eventually lead to cell death and can be life-threatening.[5] This condition is now called "eosinophilic granulomatosis with polyangiitis" to remove all eponyms from the vasculitides. To facilitate the transition, it was referred to as "eosinophilic granulomatosis with polyangiitis (Churg–Strauss)" for a period of time starting in 2012.[6] Prior to this it was known as "Churg–Strauss syndrome", named after Drs. Jacob Churg and Lotte Strauss who, in 1951, first published about the syndrome using the term "allergic granulomatosis" to describe it.[3] It is a type of systemic necrotizing vasculitis. Effective treatment of EGPA requires suppression of the immune system with medication. This is typically glucocorticoids, followed by other agents such as cyclophosphamide or azathioprine. ## Contents * 1 Signs and symptoms * 1.1 Allergic stage * 1.2 Eosinophilic stage * 1.3 Vasculitic stage * 2 Diagnosis * 2.1 Risk stratification * 3 Treatment * 4 History * 5 Society and culture * 6 References * 7 Further reading * 8 External links ## Signs and symptoms[edit] Eosinophilic granulomatosis with polyangiitis consists of three stages, but not all patients develop all three stages or progress from one stage to the next in the same order;[7] whereas some patients may develop severe or life-threatening complications such as gastrointestinal involvement and heart disease, some patients are only mildly affected, e.g. with skin lesions and nasal polyps.[8] EGPA is consequently considered a highly variable condition in terms of its presentation and its course.[7][8] ### Allergic stage[edit] The prodromal stage is characterized by allergy. Almost all patients experience asthma and/or allergic rhinitis,[9] with more than 90% having a history of asthma that is either a new development, or the worsening of pre-existing asthma,[10] which may require systemic corticosteroid treatment.[7] On average, asthma develops from three to nine years before the other signs and symptoms.[7] The allergic rhinitis may produce symptoms such as rhinorrhea and nasal obstruction, and the formation of nasal polyps that require surgical removal, often more than once.[9] Sinusitis may also be present.[9] ### Eosinophilic stage[edit] The second stage is characterized by an abnormally high level of eosinophils (a type of white blood cell) in the blood and tissues as a result of abnormal eosinophil proliferation, impaired eosinophil apoptosis, and increased toxicity due to eosinophil metabolic products.[7][11] The symptoms of hypereosinophilia depend on which part of the body is affected, but most often it affects the lungs and digestive tract.[7] The signs and symptoms of hypereosinophilia may include weight loss, night sweats, asthma, cough, abdominal pain, and gastrointestinal bleeding.[7] Fever and malaise are often present.[12] The eosinophilic stage can last months or years, and its symptoms can disappear, only to return later.[7] Patients may experience the third stage simultaneously.[7] ### Vasculitic stage[edit] The third and final stage, and hallmark of EGPA, is inflammation of the blood vessels, and the consequent reduction of blood flow to various organs and tissues.[7] Local and systemic symptoms become more widespread and are compounded by new symptoms from the vasculitis.[12] Severe complications may arise. Blood clots may develop within the damaged arteries in severe cases, particularly in arteries of the abdominal region, which is followed by infarction and cell death, or slow atrophy.[12] Many patients experience severe abdominal complaints; these are most often due to peritonitis and/or ulcerations and perforations of the gastrointestinal tract, but occasionally due to acalculous cholecystitis or granulomatous appendicitis.[12] The most serious complication of the vasculitic stage is heart disease, which is the cause of nearly one-half of all deaths in patients with EGPA.[12] Among heart disease-related deaths, the most usual cause is inflammation of the heart muscle caused by the high level of eosinophils, although some are deaths due to inflammation of the arteries that supply blood to the heart or pericardial tamponade.[12] Kidney complications have been reported as being less common.[13] Complications in the kidneys can include glomerulonephritis, which prevents the kidneys’ ability to filter the blood, ultimately causing wastes to build up in the bloodstream.[14] ## Diagnosis[edit] Diagnostic markers include eosinophil granulocytes and granulomas in affected tissue, and antineutrophil cytoplasmic antibodies (ANCA) against neutrophil granulocytes. The American College of Rheumatology 1990 criteria for diagnosis of Churg–Strauss syndrome lists these criteria:[needs update] * Asthma * Eosinophilia, i.e. eosinophil blood count greater than 500/microliter, or hypereosinophilia, i.e. eosinophil blood count greater than 1,500/microliter * Presence of mononeuropathy or polyneuropathy * Unfixed pulmonary infiltrates * Presence of paranasal sinus abnormalities * Histological evidence of extravascular eosinophils For classification purposes, a patient shall be said to have EGPA if at least four of these six criteria are positive. The presence of any four or more of the six criteria yields a sensitivity of 85% and a specificity of 99.7%.[2][needs update] ### Risk stratification[edit] The French Vasculitis Study Group has developed a five-point system ("five-factor score") that predicts the risk of death in Churg–Strauss syndrome using clinical presentations. These factors are:[citation needed] * Reduced renal function (creatinine >1.58 mg/dl or 140 µmol/l) * Proteinuria (>1 g/24h) * Gastrointestinal hemorrhage, infarction, or pancreatitis * Involvement of the central nervous system * Cardiomyopathy The lack of any of these factors indicates milder case, with a five-year mortality rate of 11.9%. The presence of one factor indicates severe disease, with a five-year mortality rate of 26%, and two or more indicate very severe disease: 46% five-year mortality rate.[15] ## Treatment[edit] Treatment for eosinophilic granulomatosis with polyangiitis includes glucocorticoids (such as prednisolone) and other immunosuppressive drugs (such as azathioprine and cyclophosphamide). In many cases, the disease can be put into a type of chemical remission through drug therapy, but the disease is chronic and lifelong.[citation needed] A systematic review conducted in 2007 indicated all patients should be treated with high-dose steroids, but in patients with a five-factor score of one or higher, cyclophosphamide pulse therapy should be commenced, with 12 pulses leading to fewer relapses than six. Remission can be maintained with a less toxic drug, such as azathioprine or methotrexate.[16] On 12 December 2017, the FDA approved mepolizumab, the first drug therapy specifically indicated for the treatment of eosinophilic granulomatosis with polyangiitis.[17] Patients taking mepolizumab experienced a "significant improvement" in their symptoms.[17] Mepolizumab is a monoclonal antibody that targets interleukin-5, a major factor in eosinophil survival. [18] ## History[edit] Eosinophilic granulomatosis with polyangiitis was first described by pathologists Jacob Churg (1910–2005) and Lotte Strauss (1913–1985) at Mount Sinai Hospital in New York City in 1951, using the term "allergic granulomatosis" to describe it.[3][19] They reported "fever...hypereosinophilia, symptoms of cardiac failure, renal damage, and peripheral neuropathy, resulting from vascular embarrassment in various systems of organs"[20] in a series of 13 patients with necrotizing vasculitis previously diagnosed as "periarteritis nodosa", accompanied by hypereosinophilia and severe asthma.[21] Drs. Churg and Strauss noted three features which distinguished their patients from other patients with periarteritis nodosa but without asthma: necrotizing vasculitis, tissue eosinophilia, and extravascular granuloma.[21] As a result, they proposed that these cases were evident of a different disease entity, which they referred to as "allergic granulomatosis and angiitis".[21] ## Society and culture[edit] The memoir Patient, by musician Ben Watt, deals with his experience with EGPA in 1992, and his recovery.[22] Watt's case was unusual in that it mainly affected his gastrointestinal tract, leaving his lungs largely unaffected; this unusual presentation contributed to a delay in proper diagnosis. His treatment required the removal of 5 m (15 ft) of necrotized small intestine (about 75%), leaving him on a permanently restricted diet.[22] Umaru Musa Yar'Adua, the president of Nigeria from 2007 to 2010, reportedly had EGPA and died in office of complications of the disease.[23] DJ and author Charlie Gillett was diagnosed with EGPA in 2006; he died four years later.[24] Japanese ski jumper Taku Takeuchi, who won the bronze medal in the team competition, has the disease and competed at the Sochi Olympics less than a month after being released from hospital treatment.[25] New Zealand reporter and television presenter Toni Street was diagnosed with the condition in 2015.[26][27] Street has had health problems for several years, including removal of her gallbladder four months prior.[28] Professional basketball player Willie Naulls died on 22 November 2018 in Laguna Niguel, California, from respiratory failure due to EGPA,[29] which he had been battling for eight years.[30] ## References[edit] 1. ^ a b c d e f g h "Churg Strauss Syndrome". NORD (National Organization for Rare Disorders). 11 February 2015. Retrieved 8 March 2020. 2. ^ a b Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP, et al. (August 1990). "The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis)". Arthritis and Rheumatism. 33 (8): 1094–100. doi:10.1002/art.1780330806. PMID 2202307. 3. ^ a b c Churg J, Strauss L (March–April 1951). "Allergic granulomatosis, allergic angiitis, and periarteritis nodosa". The American Journal of Pathology. 27 (2): 277–301. PMC 1937314. PMID 14819261. 4. ^ Adu, Emery & Madaio 2012, p. 125. 5. ^ a b c "What Is Churg-Strauss Syndrome?". WebMD. 30 January 2019. Retrieved 8 March 2020. 6. ^ Montesi SB, Nance JW, Harris RS, Mark EJ (June 2016). "CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 17-2016. A 60-Year-Old Woman with Increasing Dyspnea". The New England Journal of Medicine. 374 (23): 2269–79. doi:10.1056/NEJMcpc1516452. PMID 27276565. 7. ^ a b c d e f g h i j "Churg-Strauss syndrome - Symptoms". Mayo Clinic. Retrieved 30 June 2013. 8. ^ a b Della Rossa A, Baldini C, Tavoni A, Tognetti A, Neglia D, Sambuceti G, et al. (November 2002). "Churg-Strauss syndrome: clinical and serological features of 19 patients from a single Italian centre". Rheumatology. 41 (11): 1286–94. doi:10.1093/rheumatology/41.11.1286. PMID 12422002. 9. ^ a b c Churg & Thurlbeck 1995, p. 425. 10. ^ Rich RR, Fleisher, Thomas A., Shearer, William T., Schroeder, Harry, Frew, Anthony J., Weyand, Cornelia M. (2012). Clinical Immunology: Principles and Practice. Elsevier Health Sciences. p. 701. ISBN 9780723437109. 11. ^ Nguyen, Yann; Guillevin, Loïc (August 2018). "Eosinophilic Granulomatosis with Polyangiitis (Churg–Strauss)". Seminars in Respiratory and Critical Care Medicine. 39 (4): 471–481. doi:10.1055/s-0038-1669454. ISSN 1069-3424. PMID 30404114. S2CID 53213576. 12. ^ a b c d e f Churg & Thurlbeck 1995, p. 426. 13. ^ Rich et al. 2012, p. 701. 14. ^ https://www.mayoclinic.org/diseases-conditions/churg-strauss-syndrome/symptoms-causes/syc-20353760#:~:text=Churg%2DStrauss%20syndrome%20is%20a,sign%20of%20Churg%2DStrauss%20syndrome 15. ^ Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, et al. (January 1996). "Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients". Medicine. 75 (1): 17–28. doi:10.1097/00005792-199601000-00003. PMID 8569467. 16. ^ Bosch X, Guilabert A, Espinosa G, Mirapeix E (August 2007). "Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review". JAMA. 298 (6): 655–69. doi:10.1001/jama.298.6.655. PMID 17684188. 17. ^ a b "Press Announcements - FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome". www.fda.gov. FDA. Retrieved 13 December 2017. 18. ^ Giofreddi, Andrea; Maritati, Federica; Oliva, Elena; Buzio, Carlo (3 November 2014). "Eosinophillic Granulomatosis with Polyangiitis: An Overview". Front Immunol. 5: 549. doi:10.3389/fimmu.2014.00549. PMC 4217511. PMID 25404930. 19. ^ synd/2733 at Who Named It? 20. ^ Rich et al. 2012, p. 700. 21. ^ a b c Hellmich B, Ehlers S, Csernok E, Gross WL (2003). "Update on the pathogenesis of Churg-Strauss syndrome". Clinical and Experimental Rheumatology. 21 (6 Suppl 32): S69-77. PMID 14740430. 22. ^ a b Whiting S (10 April 1997). "Everything But the Final Song / Ben Watt lives to tell how he almost didn't". SFGate. Retrieved 30 June 2013. 23. ^ "WikiLeaks: Yar'Adua Died Of Lung Cancer And Churg Strauss Syndrome, US Cables Confirm". Sahara Reporters. 2 September 2011. Retrieved 30 June 2013. 24. ^ "Charlie Gillett - Obituary". The Daily Telegraph. 18 March 2010. Retrieved 30 June 2013. 25. ^ "Japan's Taku Takeuchi overcame illness to win Olympic medal - 'I thought I might even die'". The National. Associated Press. 18 February 2014. 26. ^ "New Zealand responds to Toni Street's illness with love and support". Stuff.co.nz. Retrieved 5 October 2015. 27. ^ "Toni Street reveals 'dark moments' as she battles deadly disease". NZ Herald. Retrieved 5 October 2015. 28. ^ "Toni Street's mystery illness revealed". NZ Herald. Retrieved 5 October 2015. 29. ^ Goldstein R (25 November 2018), "Willie Naulls, Knicks All-Star and Celtics Champion, Dies at 84", The New York Times 30. ^ Bolch B (25 November 2018). "Former UCLA great and integration pioneer Willie Naulls dies at 84". Los Angeles Times. Retrieved 26 November 2018. ## Further reading[edit] * Adu D, Emery P, Madaio M (2012). Rheumatology and the Kidney (2, illustrated ed.). Oxford University Press. ISBN 9780199579655. * Churg A, Thurlbeck W (1995). Pathology of the LungM (2, illustrated ed.). Thieme. ISBN 9780865775343. * Rich RR, Fleisher TA, Shearer WT, Schroeder H, Frew AJ, Weyand CM (2012). Clinical Immunology: Principles and Practice. Elsevier Health Sciences. ISBN 9780723437109. ## External links[edit] Classification D * ICD-10: M30.1 * ICD-9-CM: 446.4 * MeSH: D015267 * DiseasesDB: 2685 External resources * eMedicine: med/2926 derm/78 neuro/501 * Patient UK: Eosinophilic granulomatosis with polyangiitis * Orphanet: 183 * v * t * e Systemic vasculitis Large vessel * Takayasu's arteritis * Giant cell arteritis Medium vessel * Polyarteritis nodosa * Kawasaki disease * Thromboangiitis obliterans Small vessel Pauci-immune * c-ANCA * Granulomatosis with polyangiitis * p-ANCA * Eosinophilic granulomatosis with polyangiitis * Microscopic polyangiitis Type III hypersensitivity * Cutaneous small-vessel vasculitis * IgA vasculitis Ungrouped * Acute hemorrhagic edema of infancy * Cryoglobulinemic vasculitis * Bullous small vessel vasculitis * Cutaneous small-vessel vasculitis Other * Goodpasture syndrome * Sneddon's syndrome [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Eosinophilic granulomatosis with polyangiitis	c0008728	1,975	wikipedia	https://en.wikipedia.org/wiki/Eosinophilic_granulomatosis_with_polyangiitis	2021-01-18T18:57:32	{"gard": ["5776", "6111"], "mesh": ["D015267"], "umls": ["C0008728"], "icd-9": ["447.6"], "orphanet": ["183"], "wikidata": ["Q32811"]}
## Description Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010). ### Genetic Heterogeneity of Susceptibility to Cutaneous Malignant Melanoma The locus for susceptibility to familial cutaneous malignant melanoma-1 (CMM1) has been mapped to chromosome 1p36. Other CMM susceptibility loci include CMM2 (155601), caused by variation in the CDKN2A gene (600160) on chromosome 9p21; CMM3 (609048), caused by variation in the CDK4 gene (123829) on chromosome 12q14; CMM4 (608035), mapped to chromosome 1p22; CMM5 (613099), caused by variation in the MC1R gene (155555) on chromosome 16q24; CMM6 (613972), caused by variation in the XRCC3 gene (600675) on chromosome 14q32; CMM7 (612263), mapped to chromosome 20q11; CMM8 (614456), caused by variation in the MITF gene (156845) on chromosome 3p13; CMM9 (615134), caused by variation in the TERT gene (187270) on chromosome 5p15; and CMM10 (615848), caused by mutation in the POT1 gene (606478) on chromosome 7q31. Somatic mutations causing malignant melanoma have also been identified in several genes, including BRAF (164757), STK11 (602216), PTEN (601728), TRRAP (603015), DCC (120470), GRIN2A (138253), ZNF831, BAP1 (603089), and RASA2 (601589). A large percentage of melanomas (40-60%) carry an activating somatic mutation in the BRAF gene, most often V600E (164757.0001) (Davies et al., 2002; Pollock et al., 2003). Clinical Features Several writers (e.g., Moschella, 1961; Schoch, 1963; Salamon et al., 1963) commented on the usual fair complexion, blue eyes, and multiple ephelides in patients with familial melanoma. In a questionnaire study, Kopf et al. (1986) found that a positive family history for melanoma was correlated with a younger age at first diagnosis in the proband, a smaller diameter of the lesion, lower Clark level, decreased frequency of nonmelanoma skin cancer, and reduced prevalence of noncutaneous cancer. (The Clark index refers to the level of invasion.) A comparison of monozygotic and dizygotic twins for melanoma might be important because of cases of melanoma in non-blood-related members of the same household (Robinson and Manheimer, 1972). Lynch et al. (1978) suggested that a cutaneous marker indicative of susceptibility to malignant melanoma is characterized by large moles, variable in number, reddish brown to pink in color, and with an irregular border. Histologically, they show a bizarre intraepidermal pattern. The authors also described a melanoma family with distinctive freckling and dryness of the skin, suggesting xeroderma pigmentosum (278700) but with normal unscheduled DNA repair and a dominant pedigree pattern. Other malignancies such as colon cancer had an increased frequency in these families. Clark et al. (1978), Greene et al. (1978), and Reimer et al. (1978) pointed out distinctive clinical and histologic features of the moles that are precursors of familial malignant melanomas. They termed these features the 'B-K mole syndrome' after the family names of 2 patients; later, Greene et al. (1980) and Elder et al. (1980) expressed a preference for the designation 'hereditary dysplastic nevus syndrome.' The same lesion underlies some cases of nonfamilial malignant melanoma. Greene et al. (1980) referred to this as 'dysplastic nevus syndrome, sporadic type.' The clinical features include between 10 and 100 moles on the upper trunk and limbs, and variability of mole size (from 5 to 15 mm), outline, and color. Histologically, B-K moles show atypical melanocytic hyperplasia, lymphocytic infiltration, delicate fibroplasia, and new blood vessel formation. Lynch et al. (1980) referred to this as FAMMM (familial atypical mole--malignant melanoma syndrome). Arndt (1984) and Greene et al. (1985) provided photographic illustration of the familial dysplastic nevus syndrome. Lynch et al. (1980) studied 3 kindreds of the FAMMM syndrome. Father-to-son transmission was observed. One patient had 9 separate primary melanomas in 18 years. Expressivity was highly variable. Management is difficult because one cannot be certain which moles require biopsy and then, following histologic study, which require wide excision. The possibility of increased risk of cancer at other sites was raised. Hartley et al. (1987) described several cases of malignant melanoma in close relatives of children with osteosarcoma (259500) and chondrosarcoma (215300). They proposed that in certain families malignant melanoma may be a manifestation of the same gene defect that results in susceptibility to tumors characteristic of the SBLA syndrome (151623). Tucker et al. (2002) described the clinical and histologic features of dysplastic nevi and melanoma over time in families at an increased risk of melanoma with differing germline mutations in CDKN2A (600160) and CDK4 (123829). They evaluated clinically and followed prospectively for up to 25 years a total of 33 families with more than 2 living members with invasive melanoma. A total of 844 family members were examined and photographed. All the families were found to have members with dysplastic nevi and melanoma; 17 had mutations in CDKN2A, 2 had mutations in CDK4, and 14 had no mutations in either gene identified. Most of the dysplastic nevi either remained stable or regressed; few changed in a manner that should have caused concern for melanoma. The melanomas and dysplastic nevi that were found to occur in the study families did not appear to vary by the type of mutation identified in the families. Melanoma-associated retinopathy is a form of paraneoplastic visual disorder that can occur in individuals who have metastatic cutaneous malignant melanoma. Alexander et al. (2004) found that the overall pattern of contrast sensitivity loss shown by patients with melanoma-associated retinopathy was consistent with the dysfunction at the level of the retinal bipolar cells presumed to underlie the disorder. Other Features Tumor-specific antigens have been found in malignant melanoma (Hawkins et al., 1981; Pellegris et al., 1982). Some studies have observed an increased risk of Parkinson disease (PD; 168600) among individuals with melanoma (see, e.g., Constantinescu et al., 2007 and Ferreira et al., 2007), suggesting that pigmentation metabolism may be involved in the pathogenesis of PD. From 2 existing study cohorts of 38,641 men and 93,661 women who were free of PD at baseline, Gao et al. (2009) found an association between decreasing darkness of natural hair color in early adulthood and increased PD risk. The pooled relative risks for PD were 1.0 (reference risk), 1.40, 1.61, and 1.93 for black, brown, blond, and red hair, respectively. These results were significant after adjusting for age, smoking, ethnicity, and other covariates. The associations between hair color and PD were particularly strong for onset before age 70 years. In a case-control study of 272 PD cases and 1,185 controls, there was an association between the cys151 SNP of the MCR1 gene (155555.0004), which confers red hair, and increased risk of PD relative to the arg151 SNP (relative risk of 3.15 for the cys/cys genotype). Noting that melanin, like dopamine, is synthesized from tyrosine, and that PD is characterized by the loss of neuromelanin-containing neurons in the substantia nigra, Gao et al. (2009) postulated a link between pigmentation and development of PD. Herrero Hernandez (2009) independently noted the association. Inheritance Multiple authors have documented familial inheritance of malignant melanoma: see Cawley (1952); Smith et al. (1966); Andrews (1968). Katzenellenbogen and Sandbank (1966) described dizygotic twins with malignant melanoma. Anderson et al. (1967) described malignant melanoma in at least 15 members of 3 generations of 1 kindred. Early age of onset and a tendency for multiple primary lesions were features. Lynch and Krush (1968) described 2 families with malignant melanoma in 2 generations in 1 family and 3 generations in the other. Anderson (1971) reported 36 pedigrees in which a total of 106 members had cutaneous melanoma. He noted that in addition to earlier age at onset and increased frequency of multiple primary lesions, familial cases have a higher survival rate than nonfamilial cases. Rhodes et al. (1985) found that the prevalence rate of congenital nevomelanocytic nevi was 11 times greater in sibs of probands than in the general population. They had some families with 2 generations affected. In the families with CMM studied by Greene et al. (1983), further studies (Bale et al. (1985, 1986)) showed that dysplastic nevus (DN), a lesion known to be a precursor of melanoma, also segregates in an autosomal dominant manner. Pascoe (1987) challenged the concept of a single dominant gene as proposed by Bale et al. (1986). Bale and Chakravarti (1987) defended their conclusion. Traupe et al. (1989) also challenged the autosomal dominant hypothesis for dysplastic nevus syndrome on the basis of the lack of a genetic equilibrium between eliminated and newly arising mutations. Happle et al. (1982) had advanced arguments in favor of polygenic inheritance of dysplastic nevi: (1) lack of a consistent family pattern; (2) frequent sporadic occurrence of the trait; (3) continuous transition between ordinary and dysplastic nevi; and (4) analogy with an animal model. Kraemer et al. (1983) found 4 persons affected with the dysplastic nevus phenotype. The risk of developing melanoma is not constant but increases with the number of melanoma patients in the family. This is a feature typical of polygenic inheritance. Pathogenesis Gilchrest et al. (1999) reviewed the role of ultraviolet radiation in the induction of melanoma. They pointed out that even among kindreds predisposed to multiple atypical melanocytic nevi and melanomas because of germline mutations in the CDKN2A gene (600160), retrospective analyses suggest that the incidence of melanoma has increased in recent generations, a phenomenon ascribed to the independent risk factor of increased sun exposure. Not only melanoma but also the more common skin cancers, basal cell and squamous cell carcinomas, are related to ultraviolet exposure. However, unlike the more common skin cancers, which are associated with total cumulative exposure to UV radiation, melanomas are associated with intense intermittent exposure. Thus, basal cell and squamous cell carcinomas occur most commonly in maximally sun-exposed areas of the body, such as the face and the backs of the hands and forearms, and in persons with almost daily and substantial lifetime exposure to UV radiation, such as farmers and sailors. In contrast, melanoma occurs most commonly in areas of the body exposed to the sun intermittently, such as the back in men and the lower legs in women, with relative sparing of more frequently exposed sites such as the face, hands, and forearms; it is most common in persons with predominantly indoor occupations whose exposure to the sun is limited to weekends and vacations. Indeed, the large increase in the incidence of melanoma in recent decades may be attributable to the ability of large numbers of people to travel long distances to obtain intense exposure to the sun in winter. The risk of melanoma is associated specifically with exposures that induce sunburn, and a history of 5 or more severe sunburns during adolescence more than doubles the risk. Gilchrest et al. (1999) suggested a biologic basis of these phenomena. The hypothesis was based on differences in response of keratinocytic stem cells and melanocytes to UV exposure. In melanocytes, a first high dose of ultraviolet radiation will cause substantial damage but not apoptosis; therefore, the melanocytes will survive to mutate and divide. Indeed, the appearance of freckles in children, often abruptly after high-dose sun exposure, is consistent with the thought that freckles represent clones of mutated melanocytes. In contrast, intermittent high-dose exposures to UV radiation result in loss of these cells, whereas repeated low-dose exposure would be expected ultimately to cause multiple mutations in the cells retained in the basal compartment and hence give rise to keratinocytic cancers. Murine melanocytes ordinarily are confined to hair follicles. The skin of transgenic mice in which a metallothionein gene promoter forces the overexpression of hepatocyte growth factor/scatter factor (HGF/SF; 142409) has melanocytes in the dermis, epidermis, and dermal-ectodermal junction, and is thus more akin to human skin. Noonan et al. (2001) subjected albino HGF/SF transgenic mice and wildtype littermates to erythemal ultraviolet irradiation at 3.5 days of age, 6 weeks of age, or both. A single neonatal dose, which was 30-fold lower than the total ultraviolet dose administered previously to adult mice, was sufficient to induce melanoma in HGF/SF-transgenic mice after a relatively short latent period and with high cumulative incidence. This neonatal dose roughly corresponds to a sunburning dose of natural sunlight at midlatitudes in midsummer. Melanoma development in the transgenic mice after ultraviolet irradiation at both 3.5 days and 6 weeks was indistinguishable from that seen after only a single exposure at 3.5 days, whereas a similar dose at 6 weeks was not tumorigenic. However, the second exposure to ultraviolet light increased the multiplicity of melanocytic lesions as well as the incidence of nonmelanocytic tumors, including squamous cell carcinoma and sarcoma. Melanomas were not seen in either nontransgenic or untreated transgenic mice during the course of the experiment. Curtin et al. (2005) demonstrated genetic diversity in melanomas related to susceptibility to ultraviolet light. They compared genomewide alternations in the number of copies of DNA and mutational status of BRAF (164757) and NRAS (164790) in 126 melanomas from 4 clinical groups in which the degree of exposure to ultraviolet light differed: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from arms, soles, and subungual (acral) sites; and 20 mucosal melanomas. They found significant differences in the frequencies of regional changes in the number of copies of DNA and mutational frequencies in BRAF among the 4 groups of melanomas. These samples could be correctly classified into the 4 groups with 70% accuracy on the basis of changes in the number of copies of genomic DNA. In 2-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84% accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89% accuracy. In 81% of melanomas on skin without chronic sun-induced damage, they found mutations in BRAF or NRAS; most melanomas in the other groups had mutations in neither gene. Melanomas with wildtype BRAF or NRAS frequently had increases in the number of copies of genes for cyclin-dependent kinase-4 (CDK4; 123829) and cyclin-1 (CCND1; 168461), which are downstream components of the RAS-BRAF pathway. In these studies, alterations in the number of copies of DNA was determined by comparative genomic hybridization. Schatton et al. (2008) identified a subpopulation of tumor-initiating cells enriched for human malignant melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (611785) and showed that specific targeting of this tumorigenic minority population inhibits tumor growth. ABCB5-positive tumor cells detected in human melanoma patients showed a primitive molecular phenotype and correlated with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCBA5-positive melanoma cells possessed greater tumorigenic capacity than ABCB5-negative bulk populations and reestablished clinical tumor heterogeneity. In vivo genetic lineage tracking demonstrated a specific capacity of ABCB5-positive subpopulations for self-renewal and differentiation, because ABCB5-positive cancer cells generated both ABCB5-positive and ABCB5-negative progeny, whereas ABCB5-negative tumor populations gave rise, at lower rates, exclusively to ABCB5-null cells. In an initial proof-of-principle analysis designed to test the hypothesis that MMIC are also required for growth of established tumors, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5-positive MMIC, exerted tumor-inhibitory effects. While studies on diverse cancers, including melanoma, in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice indicated that only rare human cancer cells (0.1-0.0001%) form tumors, the possibility that these studies underestimate the frequency of tumorigenic human cancer cells had been raised. Quintana et al. (2008) showed that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/SCID mice (null for Il2rg, 308380), can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumors under these more permissive conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from 4 different patients formed tumors. Quintana et al. (2008) concluded that modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers. Passeron et al. (2009) found weak or absent SOX9 (608160) expression in 37 (95%) of 39 melanoma specimens. SOX9 expression was positive in normal skin areas, but weak or negative in 18 (81.8%) of 22 nevi, in 54 (96.4%) of 56 primary melanomas, and in 100% (20 of 20) metastatic melanomas. Thus, SOX9 expression decreased as melanocytic cells progressed from the normal condition to the premalignant (nevi) to the transformed state, and was completely negative in the most advanced (metastatic) state of malignancy. SOX9 functioned by binding the CDKN1A (116899) promoter, which resulted in strong suppression of cell growth in vivo. SOX9 also decreased PRAME (606021) protein levels in melanoma cells and restored sensitivity to retinoic acid. SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 (176803) increased SOX9 expression and restored sensitivity to retinoic acid. Combined treatment with PGD2 and retinoic acid substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. These results provided insight into the pathophysiology of melanoma. Kapoor et al. (2010) reported that the histone variant macroH2A (mH2A; 610054) suppresses tumor progression of malignant melanoma. Loss of mH2A isoforms, histone variants generally associated with condensed chromatin and fine-tuning of developmental gene expression programs, was positively correlated with increasing malignant phenotype of melanoma cells in culture and human tissue samples. Knockdown of mH2A isoforms in melanoma cells of low malignancy resulted in significantly increased proliferation and migration in vitro and growth and metastasis in vivo. Restored expression of mH2A isoforms rescued these malignant phenotypes in vitro and in vivo. Kapoor et al. (2010) demonstrated that the tumor-promoting function of mH2A loss is mediated, at least in part, through direct transcriptional upregulation of CDK8 (603184). Suppression of CDK8, a colorectal cancer oncogene, inhibits proliferation of melanoma cells, and knockdown of CDK8 in cells depleted of mH2A suppresses the proliferative advantage induced by mH2A loss. Moreover, a significant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient samples. Kapoor et al. (2010) concluded that mH2A is a critical component of chromatin that suppresses the development of malignant melanoma. Zaidi et al. (2011) introduced a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. They used expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of IFN-gamma (147570), but not type I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2 (601267). Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-enhanced melanoma growth and survival. IFN-gamma-producing macrophages were also identified in 70% of human melanomas examined. Zaidi et al. (2011) concluded that their data revealed an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients. Ceol et al. (2011) used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) (164757.0001) and accelerate melanoma. SETDB1 (604396), an enzyme that methylates histone H3 (see 602810) on lysine-9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes (e.g., 142950), that are transcriptionally dysregulated in response to increased levels of SETDB1. Ceol et al. (2011) concluded that their studies established SETDB1 as an oncogene in melanoma and underscored the role of chromatin factors in regulating tumorigenesis. White et al. (2011) used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (191170) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, White et al. (2011) performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH; 126064), e.g., leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. White et al. (2011) concluded that their studies, taken together, highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation. Straussman et al. (2012) developed a coculture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. They found that stroma-mediated resistance is common, particularly to targeted agents. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF; 142409) resulted in activation of the HGF receptor MET (164860), reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signaling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. Wilson et al. (2012) independently found that HGF confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells, and generalized that there is extensive redundancy of receptor tyrosine kinase (RTK)-transduced signaling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases. Johannessen et al. (2013) carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK (see 176872), ERK (see 601795), or combined RAF-MEK inhibitors. These studies revealed a cAMP-dependent melanocytic signaling network not previously associated with drug resistance that included G protein-coupled receptors, adenyl cyclase (ADCY9; 603302), protein kinase A (PRKACA; 601639), and CREB (123810). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumors. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS (164810), NR4A1 (139139), NR4A2 (601828), and MITF (156845). Combined treatment with MAPK pathway and histone deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Johannessen et al. (2013) concluded that these data suggested that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signaling- and chromatin-directed therapeutics. Sun et al. (2014) found that 6 out of 16 BRAF(V600E) (164757.0001)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK. Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday. To investigate how ultraviolet radiation (UVR) accelerates oncogenic BRAF-driven melanomagenesis, Viros et al. (2014) used a BRAF mutant (V600E) mouse model. In mice expressing the V600E mutation in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Viros et al. (2014) showed that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma but provided only partial protection. The UVR-exposed tumors showed increased numbers of single-nucleotide variants, and Viros et al. (2014) observed mutations in Trp53 (TP53; 191170) in approximately 40% of cases. TP53 is an accepted UVR target in human nonmelanoma skin cancer but was not thought to play a major role in melanoma. However, Viros et al. (2014) showed that in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that in humans TP53 mutations are linked to evidence of UVR-induced DNA damage in melanoma. Thus, the authors provided mechanistic insight into epidemiologic data linking UVR to acquired nevi in humans. Furthermore, they identified TP53/Trp53 as a UVR target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Viros et al. (2014) stated that their study validated public health campaigns that promote sunscreen protection for individuals at risk of melanoma. Chiba et al. (2017) demonstrated that TERT (187270) promoter mutations acquired at the transition from benign nevus to malignant melanoma do not support telomere maintenance. In vitro experiments revealed that TERT promoter mutations do not prevent telomere attrition, resulting in cells with critically short and unprotected telomeres. Immortalization by TERT promoter mutations requires a gradual upregulation of telomerase, coinciding with telomere fusions. These data suggested that TERT promoter mutations contribute to tumorigenesis by promoting immortalization and genomic instability in 2 phases. In an initial phase, TERT promoter mutations do not prevent bulk telomere shortening but extend cellular life span by healing the shortest telomeres. In the second phase, the critically short telomeres lead to genome instability and telomerase is further upregulated to sustain cell proliferation. ### Metastasis Bald et al. (2014) reported that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model created by Gaffal et al. (2011) promotes metastatic progression, independent of its tumor-initiating effects. UV irradiation enhanced the expansion of tumor cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box-1 (HMGB1; 163905) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor-4 (TLR4; 603030). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate toward endothelial cells and use selective motility cues on their surfaces. Bald et al. (2014) concluded that their results not only revealed how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also showed that the resulting inflammatory response catalyzes reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and hematogenous dissemination. Consistent with these findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Luo et al. (2016) provided data indicating that PGC1-alpha (604517) suppresses melanoma metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1-alpha expression inversely correlated with vertical growth in human melanoma specimens. PGC1-alpha silencing made poorly metastatic melanoma cells highly invasive and, conversely, PGC1-alpha reconstitution suppressed metastasis. Within populations of melanoma cells, there is a marked heterogeneity in PGC1-alpha levels, which predicts their inherent high or low metastatic capacity. Mechanistically, PGC1-alpha directly increases transcription of ID2 (600386), which in turn binds to and inactivates the transcription factor TCF4 (602272). Inactive TCF4 caused downregulation of metastasis-related genes, including integrins that influence invasion and metastasis. Inhibition of BRAFV600E (164757.0001) using vemurafenib, independently of its cytostatic effects, suppressed metastasis by acting on the PGC1-alpha-ID2-TCF4-integrin axis. Luo et al. (2016) concluded that PGC1-alpha maintains mitochondrial energetic metabolism and suppresses metastasis through direct regulation of parallel-acting transcriptional programs. Cytogenetics In 4 of 5 cases of malignant melanoma, Trent et al. (1983) found chromosome alterations, including deletion and translocation in the long arm of chromosome 6, specifically in the 6q15-q23 region. They pointed out that the MYB oncogene maps to this region. Becher et al. (1983), reviewing cytologic findings in malignant melanoma in their own and reported cases, likewise pointed to a high incidence of structural aberration of 6q (segment q11-q31), whereas the short arm remains structurally unchanged, though its genetic material is often duplicated, as in the case of isochromosome-6p in one of their cases. These findings accentuate the interest, they pointed out, in the relationships found between specific HLA haplotypes and familial malignant melanoma (Hawkins et al., 1981; Pellegris et al., 1982). Pathak et al. (1983), Balaban et al. (1984), and Rey et al. (1985) also reported preferential abnormalities of chromosome 6. Hecht et al. (1989) found a marked increase in chromosomal rearrangements in dysplastic nevi from patients with CMM and in their normal-looking skin but not in their lymphocytes. Mapping Linkage studies of a hypothetical dysplastic nevus (DN) locus and the cutaneous malignant melanoma (CMM) locus showed an association (lod = 3.857 at theta = 0.08). All families giving evidence on linkage were in coupling and the maximum likelihood estimate of recombination was not significantly different from 0 (Bale et al. (1985, 1986)). Bale et al. (1985) excluded linkage of CMM to HLA. Multipoint linkage analysis appeared to support the assignment of CMM to 1p (Bale et al., 1987). In 3 Utah kindreds ascertained through multiple cases of melanoma, Cannon-Albright et al. (1990) could find no evidence of linkage with the 2 markers most closely linked in the Bale study. Both melanoma alone and a combined melanoma/dysplastic nevus syndrome phenotype were analyzed. Furthermore, multipoint linkage analysis excluded the CM/DNS locus from an area of 55 cM. Bale et al. (1989) presented further evidence supporting assignment of the CMM locus to chromosome 1p36, 7.6 cM distal to PND (108780) and flanked by D1S47. Dracopoli et al. (1989) found loss of heterozygosity at loci on 1p in 43% of melanomas and 52% of melanoma cell lines. Analysis of multiple metastases derived from the same patient and of melanoma and lymphoblastoid samples from a family with hereditary melanoma showed that loss of heterozygosity at loci on distal 1p is a late event in tumor progression rather than the second mutation that would occur if melanoma were due to a cellular recessive mechanism. In neuroblastoma and in type II endocrine neoplasia also, 1p loss of heterozygosity is frequent, suggesting that this loss is a common late event of neuroectodermal tumor progression. By multipoint linkage analysis of 6 families, Dracopoli et al. (1989) found evidence that the familial melanoma gene maps to 1p36 about 8 cm distal to PND. The lod score was 5.42. Goldstein et al. (1993) extended the linkage studies to updated versions of these 6 families plus 7 new families. They concluded that there was 'significant evidence of heterogeneity,' and considered that this was responsible for the failure of some previous studies to confirm linkage to 1p in some families. Following up on previous linkage analyses of 19 cutaneous malignant melanoma/dysplastic nevi (CMM/DN) kindreds which showed significant evidence of linkage and heterogeneity to both chromosomes 1p and 9p (see CMM2; 155601), Goldstein et al. (1996) examined 2-locus hypotheses. The lod scores for CMM alone were highest using the single locus-heterogeneity model. They found much stronger evidence of linkage to 9p than to 1p for CMM alone; the lod scores were approximately 2 times greater on 9p than on 1p. A change in lod scores from an evaluation of CMM alone to CMM/DN suggested to the authors that a chromosome 1p locus contributed to both CMM and CMM/DN, whereas a 9p locus contributed more to CMM alone. For 2-locus models, the lod scores from 1p were greater for CMM/DN than for CMM alone. After conditioning on linkage to the other locus, only the 9p locus consistently showed significant evidence for linkage to CMM alone. Falchi et al. (2009) conducted a genomewide association study for nevus (see 162900) count, which is a known risk factor for cutaneous melanoma, using 297,108 single-nucleotide polymorphisms (SNPs) in 1,524 twins, with validation in an independent cohort of 4,107 individuals. Falchi et al. (2009) identified strongly associated variants in the MTAP gene (156540), which is adjacent to the familial melanoma susceptibility locus CDKN2A on 9p21 (see 155601) (rs4636294, combined p = 3.4 x 10(-15)), as well as in the PLA2G6 gene (603604) on 22q13.1 (rs2284063, combined p = 3.4 x 10(-8)). Variants in these 2 loci also showed association with melanoma risk in 3,131 melanoma cases from 2 independent studies, including rs10757257 at 9p21 (combined p = 3.4 x 10(-8), odds ratio = 1.23) and rs132985 at 22q13.1 (combined p = 2.6 x 10(-7), odds ratio = 1.23). ### Genetic Heterogeneity Millikin et al. (1991) used RFLPs to look for loss of constitutional heterozygosity (LOH) for markers on 6q. LOH on chromosome 6q was identified in 21 of 53 informative loci (40%). The chromosomal region bearing the highest frequency of 6q allelic loss was defined by the marker loci MYB (189990) and ESR (133430) located at 6q22-q23 and 6q24-q27, respectively. Possibly contradictory to chromosome 6 information is the report of Greene et al. (1983) of possible linkage to Rh (which is on 1p). A maximum lod score of 2.0 at theta 0.30 was observed. Nancarrow et al. (1992) reviewed the contradictory findings of linkage in this disorder and presented studies of 7 Australian kindreds. Both Cannon-Albright et al. (1990) and Kefford et al. (1991) had questioned the validity of dysplastic nevi as a marker for familial melanoma and excluded linkage to markers on 1p when familial melanoma alone (symbolized MLM) was used as the phenotype. Several of the Australian families studied by Kefford et al. (1991) showed little or no history of dysplastic nevus syndrome or surgical removal of histologically characterized dysplastic nevi. Of the 7 other Australian kindreds studied by Nancarrow et al. (1992), 3 had the largest number of affected individuals reported worldwide. Because they also had families without dysplastic nevi and because the data used to calculate the parameters of the model used by Kefford et al. (1991) were estimated from a population-based survey, Nancarrow et al. (1992) used the latter model but also analyzed the data with the model of Bale et al. (1989). The Kefford model was applied to MLM alone and took into account variable penetrance with age and variable frequency of sporadic cases with age. With this approach, they excluded MLM from a 40-cM region that spanned the interval between D1S47 and PND and extended approximately 15 cM on either side of these markers to a total of 70 cM. In addition, they excluded a region of about 20 cM around the D1S57/MYCL1 (164850) loci at 1p32. Nancarrow et al. (1992) carried out linkage analysis in 3 large Australian melanoma pedigrees, using 172 microsatellite markers spread across all autosomes. Three additional smaller families were typed for 70 of the same markers. In 5 of the 6 families, they found lod scores between 1.0 and 2.3, which suggested localization of melanoma genes in proximity to some of the markers. This may indicate genetic heterogeneity since there was no marker for which all families gave significantly high lods. Their data provided the basis of an exclusion map; regions of chromosome 6, 9cen, and 10qter could not be excluded in these studies. Fung et al. (2003) described an online locus-specific variant database for familial melanoma. ### Associations Pending Confirmation In a Spanish case-control study of 131 consecutive melanoma patients and 245 controls, Fernandez et al. (2008) analyzed 23 SNPs in 6 candidate genes belonging to the pigmentation pathway. The only clear association was with the F374L variant in the SLC45A2 gene (606202.0008) on chromosome 5p13.3. Following the identification of association of a SNP, rs401681, in an intron of the CLPTM1L gene (612585) on chromosome 5p15.33 with basal cell carcinoma (605462), Rafnar et al. (2009) tested rs401681 for association with 16 other cancer types in over 30,000 cancer cases and 45,000 controls. They found that rs401681 seems to confer protection against cutaneous melanoma (OR = 0.88, p = 8.0 x 10(-4)). The melanoma study included 2,381 patients and 30,839 controls. Most of the cancer types tested have a strong environmental component to their risk. Bishop et al. (2009) identified and replicated 2 loci with strong evidence of association with risk for cutaneous melanoma: 16q24 encompassing MC1R (155555) (combined P = 2.54 x 10(27) for rs258322) and 11q14-q21 encompassing TYR (606933) (P = 2.41 x 10(-14) for rs1393350). Molecular Genetics ### Somatic Mutations By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. Palavalli et al. (2009) performed mutation analysis of the matrix metalloproteinase (MMP) gene family in human melanoma and identified somatic mutations in 23% of melanomas. Five mutations in one of the most commonly mutated genes, MMP8 (120355), reduced MMP enzyme activity. Expression of wildtype but not mutant MMP8 in human melanoma cells inhibited growth on soft agar in vitro and tumor formation in vivo, suggesting that wildtype MMP8 has the ability to inhibit melanoma progression. Prickett et al. (2009) performed a mutation analysis of the protein tyrosine kinase gene family in cutaneous metastatic melanoma. They identified 30 somatic mutations affecting the kinase domains of 19 protein tyrosine kinases and subsequently evaluated the entire coding regions of the genes encoding these 19 protein tyrosine kinases for somatic mutations in 79 melanoma samples. Prickett et al. (2009) found mutations in ERBB4 (600543) in 19% of individuals with melanoma and found mutations in 2 other kinases (FLT1, 165070 and PTK2B, 601212) in 10% of individuals with melanomas. Prickett et al. (2009) examined 7 missense mutations in ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. Pleasance et al. (2010) sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalog of somatic mutations from an individual cancer. Pleasance et al. (2010) suggested that the catalog provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas an uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. Using exome sequencing followed by screening of targeted genes in melanoma samples, Wei et al. (2011) found 34 distinct somatic mutations in the GRIN2A gene (138253) in 25.2% of 135 melanomas. These findings implicated the glutamate signaling pathway in the pathogenesis of melanoma. Somatic mutations were also found in the TRRAP gene (603015) in 6 (4%) of 167 melanoma samples, and in the DCC gene (120470) in 3 (2%) of 167 melanomas. The most common somatic mutation was V600E in the BRAF gene (164757.0001), which occurred in 65.4% of tumors. Berger et al. (2012) sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per Mb of genome), intermediate in those originating from hair-bearing skin of the trunk (5 to 55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (612139), a PTEN (601728)-interacting protein and negative regulator of PTEN in breast cancer, as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumor formation of immortalized human melanocytes in vivo. Prickett et al. (2011) used exon capture and massively parallel sequencing methods to analyze the mutational status of 734 G protein-coupled receptors in melanoma. This investigation revealed that one family member, GRM3 (601115), was frequently mutated and that 1 of its mutations was recurrent. Biochemical analysis of GRM3 alterations revealed that mutant GRM3 selectively regulated the phosphorylation of MAPK/ERK kinase (MEK; see 176872), leading to increased anchorage-independent growth and migration. Melanoma cells expressing mutant GRM3 had reduced cell growth and cellular migration after short hairpin RNA-mediated knockdown of GRM3 or treatment with a selective MEK inhibitor. Prickett et al. (2011) found that 16.3% of melanomas were affected with GRM3 mutations, making this gene the second most frequently mutated in their study; the most frequently mutated was GPR98 (602851), with a mutation rate of 27.5%. Prickett et al. (2011) found the GRM3 glu870-to-lys mutation in 4 different individuals with melanoma. Nikolaev et al. (2012) performed exome sequencing to detect somatic mutations in protein-coding regions in 7 melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in 2 metastases derived from the same individual. Two melanomas with noncanonical BRAF mutations harbored gain-of-function MAP2K1 (MEK1; 176872) and MAP2K2 (MEK2; 601263) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Stark et al. (2012) sequenced 8 melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, Stark et al. (2012) found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 (602448) or MAP3K9 (600136). Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggested that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W33X variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma. Arafeh et al. (2015) analyzed 501 melanoma exomes and found that RASA2 (601589) was mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation and melanoma cell growth and migration. RASA2 expression was lost in at least 30% of human melanomas analyzed and was associated with reduced patient survival. To identify driver genes for mucosal melanoma, Ablain et al. (2018) sequenced hundreds of cancer-related genes in 43 human mucosal melanomas, cataloging point mutations, amplifications, and deletions. The SPRED1 gene (609291), which encodes a negative regulator of mitogen-activated protein kinase (MAPK) signaling, was inactivated in 37% of the tumors. Four distinct genotypes were associated with SPRED1 loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, Ablain et al. (2018) found that SPRED1 functions as a tumor suppressor, particularly in the context of KIT (164920) mutations. SPRED1 knockdown caused MAPK activation, increased cell proliferation, and conferred resistance to drugs inhibiting KIT tyrosine kinase activity. Hayward et al. (2017) reported the analysis of whole genome sequences from cutaneous, acral, and mucosal subtypes of melanoma. The heavily mutated landscape of coding and noncoding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting noncoding sequences was similar to that affected by recurrent mutations in coding sequences. Significantly mutated genes included BRAF (164757), CDKN2A (600160), NRAS (164790) and TP53 (191170) in cutaneous melanoma, BRAF, NRAS and NF1 (613113) in acral melanoma, and SF3B1 (605590) in mucosal melanoma. Mutations affecting the TERT (187270) promoter were the most frequent of all; however, neither they nor ATRX (300032) mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the MAPK and phosphoinositol kinase (PIK) pathways. ### Genetic Associations Gudbjartsson et al. (2008) found association of a single-nucleotide polymorphism (SNP), rs1408799C, which had been associated with eye color (see SHEP11, 612271), with risk of cutaneous malignant melanoma (odds ratio = 1.15, p = 4.3 x 10(-4)). Clinical Management The familial dysplastic nevus syndrome is a good example of a genetic disorder that lends itself to the practice of preventive genetics, i.e., preventive medicine, at the family level (Greene et al., 1985). Since 1960, mortality from cutaneous melanoma in the U.S. has risen more than mortality from any other cancer except carcinoma of the lung. Interferon (IFN) alfa-2b (147562) is used to treat high-risk cutaneous melanomas, although IFN alfa therapy is associated with a number of systemic side effects, including a flu-like syndrome, fatigue, malaise, weight loss, depression, nausea, anorexia, diarrhea, neutropenia, and thrombocytopenia. Hejny et al. (2001) reported 7 patients who developed retinopathy while receiving high-dose IFN alfa-2b therapy for adjuvant treatment of high-risk cutaneous melanoma. The risk of retinopathy appeared to be greater with higher dosage therapy and caused severe vision loss in 2 patients. The authors concluded that patients receiving high-dose IFN alfa-2b therapy need to be monitored for sequelae, including retinal neovascularization, until the retinopathy has resolved. Melanoma-associated retinopathy is a rare disorder characterized by metastatic melanoma, night blindness, and an electroretinographic pattern suggestive of congenital stationary night blindness (310500). Melanoma-associated retinopathy can be related to a variety of antiretinal antibodies. Potter et al. (2002) demonstrated the presence of antitransducin antibodies in the serum of a patient with a history of metastatic melanoma who had developed bilateral night blindness and decreased visual acuity. The authors postulated that recognition of transducin, a novel melanoma-associated retinopathy antigen, might be important for identifying and treating patients with night blindness and melanoma. Flaherty et al. (2010) reported complete or partial regression of BRAF V600E (164757.0001)-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK, cyclin D1, and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway. Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity. Chapman et al. (2011) conducted a phase 3 randomized clinical trial comparing vemurafenib (PLX4032) with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation (164757.0001). Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1,000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. At 6 months, overall survival was 84% (95% CI, 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P less than 0.001 for both comparisons). After review of the interim analysis, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E) (164757.0001)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations. Snyder et al. (2014) treated malignant melanoma exomes from 64 patients with CTLA4 (123890) blockade and then characterized the exomes using massively parallel sequencing. A discovery set consisted of 11 patients who derived long-term clinical benefit and 14 patients who derived either minimal or no benefit. Mutational load was associated with the degree of clinical benefit (p = 0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, Snyder et al. (2014) identified candidate tumor neoantigens for each patient. They elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA4 blockade. The authors validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab. Snyder et al. (2014) concluded that these findings defined a genetic basis for benefit from CTLA4 blockade in melanoma and provided a rationale for examining exomes of patients for whom anti-CTLA4 agents are being considered. Chan et al. (2015) clarified their use of the term 'validation set' in this article (Snyder et al., 2014) and noted corrections made to the article online. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, Van Allen et al. (2015) analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, they also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, Van Allen et al. (2015) concluded that detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors. Vetizou et al. (2015) found that the antitumor effects of CTLA4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA4 blockade. Chen et al. (2018) reported that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PDL1 (605402) on their surface. Stimulation with interferon-gamma (IFNG; 147570) increased the amount of PDL1 on these vesicles, which suppressed the function of CD8 (see 186910) T cells and facilitates tumor growth. In patients with metastatic melanoma, the level of circulating exosomal PDL1 positively correlated with that of IFNG, and varied during the course of anti-PD1 (600244) therapy. The magnitudes of the increase in circulating exosomal PDL1 during early stages of treatment, as an indicator of the adaptive response of the tumor cells to T cell reinvigoration, stratified clinical responders from nonresponders. Chen et al. (2018) concluded that their study unveiled a mechanism by which tumor cells systemically suppress the immune system, and provided a rationale for the application of exosomal PDL1 as a predictor for anti-PD1 therapy. Animal Model To build a model of human melanoma, Dankort et al. (2009) generated mice with conditional melanocyte-specific expression of Braf(V600E) (164757.0001). Upon induction of Braf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15 to 20 months. By contrast, expression of Braf(V600E) combined with Pten (601728) tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency, and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (see 601231) or Mek1/2 (see 176872) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with both drug inhibitors led to shrinkage of established melanomas. History The earliest report of familial CMM may be that of Norris (1820). In describing a case of malignant melanoma, Norris wrote: 'It is remarkable that this gentleman's father, about thirty years ago, died of a similar disease. A surgeon of this town attended him, and he informed me that a number of small tumours appeared between the shoulders...This tumour, I have remarked, originated in a mole, and it is worth mentioning, that not only my patient and his children had many moles on various parts of their bodies, but also his own father and brothers had many of them. The youngest son had one of these marks exactly in the same place where the disease in his father first manifested itself. These facts, together with a case that has come under my notice, rather similar, would incline me to believe that this disease is hereditary.' See commentary by Hecht (1989). INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Intraocular melanoma SKIN, NAILS, & HAIR Skin \- Atypical nevi (>5mm with irregular edge and pigmentation) \- Numerous nevi \- Atypical nevi often present in non-sun exposed areas NEOPLASIA \- Malignant melanoma ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 1	c0205747	1,976	omim	https://www.omim.org/entry/155600	2019-09-22T16:38:29	{"mesh": ["D004416"], "omim": ["155600"], "icd-9": ["172.9", "172"], "icd-10": ["C43", "C43.9"], "orphanet": ["404560", "618"], "synonyms": ["Alternative titles", "MELANOMA, CUTANEOUS MALIGNANT", "MELANOMA, MALIGNANT", "FAMILIAL ATYPICAL MOLE-MALIGNANT MELANOMA SYNDROME", "MELANOMA, FAMILIAL", "DYSPLASTIC NEVUS SYNDROME, HEREDITARY", "B-K MOLE SYNDROME"]}
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: "Synaptopathy" – news · newspapers · books · scholar · JSTOR (November 2012) (Learn how and when to remove this template message) Synaptopathy A common cause of synaptopathy is glutamate excitotoxicity. As shown in the animation, the over-activation of NMDA receptors leads to an increase in free intracellular calcium, which produces oxygen free-radicals and eventually neuronal dysfunction.[1] A synaptopathy is a disease of the brain, spinal cord or peripheral nervous system relating to the dysfunction of synapses. This can arise as a result of a mutation in a gene encoding a synaptic protein such as an ion channel, neurotransmitter receptor, or a protein involved in neurotransmitter release. It can also arise as a result of an autoantibody targeting a synaptic protein. Synaptopathies caused by ion channel mutations are also known as synaptic channelopathies. An example is episodic ataxia. Myasthenia gravis is an example of an autoimmune synaptopathy. Some toxins also affect synaptic function. Tetanus toxin and botulinum toxin affect neurotransmitter release. Tetanus toxin can enter the body via a wound, and botulinum toxin can be ingested or administered therapeutically to alleviate dystonia or as cosmetic treatment. Another example of synaptopathy occurs in the auditory system. This cochlear synaptopathy has been seen after prolonged noise exposure in both primate and non-primate models.[2][3] Two possible reasons for this neuronal death are both glutamate-mediated excitotoxicity in the postsynaptic terminal, and presynaptic ribbon damage which occurs by an unknown mechanism.[4] Synaptopathies are attracting research interest because they provide an insight into fundamental mechanisms of synaptic transmission and because an improved understanding of disease mechanisms may lead to new treatments. Some diseases of unknown etiology have been proposed to be synaptopathies. Examples include autism spectrum disorder[5] and schizophrenia.[6] Synaptic dysfunction can also occur in neurodegenerative disorders such as Alzheimer's.[7] Immune-mediated cerebellar ataxias represent a group of disorders causing cerebellar ataxia induced by a dysfunction of synapses.[8] Increasing knowledge of the genetic basis of these diseases has linked proteins to the function of the synapse. Age-related cochlear synaptic and neural degeneration has also been demonstrated in mice.[9] Molecules such as FMRP1 act as translational repressor thus when ablated such as in FXS result in varying degrees of cellular and behavioural abnormalities. Additional molecules thought to be involved include SynGAP and SHANK1.[10] ## References[edit] 1. ^ Mark, Leighton P; Prost, Robert W; Ulmer, John L; Smith, Michelle M; Daniels, David L; Strottmann, James M; Brown, W Douglas; Hacein-Bey, Lotfi (November 2001). "Pictorial Review of glutamate excitotoxicity: fundamental concepts for neuroimaging". American Journal of Neuroradiology. 22 (10): 1813–1824. PMID 11733308. 2. ^ Valero, MD; Burton, JA; Hauser, SN; Hackett, TA; Ramachandran, R; Liberman, MC (September 2017). "Noise-induced cochlear synaptopathy in rhesus monkeys (Macaca mulatta)". Hearing Research. 353: 213–223. doi:10.1016/j.heares.2017.07.003. PMC 5632522. PMID 28712672. 3. ^ Ruel, Jérôme; Wang, Jing; Rebillard, Guy; Eybalin, Michel; Lloyd, Ruth; Pujol, Rémy; Puel, Jean-Luc (May 2007). "Physiology, pharmacology and plasticity at the inner hair cell synaptic complex". Hearing Research. 227 (1–2): 19–27. doi:10.1016/j.heares.2006.08.017. PMID 17079104. 4. ^ Pujol, Rémy; Puel, Jean‐Luc (November 1999). "Excitotoxicity, synaptic repair, and functional recovery in the mammalian cochlea: a review of recent findings". Annals of the New York Academy of Sciences. 884 (1): 249–254. Bibcode:1999NYASA.884..249P. doi:10.1111/j.1749-6632.1999.tb08646.x. PMID 10842598. 5. ^ Wang, Xinxing; Kery, Rachel; Xiong, Qiaojie (June 2018). "Synaptopathology in autism spectrum disorders: Complex effects of synaptic genes on neural circuits". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 84 (Pt B): 398–415. doi:10.1016/j.pnpbp.2017.09.026. ISSN 0278-5846. PMID 28986278. 6. ^ Hayashi-Takagi, Akiko (January 2017). "Synapse pathology and translational applications for schizophrenia". Neuroscience Research. 114: 3–8. doi:10.1016/j.neures.2016.09.001. PMID 27633835. 7. ^ Jha, Saurabh Kumar; Jha, Niraj Kumar; Kumar, Dhiraj; Sharma, Renu; Shrivastava, Abhishek; Ambasta, Rashmi K.; Kumar, Pravir (2017). "Stress-induced synaptic dysfunction and neurotransmitter release in Alzheimer's Disease: Can neurotransmitters and neuromodulators be potential therapeutic targets?". Journal of Alzheimer's Disease. 57 (4): 1017–1039. doi:10.3233/JAD-160623. PMID 27662312. 8. ^ Mitoma, H.; Honnorat, J.; Yamaguchi, K.; Manto, M. (2020). "Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias". Int J Mol Sci. 21: E4936. doi:10.3390/ijms21144936. PMID 32668612. 9. ^ Sergeyenko, Yevgeniya; Lall, Kumud; Liberman, M Charles; Kujawa, Sharon G (21 August 2013). "Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline". The Journal of Neuroscience. 33 (34): 13686–13694. doi:10.1523/JNEUROSCI.1783-13.2013. PMC 3755715. PMID 23966690. 10. ^ Brose, Nils; O'Connor, Vincent; Skehel, Paul (April 2010). "Synaptopathy: dysfunction of synaptic function?". Biochemical Society Transactions. 38 (2): 443–4. doi:10.1042/bst0380443. PMID 20298199. ## External links[edit] * https://www.ucl.ac.uk/ion/synaptopathies [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Synaptopathy	None	1,977	wikipedia	https://en.wikipedia.org/wiki/Synaptopathy	2021-01-18T18:31:43	{"wikidata": ["Q7662053"]}
Ankyrin-B syndrome is associated with a variety of heart problems related to disruption of the heart's normal rhythm (arrhythmia). Heart rhythm is controlled by electrical signals that move through the heart in a highly coordinated way. In ankyrin-B syndrome, disruption of different steps of electrical signaling can lead to arrhythmia, and the resulting heart problems vary among affected individuals. Individuals with ankyrin-B syndrome may have problems with the sinoatrial (SA) node, which generates the electrical impulses that start each heartbeat. If the SA node is not functioning properly, the heartbeat can be too slow (bradycardia). In a small number of people with ankyrin-B syndrome, the heart takes longer than usual to recharge between beats, which is known as a prolonged QT interval (long QT). Some affected individuals have impaired progression (conduction) of electrical impulses between the chambers of the heart, which can cause a problem called heart block. Other heart problems that occur in ankyrin-B syndrome include irregular and uncoordinated electrical activity in the heart's upper chambers (atrial fibrillation) or lower chambers (ventricular fibrillation) and an abnormality called catecholaminergic polymorphic ventricular tachycardia (CPVT), in which an increase in the heart rate can trigger an abnormally fast and irregular heartbeat called ventricular tachycardia. In people with ankyrin-B syndrome, arrhythmia can lead to fainting (syncope) or cardiac arrest and sudden death. When associated with a prolonged QT interval, the condition is sometimes classified as long QT syndrome 4. However, because additional heart problems can result from changes in the same gene, long QT syndrome 4 is usually considered part of ankyrin-B syndrome. ## Frequency Ankyrin-B syndrome is a rare disorder. Its prevalence is unknown. ## Causes Ankyrin-B syndrome is caused by mutations in the ANK2 gene, which provides instructions for making a protein called ankyrin-B. This protein is active in many cell types, including heart (cardiac) muscle cells. The ankyrin-B protein inserts certain structures called ion channels into their proper locations in the cell membrane. Ion channels are complexes of proteins that transport charged atoms (ions) across cell membranes. In the heart, the flow of ions (such as sodium, potassium, and calcium) through ion channels generates the electrical signals that control the heartbeat and maintain a normal heart rhythm. Mutations in the ANK2 gene lead to production of an altered ankyrin-B protein that cannot target ion channels to their correct locations in cardiac muscle cells. The loss of functional ion channels in the heart disrupts the normal flow of ions, which alters the heart's normal rhythm and causes the heart problems associated with ankyrin-B syndrome. Not everyone with an ANK2 gene mutation has heart problems related to ankyrin-B syndrome. Researchers speculate that other genes or environmental factors may play a role in development of the condition. ### Learn more about the gene associated with Ankyrin-B syndrome * ANK2 ## Inheritance Pattern Ankyrin-B syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered ANK2 gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. Some people who have an altered ANK2 gene never develop heart problems, a situation known as reduced penetrance. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Ankyrin-B syndrome	c1833154	1,978	medlineplus	https://medlineplus.gov/genetics/condition/ankyrin-b-syndrome/	2021-01-27T08:25:10	{"gard": ["13294"], "mesh": ["C563428"], "omim": ["600919"], "synonyms": []}
A rare disorder characterized by dwarfism, severe craniofacial abnormalities and multiple unerupted teeth. ## Epidemiology Less than ten cases have been reported so far. ## Clinical description Main clinical features include craniosynostosis, acrocephaly, a prominent forehead, depressed nasal bridge, hypertelorism, midface hypoplasia, macroglossia, unerupted teeth, short neck, short and bowed limbs, short and broad hands and fingers, and flat feet. The main radiographic features are craniostenosis, fibrous dysplasia, metaphyseal lucencies and platyspondyly. Intelligence is usually normal. ## Etiology Osteoglosphonic dysplasia (OGD) is caused by mutations in the FGFR1 gene (8p11.2-p11.1). ## Genetic counseling OGD is transmitted in an autosomal dominant manner. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Osteoglosphonic dysplasia	c0432283	1,979	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2645	2021-01-23T17:52:02	{"gard": ["4142"], "mesh": ["C536050"], "omim": ["166250"], "umls": ["C0432283"], "icd-10": ["Q87.1"], "synonyms": ["Osteoglophonic dwarfism"]}
Pyridoxine-dependent epilepsy Other namesPyridoxine-dependent seizure (PDS), vitamin B6 responsive epilepsy Pyridoxine SpecialtyNeurology Pyridoxine-dependent epilepsy (PDE) is a rare genetic disorder characterized by intractable seizures in the prenatal and neonatal period. The disorder was first recognized in the 1950s, with the first description provided by Hunt et al. in 1954.[1][2][3] More recently, pathogenic variants within the ALDH7A1 gene have been identified to cause PDE.[1][2][3][4] ## Contents * 1 Genetics * 2 Treatment * 3 Monitoring * 4 References * 5 External links ## Genetics[edit] PDE is inherited in an autosomal recessive manner and is estimated to affect around 1 in 400,000 to 700,000 births, though one study conducted in Germany estimated a prevalence of 1 in 20,000 births.[1][2] The ALDH7A1 gene encodes for the enzyme antiquitin or α -aminoadipic semialdehyde dehydrogenase, which is involved with the catabolism of lysine.[1][2][4][5] ## Treatment[edit] Patients with PDE do not respond to anticonvulsant medications, but seizures rapidly cease with therapeutic intravenous doses of Vitamin B6 and remission from seizures are often maintained on daily therapeutic doses of Vitamin B6.[1][2][5] An optimal dose has not yet been established, but doses of 50–100 mg/day or 15–30 mg/kg/day have been proposed.[1][2] Importantly, excessive doses of vitamin B6 can result in irreversible neurological damage, and therefore several guidelines recommend between 200 mg (neonates) and 500 mg per day as the maximal daily dose.[1][2] Despite remission of seizure activity with vitamin B6 supplementation, intellectual disability is frequently seen in patients with PDE.[2][6] Because the affected enzyme antiquitin is involved in the cerebral lysine degradation pathway, lysine restriction as an additional treatment modality has recently been explored. Studies have been published which demonstrate potential for improved biomarkers, development, and behavior in patients treated with lysine restriction in addition to pyridoxine supplementation.[2][6] In trial, lysine restriction of 70–100 mg/kg/day in children less than 1 year of age, 45–80 mg/kg/day in children between 1–7 years of age, and 20–45 mg/kg/day in children older than 7 years of age were prescribed.[6] Despite the potential of additional benefit from lysine restriction, vitamin B6 supplementation remains the main-stay of treatment given lack of studies thus far demonstrating the safety and efficacy of lysine restriction for this purpose. ## Monitoring[edit] Plasma and cerebrospinal fluid levels of pipecolic acid are frequently elevated in patients with PDE, though it is a non-specific biomarker.[1][2][5] α-aminodipic semialdehyde is elevated in urine and plasma and is a more specific biomarker for PDE.[1][2][5] Improvements in these biomarkers have been reported with the implementation of a lysine-restricted diet.[2][5] Initial studies evaluating the safety and efficacy of lysine restriction evaluated developmental and cognitive outcomes by age-appropriate tests and parental observations.[6] ## References[edit] 1. ^ a b c d e f g h i Gospe, SM (Dec 7, 2001). "Pyridoxine-Dependent Epilepsy". GeneReviews. PMID 20301659. Retrieved June 19, 2014. 2. ^ a b c d e f g h i j k l Stockler, S; Plecko, B; Gospe, SM; Coulter-Mackie, M; et, al. (September 2011). "Pyridoxine dependent epilepsy and antiquitin deficiency: Clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up". Molecular Genetics and Metabolism. 104 (1–2): 48–60. doi:10.1016/j.ymgme.2011.05.014. PMID 21704546. 3. ^ a b Shih, JJ; Kornblum, H; Shewmon, DA (September 1996). "Global brain dysfunction in an infant with pyridoxine dependency: evaluation with EEG, evoked potentials, MRI, and PET". Neurology. 47 (3): 824–6. doi:10.1212/WNL.47.3.824. PMID 8797489. 4. ^ a b Pearl, PL; Gospe, SM (22 April 2014). "Pyridoxine or pyridoxal-5'-phosphate for neonatal epilepsy: the distinction just got murkier". Neurology. 82 (16): 1392–4. doi:10.1212/WNL.0000000000000351. PMID 24658927. 5. ^ a b c d e Parsley, LK; Thomas, JA (December 2011). "The patient with infantile seizures". Current Opinion in Pediatrics. 23 (6): 693–9. doi:10.1097/MOP.0b013e32834b930c. PMID 21926623. 6. ^ a b c d van Karnebeek, CDM; Hartmann, H; Jaggumantri, S; Bok, LA; et, al. (November 2012). "Lysine restricted diet for pyridoxine-dependent epilepsy: First evidence and future trials". Molecular Genetics and Metabolism. 107 (3): 335–344. doi:10.1016/j.ymgme.2012.09.006. PMID 23022070. ## External links[edit] Classification D * OMIM: 266100 * MeSH: C536254 External resources * eMedicine: article/985667 * GeneReview/NCBI/NIH/UW entry on Pyridoxine-Dependent Seizures * Pyridoxine-dependent epilepsy. Genetics Home Reference. June 17, 2013. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Pyridoxine-dependent epilepsy	c1849508	1,980	wikipedia	https://en.wikipedia.org/wiki/Pyridoxine-dependent_epilepsy	2021-01-18T18:30:16	{"gard": ["9298"], "mesh": ["C536254"], "umls": ["C1849508", "C1291560"], "orphanet": ["3006"], "wikidata": ["Q7263591"]}
This article is about the psychedelic experience. For the 2020 comedy film, see Bad Trip (film). Part of a series on Psychedelia Arts * Psychedelic art * Algorithmic art * Cyberdelic * Diffraction * Fractal art * Liquid light show * LSD art * Paisley * Phosphene * Psychedelic music * Acid house * Acid jazz * Acid rock * Acid techno * Acid trance * Chillwave * Hypnagogic pop * Madchester * Neo-psychedelia * Peyote song * P-Funk * Psychedelic folk * Psychedelic pop * Psychedelic rock * Psychedelic soul * Psychedelic trance * Space rock * Stoner rock * Trip hop Psychedelic film * Acid Western * Stoner film * Psychedelic literature Culture * Counterculture * Entheogen * Smart shop * Trip sitter * Psychedelic microdosing Drugs * 25I-NBOMe * 2C-B * Ayahuasca * Cannabis * DMT * Ibogaine * Ketamine * LSD * Mescaline * Peyote * Psilocybin mushrooms * Salvinorin A/Salvia * San Pedro cactus * List of psychedelic drugs * List of psilocybin mushrooms * Psychoactive cactus Experience * Bad trip * Ecology * Ego death * Serotonergic psychedelic * Therapy History * Acid Tests * Albert Hofmann * Alexander Shulgin * History of lysergic acid diethylamide * Owsley Stanley * Psychedelic era * Summer of Love * Timothy Leary * William Leonard Pickard Law * Drug policy of the Netherlands * Drug liberalization * Legality of cannabis * Legal status of psilocybin mushrooms * Legal status of Salvia divinorum Related topics * Addiction * Cannabis * MDMA * Philosophy of psychedelics * Psychonautics * Prohibition of drugs * Rave * Recreational drug use * Surrealism * v * t * e A bad trip (also known as acute intoxication from hallucinogens, psychedelic crisis, or emergence phenomenon) is a frightening and unpleasant experience triggered by psychoactive drugs, especially psychedelic drugs such as LSD and Psilocybin mushroom. The features of a bad trip can range from feelings of mild anxiety and alienation to profoundly abject terror, ultimate entrapment, or complete loss of self-identity.[citation needed] Psychedelic specialists in the therapeutic community do not necessarily consider unpleasant experiences as threatening or negative, instead focusing on their potential to greatly benefit the user when properly resolved.[citation needed] Bad trips can be exacerbated by the inexperience or irresponsibility of the user or the lack of proper preparation and environment for the trip, and are reflective of unresolved psychological tensions triggered during the course of the experience.[1] ## Contents * 1 Aspects * 1.1 Unpredictability of the experience * 2 Intervention * 3 Potential causes * 4 See also * 5 References * 6 External links ## Aspects[edit] A multitude of reactions can occur during a psychedelic crisis. Some users may experience a general sense of fear, panic, or anxiety.[2] A user may be overwhelmed with the disconnection many psychedelics cause, and fear that they are going insane or will never return to reality. The fear that is felt during a bad trip has a psychotic character, coming as it does from within the mind of the tripper and not from the external environment. For example, during Albert Hoffman's first acid trip, he hallucinated that his neighbour had turned into a malignant demon, when in fact she was only a friendly woman trying to help him. A person having a bad trip might try to harm themselves or others around them.[3][better source needed] They may experience suicidal ideation, or make full-blown suicide attempts. Because of the magnification of emotions they induce, many psychedelics could possibly cause thoughts of death and intensely adverse reactions in some users. Users can believe that their death is imminent or that the very universe itself is collapsing.[3][better source needed] Rapid "aging" of other people may be observed by the user, perpetuating the aforementioned fears to an even greater degree. Some users may experience disorientation. The normal views of time, space, and person can be substantially altered, causing fear. Some can worsen their condition by trying to fight the psychedelic experience after embarkment. There can be illusions of insects crawling over or into one's self, or of being in dirty places such as sewers. Some users may experience a feeling of losing control of their minds due to persistent racing thoughts. In rare cases an apparent complete loss of control can be observed, with an individual's behavior tending to exhibit a temporary loss of normal understanding of navigation of one's physical environment. An individual in such a state can cause accidental harm to themselves and to others, and can include behavior such as flailing about or even running into traffic, or, as such a state may not necessarily involve physical movement, may involve induction of a catatonic state or the expression of seemingly random vocalizations i.e. not limited to true speech. This may be caused by a failure to recognize external stimuli for what it is. Stanislav Grof explains this feature: > There is a tremendous danger of confusing the inner world with the outer world, so you'll be dealing with your inner realities but at the same time you are not even aware of what's happening, You perceive a sort of distortion of the world out there. So you can end up in a situation where you're weakening the resistances, your conscious is becoming more aware, but you're not really in touch with it properly, you're not really fully experiencing what's there, not seeing it for what it is. You get kind of deluded and caught into this.[4] ### Unpredictability of the experience[edit] The effects of psychedelics vary widely from one individual to the next, and from one experience to the next. Sometimes individuals under the influence of such drugs do not understand that they have taken a drug and believe that they will never return to their ordinary, sober perception, though some can be reminded verbally. In cases where the individual cannot be kept safe, hospitalization may be useful, though the value of this practice for individuals not mentally ill is disputed by proponents of the investigative or recreational use of psychoactive compounds. Psychosis is exacerbated in individuals already suffering from this condition. ## Intervention[edit] Generally, a person experiencing a psychedelic crisis can be helped either to resolve the impasse, to bypass it, or, failing that, to terminate the experience. A person's thoughts before taking or while under the influence of the psychedelic, often greatly influence the trip. Medical treatment consists of supportive therapy and minimization of external stimuli. In some cases, sedation is used when necessary to control self-destructive behavior, or when hyperthermia occurs. Diazepam is the most frequently used sedative for such treatment, but other benzodiazepines such as lorazepam are also effective.[citation needed] Such sedatives will only decrease fear and anxiety, but will not subdue hallucinations. In severe cases, antipsychotics such as haloperidol can reduce or stop hallucinations. Haloperidol is effective against acute intoxication caused by LSD and other tryptamines, amphetamines, ketamine, and phencyclidine.[5][6] ## Potential causes[edit] According to Timothy Leary, a crisis can be a result of wrong set and setting. Leary advised that users of psychedelics be sure that they are comfortable before taking the drugs. Leary claimed that the frequency of difficult trips was highly exaggerated by anecdotes and fabrications in the popular press. Alternatively, psychiatrist R. D. Laing held that psychedelic crises and other such extreme experiences, drug-induced or not, were not necessarily artificial terrors to be suppressed but rather signs of internal conflict and opportunities for self-healing. The greater the pain and pathos of an experience, the greater the urgency to explore and resolve it, rather than attempt to cover it up or dismiss it.[citation needed] Likewise, Stanislav Grof suggested that painful and difficult experiences during a trip could be a result of the mind reliving experiences associated with birth, and that experiences of imprisonment, eschatological terror, or suffering far beyond anything imaginable in a normal state, if seen through to conclusion, often resolve into emotional, intellectual and spiritual breakthroughs. From this perspective, Grof suggests that interrupting a bad trip, while initially seen as beneficial, could potentially trap the tripper in unresolved psychological states. Grof also suggests that many cathartic experiences within psychedelic states, while not necessarily crises, may be the effects of consciousness entering a perinatal space.[7] ## See also[edit] * Psychedelic experience * Existential crisis * Psychedelic therapy * Psychonautics * Psychosis * Recreational drug use * Psychedelics, dissociatives and deliriants * Responsible drug use * Hard and soft drugs * Altered state of consciousness * Lucid dreaming * Sensory deprivation * Spiritual crisis * Out-of-body experience * Overdose * Ego death * Posttraumatic stress disorder * Posttraumatic growth ## References[edit] 1. ^ Stanislav Grof, LSD Psychotherapy; passim 2. ^ The Good Drugs Guide (2006). "Avoiding Bad Trips – Essential Info". Essential Info. The Good Drugs Guide. Archived from the original on 14 December 2006. Retrieved 2006-12-12. 3. ^ a b Erowid (2006). "Erowid Psychoactive Vaults – Psychedelic Crisis FAQ" (shtml). Erowid Psychoactive Vaults. Erowid. Retrieved 2006-12-12. 4. ^ "Archived copy". Archived from the original on 2011-09-27. Retrieved 2011-04-12.CS1 maint: archived copy as title (link) 5. ^ Giannini, A. James; Underwood, Ned A.; Condon, Maggie (2000). "Acute Ketamine Intoxication Treated by Haloperidol". American Journal of Therapeutics. 7 (6): 389–91. doi:10.1097/00045391-200007060-00008. PMID 11304647. 6. ^ "Sage Journals". Archived from the original on 2014-08-24. Retrieved 2018-03-27. 7. ^ Grof, Stanislav (1975). realms of the human unconscious - Observations from LSD research. souvenir press. pp. 95–153. ISBN 0-285-64882-9. ## External links[edit] Classification D * ICD-10: F16.0 * ICD-9-CM: 305.3 * Psychedelic Crisis FAQ: Helping someone through a bad trip, psychic crisis, or spiritual crisis * Crisis Intervention in Situations Related to Unsupervised Use of Psychedelics * The Psychedelic crisis (bad trip) entry at Drugs-Wiki * Psychedelic Harm Reduction * Psychedelic Harm Reduction and Policy lecture in the Psychedelic Science in the 21st Century conference in 2010. * Psychedelics in the Psychiatric ER - Julie Holland, M.D. lecture in the Psychedelic Science in the 21st Century conference in 2010. * 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 [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Bad trip	None	1,981	wikipedia	https://en.wikipedia.org/wiki/Bad_trip	2021-01-18T18:55:14	{"icd-9": ["305.3"], "icd-10": ["F16.0"], "wikidata": ["Q622106"]}
This article's lead section may be too short to adequately summarize its key points. Please consider expanding the lead to provide an accessible overview of all important aspects of the article. (December 2015) Chronic neutrophilic leukemia Other namesCNL[1] SpecialtyHematology and oncology Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm that features a persistent neutrophilia in peripheral blood, myeloid hyperplasia in bone marrow, hepatosplenomegaly, and the absence of the Philadelphia chromosome or a BCR/ABL fusion gene.[2] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Genetics * 4 Diagnosis * 4.1 Laboratory findings * 4.2 Sites of involvement * 4.2.1 Bone marrow biopsy * 4.2.2 Spleen * 4.2.3 Liver * 4.3 Immunophenotype * 5 Epidemiology * 6 References * 7 External links ## Signs and symptoms[edit] The most common clinical finding is hepatosplenomegaly. Pruritus, gout, and mucocutaneous bleeding are occasionally seen.[3][4] ## Cause[edit] The cause of CNL is currently unknown. An association between CNL and multiple myeloma has been suggested based on the observation of myeloma in 20% of CNL cases.[5] However, a clonal genetic abnormality has not been detected in these myeloma-associated cases of CNL, raising the possibility that the neutrophilia is a reaction due to the neoplastic myeloma cells.[2] The postulated cell of origin is a limited-potential, marrow-derived stem cell.[6] ## Genetics[edit] The majority (90%) of cases have not had detectable cytogenetic abnormalities. Most importantly, the Philadelphia chromosome and other BCR/ABL fusion genes are not detected.[2] ## Diagnosis[edit] ### Laboratory findings[edit] Peripheral blood neutrophilia (> 25 x 109/L) with myeloid precursors (promyelocytes, myelocytes, metamyelocytes) comprising less than 5% of leukocytes.[3][4] ### Sites of involvement[edit] Peripheral blood, bone marrow, spleen, and liver are most common, but any organ or tissue can be infiltrated by neutrophils.[3] [4] #### Bone marrow biopsy[edit] On both the bone marrow aspirate and the core biopsy, a hypercellular marrow with an increased myeloid:erythroid ratio of 20:1 or greater. Myelocytes and neutrophils are increased, and blasts and promyelocytes are not increased. Due to the myeloproliferative nature of the disease, an increase in megakaryocytes and erythroid precursors may be observed, but dyspoiesis in not seen in any cell lineage. Also, reticulin fibrosis is rare.[3][4] There is a reported association between CNL and multiple myeloma, so the bone marrow biopsy may show evidence of a plasma cell dyscrasia with increased numbers of atypical plasma cells.[2] #### Spleen[edit] Splenic infiltrates are typically found only in the red pulp.[3] [4] #### Liver[edit] Hepatic infiltrates can be found in either the sinusoids, portal triad regions, or both.[3][4] ### Immunophenotype[edit] No distinct immunophenotype abnormality for CNL has been described.[2] See OHSU 2013 findings of gene CSF3R, mutation p. T6181 ## Epidemiology[edit] This is a rare disease, with less than 100 cases reported. Of these cases, an equal male:female ratio was observed,[3] with cases typically seen in older adults.[4] ## References[edit] 1. ^ "Chronic neutrophilic leukemia \| Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 17 November 2019. 2. ^ a b c d e Elaine Sarkin Jaffe, Nancy Lee Harris, World Health Organization, International Agency for Research on Cancer, Harald Stein, J.W. Vardiman (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumors. 3. Lyon: IARC Press. ISBN 92-832-2411-6.CS1 maint: multiple names: authors list (link) 3. ^ a b c d e f g You W, Weisbrot IM (August 1979). "Chronic neutrophilic leukemia. Report of two cases and review of the literature". Am. J. Clin. Pathol. 72 (2): 233–42. doi:10.1093/ajcp/72.2.233. PMID 289288. 4. ^ a b c d e f g Zittoun R, Réa D, Ngoc LH, Ramond S (February 1994). "Chronic neutrophilic leukemia. A study of four cases". Ann. Hematol. 68 (2): 55–60. doi:10.1007/BF01715131. PMID 8148416. 5. ^ Standen GR, Steers FJ, Jones L (April 1993). "Clonality of chronic neutrophilic leukaemia associated with myeloma: analysis using the X-linked probe M27 beta". J. Clin. Pathol. 46 (4): 297–8. doi:10.1136/jcp.46.4.297. PMC 501206. PMID 8098719. 6. ^ Yanagisawa K, Ohminami H, Sato M, et al. (March 1998). "Neoplastic involvement of granulocytic lineage, not granulocytic-monocytic, monocytic, or erythrocytic lineage, in a patient with chronic neutrophilic leukemia". Am. J. Hematol. 57 (3): 221–4. doi:10.1002/(SICI)1096-8652(199803)57:3<221::AID-AJH7>3.0.CO;2-X. PMID 9495373. ## External links[edit] Classification D * ICD-10: D47.1 * ICD-9-CM: 205.1 * ICD-O: M9963/3 * MeSH: D015467 External resources * Orphanet: 86829 * v * t * e Myeloid-related hematological malignancy CFU-GM/ and other granulocytes CFU-GM Myelocyte AML: * Acute myeloblastic leukemia * M0 * M1 * M2 * APL/M3 MP * Chronic neutrophilic leukemia Monocyte AML * AMoL/M5 * Myeloid dendritic cell leukemia CML * Philadelphia chromosome * Accelerated phase chronic myelogenous leukemia Myelomonocyte AML * M4 MD-MP * Juvenile myelomonocytic leukemia * Chronic myelomonocytic leukemia Other * Histiocytosis CFU-Baso AML * Acute basophilic CFU-Eos AML * Acute eosinophilic MP * Chronic eosinophilic leukemia/Hypereosinophilic syndrome MEP CFU-Meg MP * Essential thrombocytosis * Acute megakaryoblastic leukemia CFU-E AML * Erythroleukemia/M6 MP * Polycythemia vera MD * Refractory anemia * Refractory anemia with excess of blasts * Chromosome 5q deletion syndrome * Sideroblastic anemia * Paroxysmal nocturnal hemoglobinuria * Refractory cytopenia with multilineage dysplasia CFU-Mast Mastocytoma * Mast cell leukemia * Mast cell sarcoma * Systemic mastocytosis Mastocytosis: * Diffuse cutaneous mastocytosis * Erythrodermic mastocytosis * Adult type of generalized eruption of cutaneous mastocytosis * Urticaria pigmentosa * Mast cell sarcoma * Solitary mastocytoma Systemic mastocytosis * Xanthelasmoidal mastocytosis Multiple/unknown AML * Acute panmyelosis with myelofibrosis * Myeloid sarcoma MP * Myelofibrosis * Acute biphenotypic leukaemia [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Chronic neutrophilic leukemia	c0023481	1,982	wikipedia	https://en.wikipedia.org/wiki/Chronic_neutrophilic_leukemia	2021-01-18T19:02:56	{"gard": ["10585"], "mesh": ["D015467"], "umls": ["C0023481"], "icd-9": ["205.1"], "orphanet": ["86829"], "wikidata": ["Q1088057"]}
Lissencephaly with cerebellar hypoplasia (LCH) affects brain development, resulting in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. In addition, the part of the brain that coordinates movement is unusually small and underdeveloped (cerebellar hypoplasia). Other parts of the brain are also often underdeveloped in LCH, including the hippocampus, which plays a role in learning and memory, and the part of the brain that is connected to the spinal cord (the brainstem). Individuals with LCH have moderate to severe intellectual disability and delayed development. They have few or no communication skills, extremely poor muscle tone (hypotonia), problems with coordination and balance (ataxia), and difficulty sitting or standing without support. Most affected children experience recurrent seizures (epilepsy) that begin within the first months of life. Some affected individuals have nearsightedness (myopia), involuntary eye movements (nystagmus), or puffiness or swelling caused by a buildup of fluids in the body's tissues (lymphedema). ## Frequency LCH is a rare condition, although its prevalence is unknown. ## Causes LCH can be caused by mutations in the RELN or TUBA1A gene. The RELN gene provides instructions for making a protein called reelin. In the developing brain, reelin turns on (activates) a signaling pathway that triggers nerve cells (neurons) to migrate to their proper locations. The protein produced from the TUBA1A gene is also involved in neuronal migration as a component of cell structures called microtubules. Microtubules are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules form scaffolding within the cell that elongates in a specific direction, altering the cytoskeleton and moving neurons. Mutations in either the RELN or TUBA1A gene impair the normal migration of neurons during fetal development. As a result, neurons are disorganized, the normal folds and grooves of the brain do not form, and brain structures do not develop properly. This impairment of brain development leads to the neurological problems characteristic of LCH. ### Learn more about the genes associated with Lissencephaly with cerebellar hypoplasia * RELN * TUBA1A ## Inheritance Pattern When LCH is caused by mutations in the RELN gene, the 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. When LCH is caused by mutations in the TUBA1A gene, the 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. Most of these cases result from new mutations in the gene and occur in people with no history of the disorder in their family. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Lissencephaly with cerebellar hypoplasia	c0796089	1,983	medlineplus	https://medlineplus.gov/genetics/condition/lissencephaly-with-cerebellar-hypoplasia/	2021-01-27T08:24:59	{"gard": ["3277"], "mesh": ["C537848"], "omim": ["257320", "611603"], "synonyms": []}
Deep dyslexia is a form of dyslexia that disrupts reading processes. Deep dyslexia may occur as a result of a head injury, stroke, disease, or operation.[1] This injury results in the occurrence of semantic errors during reading and the impairment of nonword reading.[2][3] The term dyslexia comes from the Greek words 'dys' meaning 'impaired', and 'lexis' meaning 'word' and is used to describe disorders of language concerning reading and spelling. Numerous models and hypotheses have been proposed in attempt to explain the broad range of symptoms experienced by deep dyslexics, but a definite consensus has yet to be reached. The proposed models and hypotheses have helped in treatment of some suffering patients, but only with certain specific symptoms. Additionally, the recovery seen is not experienced equally in all patients. ## Contents * 1 Signs and symptoms * 1.1 Imageability effect and ease of predication * 2 Mechanism * 2.1 Continuum model * 2.2 Connectionist model * 2.3 Distributed attractor networks * 2.4 Failure of inhibition hypothesis * 2.5 Dual route model * 2.6 Right and left hemisphere hypotheses * 3 Diagnosis * 3.1 Classification * 4 Treatment * 5 References ## Signs and symptoms[edit] Deep dyslexia is mainly characterized by the occurrence of semantic reading errors or semantic paralexias (transposition of letters or words) when reading aloud (e.g. the written word "view" is read aloud as "scene", the word "bird" is read as "canary").[4][5][6] These semantic errors are the major distinguishing feature of deep dyslexia in comparison to other central dyslexias.[4] There are many other symptoms of deep dyslexia, including visual errors (e.g. the written word "thing" is read aloud as "think", the word "skate" is read as "scale") and derivational errors (e.g. the written word "alcohol" is read aloud as "alcoholic", the word "governor" is read as "government"), and poor reading of function words.[4][5][6] Additionally, deep dyslexics have more difficulty reading abstract than concrete and highly imaginable words, more difficulty reading adjectives, adverbs, and verbs than nouns, a complete inability to read non-words, and often impairments on tasks of verbal working memory.[4][5][6][7][8] While the symptoms of deep dyslexia listed above are different and independent impairments of reading, it is rare to find an individual who only displays some of the characteristics of it; indeed, most patients presenting with semantic paralexias, a hallmark symptom of the disorder, also demonstrate all of the other symptoms.[6][9] This has resulted in deep dyslexia being considered a symptom-complex and has led to much research into why this variety of symptoms may co-occur in so many patients.[6][9] ### Imageability effect and ease of predication[edit] The difficulty of deep dyslexics in reading abstract words has been referred to as the "imageability effect".[10][4][11][12] According to this idea, the ease with which a mental image can be created for a word is strongly related to the ease of reading the word.[11] In an attempt to explain this relationship, researchers have developed a variable to link the mental imagery created by a word and the ease of reading it.[11] This variable, ease of predication, is a rating of how easy it is to come up with simple factual statements or attributes of a word.[11][13] For example, when presented with the word "dog", an individual may come up with statements, or predicates, such as "has four legs", "is an animal", or "barks and wags its tail". Words with higher ease of predication scores are more easily read aloud by deep dyslexics than words with lower ease of predicaton scores, yet there is no correlation between ease of predication and ease of reading seen in normal adult readers.[11][13] Ease of predication may not explain specific symptoms of deep dyslexia, but rather indicates that deep dyslexics read using imagery, or a predicational route, rather than the more precise mechanisms used in normal reading.[11] ## Mechanism[edit] There are many different, and often conflicting, hypotheses that attempt to explain the deficits associated with deep dyslexia.[14] These theories have resulted in several models designed to conceptualize the symptom-complex found in deep dyslexics. These models are not ordered chronologically, but rather follow a general increasing trend of presence in the field of knowledge regarding deep dyslexics. Some models may be stronger than others, but that is not necessarily reflected here. Models and hypothesis toward the end of the list are more heavily debated and thus typically have a greater wealth of knowledge surrounding their topic.[2] ### Continuum model[edit] The "Glosser and Friedman (continuum) model" is based upon the concept that deep dyslexia and phonological dyslexia are opposite endpoints on a "continuum" of reading disability.[2][15] Deep dyslexia appears to be a more severe form of phonological dyslexia;[16][17][18] however, symptoms in patients can change over time so that an initial diagnosis of deep dyslexia is later better described as strictly a phonological dyslexia.[2] These observations suggest recovery is possible along the semantic pathway.[2] Friedman justifies the continuum hypothesis with two sets of evidence. The first involves five patients who started with deep dyslexia, but whose disorders shifted to phonological dyslexia during recovery. Semantic paralexias were the first symptom to diminish, either partially or totally, in each case and then other symptoms were resolved to varying degrees after that. However, nonword reading was always the last symptom to go and complete recovery was never reached by any patient.[19] Her second set of evidence in support of the continuum was found in her review of eleven patients with deep or phonological dyslexia in whom she found a predictable succession of symptoms. She placed great emphasis on the order in which reading symptoms emerged (poor nonword reading first, then visual errors, then noun > functor, then noun > verb, concrete > abstract, and finally, semantic errors) and suggested that the continuum hypothesis was supported by this pattern of symptoms.[19] ### Connectionist model[edit] Deep dyslexics have sufficient activation of a written word's features; but, this activation decays quickly, leading to errors in speech output. The "connectionist model" suggests that the phonological and semantic features of a word are activated, but this activation decays at a rate too quick for cognitive processing- thus, errors in speech output are produced as a result of this fading activation.[2][3] This hypothesis explains the broad symptom-complex of deep dyslexics without resorting to a multiple loci damage approach as seen in other models.[2][3] It eliminates the need to attribute a specific locus of damage to each symptom of deep dylsexia, and instead states that all symptoms are due to decay of a large activation area.[2][3] ### Distributed attractor networks[edit] Plaut and Shallice have hypothesized that units in the brain interact in such a way that semantic features form stable attractors in the space of all possible representations of words. These unit interactions correspond to particular attractor patterns, and if the particular attractor pattern is activated, the network remains in that pattern. However, they hypothesize that when the pattern is distorted, there is a pull on the pattern, and it gravitates toward the correct pattern, almost as if this semantic space is filled with basins, where if one point on the pattern falls to the edge of the basin, it will still gravitate toward the middle. If you lesion this area, the neurons die and the basins change their shape. When this happens, you may now have the same distorted starting pattern that will end up in a neighboring basin, which is a semantically related area, but not the correct one, and this would account for deep dyslexic patients to incorrectly identify "river" as "ocean". Lesions that occur early in the network change the basins that send different semantic words to different areas of the network, whereas if they occur later, the words will be much closer semantically. This may account for severity of the deficit in individual patients.[20] ### Failure of inhibition hypothesis[edit] The "failure of inhibition hypothesis" states that the presentation of a target word activates semantic memory of that word, along with memory for other words that are semantically related.[21] For example, the target word "dog" may activate "bark", "cat", "squirrel", "ball", "fetch". Deep dyslexic patients are unable to inhibit the other related words, so they are likely to substitute one of these words for the target word in speech production (explicit output).[21] This hypothesis contradicts the belief of other researchers that the deficits seen in deep dyslexics are due to processing problems. Researchers believe that "failure of inhibition" has no effect on implicit processing, but instead is the cause of impairments in the explicit task of speech production.[21] They believe that explicit characteristics of reading involve only the conscious production of speech (reading).[21] Information about written words is internalized without awareness (implicitly); the ability to access this information and process it into words that can be read or spoken is an explicit process. Implicit knowledge involves phonological awareness, understanding of the morphology, and a semantic understanding of written words.[21] This implicit aspect of reading may be completely intact, and yet reading errors can still occur through defects in explicit output, or production.[21] Researchers have studied the dissociation of implicit and explicit processes to thus unravel the underlying deficiencies in deep dyslexia. Studies in support of "failure of inhibition" show intact implicit processing of deep dyslexics.[21] For instance, studies have shown deep dyslexics that are equally fast in a lexical decision task with a rhyming pair of words (book-took) in comparison to a non-rhyming pair of words (bough-tough), indicating that the patients are able to use implicit phonological knowledge and phonics to process the words.[21] Additionally, they are faster in a lexical decision task with words that sound like they are spelled (couch, pouch) than they are with words that do not sound like they are spelled (touch), again showing that patients are using phonology.[21] These data show that implicit processing is in fact occurring in deep dyslexic patients. Thus, some researchers believe that the impairments present in deep dyslexics are only in explicit phonological output (i.e., reading aloud).[21] They believe that the problems of deep dyslexics are due to production errors, and that deep dyslexics have normal phonological processing at the implicit level.[21] This is supported by the fact that deep dyslexia is often present in patients suffering from production errors resulting from Expressive aphasia.[18] Riley and Thompson expanded on this theory in 2010. Previous studies had shown that typical in patients with deep dyslexia, typical members of a semantic category (like "robin" in the category of "birds") are processed faster than atypical members of the same category (like "ostrich"), known as the semantic typicality effect. According to their research, this typicality effect may indicate an inability to efficiently select a correct lexical-semantic representation. They suggest that selection inhibition becomes impaired beginning at the level of semantics rather than the later levels of production like the original failure of inhibition hypothesis suggests.[12] ### Dual route model[edit] Deep dyslexia can affect both pathways in the dual-route hypothesis of reading. Main article: Dual-route hypothesis to reading aloud The "Morton and Patterson (dual route) model" is based upon the dual route hypothesis of reading. It proposes that the occurrence of semantic errors alongside an inability to read non-words aloud must be due to multiple loci of damage within this dual-route model.[2] Because a deep dyslexic cannot read aloud non-words, a disruption in the phonological process is assumed, forcing reading to proceed through the semantic route.[2] However, deep dyslexics also produce semantic errors while reading, alluding to damage in this pathway as well.[2] Other researchers refer to the phonological and semantic route as "modules".[21][17] They believe that patients have a partially functioning lexical module and a completely deficient nonlexical module.[17] The lexical module is analogous to the semantic route in the dual route model and relies on lexical memory, or the memory for words, to name words.[21][17] In using the lexical module, an individual accesses a "mental dictionary" of words. The nonlexical module is comparable to the phonological route and uses knowledge of spelling and graphemes to create phonemes to name words and nonwords.[17] The absent nonlexical module in deep dyslexics explains why patients cannot name nonwords.[17] ### Right and left hemisphere hypotheses[edit] Activation areas in the left hemisphere when hearing or reading a word. The "left-hemisphere hypothesis", supports the idea of a damaged left hemisphere-based reading system. Normal reading is typically a function of a left hemisphere-based system.[4] The right hemisphere plays a minimal role in reading.[4][14] One hypothesis, the "left hemisphere hypothesis", supports the idea of a damaged left hemisphere-based reading system associated with deep dyslexia.[4][22][23] Deep dyslexics may be attempting to use this damaged left hemisphere, resulting in severe reading deficits.[4][22][23][24] On the other hand, the "right hemisphere hypothesis" states that deep dyslexics attempt to read using a completely different reading system.[4][14][22] According to this hypothesis, they are using the right hemisphere for orthographic and semantic processing, but given that this system does not usually play a role in reading, deep dyslexics have many reading disabilities.[4][22] Strong support for this hypothesis comes from studies of split-brain patients who use the right hemisphere for reading. These patients makes semantic errors similar to those seen with deep dyslexia.[25] Numerous studies have shown that the right hemisphere can contribute to reading when a patient's left hemisphere is damaged.[4][14] Brain imaging studies, performed both on deep dyslexics and in other patients with left hemisphere injury, have shown that the damaged left hemisphere is still playing a role in reading.[22][23] However, the imaging has also shown that areas of the right hemisphere are also active during reading.[22][23] Thus, it currently appears that there is greater support in favor of the right-hemisphere hypothesis.[22] ## Diagnosis[edit] ### Classification[edit] Computerized tomography (CT) scan showing brain multiple frontal, parietal, and temporal lobe lesions.[26] The cause of deep dyslexia is damage in the left hemisphere of the brain Deep dyslexia is usually classified as an acquired reading disorder, as opposed to a developmental dyslexia, in previously literate adults as a consequence of a brain injury.[2][21][10][4] However, recently, developmental deep dyslexia has also been reported in children with Williams syndrome.[10][27] Deep dyslexia is considered to be a "central dyslexia" as compared to a "peripheral dyslexia". Peripheral dyslexics have difficulty matching the visual characteristics of letters that comprise a word to a stored memory of this word from prior encounters.[4] Central dyslexics are unable to properly match the visual word to the word's meaning.[4] They may also be incapable of speaking, or phonating, the sequence of written letters that they see into the word these letters represent.[4] Deep dyslexia differs from other forms of central dyslexia (phonological dyslexia and surface dyslexia) in that deep dyslexics have many more symptoms and these symptoms are generally more severe.[4][16][17] According to the "continuum" hypothesis, deep dyslexia is a more severe form of phonological dyslexia.[16][17][18] ## Treatment[edit] There have been many different studies done in an attempt to treat deep dyslexics, all which have been met with varying success. One method that has been frequently used is to teach patients to sound out words using grapheme-to-phoneme correspondence rules (for example, using single letter graphemes such as the letter 'B" to link with larger words such as "Baby", allowing for association of phonemes).[28] Such methods are known as "non-lexically based reading treatments". Other studies have looked at attempting to repair the semantic-lexical route, known as "lexically based treatment".[29] Regardless of the methodology, treatment studies with deep dyslexics are difficult because much of the information regarding this disability is still heavily debated.[citation needed] Treatment options may be successful on repairing one route of reading but not another, and success for one patient may not translate to success in another.[citation needed] ## References[edit] 1. ^ Harley, Trevor A. (2001). The psychology of language: from data to theory. Taylor & Francis. pp. 189–195. ISBN 978-0-86377-867-4. OCLC 469913878. 2. ^ a b c d e f g h i j k l Colangelo, Annette; Buchanan, Lori (2007). "Localizing damage in the functional architecture: The distinction between implicit and explicit processing in deep dyslexia". Journal of Neurolinguistics. 20 (2): 111–144. doi:10.1016/j.jneuroling.2006.08.001. 3. ^ a b c d Buchanan, Lori; McEwen, Shannon; Westbury, Chris; Libben, Gary (2003). "Semantics and semantic errors: Implicit access to semantic information from words and nonwords in deep dyslexia". Brain and Language. 84 (1): 65–83. doi:10.1016/S0093-934X(02)00521-7. PMID 12537952. 4. ^ a b c d e f g h i j k l m n o p q Coslett, HB (2000). "Acquired dyslexia". Seminars in Neurology. 20 (4): 419–26. doi:10.1055/s-2000-13174. PMID 11149697. 5. ^ a b c Plaut, David C.; Shallice, Tim (1993). "Deep dyslexia: A case study of connectionist neuropsychology". Cognitive Neuropsychology. 10 (5): 377–500. doi:10.1080/02643299308253469. 6. ^ a b c d e Weekes, Brendan; Coltheart, Max; Gordon, Evian (1997). "Deep dyslexia and right hemisphere reading-a regional cerebral blood flow study". Aphasiology. 11 (12): 1139–1158. doi:10.1080/02687039708249437. 7. ^ Harley, Trevor (2005). The psychology of language : from data to theory (2nd ed.). Hove: Psychology Press. ISBN 978-0-86377-867-4. 8. ^ Kolb, Bryan; Whishaw, Ian Q. (2008). Fundamentals of human neuropsychology (6th ed.). Basingstoke: Palgrave Macmillan. ISBN 978-0-7167-9586-5. 9. ^ a b Coltheart, Edited by Max; Patterson, Karalyn; Marshall, John C. (1980). Deep dyslexia ([1st publ.]. ed.). London: Routhledge & Kegan Paul. ISBN 0-7100-0456-7.CS1 maint: extra text: authors list (link) 10. ^ a b c Temple, CM (2006). "Developmental and acquired dyslexias". Cortex. 42 (6): 898–910. doi:10.1016/S0010-9452(08)70434-9. PMID 17131596. 11. ^ a b c d e f Jones, GV (1985). "Deep dyslexia, imageability, and ease of predication". Brain and Language. 24 (1): 1–19. doi:10.1016/0093-934x(85)90094-x. PMID 3971130. 12. ^ a b Riley, EA; Thompson, CK (2010). "Semantic Typicality Effects in Acquired Dyslexia: Evidence for Semantic Impairment in Deep Dyslexia". Aphasiology. 24 (6–8): 802–813. doi:10.1080/02687030903422486. PMC 2907924. PMID 20657815. 13. ^ a b Harley, Trevor A. (1993). "Connectionist approaches to language disorders". Aphasiology. 7 (3): 221–249. doi:10.1080/02687039308249508. 14. ^ a b c d Shallice, Tim (1988). From neuropsychology to mental structure (Reprint. ed.). Cambridge [England]: Cambridge University Press. ISBN 0521308747. 15. ^ Friedman, Rhonda B. (1996). "Recovery from Deep Alexia to Phonological Alexia: Points on a Continuum". Brain and Language. 52 (1): 114–128. doi:10.1006/brln.1996.0006. PMID 8741978. 16. ^ a b c Rapcsak, Steven Z.; Beeson, Pélagie M.; Henry, Maya L.; Leyden, Anne; Kim, Esther; Rising, Kindle; Andersen, Sarah; Cho, HyeSuk (2009). "Phonological dyslexia and dysgraphia: Cognitive mechanisms and neural substrates". Cortex. 45 (5): 575–591. doi:10.1016/j.cortex.2008.04.006. PMC 2689874. PMID 18625494. 17. ^ a b c d e f g h Van Orden, G (2001). "What do double dissociations prove?". Cognitive Science. 25 (1): 111–172. doi:10.1016/S0364-0213(00)00036-7. 18. ^ a b c Lambon Ralph, Matthew A.; Graham, Naida L. (2000). "Acquired phonological and deep dyslexia". Neurocase. 6 (2): 141–178. doi:10.1080/13554790008402767. 19. ^ a b Crisp, J.; Ralph, M.A. (2006). "Unlocking the Nature of the Phonological-Deep Dyslexia Continuum: The Keys to Reading Aloud Are in Phonology and Semantics". Journal of Cognitive Neuroscience. 18 (3): 348–362. doi:10.1162/089892906775990543. PMID 16513001. 20. ^ Plaut, D.C. (1995). "Double Dissociation Without Modularity: Evidence from Connectionist Neuropsychology". Journal of Clinical and Experimental Neuropsychology. 17 (2): 291–321. doi:10.1080/01688639508405124. PMID 7629273. 21. ^ a b c d e f g h i j k l m n Colangelo, Annette; Buchanan, Lori (2006). "Implicit and explicit processing in deep dyslexia: Semantic blocking as a test for failure of inhibition in the phonological output lexicon". Brain and Language. 99 (3): 258–271. doi:10.1016/j.bandl.2005.07.048. PMID 16129479. 22. ^ a b c d e f g Coltheart, Max (2000). "Deep Dyslexia Is Right-Hemisphere Reading". Brain and Language. 71 (2): 299–309. doi:10.1006/brln.1999.2183. PMID 10716863. 23. ^ a b c d Salmelin, R; Helenius, P; Service, E (2000). "Neurophysiology of fluent and impaired reading: a magnetoencephalographic approach". Journal of Clinical Neurophysiology. 17 (2): 163–74. doi:10.1097/00004691-200003000-00005. PMID 10831107. 24. ^ Warrington, Rosaleen A. McCarthy, Elizabeth K. (1990). Cognitive neuropsychology : a clinical introduction ([7. Nachdr.] ed.). San Diego: Academic Press. ISBN 0124818463. 25. ^ Shallice, Tim (1988). From neuropsychology to mental structure (Reprint. ed.). Cambridge [England]: Cambridge University Press. p. 112. ISBN 0521308747. 26. ^ Rehman T, Ali R, Tawil I, Yonas H (2008). "Rapid progression of traumatic bifrontal contusions to transtentorial herniation: A case report". Cases Journal. 1 (1): 203. doi:10.1186/1757-1626-1-203. PMC 2566562. PMID 18831756. 27. ^ Johnston, RS (1983). "Developmental deep dyslexia?". Cortex. 19 (1): 133–9. doi:10.1016/s0010-9452(83)80057-4. PMID 6851588. 28. ^ Friedman, Rhonda B.; Lott, Susan Nitzberg (2002). "Successful blending in a phonological reading treatment for deep alexia". Aphasiology. 16 (3): 355–372. doi:10.1080/02687040143000627. 29. ^ Stadie, Nicole; Rilling, Eva (2006). "Evaluation of lexically and nonlexically based reading treatment in a deep dyslexic". Cognitive Neuropsychology. 23 (4): 643–672. doi:10.1080/02643290500538364. PMID 21049348. 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 [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Deep dyslexia	c0454592	1,984	wikipedia	https://en.wikipedia.org/wiki/Deep_dyslexia	2021-01-18T18:56:50	{"umls": ["C0454592"], "wikidata": ["Q5250381"]}
Bullous lichen planus is a variant of rare lichen planus (see this term) characterized by the development of vesico-bullous lesions. ## Epidemiology Prevalence is unknown and only a few cases, both sporadic and familial, have been described in the literature. ## Clinical description The disease manifests during childhood or adolescence. Bullous lesions develop on top of preexisting lichen planus papules or on normal skin and generally affect the lower limbs or the lower mucosal lip, and in some rare cases the torso. In this condition, the epithelium separates from the dermis. In the case of oral bullous lichen planus, the vesicles and bullae burst soon after they appear which results in erosions. ## Etiology Etiology is unknown. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Bullous lichen planus	c0023648	1,985	orphanet	https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=33408	2021-01-23T18:27:21	{"umls": ["C0023648"], "icd-10": ["L43.1"]}
Pulled hamstring Two images of the same strain. One of the pictures was shot through a mirror. Straining of the hamstring, also known as a pulled hamstring, is defined as an excessive stretch or tear of muscle fibers and related tissues. Hamstring injuries are common in athletes participating in many sports. Track and field athletes are particularly at risk, as hamstring injuries have been estimated to make up 29% of all injuries in sprinters.[1] The biceps femoris long head is at the most risk for injury, possibly due to its reduced moment of knee and hip flexion as compared to the medial hamstrings.[2] ## Contents * 1 Diagnosis * 1.1 Grades * 1.1.1 Grade 1 * 1.1.2 Grade 2 * 1.1.3 Grade 3 * 2 Treatment * 3 Epidemiology * 4 References * 5 External links ## Diagnosis[edit] This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Pulled hamstring" – news · newspapers · books · scholar · JSTOR (June 2020) ### Grades[edit] Pulled hamstring #### Grade 1[edit] Sensation of cramp or tightness and a slight feeling of pain when the muscles are stretched or contracted.[citation needed] #### Grade 2[edit] With a grade two hamstring strain there is immediate pain which is more severe than the pain of a grade one injury. It is confirmed by pain on stretch, swelling and contraction of the muscle. #### Grade 3[edit] Bruising due to strained hamstring, horizontal lines show where bandage was. A grade three hamstring strain is a severe injury. There is an immediate burning or stabbing pain and the individual is unable to walk without pain. The muscle is completely torn and there may be a large lump of muscle tissue above a depression where the tear is. After a few days with grade two and three injuries, a large bruise may appear below the injury site caused by the bleeding within the tissues. ## Treatment[edit] This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Pulled hamstring" – news · newspapers · books · scholar · JSTOR (June 2020) Recommended treatment for this injury consists of the RICE protocol — rest, ice, compression and elevation.[3] The RICE method is primarily used to reduce bleeding and damage within the muscle tissue. Lower grade strains can easily become worse if the hamstring is not rested properly. Complete ruptures require surgical repair and rehabilitation. Initial treatment of the injury, regardless of the severity of the strain, is the same. Within the first five days, the hamstring is rested in an elevated position with an ice pack applied for twenty minutes every two hours. A compression bandage is applied to limit bleeding and swelling in the tissues. After five days of rest, active rehabilitation begins. ## Epidemiology[edit] An academic study found that the most common and prevalent musculoskeletal injury in the world is a hamstring strain.[4] The study further explains that hamstring strains represented 15% of all injuries per club per season also had a 34% chance of recurrence.[4] Another study showed that a previous hamstring injury is one of the most cited risks for future injury, with as many as one-third of active individuals experiencing a re-injury within 2 weeks of returning to activity.[5] A meta-analysis article showed evidence that a history of hamstring injury and being of older age were associated with increased risk of hamstring strains.[6] One study found that men and master athletes (athletes older than forty) were at an increased risk of hamstring strains compared with women and younger athletes.[7] Women were approximately 3 times more likely to suffer hamstring strain than males with the majority of these being non-sporting scenarios.[8] Similarly the average age of non-sporting hamstring strains are from the ages of 40–60.[8] Many of these non-sporting injuries are sustained during road traffic accidents, slipping, and falling.[8] These results also show that hamstring strains account for 50% of muscle injuries received by sprinters and are the most common injury in hurdling.[9] One explanation is that older active individuals may be at greater risk due to lower levels of eccentric knee flexor strength compared with their younger counterparts.[7] However, it is unclear whether flexibility serves as a risk factor; this topic should be researched in the future to further understand the relationship between flexibility and risk of injury.[10] Muscle weakness has also been an implication as a predisposing factor for both primary and recurring hamstring strain injuries.[11] Over a 10-year study more than 51.3% of hamstring strains occurred during the preseason of athletics.[11] In another study, that analyzed 25 NCAA sports over four years, it was clearly shown that hamstring strain rates are higher in the preseason.[10] The factors that are being implicated in this trend are the relative deterioration and muscle weakness that occur during the off-season.[9] The hamstrings undergo a complex dynamic process during gait, making it unsurprising that they are frequently injured. They must first contract concentrically during the end of the stance phase in order to bend the knee and allow the foot (along with dorsiflexion at the ankle) to clear the ground. At the end of the swing phase, the hamstrings must eccentrically contract while applying a braking moment to knee extension, then immediately change functions to again concentrically contract and produce hip extension. Studies have shown that “the hamstring group reaches peak elongation and acts eccentrically at the hip and knee during the late swing phases of running”[12] and that “the hamstrings are most active and develop the greatest torques at the hip and knee during the late swing through midstance phase of running.”[12] Thus, the hamstrings reach their maximum length while attempting to forcefully contract eccentrically and switch functions to immediately produce a concentric contraction, which makes the terminal part of swing phase the most vulnerable for injury. There have been many other proposed predisposing factors to injury. These include muscle weakness, muscle imbalance, poor flexibility, fatigue, inadequate warm up, poor neuromuscular control, and poor running technique.[12] One of the few predisposing factors that most researchers agree upon however is previous hamstring injury. Brokett et al. (2004) [13] stated that “the athletes most at risk of a hamstring strain are those with a previous history of such injury” and noted that 34% of the hamstring injuries were recurrences.” Cameron et al. also found that 34% of injuries recur in the same season. Arnason et al.[1] generalized these numbers, saying that previous injury was in itself an independent risk factor for re-injury. ## References[edit] 1. ^ a b Arnason A, Andersen TE, Holme I, Engebretsen L, Bahr R (2008). "Prevention of hamstring strains in elite soccer: an intervention study". Scand J Med Sci Sports. 18 (1): 40–8. doi:10.1111/j.1600-0838.2006.00634.x. PMID 17355322. S2CID 23545542. 2. ^ Carlson C (2008). "The natural history and management of hamstring injuries". Curr Rev Musculoskelet Med. 1 (2): 120–3. doi:10.1007/s12178-007-9018-8. PMC 2684206. PMID 19468884. 3. ^ "Marshall University Orthopaedics". Archived from the original on 2008-02-03. Retrieved 2008-01-08. 4. ^ a b Orchard, J., & Seward, H. (2002, February). Epidemiology of injuries in the Australian Football League, seasons 1997-2000. British Journal of Sports Medicine, 36(1), 39-45. 5. ^ Sherry, M. A., Johnston, T. S., & Heiderscheit, B. C. (2015, April). Rehabilitation of Acute Hamstring Strain Injuries. Clinics in Sports Medicine, 34(2), 263-284. 6. ^ Freckleton, G., & Pizzari, T. (2013, April). Risk factors for hamstring muscle strain injury in sport: a systematic review and meta-analysis. British Journal of Sports Medicine, 47(6), 351-358. 7. ^ a b Opar, D. A., Drezner, J., Williams, M., Webner, D., Sennett, B., Kapur, R., Cronholm, P.F.(2014). Acute hamstring strain injury in track-and-field athletes: A 3-year observational study at the Penn Relay Carnival. Scandinavian Journal of Medicine & Science in Sports, 254-259. 8. ^ a b c Kuske, Barbara; Hamilton, David F.; Pattle, Sam B.; Simpson, A. Hamish R. W. (2016-05-04). "Patterns of Hamstring Muscle Tears in the General Population: A Systematic Review". PLOS ONE. 11 (5): e0152855. Bibcode:2016PLoSO..1152855K. doi:10.1371/journal.pone.0152855. ISSN 1932-6203. PMC 4856270. PMID 27144648. 9. ^ a b Ahmad, C.S., Redler, L.H., Ciccotti, M.G., Maffulli, N., Longo, U.G., & Bradley, J. (2013, December). Evaluation and Management of Hamstring Injuries. The American Journal of Sports Medicine, 41(12), 2933-2947. 10. ^ a b Dalton, S. L., Kerr, Z.Y., & Dompier, T.P.(2015). Epidemiology of Hamstring Strains in 25 NCAA Sports in the 2009-2010 to 2013-2014 Academic Years. American Journal of Sports Medicine, 43(11), 2671-2679. 11. ^ a b Kuske B, Hamilton DF, Pattle SB, Simpson AHRW (2016) Patterns of Hamstring Muscle Tears in the General Population: A Systematic Review. PLoS ONE 11(5):e0152855.doi:10.1371/journal.pone.0152855 12. ^ a b c Cameron, M.; Adams, R.; Maher, C. (2003). "Motor control and strength as predictors of hamstring injury in elite players of Australian football" (PDF). Physical Therapy in Sport. 4 (4): 159–166. doi:10.1016/s1466-853x(03)00053-1. Archived from the original (PDF) on 2014-03-19. Retrieved 2014-03-18. 13. ^ Brockett CL, Morgan DL, Proske U (2004). "Predicting hamstring strain injury in elite athletes". Med Sci Sports Exerc. 36 (3): 379–87. doi:10.1249/01.mss.0000117165.75832.05. PMID 15076778. ## External links[edit] * Hamstring Injuries * v * t * e Dislocations/subluxations, sprains and strains Joints and ligaments Head and neck * Dislocation of jaw * Whiplash Shoulder and upper arm * GH (Dislocated shoulder) * AC (Separated shoulder) * ALPSA lesion * SLAP tear * Bankart lesion Elbow and forearm * Pulled elbow * Gamekeeper's thumb Hip and thigh * Hip dislocation Knee and leg * Tear of meniscus * Anterior cruciate ligament injury * Unhappy triad * Patellar dislocation * Knee dislocation Ankle and foot * Sprained ankle (High ankle sprain) * Turf toe Muscles and tendons Shoulder and upper arm * Rotator cuff tear Hip and thigh * Pulled hamstring Knee and leg * Patellar tendon rupture * Achilles tendon rupture * Shin splints [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Pulled hamstring	c0434423	1,986	wikipedia	https://en.wikipedia.org/wiki/Pulled_hamstring	2021-01-18T18:54:09	{"umls": ["C0434423"], "wikidata": ["Q359090"]}
A number sign (#) is used with this entry because of evidence that craniolenticulosutural dysplasia (CLSD) is caused by homozygous mutation in the SEC23A gene (610511) on chromosome 14q21. Description Craniolenticulosutural dysplasia is an autosomal recessive disorder characterized by facial dysmorphism, late-closing fontanels, cataract, and skeletal defects (summary by Boyadjiev et al., 2011). Clinical Features Boyadjiev et al. (2003) suggested the designation craniolenticulosutural dysplasia (CLSD) for a dysmorphic syndrome in 5 males and 1 female in an inbred Saudi Arabian family. The craniofacial features included wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. All affected individuals had Y-shaped sutural cataracts diagnosed by 1 to 2 years of age. Boyadjiev et al. (2011) reported a 4.5-year-old boy with CLSD who had a characteristic facial appearance as well as clinical and skeletal features similar to those of the original patients described by Boyadjiev et al. (2003). Facial features common to all CLSD patients included high and prominent forehead with increased vascular markings in the area of the open anterior fontanel, similar shape of the eyebrows, obvious hypertelorism, wide and prominent nasal ridge, and anteverted nares, with lateral skull x-rays documenting large and hypomineralized calvaria in the area of the anterior fontanel. However, the eye phenotypes differed, with esotropia, bilateral optic atrophy, and double-ring sign of the lens present in the new case, but no cataract detected by 4.5 years of age. Other previously undescribed features included macrocephaly, anterior frenulum linguae requiring frenulectomy, bifid uvula, cleft palate, gastroesophageal reflux with postnatal failure to thrive, valvular pulmonic stenosis, and osteopenia. Mapping By a genomewide scan, Boyadjiev et al. (2003) found linkage of craniolenticulosutural dysplasia in a Saudi Arabian family to chromosome 14q13-q21; the maximum 2-point lod score, assuming recessive inheritance, was 4.58 at theta = 0.0 with marker GATA126A04. Haplotype analysis narrowed the disease locus to a region of approximately 7.26 Mb. Molecular Genetics In affected members of a Saudi Arabian family with CLSD, Boyadjiev et al. (2006) identified a homozygous missense mutation in the SEC23A gene (F382L; 610511.0001). SEC23A is an essential component of the COPII-coated vesicles that transport secretory proteins from the endoplasmic reticulum to the Golgi complex. In fibroblasts from individuals affected with CLSD, a gross dilatation of the endoplasmic reticulum was demonstrated by electron microscopy and immunofluorescence. These cells also exhibited cytoplasmic mislocalization of SEC31 (see 610257). In a 4.5-year-old boy with CLSD, Boyadjiev et al. (2011) identified heterozygosity for a paternally inherited missense mutation in the SEC23A gene (M702V; 610511.0002); no mutations were identified in the coding region or 5-prime or 3-prime UTR of maternal SEC23A, and SNP and RT-PCR analysis excluded deletion of the maternal allele. Cultured skin fibroblasts from the patient showed a severe secretion defect of collagen with enlarged endoplasmic reticulum (ER); milder collagen secretion defects and ER distention were present in fibroblasts from the clinically unaffected father, indicating that an additional mutation was present in the proband. Boyadjiev et al. (2011) suggested that digenic inheritance might be involved in CLSD; RT-PCR DNA sequencing of the SEC23B (610512), SEC31A, and SEC13 (600152) genes revealed no mutations. ### Exclusion Studies Boyadjiev et al. (2003) performed sequence analysis of the PAX9 gene (167416) in members of the Saudi Arabian family with CLSD and found no mutations. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Failure to thrive, postnatal, due to gastroesophageal reflux (in some patients) HEAD & NECK Head \- Large anterior fontanel \- Delayed closure anterior fontanel \- Macrocephaly Face \- Frontal bossing \- Forehead hyperpigmentation \- Prominent supraorbital ridge \- Midface hypoplasia \- Long, smooth philtrum Eyes \- Hypertelorism \- Y-shaped sutural cataract (in some patients) \- Punctate lenticular opacities \- Esotropia (in some patients) \- Optic atrophy, bilateral (in some patients) \- Double-ring sign of lens (in some patients) Nose \- Broad nasal bridge \- Anteverted nares Mouth \- Wide mouth \- Thin upper lip \- Bifid uvula (in some patients) \- Cleft palate (in some patients) \- Anteriorly displaced frenulum linguae (in some patients) Teeth \- Delayed eruption \- Dental caries (secondary teeth) \- Hypoplastic teeth (secondary teeth) ABDOMEN Gastrointestinal \- Gastroesophageal reflux (in some patients) GENITOURINARY Internal Genitalia (Male) \- Cryptorchidism SKELETAL \- Joint laxity \- Osteopenia (in some patients) Skull \- Ossification defects Spine \- Scoliosis \- Posterior wedging of vertebral bodies Pelvis \- High, narrow iliac wings Feet \- Flat feet SKIN, NAILS, & HAIR Skin \- Hyperpigmentation (forehead) \- Capillary hemangioma (forehead) Hair \- Coarse hair \- Brittle hair \- Sparse hair MOLECULAR BASIS \- Caused by mutation in the human homolog A of the S. cerevisiae SEC23 gene (SEC23A, 610511.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	CRANIOLENTICULOSUTURAL DYSPLASIA	c1843042	1,987	omim	https://www.omim.org/entry/607812	2019-09-22T16:08:43	{"doid": ["0070307"], "mesh": ["C564332"], "omim": ["607812"], "orphanet": ["50814"], "synonyms": ["Alternative titles", "BOYADJIEV-JABS SYNDROME"]}
Von Graefe's sign Differential diagnosisexophthalmic goiter Von Graefe's sign is the lagging of the upper eyelid on downward rotation of the eye, indicating exophthalmic goiter (Graves' Disease).[1] It is a dynamic sign, whereas lid lag is a static sign which may also be present in cicatricial eyelid retraction or congenital ptosis. A pseudo Graefe's sign (pseudo lid lag) shows a similar lag, but is due to aberrant regeneration of fibres of the oculomotor nerve (III) into the elevator of the upper lid.[2] It occurs in paramyotonia congenita.[3] A pseudo Graefe's sign is most commonly manifested in just one eye but can occasionally be observed in both. The reason only one eye is affected is not yet clear. ## See also[edit] * Albrecht von Gräfe * Boston's sign * Griffith's sign * Graves orbitopathy * Hyperthyroidism, as lid lag may be in hyperthyroid patients lacking Graves' disease. ## References[edit] 1. ^ Cline D; Hofstetter HW; Griffin JR. Dictionary of Visual Science. 4th ed. Butterworth-Heinemann, Boston 1997. ISBN 0-7506-9895-0 2. ^ Definition: pseudo-Graefe sign from Online Medical Dictionary 3. ^ Fowler, Timothy J.; John W. Scadding (2003). Clinical Neurology 3rd ed. p. 145. ISBN 0-340-80798-9. * v * t * e Thyroid disease Hypothyroidism * Iodine deficiency * Cretinism * Congenital hypothyroidism * Myxedema * Myxedema coma * Euthyroid sick syndrome * Signs and symptoms * Queen Anne's sign * Woltman sign * Thyroid dyshormonogenesis * Pickardt syndrome Hyperthyroidism * Hyperthyroxinemia * Thyroid hormone resistance * Familial dysalbuminemic hyperthyroxinemia * Hashitoxicosis * Thyrotoxicosis factitia * Thyroid storm Graves' disease * Signs and symptoms * Abadie's sign of exophthalmic goiter * Boston's sign * Dalrymple's sign * Stellwag's sign * lid lag * Griffith's sign * Möbius sign * Pretibial myxedema * Graves' ophthalmopathy Thyroiditis * Acute infectious * Subacute * De Quervain's * Subacute lymphocytic * Palpation * Autoimmune/chronic * Hashimoto's * Postpartum * Riedel's Enlargement * Goitre * Endemic goitre * Toxic nodular goitre * Toxic multinodular goiter * Thyroid nodule * Colloid nodule This article about the eye is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Von Graefe's sign	c0278217	1,988	wikipedia	https://en.wikipedia.org/wiki/Von_Graefe%27s_sign	2021-01-18T18:37:25	{"wikidata": ["Q913912"]}
Lysosomal acid lipase deficiency Other namesWolman disease LAL-D has an autosomal recessive pattern of inheritance. SpecialtyMedical Genetics, Hepatology Lysosomal acid lipase deficiency (LAL deficiency or LAL-D), is an autosomal recessive inborn error of metabolism that results in the body not producing enough active lysosomal acid lipase (LAL) enzyme. This enzyme plays an important role in breaking down fatty material (cholesteryl esters and triglycerides) in the body.[1] Infants, children and adults that suffer from LAL deficiency experience a range of serious health problems. The lack of the LAL enzyme can lead to a build-up of fatty material in a number of body organs including the liver, spleen, gut, in the wall of blood vessels and other important organs. Very low levels of the LAL enzyme lead to LAL deficiency. LAL deficiency typically affects infants in the first year of life. The accumulation of fat in the walls of the gut in early onset disease leads to serious digestive problems including malabsorption, a condition in which the gut fails to absorb nutrients and calories from food. Because of these digestive complications, affected infants usually fail to grow and gain weight at the expected rate for their age (failure to thrive). As the disease progresses, it can cause life-threatening liver dysfunction or liver failure.[2] Until 2015, there was no treatment, and very few infants with LAL-D survived beyond the first year of life. In 2015, an enzyme replacement therapy, sebelipase alfa, was approved in the US and EU. The therapy was additionally approved in Japan in 2016. ## Contents * 1 Symptoms * 2 Cause * 3 Diagnosis * 4 Screening * 5 Management * 6 Prognosis * 7 Epidemiology * 8 History * 9 Research directions * 10 References * 11 External links ## Symptoms[edit] Infants may present with feeding difficulties with frequent vomiting, diarrhea, swelling of the abdomen, and failure to gain weight or sometimes weight loss.[3] As the disease progresses in infants, increasing fat accumulation in the liver leads to other complications including yellowing of the skin and whites of the eyes (jaundice), and a persistent low-grade fever. An ultrasound examination shows accumulation of chalky material (calcification) in the adrenal gland in about half of infants with LAL-D.[3][4] Complications of LAL-D progress over time, eventually leading to life-threatening problems such as extremely low levels of circulating red blood cells (severe anemia), liver dysfunction or failure, and physical wasting (cachexia).[3] People who are older children or adults generally present with a wide range of signs and symptoms that overlap with other disorders.[5] They may have diarrhoea, stomach pain, vomiting, or poor growth, a sign of malabsorption. They may have signs of bile duct problems, like itchiness, jaundice, pale stool, or dark urine. Their feces may be excessively greasy. They often have an enlarged liver, liver disease, and may have yellowish deposits of fat underneath the skin, usually around their eyelids.[3][5] The disease is often undiagnosed in adults.[6] The person may have a history of premature cardiac disease or premature stroke.[3] ## Cause[edit] Lysosomal acid lipase deficiency is a genetic disease that is autosomal recessive. It is an inborn error of metabolism that causes a lysosomal storage disease.[3] The condition is caused by a mutation of the LIPA gene, which is responsible for the gene coding of the lysosomal lipase protein (also called lysosomal acid lipase or LAL), which results in a loss of the protein's normal function.[2] When LAL functions normally, it breaks down cholesteryl esters and triglycerides in low density lipoprotein particles into free cholesterol and free fatty acids that the body can reuse; when LAL doesn't function, cholesteryl esters and triglycerides build up in the liver, spleen and other organs.[3][5] The accumulation of fat in the walls of the gut and other organs in leads to serious digestive problems including malabsorption, a condition in which the gut fails to absorb nutrients and calories from food, persistent and often forceful vomiting, frequent diarrhea, foul-smelling and fatty stools (steatorrhea), and failure to grow.[3] Lysosomal acid lipase deficiencies occur when a person has defects (mutations) in both copies of the LIPA gene. Each parent of a person with LAL deficiency carries one copy of the defective LIPA gene. With every pregnancy, parents with a son or daughter affected by LAL deficiency have a 1 in 4 (25%) chance of having another affected child. A person born with defects in both LIPA genes is not able to produce adequate amounts of the LAL enzyme.[5] ## Diagnosis[edit] Blood tests may show anaemia and their lipid profiles are generally similar to people with more common familial hypercholesterolemia, including elevated total cholesterol, elevated low-density lipoprotein cholesterol, decreased high-density lipoprotein cholesterol and elevated serum transaminases.[3] Liver biopsy findings will generally show a bright yellow-orange color, enlarged, lipid-laden hepatocytes and Kupffer cells, microvesicular and macrovesicular steatosis, fibrosis, and cirrhosis.[3] The only definitive tests are genetic, which may be conducted in any number of ways.[5] ## Screening[edit] Because LAL deficiency is inherited, each sibling of an affected individual has a 25% chance of having pathological mutations in LAL genes from both their mother and their father, a 50% chance of having a pathological mutation in only one gene, and a 25% chance of having no pathological mutations. Genetic testing for family members and genetic prenatal diagnosis of pregnancies for women who are at increased risk are possible if family members carrying pathological mutations have been identified.[5] ## Management[edit] LAL deficiency can be treated with sebelipase alfa is a recombinant form of LAL that was approved in 2015 in the US and EU.[7][8] The disease of LAL affects < 0.2 in 10,000 people in the EU.[8] According to an estimate by a Barclays analyst, the drug will be priced at about US$375,000 per year.[8] It is administered once a week via intraveneous infusion in people with rapidly progressing disease in the first six months of life. In people with less aggressive disease, it is given every other week.[9] Before the drug was approved, treatment of infants was mainly focused on reducing specific complications and was provided in specialized centers. Specific interventions for infants included changing from breast or normal bottle formula to a specialized low fat formula, intravenous feeding, antibiotics for infections, and steroid replacement therapy because of concerns about adrenal function.[3] Statins were used in people with LAL-D prior to the approval of sebelipase alfa; they helped control cholesterol but did not appear to slow liver damage; liver transplantation was necessary in most patients.[3] ## Prognosis[edit] Infants with LAL deficiencies typically show signs of disease in the first weeks of life and if untreated, die within 6–12 months due to multi-organ failure.[3] Older children or adults with LAL-D may remain undiagnosed or be misdiagnosed until they die early from a heart attack or stroke or die suddenly of liver failure.[3] The first enzyme replacement therapy was approved in 2015. In those clinical trials nine infants were followed for one year; 6 of them lived beyond one year.[9] Older children and adults were followed for 36 weeks.[9] ## Epidemiology[edit] Depending on ethnicity and geography, prevalence has been estimated to be between 1 in 40,000 and 1 in 300,000; based on these estimates the disease may be underdiagnosed. Jewish infants of Iraqi or Iranian origin appear to be most at risk based on a study of a community in Los Angeles in which there was a prevalence of 1 in 4200.[3][5] ## History[edit] In 1956, Moshe Wolman, along with two other doctors, published the first case study of a LAL deficiency in a child born to closely related Persian Jews; 12 years later a case study on an older boy was published, which turned out to be the first case study of LAL-D.[3][10][11][12] LAL-D was historically referred to as 2 separate disorders: * Wolman disease, presenting in infant patients * Cholesteryl Ester Storage Disease, presenting in pediatric and adult patients Around 2010 both presentations have come to be known as LAL-D, as both are due to a deficiency of the LAL enzyme.[2] In 2015 an enzyme replacement therapy, sebelipase alfa, was approved in the US and EU for the treatment of human LAL enzyme deficiency.[13] Before the approval of that drug, as of 2009 the two oldest survivors of LAL-D in the world were then aged 4 and 11; both of them had been treated with hematopoietic stem cell treatment.[14] ## Research directions[edit] Some children with LAL-D have had an experimental therapy called hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant, to try to prevent the disease from getting worse. Data are sparse but there is a known high risk of serious complications including death, graft-versus-host disease.[3] ## References[edit] 1. ^ "Wolman disease". Genetics Home Reference. 2016-03-21. Retrieved 2016-03-25. 2. ^ a b c Reiner, Željko; Guardamagna, Ornella; Nair, Devaki; Soran, Handrean; Hovingh, Kees; Bertolini, Stefano; Jones, Simon; Ćorić, Marijana; Calandra, Sebastiano; Hamilton, John; Eagleton, Terence; Ros, Emilio (July 2014). "Lysosomal acid lipase deficiency – An under-recognized cause of dyslipidaemia and liver dysfunction". Atherosclerosis. 235 (1): 21–30. doi:10.1016/j.atherosclerosis.2014.04.003. PMID 24792990. 3. ^ a b c d e f g h i j k l m n o p q Reiner Ž; et al. (Jul 2014). "Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction". Atherosclerosis. 235 (1): 21–30. doi:10.1016/j.atherosclerosis.2014.04.003. PMID 2479299. 4. ^ Learning Radiology.com Adrenal calcification 5. ^ a b c d e f g Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal Acid Lipase Deficiency. 2015 Jul 30. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. 6. ^ Bernstein, Donna L.; Hülkova, Helena; Bialer, Martin G.; Desnick, Robert J. (Jun 2013). "Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease". Journal of Hepatology. 58 (6): 1230–1243. doi:10.1016/j.jhep.2013.02.014. PMID 23485521. 7. ^ Burton, B. K.; et al. (September 10, 2015). "A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency". New England Journal of Medicine. 373 (11): 1010–1020. doi:10.1056/NEJMoa1501365. PMID 26352813. 8. ^ a b c "New Drugs Online Report for sebelipase alfa". UK Medicines Information. Archived from the original on March 4, 2016. Retrieved December 10, 2015. 9. ^ a b c Sebelipase alfa Label Last updated Dec 2015. See FDA index page for labels here 10. ^ synd/3122 at Who Named It? 11. ^ Abramov A, Schorr S, Wolman M (Mar 1956). "Generalized xanthomatosis with calcified adrenals". AMA J Dis Child. 91 (3): 282–6. doi:10.1001/archpedi.1956.02060020284010. PMID 13301142.CS1 maint: multiple names: authors list (link) 12. ^ Fredrickson DS (1963). "Newly recognized disorders of cholesterol metabolism". Ann Intern Med. 58 (4): 718. doi:10.7326/0003-4819-58-4-718_1. 13. ^ "FDA approves first drug to treat a rare enzyme disorder in pediatric and adult patients". FDA. December 8, 2015. Retrieved December 10, 2015. 14. ^ Tolar, J.; Petryk, A.; Khan, K.; Bjoraker, K. J.; Jessurun, J.; Dolan, M.; Kivisto, T.; Charnas, L.; Shapiro, E. G. (2009-01-01). "Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease". Bone Marrow Transplantation. 43 (1): 21–27. doi:10.1038/bmt.2008.273. ISSN 1476-5365. PMID 18776925. ## External links[edit] Classification D * ICD-10: E75.5, E75.6 * ICD-9-CM: 272.7 * OMIM: 278000 * MeSH: D015223 * DiseasesDB: 31220 External resources * Orphanet: 275761 * National Organization for Rare Disorders (NORD) * Article - LYSOSOMAL ACID LIPASE/NIH.gov * Article - LYSOSOMAL ACID LIPASE DEFICIENCY/NIH.gov * Lipid Storage Diseases Fact Sheet at ninds.nih.gov * 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 * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Lysosomal acid lipase deficiency	c0043208	1,989	wikipedia	https://en.wikipedia.org/wiki/Lysosomal_acid_lipase_deficiency	2021-01-18T19:10:18	{"gard": ["7899"], "mesh": ["D015223"], "umls": ["C0043208"], "icd-9": ["272.7"], "orphanet": ["75233"], "wikidata": ["Q6710283"]}
Norrie disease is an inherited eye disorder that leads to blindness in male infants at birth or soon after birth. Additional symptoms may occur in some cases, although this varies even among individuals in the same family. Most affected individuals develop sensorineural hearing loss and many exhibit cognitive abnormalities such as developmental delays, behavioral issues, or psychotic-like features. Norrie disease is caused by mutations in the NDP gene. It is inherited in an X-linked recessive pattern. Treatment is directed toward the specific symptoms present in each individual. The coordinated efforts of a team of specialists, including pediatricians, ophthalmologists, and audiologists may be needed. Early intervention and special education services are important to ensure that children with Norrie disease reach their full potential. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Norrie disease	c0266526	1,990	gard	https://rarediseases.info.nih.gov/diseases/7224/norrie-disease	2021-01-18T17:58:40	{"mesh": ["C537849"], "omim": ["310600"], "orphanet": ["649"], "synonyms": ["Atrophia bulborum hereditaria", "Pseudoglioma", "Episkopi blindness", "Norrie syndrome", "Norrie-Warburg syndrome", "Anderson-Warburg syndrome", "NDP", "Fetal iritis syndrome"]}
This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article 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: "Thrombotic storm" – news · newspapers · books · scholar · JSTOR (May 2011) (Learn how and when to remove this template message) This article includes a list of references, related reading or external links, but its sources remain unclear because it lacks inline citations. Please help to improve this article by introducing more precise citations. (August 2012) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Blood clots are a relatively common occurrence in the general population and are seen in approximately 1-2% of the population by age 60. Typically blood clots develop in the deep veins of the lower extremities, deep vein thrombosis (DVT) or as a blood clot in the lung, pulmonary embolism (PE). A very small number of people who develop blood clots have a more serious and often life-threatening condition, known as Thrombotic Storm (TS). TS is characterized by the development of more than one blood clot in a short period of time. These clots often occur in multiple and sometimes unusual locations in the body and are often difficult to treat. TS may be associated with an existing condition or situation that predisposes a person to blood clots such as injury, infection, or pregnancy. In many cases a risk assessment will identify interventions that will prevent the formation of blood clots. While the mechanism or pathogenesis is not completely understood mostly due to its rarity, the medical community has developed a new interest in learning more about this syndrome. Dr. Craig S. Kitchens first described TS in six case studies. In these cases he described a collection of similar features observed in six patients, suggesting this may be accounted for by a new syndrome. ## Contents * 1 Presentation * 2 Diagnosis * 2.1 Hypercoagulable states * 3 Treatment * 4 References ## Presentation[edit] Thrombotic Storm has been seen in individuals of all ages and races. The initial symptoms of TS present in a similar fashion to the symptoms experienced in deep vein thrombosis. Symptoms of a DVT may include pain, swelling and discoloration of the skin in the affected area. As with DVTs patients with TS may subsequently develop pulmonary emboli. Although the presentation of TS and DVTs are similar, TS typically progresses rapidly, with numerous clots occurring within a short period of time. After the formation of the initial clot a patient with TS typically begins a “clotting storm” with the development of multiple clots throughout the body. Rapid progression within a short period of time is often seen, affecting multiple organs systems. The location of the clot is often unusual or found in a spot in the body that is uncommon such as the dural sinus. Patients tend to respond very well to anticoagulation such as coumadin or low molecular weight heparin but may become symptomatic when treatment is withheld. While the key clinical characteristics of thrombotic storm are still being investigated, it is believed that the clinical course is triggered by a preexisting condition, known as a hypercoagulable state. These can include such things as pregnancy, trauma or surgery. Hypercoagulable states can be an inherited or acquired risk factor that then serves as a trigger to initiate clot formation. However, in a subset of patient with TS a trigger cannot be identified. Typically people with TS will have no personal or family history of coagulations disorders. ## Diagnosis[edit] Currently laboratory testing is not as reliable as observation when it comes to defining the parameters of Thrombotic Storm. Careful evaluation of possible thrombosis in other organ systems is pertinent in expediting treatment to prevent fatality. Preliminary diagnosis consists of evidence documented with proper imaging studies such as CT scan, MRI, or echocardiography, which demonstrate a thromboembolic occlusion in the veins and/or arteries. Vascular occlusions mentioned must include at least two of the clinic events: * Deep venous thrombosis affecting one (or more) limbs and/or pulmonary embolism. * Cerebral vein thrombosis. * Portal vein thrombosis, hepatic vein, or other intra-abdominal thrombotic events. * Jugular vein thrombosis in the absence of ipsilateral arm vein thrombosis and in the absence of ipsilateral central venous access. * Peripheral arterial occlusions, in the absence of underlying atherosclerotic vascular disease, * resulting in extremity ischemia and/or infarction. * Myocardial infarction, in the absence of severe coronary artery disease * Stroke and/or transient ischemic attack, in the absence of severe atherosclerotic disease and at an age less than 60 years. * Central retinal vein and/or central retinal arterial thrombosis. * Small vessel thrombosis affecting one or more organs, systems, or tissue; must be documented by histopathology. In addition to the previously noted vascular occlusions, development of different thromboembolic manifestations simultaneously or within one or two weeks must occur and the patient must have an underlying inherited or acquired hypercoagulable state (other than Antiphospholipid syndrome) ### Hypercoagulable states[edit] Congenital Acquired Protein C deficiency CAPS Protein S deficiency Autoimmune Disorder i.e. APS Factor V Leiden Illness that causes or promote tissue necrosis Prothrombin Mutation Malignancy Antithrombin Deficiency Pregnancy Immobility Surgery Trauma Thrombocytopenic Purpura ## Treatment[edit] Treatment for Thrombotic Storm may include lifelong anticoagulation therapy and/or thrombolytic therapy, plasmapherisis, and corticosteroids. Studies have shown that when anticoagulant therapy is withheld recurrence of thrombosis usually follows. INR is closely monitored in the course of treatment. ## References[edit] * Kitchens, Craig S.; Erkan, Doruk; Brandão, Leonardo R.; Hahn, Susan; James, Andra H.; Kulkarni, Roshni; Pericak-Vance, Margaret; Vance, Jeffery; Ortel, Thomas L. (2011). "Thrombotic Storm Revisited: Preliminary Diagnostic Criteria Suggested by the Thrombotic Storm Study Group". The American Journal of Medicine. 124 (4): 290–6. doi:10.1016/j.amjmed.2010.10.018. PMID 21435416. * Kitchens, Craig S. (1998). "Thrombotic Storm: When Thrombosis Begets Thrombosis". The American Journal of Medicine. 104 (4): 381–5. doi:10.1016/S0002-9343(98)00061-8. PMID 9576413. * Asherson, R; Espinosa, G; Menahem, S; Yinh, J; Bucciarelli, S; Bosch, X; Cervera, R (2008). "Relapsing Catastrophic Antiphospholipid Syndrome: Report of Three Cases". Seminars in Arthritis and Rheumatism. 37 (6): 366–72. doi:10.1016/j.semarthrit.2007.08.001. PMID 17977582. * Triplett, Douglas A.; Asherson, Ronald A. (2000). "Pathophysiology of the catastrophic antiphospholipid syndrome (CAPS)". American Journal of Hematology. 65 (2): 154–9. doi:10.1002/1096-8652(200010)65:2<154::AID-AJH11>3.0.CO;2-A. PMID 10996834. * Asherson, RA; Piette, JC (1996). "The catastrophic antiphospholipid syndrome 1996: Acute multi-organ failure associated with antiphospholipid antibodies: A review of 31 patients". Lupus. 5 (5): 414–7. doi:10.1177/096120339600500516. PMID 8902772. * Christiansen, S. C.; Cannegieter, SC; Koster, T; Vandenbroucke, JP; Rosendaal, FR (2005). "Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events". JAMA. 293 (19): 2352–61. doi:10.1001/jama.293.19.2352. PMID 15900005. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Thrombotic storm	None	1,991	wikipedia	https://en.wikipedia.org/wiki/Thrombotic_storm	2021-01-18T18:45:46	{"wikidata": ["Q7798346"]}
Index of articles associated with the same name This article includes a list of related items that share the same name (or similar names). If an internal link incorrectly led you here, you may wish to change the link to point directly to the intended article. Ductal carcinoma Micrograph of breast tissue with ductal carcinoma. H&E stain. Ductal carcinoma is a type of tumor that primarily presents in the ducts of a gland.[1] Types include: * Mammary * Ductal carcinoma in situ * Invasive ductal carcinoma * Pancreatic ductal carcinoma ## References[edit] 1. ^ "NCI Dictionary of Cancer Terms". National Cancer Institute. 2 February 2011. Retrieved 21 November 2019. ## External links[edit] Classification D * MeSH: D044584 Media related to Ductal carcinomas at Wikimedia Commons * v * t * e Glandular and epithelial cancer Epithelium Papilloma/carcinoma * Small-cell carcinoma * Combined small-cell carcinoma * Verrucous carcinoma * Squamous cell carcinoma * Basal-cell carcinoma * Transitional cell carcinoma * Inverted papilloma Complex epithelial * Warthin's tumor * Thymoma * Bartholin gland carcinoma Glands Adenomas/ adenocarcinomas Gastrointestinal * tract: Linitis plastica * Familial adenomatous polyposis * pancreas * Insulinoma * Glucagonoma * Gastrinoma * VIPoma * Somatostatinoma * Cholangiocarcinoma * Klatskin tumor * Hepatocellular adenoma/Hepatocellular carcinoma Urogenital * Renal cell carcinoma * Endometrioid tumor * Renal oncocytoma Endocrine * Prolactinoma * Multiple endocrine neoplasia * Adrenocortical adenoma/Adrenocortical carcinoma * Hürthle cell Other/multiple * Neuroendocrine tumor * Carcinoid * Adenoid cystic carcinoma * Oncocytoma * Clear-cell adenocarcinoma * Apudoma * Cylindroma * Papillary hidradenoma Adnexal and skin appendage * sweat gland * Hidrocystoma * Syringoma * Syringocystadenoma papilliferum Cystic, mucinous, and serous Cystic general * Cystadenoma/Cystadenocarcinoma Mucinous * Signet ring cell carcinoma * Krukenberg tumor * Mucinous cystadenoma / Mucinous cystadenocarcinoma * Pseudomyxoma peritonei * Mucoepidermoid carcinoma Serous * Ovarian serous cystadenoma / Pancreatic serous cystadenoma / Serous cystadenocarcinoma / Papillary serous cystadenocarcinoma Ductal, lobular, and medullary Ductal carcinoma * Mammary ductal carcinoma * Pancreatic ductal carcinoma * Comedocarcinoma * Paget's disease of the breast / Extramammary Paget's disease Lobular carcinoma * Lobular carcinoma in situ * Invasive lobular carcinoma Medullary carcinoma * Medullary carcinoma of the breast * Medullary thyroid cancer Acinar cell * Acinic cell carcinoma This article about a neoplasm is a stub. You can help Wikipedia by expanding it. * v * t * e [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Ductal carcinoma	c1176475	1,992	wikipedia	https://en.wikipedia.org/wiki/Ductal_carcinoma	2021-01-18T18:49:56	{"mesh": ["D044584"], "wikidata": ["Q5311598"]}
A number sign (#) is used with this entry because of evidence that early-onset vitamin B6-dependent epilepsy (EPVB6D) is caused by homozygous or compound heterozygous mutation in the PROSC gene (PLPBP; 604436) on chromosome 8p11. Description Early-onset vitamin B6-dependent epilepsy is an autosomal recessive neurologic disorder characterized by onset of seizures in the neonatal period or first months of life. The seizures show favorable response to treatment with activated vitamin B6 (pyridoxal 5-prime-phosphate; PLP) and/or pyridoxine. However, most patients show delayed psychomotor development (summary by Darin et al., 2016). Clinical Features Darin et al. (2016) reported 3 patients from a consanguineous Syrian family and 4 unrelated additional patients with infantile-onset seizures. Three of the patients showed abnormal intrauterine movements, and 4 showed signs of fetal distress. One infant from the Syrian family died at 4.5 months of age, and the other patients ranged in age from 3 to 16 years. All presented with seizures on the first day of life, except 1 patient who developed seizures at 1 month of age. Seizure manifestations included myoclonus, clonus, hypertonia, grimacing, apnea, respiratory distress, chewing, twitching, generalized tonic-clonic seizures, and stiffness. EEG tended to show a burst suppression pattern, often with reduced background activity. All patients had an immediate response to treatment with pyridoxine. After initial presentation, all children continued to have less frequent seizures and needed to be treated with multiple anticonvulsants. Four patients had their B6 treatment changed from pyridoxine to PLP, and all showed an improvement in seizure control. Several patients showed recurrence of seizures upon withdrawal of B6 treatment. The patients showed delayed psychomotor development with delayed language of variable severity and acquired microcephaly, although the 16-year-old was able to attend normal school. Brain imaging of most patients showed global underdevelopment of the brain, brain atrophy, enlarged ventricles, broad gyri, shallow sulci, reduced white matter, thin corpus callosum, and cysts, although 3 patients had normal brain imaging. Additional features included neonatal metabolic acidosis with increased lactate in 4 patients, anemia in 2 patients, and gastrointestinal dysfunction, including abdominal distention, vomiting, and necrotizing enterocolitis, in 3 patients. Four patients had minor dysmorphic features. Laboratory studies were consistent with abnormalities in B6 metabolism: 2 patients had low CSF PLP concentrations, and 3 had decreased activities of B6-dependent enzymes. Inheritance The transmission pattern of EPVB6D in the families reported by Darin et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 7 patients from 5 unrelated families with EPVB6D, Darin et al. (2016) identified homozygous or compound heterozygous mutations in the PROSC gene (see, e.g., 604436.0001-604436.0006). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing. Mutations in the 4 other patients were found by Sanger sequencing of the PROSC gene in 29 children with B6-responsive epilepsy. Patient plasma PLP levels in those receiving B6 treatment were increased compared to controls, and PLP levels in cultured patient fibroblasts were also increased. Complementation studies in PROSC-deficient E. coli showed that several of the mutations could not restore growth, indicating a loss-of-function effect. Darin et al. (2016) noted that PLP is a highly reactive aldehyde and may interact nonspecifically with intracellular proteins and small molecules, resulting in a toxic effect. The genetic findings were consistent with a defect in intracellular homeostatic regulation of PLP. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly, acquired Face \- Dysmorphic facial features, mild (in some patients) RESPIRATORY \- Respiratory insufficiency, neonatal \- Apnea, neonatal ABDOMEN Gastrointestinal \- Gastrointestinal dysfunction (in some patients) MUSCLE, SOFT TISSUES \- Hypertonia NEUROLOGIC Central Nervous System \- Seizures, neonatal, refractory \- Myoclonus \- Tonic-clonic seizures \- Clonus \- Delayed psychomotor development \- Poor speech \- Learning disabilities \- Intellectual disability \- Burst suppression pattern seen on EEG \- Reduced background activity seen on EEG \- Brain atrophy (in some patients) \- Enlarged ventricles \- Broad gyri \- Shallow sulci METABOLIC FEATURES \- Metabolic acidosis (in some patients) PRENATAL MANIFESTATIONS Movement \- Abnormal fetal movements LABORATORY ABNORMALITIES \- Increased lactate (in some patients) MISCELLANEOUS \- Onset in first days or months of life \- Seizures are responsive to treatment with pyridoxine or activated vitamin B6 \- Multiple anticonvulsants are needed to control seizures MOLECULAR BASIS \- Caused by mutation in the pyridoxal phosphate-binding protein gene (PLBP, 604436.0001 ) ▲ Close [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	EPILEPSY, EARLY-ONSET, VITAMIN B6-DEPENDENT	c1291560	1,993	omim	https://www.omim.org/entry/617290	2019-09-22T15:46:16	{"omim": ["617290"], "orphanet": ["3006"]}
A number sign (#) is used with this entry because it represents a contiguous gene duplication syndrome. A locus for autism-7 (AUTS7; 610676) has been mapped to chromosome 17q21. See also chromosome 17q21.31 deletion syndrome (610443). Clinical Features Kirchhoff et al. (2007) reported a 10-year-old Moroccan girl with severe psychomotor delay who was found to have a de novo duplication at the chromosome 17q21.31 deletion syndrome locus. She had facial dysmorphism, short stature, microcephaly, abnormal digits, and hirsutism. Brain imaging was normal. She walked independently at age 5 years and only said a few words at age 10 years. She was a happy girl and was often singing and dancing. Her general health was good, but she had atopic dermatitis and constipation. Facial features included a short nose with prominent nasal tip and columella, smooth philtrum, small mouth, and micrognathia. The ears were normally positioned, but with unfolded helixes. She had a high-arched palate and protruding upper incisors. The thumbs were short and broad, and there was terminal broadening of the remaining fingers; her feet were broad with a long first toe. Grisart et al. (2009) reported 4 unrelated individuals with different duplications of chromosome 17q21.31 identified by array-comparative genomic hybridization (CGH) analysis of 13,070 patients with mental retardation and congenital malformations. The patients ranged in age from 6 to 18 years. Although all had some degree of psychomotor retardation and poor social interaction and communication difficulties reminiscent of autism spectrum disorder (ASD; 209850), specific features were more variable. Two had hypotonia, 2 had hyperactivity, 2 had aggressive behavior, and 1 had obsessive behavior. Two had poor motor skills, and 2 showed tiptoe walking. Dysmorphic features were variable and included synophrys (2), dysplastic ears (3), upturned nose (2), flat midface (2), prominent incisor (2), fifth finger clinodactyly (2), and syndactyly (2). One had hirsutism, and another had a low posterior hairline. The 18-year-old showed hypogonadism. Cytogenetics In a Moroccan girl with severe psychomotor delay and dysmorphic features, Kirchhoff et al. (2007) identified a de novo 485-kb duplication at chromosome 17q21.31 using array CGH analysis. The duplication was paternally inherited and derived from meiotic recombination of paternal H1 and H2 haplotypes in the 17q21.31 chromosomal region (see MAPT; 157140). The duplication was believed to result from nonallelic homologous recombination (NAHR) between the 2 alleles. Grisart et al. (2009) reported 4 unrelated individuals with duplications of chromosome 17q21.31 identified by array CGH analysis. The duplication breakpoints were different but were ascertained by different microarray technologies. The size of the duplications ranged from 585 to 763 kb. Three patients with complete testing available had de novo duplications, all of which occurred on the maternal chromosome. Microsatellite and haplotype analysis showed that the duplication occurred by interchromosomal rearrangement between H1 and H2 haplotypes in 2 patients and by interchromatid rearrangement between 2 H2 haplotypes in 1 patient. Grisart et al. (2009) suggested that the duplications likely resulted from NAHR. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	CHROMOSOME 17q21.31 DUPLICATION SYNDROME	c3150787	1,994	omim	https://www.omim.org/entry/613533	2019-09-22T15:58:20	{"doid": ["0060434"], "omim": ["613533"], "orphanet": ["217340"], "synonyms": ["Dup(17)(q21.31)", "Trisomy 17q21.31"]}
Central nervous system primitive neuroectodermal tumor Primitive neuroectodermal tumor of the central nervous system in a 5-year-old A central nervous system primitive neuroectodermal tumor, often abbreviated as PNET, supratentorial PNET, or CNS-PNET,[1] is one of the 3 types of embryonal central nervous system tumors defined by the World Health Organization (medulloblastoma, atypical teratoid rhabdoid tumor, and PNET).[2] It is considered an embryonal tumor because it arises from cells partially differentiated or still undifferentiated from birth.[1] Those cells are usually neuroepithelial cells,[1][2][3] stem cells destined to turn into glia or neurons.[4] It can occur anywhere within the spinal cord and cerebrum and can have multiple sites of origins, with a high probability of metastasis through cerebrospinal fluid (CSF).[1][2] PNET has five subtypes of tumors: neuroblastoma, ganglioneuroblastoma, medulloepithelioma, ependymoblastoma, and not otherwise specified PNET.[1] It is similar to medulloblastoma regarding histology but different regarding genetic factors and tumor site. It is a rare disease occurring mostly among children,[1][2] accounting for 1.9 to 7% of childhood brain tumors.[2] Symptoms involve emotional, visual, motor, and speech defects.[2] Magnetic resonance imaging (MRI) and computed tomography (CT) are used to diagnose PNETs.[2] Even though a universal treatment plan hasn't been stablished yet, common strategies involve chemotherapy and radiotherapy for individuals older than 3 years of age.[1][2] Their efficacy, however, is still controversial.[2] Surgery can be used to remove mass affected by tumorous cells.[2] The prognosis of the disease is more positive for adults than for children, who have a higher probability of having sequelae from the tumor.[1][2] It is important to note that this classification term has been removed from the latest WHO classification of CNS tumors as of 2016. Instead PNETs are now included into the category of "Embryonal Tumors with Multilayered Rosettes" along with ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes (ETANTR). [5] ## Contents * 1 Classification * 1.1 PNET vs. medulloblastoma * 2 Risk factors * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 References ## Classification[edit] Histology of Medulloepithelioma The World Health Organization has classified the central nervous system primitive neuroectodermal tumors into five subtypes: neuroblastoma, ganglioneuroblastoma, medulloepithelioma, ependymoblastoma, and not otherwise specified PNET.[1] The last one encompasses the PNETs with varying characteristics that hasn't been well defined yet.[1] Neuroblastomas are PNETS that involve the process of cell differentiation into neurons,[1][2] while ganglioneuroblastomas are PNETs that involve ganglion cells.[1] Medulloepithelioma, on the other hand, are tumors involving the constant cell division on the epithelium tissue where bundle of neuron endings are located.[1] Such tissue will differentiate into a similar form as the embryonic neural tube, also known as the starting structure of the central nervous system.[1][2][3] Medulloepitheliomas also present a pattern known as rosettes, characterized by the arrangement of a bundle of cells into circular shapes and around a center or a neuropil.[1] Ependymoblastoma also present rosettes as well as a higher density of cells.[1][3] It involves the process of differentiation into ependymal cells.[2][3] Rosettes in Ependymoblastoma histology Further classification types have come up but not yet approved by the World Health Organization.[1] The term "embryonal tumor with abundant neuropil and true rosettes", or ETANTR, has been proposed as a sixth subtype of PNET.[1] However, the still unofficial term "embryonal tumor with multilayered rosettes" (ETMR) has been more frequently used and encompasses ETANTRs, medulloepitheliomas, ependymoblastomas, and variants of PNETs with presence of rosettes and with no well defined classification.[3] ### PNET vs. medulloblastoma[edit] The differentiation between primitive neuroectodermal tumor in the central nervous system and medulloblastoma is recent.[1][2] According to the World Health Organization, both tumors have the same histology but primitive neuroectodermal tumors occur outside the cerebellum.[2] Moreover, it has been documented that both have different genetic expression and mutations.[1][2] Another essential difference between them is the location of their respective blood vessels within the brain.[2] It has also been theorized that PNETs influence mainly glia cells while medulloblastomas influence mainly neural behavior, however such theory hasn't been confirmed yet.[1] Medulloblastomas are more frequent than PNETs, representing 10% of all child deaths caused by cancer.[2] They also present better prognosis: children affected by medulloblastoma reach the 5 year survival mark in 70-80% of cases, while children affected by PNET reach the 5 year survival mark in less than 50% of cases.[1] ## Risk factors[edit] The rate of PNETs in not correlated with sex, but it shows a correlation with age.[1] Most cases occur in children around 5 years of age, having a very low frequency in adults.[1] Regarding genetic mutations, a specific type of gene alteration that directly leads to this tumor hasn't been defined yet.[1] However, a positive correlation between individuals with Li-Fraumeni syndrome with a mutation in the gene p53 and PNET has been reported.[2] A significant number of individuals with mutations on the rb tumor suppressor gene have also developed the tumor.[2] Such gene encodes for the protein Rb responsible for stopping the cell cycle at the G1 phase.[6] Another possible contributing factor are mutations in the CREB-binding protein, whose function includes activating transcription,[6] but this interaction still need to be studied further.[2] It has also been presumed that the tumor can arise from cranial irradiation.[2] ## Diagnosis[edit] Magnetic resonance image of PNET Most children that develop primitive neuroectodermal tumors are diagnosed early in life, usually at around 3-6.8 years of age.[2] Symptoms patients present at time of diagnosis include irritable mood, visual difficulties, lethargy, and ataxia.[2] The circumference of the patient's head might also suffer an enlargement and they might be subject to seizures, especially if they have less than one year of life.[2] Several analysis can be used to determine the presence of the disease. Physical examinations showing papilledema, visual field defects, cranial nerves palsy, dysphasia, and focal neurological deficits are evidences for possible tumor.[2] PNETs can also be spotted through computed tomography (CT) and magnetic resonance imaging (MRI).[2] In images produced by MRIs, an irregular augmentation among a solid mass will indicated the presence of tumor.[3] However, the results of MRIs are usually ambiguous in defining the presence for this specific tumor.[2] In CT scans, the presence of PNETs will be indicated by an elevated density and an increase in volume of the brain.[2] The CT scan can also show calcification,[3] which is present in 41-44% of PNET cases.[2] Since the tumor can be replicated in other parts of the nervous system through the cerebrospinal fluid (CSF), a CSF analysis can also be conducted.[2] A spinal MRI is a fourth type of analysis that is useful in investigating the level of tumor propagation to the spinal cord.[2] ## Treatment[edit] There is not a standardized procedure to treat primitive neuroectodermal tumors.[2] Common strategies involve risk-adapted radiotherapy combined with chemotherapy and stem cell rescue.[1] For patients younger than 2–3 years of age, treatment with radiation is not used, once they are in a more vulnerable phase and, thus, more prone to risks in development.[1] Examinations such as CSF analysis and spinal MRIs are used to investigate the effectiveness of treatment in preventing metastasis.[2] A method for eliminating tumorous mass is surgery, where the best outcome would be total resection, meaning the complete removal of the tumor.[2] Along with the surgery, several measures that contribute to a safe procedure can be taken: urine exams, transfusion, and the constant supervision of arterial pressure.[2] Possible problems that arise from the surgery include hemorrhage, brain edema, and hemiparesis.[2] MRIs are typically done after 1 or 2 days of postoperative in order to inspect the amount of tumor remaining.[2] ## Prognosis[edit] The probability of primitive neuroectodermal tumors to have recurrence and metastasize through cerebrospinal fluid is relatively high.[3] The outcome of PNET is more positive when the individual is an adult, independent of age subgroups, or an older child.[2] Less than 50% of children survive more than 5 years,[1] while the majority of adults live to 7 years.[2] The reason the prognosis for such tumor is worst in children is due to the higher probability of the tumor spreading to the rest of the nervous system through the cerebrospinal fluid and growing again.[2] Moreover, children have the probability of developing deficiencies in cognitive processes, problems in the endocrine system, and psychological obstacles after the disease.[2] Adults, on the other hand, don't show such propensity.[2] As a consequence, 37.7% of children affected by the tumor live to 4 years.[2] The effect of treatment strategies such as chemotherapy and radiation therapy on the prognosis of the disease is still controversial, with studies claiming either their benefits or their ineffectiveness.[2] The same holds true for the relationship between volume of tumor removed by surgery and survival.[2] Furthermore, factors such as tumor size, location of origin, race, and sex of individual don't show any influence on the outcome of the disease.[2] However, interactions of some factors such as tumor site, age, and treatment strategy can affect one's prognosis.[2] For instance, when younger children below the age of 3 suffering from tumors originating in places other than the pineal gland are treated with chemotherapy, they present better outcomes than those suffering from pineal tumors and treated with chemotherapy.[2] ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Karajannis, Matthias A.; Zagzag, David, eds. (2015). "Molecular Pathology of Nervous System Tumors". Molecular Pathology Library. 8. doi:10.1007/978-1-4939-1830-0. ISBN 978-1-4939-1829-4. ISSN 1935-987X. 2. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax Hayat, M.A., ed. (2014). "Tumors of the Central Nervous System, Volume 13". Tumors of the Central Nervous System. 13. doi:10.1007/978-94-007-7602-9. ISBN 978-94-007-7601-2. ISSN 2215-096X. 3. ^ a b c d e f g h Fuller, Christine E. (2009-10-23), "Oligodendroglial Tumors", Atlas of Pediatric Brain Tumors, Springer New York, pp. 39–46, doi:10.1007/978-1-4419-1062-2_4, ISBN 9781441910615 4. ^ Nelesen, Richard A (March 2000). "Biological Psychology: An Introduction to Behavioral, Cognitive, and Clinical Neuroscience, 2nd edition. Mark R. Rosenweig, Arnold L. Leiman, and S. Marc Breedlove, Sinauer Associates, Inc., Sunderland MA, 1999. 561+92 pp. ISBN 0-87893-791-9". Biological Psychology. 52 (2): 185–186. doi:10.1016/s0301-0511(99)00025-3. ISSN 0301-0511. 5. ^ Louis DN, Ohgaki H, Wiestler OD, Cavenee WK "WHO Classification of Tumours of the Central Nervous System. 4th Edition Revised" 6. ^ a b Baker, Henry V (June 2003). "Essential Genetics: A Genomics Perspective. Third Edition. By Daniel L Hartl and , Elizabeth W Jones. Sudbury (Massachusetts): Jones and Bartlett Publishers. $78.95 (paper). xxvi + 613 p; ill.; index. 2002". The Quarterly Review of Biology. 78 (2): 225–226. doi:10.1086/377959. ISBN 0-7637-1852-1. ISSN 0033-5770. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Central nervous system primitive neuroectodermal tumor	c3887678	1,995	wikipedia	https://en.wikipedia.org/wiki/Central_nervous_system_primitive_neuroectodermal_tumor	2021-01-18T18:36:11	{"umls": ["C3887678"], "wikidata": ["Q18553662"]}
Hyper IgM syndrome type 4 Immunoglobulin M SpecialtyHematology TypesHyper-IgM syndrome type 1,2,3,4 and 5[1][2][3][4][5] Diagnostic methodMRI, Chest radiography and genetic testing[6] TreatmentAllogeneic hematopoietic cell transplantation[7] Hyper-IgM syndrome type 4 is a form of Hyper IgM syndrome which is a defect in class switch recombination downstream of the AICDA gene that does not impair somatic hypermutation.[8] ## Contents * 1 Hyper IgM syndromes * 2 Signs and symptoms * 3 Cause * 4 Pathophysiology * 5 Diagnosis * 6 Treatment * 7 References ## Hyper IgM syndromes[edit] Hyper IgM syndromes is a group of primary immune deficiency disorders characterized by defective CD40 signaling; via B cells affecting class switch recombination (CSR) and somatic hypermutation. Immunoglobulin (Ig) class switch recombination deficiencies are characterized by elevated serum IgM levels and a considerable deficiency in Immunoglobulins G (IgG), A (IgA) and E (IgE). As a consequence, people with HIGM have an increased susceptibility to infections.[9][7][10] ## Signs and symptoms[edit] Hyper IgM syndrome can have the following syndromes:[6][11] * Infection/Pneumocystis pneumonia (PCP), which is common in infants with hyper IgM syndrome, is a serious illness.[9] PCP is one of the most frequent and severe opportunistic infections in people with weakened immune systems. * Hepatitis (Hepatitis C) * Chronic diarrhea * Hypothyroidism * Neutropenia * Arthritis * Encephalopathy (degenerative) ## Cause[edit] Class switch recombination Different genetic defects cause HIgM syndrome, the vast majority are inherited as an X-linked recessive genetic trait and most sufferers are male.[7][1][2] [3][12][4] IgM is the form of antibody that all B cells produce initially before they undergo class switching. Healthy B cells efficiently switch to other types of antibodies as needed to attack invading bacteria, viruses, and other pathogens. In people with hyper IgM syndromes, the B cells keep making IgM antibodies because can not switch to a different antibody. This results in an overproduction of IgM antibodies and an underproduction of IgA, IgG, and IgE.[13][7] ## Pathophysiology[edit] CD40 is a costimulatory receptor on B cells that, when bound to CD40 ligand (CD40L), sends a signal to the B-cell receptor.[14] When there is a defect in CD40, this leads to defective T-cell interaction with B cells. Consequently, humoral immune response is affected. Patients are more susceptible to infection.[6] ## Diagnosis[edit] The diagnosis of hyper IgM syndrome can be done via the following methods and tests:[6] * MRI * Chest radiography * Pulmonary function test * Lymph node test * Laboratory test (to measure CD40) ## Treatment[edit] In terms of treatment for hyper IgM syndrome, there is the use of allogeneic hematopoietic cell transplantation. Additionally, anti-microbial therapy, use of granulocyte colony-stimulating factor, immunosuppressants, as well as other treatments, may be needed.[7] ## References[edit] 1. ^ a b "OMIM Entry - # 308230 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1; HIGM1". www.omim.org. Retrieved 16 November 2016. 2. ^ a b "OMIM Entry - # 605258 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 2; HIGM2". omim.org. Retrieved 16 November 2016. 3. ^ a b "OMIM Entry - # 606843 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 3; HIGM3". www.omim.org. Retrieved 16 November 2016. 4. ^ a b "OMIM Entry - # 608106 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 5; HIGM5". omim.org. Retrieved 16 November 2016. 5. ^ "OMIM Entry - 608184 - IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 4; HIGM4". www.omim.org. Retrieved 2 January 2018. 6. ^ a b c d "X-linked Immunodeficiency With Hyper IgM Clinical Presentation: History, Physical, Causes". emedicine.medscape.com. Retrieved 27 November 2016. 7. ^ a b c d e Johnson, Judith; Filipovich, Alexandra H.; Zhang, Kejian (1 January 1993). "X-Linked Hyper IgM Syndrome". GeneReviews. Retrieved 12 November 2016.update 2013 8. ^ Lougaris V, Badolato R, Ferrari S, Plebani A (2005). "Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features". Immunol. Rev. 203: 48–66. doi:10.1111/j.0105-2896.2005.00229.x. PMID 15661021. 9. ^ a b Etzioni, Amos; Ochs, Hans D. (1 October 2004). "The Hyper IgM Syndrome—An Evolving Story". Pediatric Research. 56 (4): 519–525. doi:10.1203/01.PDR.0000139318.65842.4A. ISSN 0031-3998. PMID 15319456. 10. ^ "Hyper-Immunoglobulin M (Hyper-IgM) Syndromes \| NIH: National Institute of Allergy and Infectious Diseases". www.niaid.nih.gov. Retrieved 27 November 2016. 11. ^ Davies, E Graham; Thrasher, Adrian J (27 November 2016). "Update on the hyper immunoglobulin M syndromes". British Journal of Haematology. 149 (2): 167–180. doi:10.1111/j.1365-2141.2010.08077.x. ISSN 0007-1048. PMC 2855828. PMID 20180797. 12. ^ Lougaris V, Badolato R, Ferrari S, Plebani A (2005). "Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features". Immunol. Rev. 203: 48–66. doi:10.1111/j.0105-2896.2005.00229.x. PMID 15661021.subscription needed 13. ^ Reference, Genetics Home. "X-linked hyper IgM syndrome". Genetics Home Reference. Retrieved 27 November 2016. 14. ^ Reference, Genetics Home. "CD40 gene". Genetics Home Reference. Retrieved 27 November 2016. Classification D * ICD-10: D80.5 * OMIM: 608106 External resources * Orphanet: 101092 * 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 [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Hyper-IgM syndrome type 4	c1842413	1,996	wikipedia	https://en.wikipedia.org/wiki/Hyper-IgM_syndrome_type_4	2021-01-18T18:44:31	{"gard": ["10580"], "mesh": ["C564277"], "icd-9": ["279.05"], "orphanet": ["101091", "183666"], "wikidata": ["Q5957524"]}
## Description Familial idiopathic basal ganglia calcification (IBGC) is characterized by bilateral basal ganglia calcification and has been associated with a variety of neurologic, cognitive, and psychiatric abnormalities. However, some affected individuals may be clinically asymptomatic (summary by Volpato et al., 2009). For a detailed phenotypic description and a discussion of genetic heterogeneity of IBGC, see IBGC1 (213600). Clinical Features Volpato et al. (2008) reported a large multigenerational Italian family from South Tyrol with IBGC. Twenty individuals over the age of 40 had positive CT scans revealing intracranial calcifications, with 14 having bilateral moderate to severe calcification of the basal ganglia, dentate nucleus, and subcortical white matter. Six had calcifications only in the pineal gland and/or choroid plexus. The calcification was age-dependent. Four individuals had hyperreflexia, 2 of whom also had gait and upper limb ataxia, slurred speech, and intellectual impairment. Four patients had short stature, 2 had short neck, and 1 had frontal hyperostosis and upper limb hypotrophy. In this family, the radiologic penetrance was much higher than the clinical penetrance, which was low. Linkage to the IBGC1 locus on 14q was excluded. Mapping By genomewide linkage analysis of the family reported by Volpato et al. (2008), Volpato et al. (2009) found evidence supporting a locus on chromosome 2q37 (maximum nonparametric lod score of 2.44 at D2S2973). This locus was downstream of the SLC19A3 gene (606152). Dai et al. (2010) referred to the locus on 2q37 as IBGC2. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 2	c0393590	1,997	omim	https://www.omim.org/entry/606656	2019-09-22T16:10:16	{"doid": ["0060230"], "omim": ["606656"], "orphanet": ["1980"], "genereviews": ["NBK1421"]}
X-linked acrogigantism (X-LAG) is a condition that causes abnormally fast growth beginning early in life. Babies with this condition are a normal size at birth but begin to grow rapidly in infancy or early childhood, and affected children are taller than their peers. This rapid growth is caused by an abnormality of the pituitary gland. The pituitary gland, which is found at the base of the brain, produces hormones that control many important body functions, including growth. Individuals with X-LAG may have the condition as a result of enlargement (hyperplasia) of the gland or development of a noncancerous tumor in the gland (called a pituitary adenoma). Rarely, an affected individual has both pituitary hyperplasia and an adenoma. The abnormal gland releases excess amounts of growth hormone, a hormone that normally helps direct growth of the body's bones and tissues. Some people with X-LAG also have excess amounts of a hormone called growth hormone releasing hormone (GHRH), which is produced by a part of the brain called the hypothalamus. This hormone stimulates the release of growth hormone from the pituitary gland. Some people with X-LAG have additional signs and symptoms such as facial features that are described as coarse; disproportionately large hands or feet (acral enlargement); an increased appetite; and a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick, dark, and velvety. ## Frequency X-LAG is thought to be a rare condition, although the prevalence is not known. It occurs more frequently in females than in males. X-LAG accounts for one in ten cases of abnormally fast growth in children that is caused by pituitary gland abnormalities (pituitary gigantism). ## Causes X-LAG is caused by a genetic change in which a small amount of genetic material on the X chromosome is abnormally copied (duplicated). The duplication, often referred to as an Xq26.3 microduplication, occurs on the long (q) arm of the chromosome at a location designated q26.3. It can include several genes, but only duplication of the GPR101 gene is necessary to cause X-LAG. The GPR101 gene provides instructions for making a protein whose function is unknown. Studies suggest that the GPR101 protein is involved in the growth of cells in the pituitary gland or in the release of growth hormone from the gland. Duplication of the GPR101 gene leads to an excess of GPR101 protein. It is unclear how extra GPR101 protein results in the development of a pituitary adenoma or hyperplasia or in the release of excess growth hormone or GHRH. ### Learn more about the gene and chromosome associated with X-linked acrogigantism * GPR101 * x chromosome ## Inheritance Pattern X-LAG follows an X-linked dominant inheritance pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a duplication of one of the two copies of the GPR101 gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a duplication of the only copy of the gene in each cell causes the disorder. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. In females, the condition results from new (de novo) duplications involving the GPR101 gene that occur during the formation of a parent's reproductive cells (eggs or sperm). The duplication is found in all of the cells in the affected person's body. In males, the condition often results from somatic mosaicism, in which some of an affected person's cells have the duplication and others do not. The genetic changes, which are called somatic mutations, arise randomly in one cell during embryonic development. As cells continue to divide, only cells arising from the first abnormal cell will have the mutation. Other affected males inherit the duplication from their affected mother, and it is found in all the body's cells. [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	X-linked acrogigantism	c3891556	1,998	medlineplus	https://medlineplus.gov/genetics/condition/x-linked-acrogigantism/	2021-01-27T08:24:41	{"gard": ["6506"], "omim": ["300942"], "synonyms": []}
Fear or hatred of books Qin Shi Huangdi, the first Chinese emperor, ordered a mass destruction of books for fear of the Confucian ideas that they contained. Bibliophobia is the fear or hatred of books.[1] Such fear often arises from fear of the effect books can have on society or culture.[2]:2 Bibliophobia is a common cause of censorship and book burning. Bibliophobia and bibliophilia are antonyms. ## Contents * 1 History * 2 Notable examples * 3 See also * 4 References * 5 Further reading ## History[edit] In his 1999 Matthews lecture at Birkbeck College, Tom Shippey discussed bibliophobia in the Middle Ages. This arose when the literate professions, such as the clergy and beadles, would exploit and terrify the illiterate masses by their command of texts such as religious and legal documents. He illustrated this with examples from Anglo-Saxon literature such as The Pardoner's Tale.[3] ## Notable examples[edit] * Fahrenheit 451 and other works by Ray Bradbury[4][5] ## See also[edit] * List of banned books * Bibliophilia ## References[edit] 1. ^ Oxford English Dictionary, 2014 2. ^ Jackson, Holbrook (1932), The Fear of Books, University of Illinois Press, ISBN 9780252070402 3. ^ Shippey, Tom (2001), Bibliophobia: hatred of the book in the Middle Ages, Birkbeck College 4. ^ The History of Science Fiction - Adam Roberts - Google Books (p.388) 5. ^ The Pulpy Roots of ‘Fahrenheit 451’\|The Russel Kirk Center ## Further reading[edit] * Dibdin, Thomas (1832), Bibliophobia, H. Bohn [v]: View this template [t]: Discuss this template [e]: Edit this template [c.]: circa [AA]: Adrenergic agonist [AD]: Acetaldehyde dehydrogenase [HAART]: highly active antiretroviral therapy [Ki]: Inhibitor constant [nM]: nanomolars [MOR]: μ-opioid receptor [DOR]: δ-opioid receptor [KOR]: κ-opioid receptor [SERT]: Serotonin transporter [NET]: Norepinephrine transporter [NMDAR]: N-Methyl-D-aspartate receptor [M:D:K]: μ-receptor:δ-receptor:κ-receptor [ND]: No data [NOP]: Nociceptin receptor [BMI]: body mass index [OCD]: Obsessive-compulsive disorder [SSRIs]: Selective serotonin reuptake inhibitors [SNRIs]: Serotonin–norepinephrine reuptake inhibitors [TCAs]: Tricyclic antidepressants [MAOIs]: Monoamine oxidase inhibitors	Bibliophobia	None	1,999	wikipedia	https://en.wikipedia.org/wiki/Bibliophobia	2021-01-18T18:44:34	{"wikidata": ["Q18169108"]}

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